Clinical and biological phenotypes of frontotemporal dementia: Perspectives for disease modifying therapies

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Clinical and biological phenotypes of frontotemporal dementia: Perspectives for disease modifying therapies ⁎

S. Gazzina, M.A. Manes, A. Padovani, B. Borroni

Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Spedali Civili, Italy

A R T I C L E I N F O

A BS T RAC T

Keywords: FTD Therapy Frontotemporal

Frontotemporal Dementia (FTD) is a progressive neurodegenerative condition which encompasses a group of clinically, neuropathologically and genetically heterogeneous disorders characterized by selective involvement of the frontal and temporal lobes. FTD is characterized by changes in behaviour and personality, frontal executive deficits and language dysfunction. Different phenotypes have been defined on the basis of presenting clinical symptoms, behavioural variants of FTD (bvFTD) and primary progressive aphasia (PPA), which includes nonfluent/agrammatic variant PPA (avPPA) and semantic variant PPA (svPPA). These presentations can overlap with atypical parkinsonian disorders (i.e., corticobasal syndrome, progressive supranuclear palsy) and amyotrophic lateral sclerosis. Each syndrome can be associated with one or more neuropathological hallmark, and in some cases it may be due to autosomal inherited disorder caused by mutations in a number of genes. Currently, there is no specific treatment available to prevent disease progression. FTD treatment is based on symptomatic management, and most therapies lack quality evidence from randomized, placebo-controlled clinical trials. Recent advances in the understanding of FTD pathophysiology and genetics have led to the development of potentially disease-modifying therapies. In this review, we discussed current knowledge and recommendations with regards to symptomatic and disease-modifying therapies.

1. Introduction Since the first description of circumscribed cerebral cortical atrophy, published by Arnold Pick in 1892, our knowledge of Frontotemporal Dementia (FTD) has received a great boost. From 1911, with the identification of argyrophilic globular neuronal cytoplasmic inclusions named Pick's bodies, this group of heterogeneous conditions was labelled “Pick's Disease” (PiD). However, the clinical and neuropathological heterogeneity of cases with frontotemporal lobar atrophy led Constantinidis and colleagues to remark on the presence of cases with Pick's bodies and swollen, achromatic cells (group A), cases with only swollen, achromatic cells (group B), and cases with neither Pick's Bodies nor swollen neurons (group C) (Constantinidis et al., 1974). The subsequent works by Brun in the late eighties (Brun, 1987) and Mann in the early nineties (Mann et al., 1993), which underlined the high frequency of non-specific neuropathological changes in these cases, led to the coining of the term “dementia lacking distinctive histological features” (DLDH) (Knopman et al., 1990). It was in the nineties that researchers made the most important

⁎

discoveries in this field. In 1990, Okamoto described the presence of ubiquitin-positive intraneuronal inclusions in the cortex of patients with amyotrophic lateral sclerosis (ALS) (Okamoto et al., 1991). This evidence was rapidly followed by similar findings in the cortex of patients with ALS plus dementia (Wightman et al., 1992) and FTD (Tolnay and Probst, 1995). These cases, neuropathologically defined FTLD-U, accounted for a large part of the previously defined DLDH. The nineties also led to the identification of Tau aggregates in Pick's Disease, Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP) (Delacourte et al., 1996; Sergeant et al., 1999). Only in the last ten years has the neurobiology of FTD been characterized appropriately. In 2006, Neumann and colleagues discovered that ubiquitin-positive inclusions (both in ALS and FTD cases) consisted of TDP-43 aggregates (Neumann et al., 2006). This historical introduction shows how complex FTD is. So far, neuropathological criteria recognise two main pictures, namely FTDTau, FTD-TDP43, covering most cases (Cairns et al., 2007). At autopsy, some cases lack both Tau and TDP43 inclusions, being rarer forms of the disease. Until now, FTD has been overshadowed by disease-modifying trials

Correspondence to: Neurology Unit, University of Brescia, Piazza Spedali Civili 1, Brescia 25125, Italy. E-mail address: [email protected] (B. Borroni).

http://dx.doi.org/10.1016/j.ejphar.2017.05.056 Received 18 October 2016; Received in revised form 28 March 2017; Accepted 30 May 2017 0014-2999/ © 2017 Elsevier B.V. All rights reserved.

Please cite this article as: Gazzina, S., European Journal of Pharmacology (2017), http://dx.doi.org/10.1016/j.ejphar.2017.05.056

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paraphasias, generalizations, omissions, and circumlocutions (Kertesz and Harciarek, 2014). Patients often have difficulties with reading and writing, particularly with irregular or ambiguous words, leading to the phenomenon of surface dyslexia or surface dysgraphia (Baxter and Warrington, 1987; Warrington, 1975). Other cognitive domains are usually spared, including episodic and topographical memory, visuoperceptual function, praxis, calculation and non-verbal executive function (Cipolotti and Maguire, 2003; Warrington, 1975). svPPA shows markedly asymmetrical anterior left temporal lobe atrophy, particularly affecting the temporal pole, the fusiform and middle temporal gyri, but also the anterior hippocampus and amygdala (Hodges et al., 1992; Mummery et al., 2000; Mummery et al., 1999; Rohrer et al., 2009b). Less frequently, patients present with predominant right temporal lobe atrophy at onset, often called right semantic dementia (Chan et al., 2009; Evans et al., 1995; Thompson et al., 2003). When extrapyramidal features are the main complaint at onset, they can configure an atypical parkinsonism, namely PSP or CBS. PSP is characterized by oculomotor disturbances and severe postural instability with frequent falls. CBS, instead, presents with an asymmetrical parkinsonian syndrome with additional motor and non-motor manifestations such as myoclonus and dystonia, followed by focal cortical deficits (Siuda et al., 2014). Coexistence of FTD and motor neuron disease (MND) occurs in about 15–20% of subjects receiving diagnosis of amyotrophic lateral sclerosis (ALS) (Burrell et al., 2011; Lomen-Hoerth et al., 2002).

for Alzheimer's Disease (AD), but expanding knowledge and the strong genetic influence in this condition could lead to better patients’ selection and to pharmacological trials in prodromal or presymptomatic phases. After giving a clinical and pathogenic background, this review will address current recommendations and advances in symptomatic and disease-modifying therapy. 2. Clinical phenotypes The term FTD encompasses a group of clinically and pathologically heterogeneous disorders (Armstrong et al., 2013; Gorno-Tempini et al., 2011; Litvan et al., 1996; Neary et al., 1998; Strong et al., 2009) (Rascovsky et al., 2011) characterized by relatively selective atrophy of the frontal and temporal lobes (Cairns et al., 2007). It represents the second most common dementing disorder in individuals younger than 65 years, and accounts for 5–15% of all cases of dementia. The estimated prevalence is 15–22 per 100,000 and population studies indicate an equal gender distribution (Hogan et al., 2016; Onyike and Diehl-Schmid, 2013). FTD is a highly heritable disorder with approximately 30–50% of cases reporting a positive family history (Rohrer et al., 2009a) and about 10–20% showing a clear autosomal-dominant inheritance (Rohrer et al., 2015). Current clinical criteria identify different phenotypes on the basis of presenting clinical symptoms: a behavioural-dysexecutive disorder, i.e. behavioural variant of FTD (bvFTD) (Rascovsky et al., 2011) and the language variants, i.e. the nonfluent/agrammatic variant of primary progressive aphasia (avPPA) and the semantic variant of PPA (svPPA) (Gorno-Tempini et al., 2011; Mesulam, 1982). Finally, FTD can overlap with atypical parkinsonian disorders, such as progressive supranuclear palsy (PSP) (Litvan et al., 1996), corticobasal syndrome (CBS) (Armstrong et al., 2013) and with motor neuron disease/amyotrophic lateral sclerosis (FTD–MND/ALS) (Strong et al., 2009). BvFTD manifests itself in progressive decline in social skills, difficulties with planning and higher level thinking due to executive dysfunction and progressive changes in personality, lack of insight, disinhibition, apathy, binge eating, obsessive-compulsive behaviours, yet with relative preservation of other cognitive areas such as episodic memory and visuospatial function in the early stages (Rascovsky et al., 2011). These cognitive and behavioural changes are due to the atrophy of the frontal and anterior temporal regions as well as the anterior cingulate, anterior insula, and anterior temporal and parietal regions (Rohrer et al., 2009b). The most recent diagnostic criteria for bvFTD (Rascovsky et al., 2011) have 85–95% sensitivity and 82% specificity for a diagnosis of possible bvFTD, and 75–85% sensitivity and 95% specificity for probable bvFTD (Harris et al., 2013; Rascovsky et al., 2011). The PPAs are characterized by isolated language deficits during the initial stage, with an insidious onset (Gorno-Tempini et al., 2011). Patients with avPPA have non-fluent speech, with the two core features being agrammatism and speech apraxia (Gorno-Tempini et al., 2011). Agrammatism presents with short, simple sentences, with changes in the morphology of nouns and verbs, word order, and phrase structure (Mesulam, 2003; Rohrer et al., 2008). Speech apraxia impairs the patient's ability to program and plan the motor aspects of speech production properly, leading to slow speaking rate, abnormal prosody and distorted sound substitutions, additions, repetitions and prolongations, sometimes accompanied by groping and trial and error articulatory movements (Josephs et al., 2006). The classical neuroimaging feature is atrophy of the left posterior (and inferior) frontal lobe and left superior temporal lobe with associated insular atrophy (Rohrer et al., 2009b). Conversely, in svPPA, spontaneous speech is fluent whilst anomia and impaired single word comprehension are the core features (Gorno-Tempini et al., 2011). Poor understanding of single words is frequently one of the early symptoms. Initially naming errors occur, mainly for unfamiliar or atypical items, and consist of semantic

3. Genetics Many cases of FTD have a family history for dementia or psychiatric illnesses, typically with a dominant inheritance pattern (Rohrer et al., 2009a). Genetic studies have identified several genes associated with FTD. A core clinical and pathological phenotype is recognized for each gene, although clinical distinction is still poorly defined; thus, no clearcut genotype–phenotype correlations have been identified yet. The first gene found to be associated with hereditary FTD was the microtubule-associated protein tau (MAPT) gene on chromosome 17, discovered in 1998 (Hutton et al., 1998; Spillantini et al., 1998). MAPT codes for the protein tau and individuals with MAPT mutations have abnormal accumulation of this protein in affected neurons. Mutations in MAPT account for 5–10% of all FTD cases, with over 50 different causal mutations known (Spillantini and Goedert, 2013). MAPT mutations are rare in sporadic patients, whereas in familial patients frequency range from 5% to 20% (Pottier et al., 2016). Intronic and some exonic mutations may affect the alternative splicing of exon 10, leading to tau dysfunction and consequently to accumulation. Missense mutations impair the ability of tau to bind microtubules and to promote microtubule assembly (Irwin et al., 2015). Mutations in the MAPT gene are associated with the clinical diagnosis of FTDP-17, which stands for FTD with parkinsonism on chromosome 17. MAPT mutations are associated with Tau inclusions (FTD-Tau) and present clinically with an extremely heterogeneous picture: they have been associated largely with bvFTD and PPA, but PSP and CBS clinical phenotypes have also been described (Charlesworth et al., 2012; Forman et al., 2006; Forman et al., 2002). In 2006, mutations of the Granulin gene were identified as causative of autosomal dominant FTD (Baker et al., 2006; Cruts et al., 2006). The protein product, progranulin, is a secreted glycoprotein, cleaved into granulin peptides and found in the brain and serum with roles in inflammatory diseases, diabetes and obesity. Pathogenic mutations in GRN are mainly nonsense and splice site mutations resulting in the loss of one GRN allele with functional haploinsufficiency; some mutations, however, are missense mutations causing mistrafficking within the cell (Irwin et al., 2015). Serum levels of progranulin are reduced by about 50% in mutation carriers (Finch et al., 2009; Ghidoni et al., 2008; Lashley et al., 2015; Sleegers et al., 2

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on the basis of the deposited abnormal intracellular protein aggregate (Mackenzie et al., 2010). About 40% of patients examined immunohistologically shows taupositive inclusions (FTLD-tau); these include those cases of illness associated with mutations in the MAPT gene (Josephs et al., 2006; Mackenzie et al., 2009, 2010). In recent years it has become evident that about 50% of cases of FTLD are tau-negative and they are characterized by the presence of ubiquitin deposits, indeed named FTLD-U (Mackenzie et al., 2006). The majority of the FTLD-U cases are associated with accumulation of TDP-43 (TAR DNA-binding protein 43) and named FTLD-TDP (Mackenzie et al., 2009; Neumann et al., 2009; Neumann et al., 2006). Recently incidences of the disease have been described with a positive attitude to accumulate protein FUS (Fused in Sarcoma) in patients with ALS and FTLD (Neumann et al., 2009). Such cases are responsible for the majority of tau and TDP-43-negative FTLDs, representing about 5–10% of ubiquitin-positive FTLDs. FTLD-FUS includes three diseases: neurofilament inclusion body disease (NIFID), atypical FTLD-U (aFTLD-U) and basophilic inclusions body disease (BIBD) (Lashley et al., 2015). In a small number of cases protein nature of the ubiquitin-positive inclusions remain unknown and were classified as FTLD-related proteasome system (FTLD-UPS) (Mackenzie et al., 2010), represented mostly by cases of affected individuals of a Danish pedigree due to mutation in the CHMP2B gene. While no inclusions are found in a small minority of the cases, designated as FTLD-ni.

2009) and thus could represent a promising biomarker for emerging progranulin-restorative therapies (Boxer et al., 2013a; Ghidoni et al., 2012). Individuals with GRN mutations have abnormal accumulations of the TDP-43 protein in affected neurons (FTD-TDP). The most frequent clinical presentation of FTLD with GRN mutations is bvFTD and avPPA. There is however considerable heterogeneity of clinical presentation and of age at disease onset in patients with the same mutation and belonging to the same family (Chen-Plotkin et al., 2011). GRN mutations account for 5–20% of patients with positive family history and 1–5% of sporadic cases (Rademakers et al., 2012). In 2011, two separate groups identified a novel gene associated with FTD, namely an expanded hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 (C9orf72) (DeJesus-Hernandez et al., 2011; Renton et al., 2011). The function of the protein that C9orf72 codes is not yet understood. Although the repeat region is variable in length in the healthy population (up to around 30 repeats), repeat expansions typically seen in patients are more massively expanded, typically > 400 repeats, although there is no direct association between the severity of the disease and expansions size (Beck et al., 2013; DeJesus-Hernandez et al., 2011; van Blitterswijk et al., 2014). The core clinical phenotype is the combination of FTD and MND/ALS: however, the expansion mutation is commonly associated with bvFTD, pure MND/ALS and may be reported in patients labelled with AD, movement disorders, ataxias and nonspecific neuropsychiatric/ neurodegenerative syndromes (Cooper-Knock et al., 2014). C9orf72 expansion accounts for 37% of familial ALS, 6% of sporadic ALS, 21% of familial FTD and 6% of sporadic FTD cases (Rademakers et al., 2012). Other genes are associated with rare FTD cases: ValosinContaining Protein (VCP) mutations are linked to a specific condition called inclusion body myopathy with Paget disease of the bone and FTD (IBMPFD) (Watts et al., 2004); Charged multivesicular body protein 2B (CHMP2B) mutations, involved in the endosomal–lysosomal pathway (Skibinski et al., 2005); Fused in sarcoma (FUS) mutations (Broustal et al., 2010; Van Langenhove et al., 2010) and TAR DNAbinding protein (TARDBP) mutations (Arai et al., 2006; Neumann et al., 2006). In Table 1, the most common genes causative of inherited FTD are reported, while Fig. 1 shows the relationship between the more common genes, clinical pictures and underlying neuropathology.

5. Therapeutic options Clinicians are always required by caregivers to answer two main questions: how to manage FTD symptoms, and if it is plausible to stop, or at least to slow down, the clinical course. FTD symptomatology roughly includes behavioural disturbances, executive function and language deficits. While some knowledge about symptomatic management has been acquired, there is still no experimental evidence suggesting that clinical course can be modified. This is partly due to still unsatisfactory knowledge of FTD pathophysiology and to the lack of biomarkers able to distinguish between the different neuropathological substrates. 5.1. Symptomatic therapies: targeting neurotransmission

4. Neuropathology The rationale for use of symptomatic therapies in behavioural disturbances in FTD is based on efficacy in treating other neurodegenerative disorders or psychiatric conditions with similar behavioural involvement. A summary of evidence and efficacy of each pharmacological class is available in Table 2. Classically, FTD brains are considered to be defective of serotonin

Clinical FTD is associated with different types of underlying neuropathology. Currently the frontotemporal lobar degeneration (FTLD) is a term used to describe the pathological hallmarks of the disease. Thanks to the progress of immunohistochemical techniques it is possible to identify the categories of FTLD, subdivided pathologically Table 1 Overview of the molecular genetics of frontotemporal dementia. Gene

Abb.

Year of identification

Genomic Location

N° Mutations

N° Families

Most commonly associated phenotype

Microtubule associated protein tau Granulin Chromosome 9 open reading frame 72 Valosin-containing protein

MAPT GRN C9orf72

1998 2006 2011

17 q21.3 17 q21.31 9 p21.2

44 79 1

134 259 336

bvFTD; CBS; PSP bvFTD; avPPA; CBS bvFTD; FTD-MND; MND

VCP

2004

9 p13.3

19

49

Chromatin modifying protein 2B

CHMP2B

2005

3 p11.2

4

5

Transactive response DNA-binding protein 43 Fused in sarcoma

TARDP

2008

1 p36.22

33

134

Paget disease of bone and/or FTD; MND/ ALS bvFTD, dystonia, myoclonus, and pyramidal symptoms FTD-MND; bvFTD

FUS

2009

16 p11.2

23

49

FTD-MND/ALS

Cruts et al., 2012. bvFTD: behavioural variant of FTD; avPPA: nonfluent/agrammatic variant of primary aphasia; MND: motoneuron disease; ALS: Amyotrophic Lateral Sclerosis; PSP: progressive supranuclear palsy; CBS: corticobasal syndrome.

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Fig. 1. Simplified representation of genotype-phenotype association of MAPT, GRN and C9orf72 mutations, and neuropathological correlations. Arrows connect each gene to related phenotypes. Boxes reporting clinical phenotypes are also colored according to the underlying neuropathology (blue = FTD-TDP; red = FTD-Tau). bvFTD: behavioural variant of FTD; avPPA: nonfluent/agrammatic variant of primary aphasia; svPPA: semantic variant of primary aphasia; MND: motoneuron disease; PSP: progressive supranuclear palsy; CBS: corticobasal syndrome. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Evidence of efficacy of serotonin replacement in FTD comes from few trials in small samples (Knopman et al., 2008; Vossel and Miller, 2008). Only two randomised-controlled trials (RCTs) have explored selective serotonin reuptake inhibitors (SSRIs) efficacy in FTD, with contrasting results: the first one, based on treatment with paroxetine 40 mg for 6 weeks, showed worsening of cognition without behavioural improvement (Deakin et al., 2004). Instead, treatment with trazodone

(Sparks and Markesbery, 1991), mainly of 5-HT1A and 5-HT2A receptors in the postsynaptic region of the orbitofrontal, frontal medial, and cingulate cortices (Franceschi et al., 2005). Serotonin defect has been linked with aggression and impulsiveness (Asberg, 1997), depressive symptoms (Moore et al., 2000), binge eating (McIntyre et al., 2001) and has been associated with frontal hypometabolism (Dhaenen, 2001). Table 2 Efficacy and level of evidence for the use of symptomatic drugs. Class

Drug

Dose

Primary outcome

Results

Type of evidence

References

SSRIs

Paroxetine

40 / 20 / 20 mg

Behavioural improvement

-/+/+

Trazodone Fluvoxamine Fluoxetine Sertraline Citalopram

50–100 mg TID 50–150 mg 20 mg 50–125 mg 30 mg

Behavioural Behavioural Behavioural Behavioural Behavioural

improvement improvement improvement improvement improvement

+ + + + +

RCT / Openlabel RCT Open-label Open-label Open-label Open-label

Deakin et al. (2004), Moretti et al. (2003a) and Swartz et al. (1997) Lebert et al. (2004) Ikeda et al. (2004) Swartz et al. (1997) Swartz et al. (1997) Herrmann et al. (2012)

Antipsychotics

Olanzapine Risperidone Aripiprazole

2.5–10 mg 3 mg BID 10 mg

Behavioural improvement Behavioural improvement Behavioural improvement

+ + +

Open-label Case report Case report

Moretti et al. (2003b) Curtis and Resch (2000) Fellgiebel et al. (2007)

AchIs

Galantamine

8–24 mg

None

RCT

Kertesz et al. (2008)

Rivastigmine Donepezil

3–9 mg 10 mg

Behaviour / Language improvement Behavioural improvement Behavioural improvement

+ –

Open-label Open-label

Moretti et al. (2004) Mendez et al. (2007)

Dopamine agonists

Methylphenidate Dextroamphetamine

40 mg 20 mg

Behavioural improvement Behavioural improvement

+ +

RCT RCT

Rahman et al. (2006) Huey et al. (2008)

NMDA antagonists

Memantine

10 mg BID

None

RCT

AEDs

Carbamazepine Valproic acid

+ +

Case report Case report

Vercelletto et al. (2011) and Boxer et al. (2013b) Poetter and Stewart (2012) Chow and Mendez (2002)

Topiramate

200 mg up to 1125 mg BID 25–100 mg BID

Stabilization / Behavioural improvement Inappropriate sexual behaviour Behavioural improvement Alcohol abuse / abnormal eating

+

Case report

Cruz et al. (2008), Nestor (2012) and Singam et al. (2013)

Oxytocin

24 IU

Behaviour / Emotion processing Safety / Tolerability

+

RCT

Jesso et al. (2011)

+

RCT

Finger et al. (2015)

Reaction time / fMRI signal intensity

Ongoing

RCT

NCT00604591

Neuropeptides

24–72 IU BID COMT inhibitors

Tolcapone

100 mg TID

For each drug, pharmacological class, utilized dose, primary outcome, results and type of evidence are reported. The sign “+” indicates reported beneficial effect, while “-“ indicates worsening of symptoms. SSRIs: selective serotonin reuptake inhibitors; AchIs: Acetylcholinesterase inhibitors; AEDs: antiepileptic drugs; COMT: catecholamine-O-methyltransferase; BID: two times/day; TID: three times /day; RCT: randomized controlled trial.

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2008). In 2011, Jesso et al. performed a double-blind, placebocontrolled crossover study which showed that a single intranasal dose of 24 IU of oxytocin was associated with a transient improvement in social and neuropsychiatric behaviours in patients with FTD (Jesso et al., 2011). A randomized, double-blind, placebo-controlled trial of 3 doses of intranasal oxytocin confirmed that doses up to 72 IU, twice daily, were well tolerated in FTD, with significant, dose-related improvement on apathy subitems (Finger et al., 2015). In this light, oxytocin could be a promising drug for treatment of negative symptoms (such as apathy and loss of empathy) but an efficacy trial is warranted. An ongoing symptomatic trial is testing the effect of tolcapone, a catecholamine-O-methyltransferase (COMT) inhibitor, on cognitive, behavioural, and language symptoms in FTD (NCT00604591). Tolcapone selectively increases prefrontal dopamine, and has been demonstrated to enhance prefrontal cortical function in normal human subjects (Apud et al., 2007). With regard to amantadine, no data about efficacy are available, as the only reported clinical trial (NCT00127114) was interrupted because of recruitment difficulties.

up to 300 mg for 12 weeks showed significant improvement of behavioural disturbances, although fatigue, dizziness and hypotension were common at high dosage, and no effect on cognition was found (Lebert et al., 2004). Positive results have also been found in open-label studies with fluvoxamine (Ikeda et al., 2004), fluoxetine, sertraline (Swartz et al., 1997), citalopram (Herrmann et al., 2012), and paroxetine (Moretti et al., 2003a; Swartz et al., 1997). Dopamine depletion has also a role in FTD: both frontal cortices and basal ganglia receive dopaminergic input. There is evidence of presynaptic dopamine deficiency in the basal ganglia (Rinne et al., 2002) and postsynaptic dopamine frontal deficiency in FTD brains (Frisoni et al., 1994). Dopamine deficiency correlates with parkinsonism (Rinne et al., 2002) and could also contribute to attention and executive dysfunction (Weinberger et al., 2001; Zametkin et al., 1990). Dopamine antagonists (i.e. antipsychotics), though in contrast with the underlying dopamine depletion, are used in the clinical setting to treat positive behavioural symptoms (such as agitation, aggression and disinhibition), especially when severe. This indication is supported only by one open-label study with olanzapine, which showed similar efficacy in controlling positive behaviours when compared to antidepressants (Moretti et al., 2003b). Extrapyramidal symptoms are usually unresponsive to levodopa, but a mild, transient success can be achieved in about one third of PSP and CBD patients, where parkinsonism represents the main clinical feature (Constantinescu et al., 2007). Use of dopamine agonists, such as dextroamphetamine and methylphenidate, is not suggested as a first line treatment for motor symptoms because of the risk of increasing positive behaviours and hallucinations. However, two small cross-over trials have shown efficacy of both dextroamphetamine and methylphenidate in improving behavioural scores (Huey et al., 2008; Rahman et al., 2006). Further studies on larger samples are needed in order to determine the real efficacy and tolerability of these drugs. Conversely to Alzheimer's Disease, the cholinergic system is relatively preserved in FTD, as demonstrated by preservation or increase in cortical choline acetyltransferase (Wood et al., 1983), intact acetylcholinesterase levels (Meier-Ruge et al., 1984), intact postsynaptic muscarinic receptor binding, preservation of neurons in the nucleus basalis of Meynert (Tagliavini and Pilleri, 1983). Acetylcholinesterase inhibitors (AChIs) are frequently prescribed to FTD patients. However, the only double-blinded study, testing galantamine, did not show any change in cognition or language (Kertesz et al., 2008). One open-label study testing rivastigmine reported reductions in behavioural scores (Moretti et al., 2004), while a casecontrol study with donepezil showed a worsening of behavioural symptoms (Mendez et al., 2007). In general, absence of involvement of the cholinergic system and prevailing evidence for negative effects of AChIs do not support their use in clinical practice. There is little proof of glutamate transmission abnormalities in FTD, with some evidence showing reduced AMPA and NMDA receptors in the frontotemporal cortices (Ferrer, 1999; Procter et al., 1999). Despite some prior evidence for transient improvement of behavioural and cognitive symptoms in FTD after memantine administration (Boxer et al., 2009), two randomized, double-blind, placebo-controlled studies have shown the inefficacy of this molecule (Boxer et al., 2013b; Vercelletto et al., 2011). Of note, some beneficial effects on inappropriate behaviours have also been reported by use of antiepileptic drugs (AEDs) with mood stabilizing effects, such as valproic acid (Chow and Mendez, 2002), topiramate (Cruz et al., 2008; Nestor, 2012; Shinagawa et al., 2013; Singam et al., 2013) and carbamazepine (Poetter and Stewart, 2012), but evidence is limited to case reports. Oxytocin is a hypothalamic neuropeptide which is delivered to the pituitary gland, amygdala, nucleus accumbens and prefrontal cortex, where it seems to be an important mediator of social behaviour, potentially enhancing empathy behaviours (Donaldson and Young,

5.2. Disease-modifying therapies: targeting neuropathology Beside symptomatic therapies, the attention of researchers has moved to test drugs modulating pathogenic pathways, in order to slow down progression. In order to test experimental drugs, two key points are required: first of all, the ability to correctly identify the underlying neuropathological substrate. As previously said, nowadays we can count for 3 main underlying pathologies: FTLD-tau, FTLD-TDP and FTLD-FUS. With this caveat, it is possible to offer to patients the opportunity to participate in disease-modifying pharmacological trials according to their clinical and genetic background. The most interesting populations are represented by PSP patients and subjects carrying MAPT mutations, who have FTD-Tau pathology. Conversely, patients with FTDALS, and subjects carrying mutations within GRN, C9orf72 and VCP have FTD-TDP pathology. The second key point is represented by the knowledge of mechanisms responsible for neurodegeneration. Although this field is in expansion, possible targets have been identified. However, there is no clear cut candidate above all others. The pharmacological trials conducted with the goal to modulate FTD course are reported in Table 3. Tau-related pathology undoubtedly has some advantages with respect to TDP-43, due to the similar accumulation of hyperphosphorylated tau, which allows for some interventions already used in AD (NCT00515333; NCT01350362) (del Ser et al., 2013; Wischik et al., 2015). Tau undergoes a host of conformational and biochemical changes indicating that there are a wide range of pathways acting upon it at a number of different junctures. During this evolution, tau may be toxic at one or several points via a number of different mechanisms that may occur simultaneously, and none of them has emerged as the dominant candidate for therapy development (D'Alton and Lewis, 2014). When facing tau mutations, however, depending upon the function of tau that is affected and the way it is affected, a tau mutation can cause either a ‘‘gain of function’’ or a ‘‘loss of function’’ condition. Complex pathological mechanisms must then be considered when investigating tau-driven neurodegeneration. Accordingly, therapeutic strategies for tauopathies should take into account all the possible functions of tau to be successful, targeting tau phosphorylation and aggregation, oligomer toxicity, microtubule destabilization/overstabilisation (Rossi and Tagliavini, 2015). Until now, Tau-based therapies have been developed to reduce Tau phosphorylation (GSK3β inhibitors, phosphotau-immunotherapy) (Castillo-Carranza et al., 2014; Wischik et al., 2014), inhibition of 5

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Table 3 Ongoing and completed trials of disease-modifying compounds. Class

Compound

Phenotype

Primary outcome

Results

Phase

ClinicalTrials.gov Identifier

TAU

Tau aggregation inhibitor Benzothiazole Microtubule stabilizer Mitochondrial cofactor GSK-3β inhibitor GSK-3β inhibitor Microtubule stabilizer Tau acetylation inhibitor Anti-Tau antibody Anti-Tau antibody

TRx0237 Riluzole Davunetide Coenzyme Q10 Tideglusib Lithium TPI-287 Salsalate C2N-8E12 BMS-986168

bvFTD PSP, MSA PSP PSP PSP PSP, CBS PSP, CBS PSP PSP PSP

Safety, efficacy Efficacy Safety, efficacy Safety, efficacy Efficacy Tolerability Safety, tolerability Safety, tolerability Safety, tolerability Safety, tolerability

Completed No effect No effect + No effect Not tolerated Recruiting Recruiting Recruiting Recruiting

Phase Phase Phase Phase Phase Phase Phase Phase Phase Phase

NCT01626378 NCT00211224 NCT01110720 NCT00328874 NCT01049399 NCT00703677 NCT02133846 NCT02422485 NCT02494024 NCT02460094

TDP-43

Histone deacetylase inhibitor Calcium channel blocker

FRM-0334 Nimodipine

GRN carriers GRN carriers

Safety, tolerability, pharmacodynamics Safety, tolerability

Completed Completed

Phase 2 Phase 1

3 3 2/3 2 2 1/2 1 1 1 1

NCT02149160 NCT01835665

For each compound, pharmacological class, phenotype(s), primary outcome, obtained results and trial phase are reported. The sign “+” indicates reported beneficial effects. bvFTD: behavioural variant FTD; MSA: multiple system atrophy; PSP: progressive supranuclear palsy; CBS: corticobasal syndrome; GRN: granulin mutation.

the toxic mechanism, it must be stated that aggregates are capable of sequestering the full-length protein thus leading to a possible loss of function, with evidence of cellular death in knockout animals (Kraemer et al., 2010; Wu et al., 2010). Thus, possible therapeutic approaches would be restoration of nuclear function and reduction in formation or increased clearance of aggregates. Yamashita and colleagues demonstrated in vitro that the combined use of methylene blue and dimebon resulted in an 80% reduction in the number of TDP-43 aggregates (Yamashita et al., 2009). Actually, only monogenic disorders related to TDP-43 pathology have been taken into account for therapeutic trials. GRN mutations, thought to act through loss of function mechanisms, are associated with decreased levels of the protein in serum and CSF (Finch et al., 2009; Ghidoni et al., 2008; Sleegers et al., 2009). Thus, restoring GRN function targeting its receptors (Tang et al., 2011; Zheng et al., 2011) or increasing GRN synthesis are promising strategies. In vitro studies have shown that both chemicals that upregulate progranulin levels through enhanced transcription (suberoylanilide hydroxamic acid) and alkalizing agents (chloroquine, bepridil, and amiodarone) could be effective (Capell et al., 2011). However, these results have not been replicated in vivo in a phase 2 trial with amiodarone (Alberici et al., 2014). Two pharmacological trials have recently completed recruitment and results will be available soon. The first one is a phase 1 trial exploring safety and tolerability of the CNS-penetrant calcium channel blocker nimodipine in asymptomatic or symptomatic GRN positive individuals (NCT01835665), while the second is a randomized, doubleblind, placebo-controlled, dose-escalating, phase 2a trial assessing safety and tolerability of the histone deacetylase inhibitor FRM-0334 (NCT02149160). Given the relationship between autoimmune disorders and GRNrelated pathology (Z.A. Miller et al., 2013), a possible role of inflammation should be taken in account for future further strategies. With regard to the C9orf72 hexanucleotidic expansion, one promising perspective seems that of antisense oligonucleotides (ASOs), short oligonucleotide sequences that are able to interfere with RNA processing/transduction either activating RNA degradation or preventing the ligation with specific RNA-binding proteins (Dias and Stein, 2002). One clinical trial in ALS demonstrated good tolerability of intrathecal injection of ISIS 333611 in ALS patients (TM Miller et al., 2013), suggesting that ASOs might be a feasible treatment for neurological disorders (Riboldi et al., 2014).

early aggregation or clearance of oligomers (microtubule stabilizing reagents) (Brunden et al., 2011), inhibition of fibrillisation or clearance of fibrillary species (Kfoury et al., 2012; Li et al., 2009). In the FTLD spectrum, PSP represents the most studied tauopathy in clinical trials. Both lithium (NCT00703677) and tideglusib, which have shown GSK3β inhibition effects, failed in phase 2 trials. Lithium was not tolerated due to adverse events, while tideglusib did not show clinical efficacy after 52 weeks of treatment (Tolosa et al., 2014). Riluzole, rasagiline and davunetide did not show any effect on survival or rate of functional deterioration in phase 3 trials (Bensimon et al., 2009; Boxer et al., 2014; Nuebling et al., 2016), while coenzyme Q10, in a phase 2 trial, showed slight but significant clinical improvement in PSP patients (Stamelou et al., 2008), with also some evidence of behavioural and survival improvement in mouse model of P301S tau mutation (Elipenahli et al., 2012). Phase 1 trials in PSP are currently undergoing for TPI-287 (NCT02133846), C2N-8E12 (NCT02494024), BMS-986168 (NCT02460094) and salsalate (NCT02422485). With regard to FTD, interesting results have been obtained in a phase 2 trial using a tau aggregation inhibitor (methylthioninium), demonstrating improvement in the cognitive performances in both mild and moderate AD subjects at 50 weeks (Wischik et al., 2015). A new compound, called leucomethylthioninium, claimed to be more bioavailable and less toxic than methylthioninium, is now under investigation in bvFTD (NCT01626378). These molecules were originally designed to inhibit tau-tau interaction, but it may also induce autophagy and reduce soluble tau through other mechanisms (Congdon et al., 2012). At preclinical level, a new promising molecule is represented by temsirolimus, which induces autophagic clearance of hyperphosphorylated tau in the brain of P301S transgenic mice (Jiang et al., 2014). Instead, new possible therapeutic targets are represented by the Hsp70/CHIP chaperone system, which plays an important role in the regulation of tau turnover (Petrucelli et al., 2004), Hsp90, which prevents tau degradation (Blair et al., 2013), NPAS4, acting through autophagy and facilitation of Tau clearance (Fan et al., 2016). Knowledge of TDP-43 is limited by its relatively recent identification. TDP-43 is an RNA-binding protein that forms heterogeneous nuclear ribonucleoprotein complexes, which regulate RNA splicing, translation, miRNA processing, and mRNA transport (Ling et al., 2010). C-terminal fragments of TDP-43 are aggregate-prone, undergo phosphorylation and ubiquitination and are cytotoxic in cell culture (Zhang et al., 2011). Furthermore, a possible prion-like behaviour has been identified (Nonaka et al., 2013; Udan-Johns et al., 2014). Besides

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6. Conclusions FTD is a heterogeneous disorder manifesting with different clinical phenotypes and with different possible underlying neuropathological processes. Currently there are no FDA approved treatments for FTD, and most treatments are symptomatic therapies for other disorders used off-label. While symptomatic therapies are widely used, the same cannot be stated for disease-modifying therapies, which require better clarification about the mechanisms of neurodegeneration. In order to establish the effectiveness of future disease-modifying therapies, the accurate selection of candidate patients should be considered. To this, more accurate biomarkers able to predict the underlying pathology are needed. Indeed, patients with known neuropathology, such as PSP patients, MAPT mutation carriers and GRN/ C9orf72 mutation carriers, represent the best candidates to test the efficacy of specific pharmacological interventions. 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