Antidepressants

The serotonergic system has been suggested to mediate behaviors such as impulsivity, aggression, and disinhibition [2]. These behaviors are also commonly seen in behavioral variant (bvFTD) patients. Neuropathologic analyses have shown FTD patients to have a dysfunctional serotonergic system, with reduction of 5-HT1 and 5-HT2A serotonin receptors in orbital frontal, cingulate, medial frontal, and temporal regions [3, 4]. Another study also demonstrated a 40% loss of neurons in the serotonergic raphe nuclei [5]. Selective serotonin reuptake inhibitors (SSRIs) are attractive agents for use in FTD patients as they increase serotonin levels, and have historically been successful in treating clinical symptoms in psychiatric patients that resemble some of the problematic FTD behaviors. As shown in Table 18.1, SSRIs such as citalopram, fluoxetine, paroxetine, sertraline, fluvoxamine, and clomipramine have all been described to be beneficial for managing FTD behaviors in small open label clinical trials or case series [6–14]. Unfortunately, as is often the case, efficacy in small preliminary studies has not been replicated in randomized placebo-controlled clinical trials. Paroxetine showed significant behavioral improvements in two open label trials but failed to demonstrate improvements in a subsequent six-week, double-blind, placebo-controlled crossover trial [15]. The only medication with serotonergic activity with proven efficacy in a small randomized, double-blind, placebo-controlled trial was trazodone, which demonstrated improvements in Neuropsychiatric Inventory (NPI) scores 12 weeks after treatment [16]. Most clinicians believe that antidepressants may help to manage various behavioral symptoms in FTD patients, but with most evidence coming from open label trials or case series, the evidence to support this opinion is mainly anecdotal.

Acetylcholinesterase inhibitors

Acetylcholinesterase inhibitors have long been a mainstay of AD symptomatic treatment, based on the loss of cholinergic neurons from the nucleus basalis of Meynert. Perhaps because of their success in AD, acetylcholinesterase inhibitors have been studied more rigorously than other off-label treatments in FTD (Table 18.2). However, as reviewed by Huey et al. in 2006, in contrast to AD, the cholinergic system in FTD patients is relatively spared from pathology [17]. Clinical trials for the three most commonly used acetylcholinesterase inhibitors have produced disappointing results, although none were large enough or designed to allow for a true efficacy determination. A 12-month open label study of rivastigmine dosed 3–9 mg/day showed some improvements in NPI score but did not prevent cognitive deterioration as measured by the Mini-Mental State Examination(MMSE) [18]. A second study investigated galantamine in 36 bvFTD and primary progressive aphasia (PPA) patients. All patients were treated in an open label fashion for 18 weeks followed by a randomized, double-blind, placebo-controlled withdrawal period for 8 weeks. No significant differences were found in the bvFTD group, while language function remained stable in some of the treated PPA group compared with placebo, who likely had the logopenic form of PPA caused by underlying Alzheimer’s pathology [19]. Donepezil, perhaps the most widely used cholinesterase inhibitor, was studied in a 6-month, open label study in 24 bvFTD patients. The donepezil-treated group had greater worsening on the FTD inventory, and four of the treated patients had worsening behavior. Discontinuation of donepezil led to an abatement of behavioral symptoms, which was replicated in a more recent discontinuation trial of donepezil in FTD patients conducted in Japan [20, 21]. Currently, the evidence suggests cholinesterase inhibitors are not effective treatments in FTD patients and may exacerbate behavioral symptoms. Routine use is not recommended.

Antipsychotics and dopaminergic therapies

The dopaminergic system is a potential therapeutic target for FTD but poses an interesting treatment paradox. Patients with frontotemporal dementia with parkinsonism-17 (FTDP-17), a rare form of autosomal dominant FTD usually due to MAPT or GRN mutations, with symptoms of parkinsonism and FTD, have evidence of dopaminergic system dysfunction. Imaging studies such as PET and single-photon emission computed tomography (SPECT) have shown decreased presynaptic dopamine transporter binding in the striatum of FTD patients and decreased postsynaptic dopamine receptor binding in FTDP-17 patients respectively [22, 23]. Dopamine reduction in the striatum of FTD patients has also been demonstrated [24]. However, behavioral symptoms in FTD can be similar to symptoms in schizophrenia, especially in agitation and disinhibition, which are thought to be due to increased dopaminergic activity. Although it should be noted that most dopaminergic abnormalities in schizophrenia are thought to be attributed to the cortical as opposed to striatal dopaminergic system, antipsychotics with dopamine receptor antagonistic properties have successfully treated such symptoms in psychiatric patients. Thus despite the contrary evidence described above, both dopamine blockade and augmentation therapies have been evaluated in FTD patients, as listed in Tables 18.3 and 18.4.

Evidence for the use of antipsychotics in FTD patients comes mainly from anecdotal case reports and series. Risperidone, quetiapine, and aripiprazole have been suggested to mitigate behavioral disturbances [8, 25–27]. A 24-month open label trial evaluated olanzapine in five groups of patients with various dementia diagnoses. Of the 17 patients with FTD, improvements in delusions, NPI scores, and caregiver stress were observed. Other groups with diagnoses of Lewy body dementia, vascular dementia, and Parkinson’s disease dementia also experienced significant behavioral improvements [28]. In a small, double-blind, crossover study with dextroamphetamine and quetiapine involving eight FTD patients with behavioral symptoms, no difference in NPI was shown between baseline and quetiapine treatment [29]. Currently, the evidence for antipsychotic use in FTD is limited, and use carries the risk of extrapyramidal side effects, to which FTD patients are particularly vulnerable [30]. In addition, the FDA recently determined the use of atypical antipsychotics for behavioral symptoms treatment of dementia to be associated with higher mortality than placebo, related to cardiac or infectious events, and issued a black box warning for all antipsychotics.

With the dopamine deficiencies described above, medications that augment dopamine levels or signal transduction have also been tested in FTD patients. A small series of three FTD patients evaluated the monoamine oxidase (MAO)-B inhibitor selegiline and reported improvements in NPI scores [31]. Similar results were shown in a small, randomized, double-blind crossover study in eight FTD patients using dextroamphetamine along with quetiapine, which is thought to augment dopamine levels by preventing reuptake and inducing release of dopamine [29]. Another double-blind, placebo-controlled, crossover study using methylphenidate, a dopamine and norepinephrine reuptake inhibitor, in eight FTD patients demonstrated improvements in risk-taking behaviour [32]. Six PPA patients of unspecified variant were enrolled in a double-blind, placebo-controlled, crossover trial using bromocriptine, a dopamine agonist. Mild slowing of language deterioration was detected but bromocriptine did not appear to significantly alter disease course [33]. In summary, while a variety of dopamine-modulating therapeutics have shown potentially promising preliminary results in FTD, rigorous placebo-controlled studies should be performed to determine their true safety and efficacy. Safety is a particular concern for these drugs in light of their potential adverse effects such as increased behavioral disturbances, risk-taking behavior, hallucinations; symptoms that have been observed in patients receiving dopamine replacement therapy for Parkinson’s disease.

Anti-epileptics

Anti-epileptic (anticonvulsant) agents have been used as mood stabilizers for manic behaviors, but none have been studied rigorously in the treatment of FTD. Currently there are case reports and case series, as shown in Table 18.5, that report experiences with such medications in FTD. The choice of anti-epileptics has typically been those with mood stabilizing effects such as carbamazepine and valproic acid, with reported improvements in behavior. [8, 34] Topiramate is an anti-epileptic with a migraine treatment indication and mood stabilizing effects and has been incorporated into some weight loss drugs based on a known propensity to cause anorexia. Interestingly, in several case reports it has been shown to reduce hyperorality in FTD patients but no placebo-controlled trials have been done [35–38].

Memantine

Memantine is a (N-methyl D-asparate) NMDA receptor antagonist that is indicated for the treatment of moderate to severe AD. Previously, a randomized, double-blind, placebo-controlled trial of 252 patients with moderate to severe AD demonstrated improvements in activities of daily living, cognition, and clinician impression on memantine compared with placebo [39]. Subsequently a randomized, double-blind, placebo-controlled clinical trial of 404 moderate to severe patients already on donepezil showed that addition of memantine resulted in improvements in cognition, activities of daily living, global outcome, and behavior symptoms [40]. Although the underlying pathology and neurotransmitter changes are different in AD compared with FTD, the NMDA receptor is thought to play a role in neurologic dysfunction due to range of different neurologic disorders. Excitotoxicity via overactivation of NMDA receptors by glutamate may be a final common pathway responsible for neuronal death. Whereas one small open label study demonstrated no effects of memantine in bvFTD [41], a small case series and a phase IV open label memantine study suggested improvements in behavioral symptoms as measured by the NPI [42–44]. The efficacy of memantine was further tested in two rigorous randomized, placebo-controlled clinical trials, one 52 weeks and one 26 weeks (Table 18.6) [45, 46]. Although both did not enroll the number of patients originally planned, both failed to demonstrate significant benefits on the NPI or Clinical Global Impression of Change. In addition, memantine treatment was associated with worse performance on a number of cognitive tests [46]. These studies provide fairly strong evidence that memantine is not an effective treatment for FTD. Experience with memantine in FTD underscores the limitations of attempting to extrapolate the efficacy of drugs for FTD based on placebo-controlled trials in AD and other disorders, even when there is a strong scientific rationale for use of the drug in FTD.

Parkinsonism treatment

A substantial portion of FTD patients also present with parkinsonism. FTDP-17 refers to autosomal dominantly inherited FTD associated with mutations in the tau (MAPT) or progranulin (GRN) genes and also frequently associated with parkinsonism. Moreover the disorders such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) which are defined by atypical parkinsonism, typically with substantial rigidity but infrequent tremor or levodopa response, overlap both clinically and neuropathologically with FTD. FTD patients with parkinsonism typically do not respond to dopaminergic therapy such as levodopa/carbidopa, although a few cases of potential benefit have been reported [8]. When significant parkinsomism arises in the setting of FTD, dopaminergic therapy can be attempted, although there is little evidence to suggest a benefit. Moreover, side effects such as nausea, hypotension, psychosis, and livedo reticularis are major issues that often limit the ability to escalate the dose of dopaminergic agents.

Targets

C9ORF72

FTD and ALS are both neurodegenerative processes. ALS affects both upper and lower motor neurons, presenting with weakness, atrophy, and rapid progression to death; up to 22% of ALS patients meet FTD diagnostic criteria, and 48% manifest cognitive or behavioral abnormalities without meeting the full criteria. Conversely, up to 15% of FTD patients display signs of motor neuron disease or ALS [89]. Both diseases have a 10% prevalence of autosomal dominant pattern as well, suggesting some shared pathophysiology (see Chapter 6).

In 2011, a hexanucleotide repeat expansion in a 5′ non-coding region of the C9orf72 gene was found to be the cause of FTD and ALS in a strongly chromosome 9p-linked family [90–92]. Subsequent analysis revealed this mutation to be the cause of 11.7% of familial FTD and 23% of familial FTD–ALS in one large series. Clinical phenotypes most frequently associated with this mutation are FTD, ALS, and FTD–ALS, but corticobasal syndrome, nfvPPA, and svPPA with and without motor neuron disease have been described. The pathology associated with C9orf72 mutation carriers have been overwhelmingly FTLD-TDP, specifically subtypes A and B, but also with unique p62-positive, TDP-43-negative inclusions, especially in the cerebellum and hippocampus [93].

Although the precise function of C9ORF72 remains unknown, a bioinformatics approach has recently shown that it is structurally similar to differentially expressed in normal and neoplastic cells (DENN) proteins, a class of GDP/GTP exchange factors important for Rab-GTPases, suggesting a role in vesicular trafficking [94]. Expanded repeats may result in untranslated regions causing loss of function. In addition, similar to myotonic dystrophy, expanded RNA transcripts may result in toxic nuclear inclusions that sequester other RNAs or RNA-binding proteins, a class of proteins in which both FUS and TDP-43 belong. The GGGGCC repeat RNA structure also allows for an unconventional means of translation, termed repeat-associated non-ATG (RAN) translation. Recently, antibodies generated against these RAN translation products have identified unique accumulations of poly-(glycine-proline) peptides [95]. Similar polypeptides have also been observed in myotonic dystrophy type 1 and spinal cerebellar ataxia 8. Whether this polypeptide is simply an accumulation of translated products via RAN translation or causes toxic effects remain to be seen, but may serve as a potential sensitive, specific, and early biomarker for C9ORF72 causes of FTD and ALS.

As expanded RNA transcripts may be a possible culprit of neurodegeneration, antisense oligonucleotides (ASO) may serve as a possible therapeutic strategy for FTLD due to C9orf72 hexanucleotide repeat expansions. ASO are synthetic nucleic acids that inactivate the mRNA of a target gene by direct binding or inducing RNase H-mediated cleavage via DNA/RNA heteroduplex. For C9orf72 mutation carriers, this strategy is attractive as it might lower both expanded RNA transcripts and limit RAN translation. Preliminary steps for ASO treatment have been studied in ALS caused by superoxide dismutase (SOD1) and were well tolerated in animal models and a recent phase I clinical trial in human SOD1 mutation carriers [96]. ASO directed against C9orf72 sequences have been shown to reduce C9orf72 RNA expansion-dependent pathology in cultured neurons derived from human C9ORF72-induced pluripotent stem cells (iPS) [97]. Furthermore, injection of ASO directed against C9orf72 sequences into mice did not demonstrate behavioral or neuropathologic abnormalities, suggesting that broad reduction of C9orf72 translation is likely to be safe [98].

The discovery of C9ORF72 may reveal important mechanistic information about the molecular pathophysiology of FTD and ALS and may provide novel treatment strategies. If loss of function is implicated, strategies to increase levels of C9ORF72 or augment C9ORF72 function may be needed. If expanded RNA transcripts are responsible, ongoing clinical trials for non-coding repeat expansion disease such as myotonic dystrophy type 1 (DM1) and fragile X-associated tremor/ataxia syndrome (FXTAS) may provide starting points for decreasing RNA transcription or altering RNA structure and aggregation. ASOs may be a unique, targeted therapy for patients carrying the C9orf72 expansion. The discovery of poly-(glycine-proline) peptides may provide a useful early, sensitive and specific biomarker for C9ORF72 causes of FTD, both diagnostically and as a pharmacodynamic tool, allowing for accurate targeted intervention.