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The Journal of Neuropsychiatry and Clinical Neurosciences, VOL. 22, No. 1

Special | December 01, 2010

Frontotemporal Dementia and Pharmacologic Interventions

Edward D. Kaye; Ana Petrovic-Poljak; Nicolaas P. L. G. Verhoeff; Morris Freedman

The Journal of Neuropsychiatry and Clinical Neurosciences 2010;22:19-29.

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Received April 17, 2009; accepted May 26, 2009. Mr. Kaye and Dr. Verhoeff are affiliated with Kunin-Lunenfeld Applied Research Unit at Baycrest, Toronto, Ontario; Mr. Kaye is also affiliated with the Institute of Medical Science at the University of Toronto; Mrs. Petrovic-Poljak and Drs. Verhoeff and Freedman are affiliated with the Sam and Ida Ross Memory Clinic, Brain Health Centre Clinics, at Baycrest; Mrs. Petrovic-Poljak is also affiliated with the Mood and Related Disorders Clinic, Brain Health Centre Clinics, at Baycrest; Dr. Verhoeff is also affiliated with the Department of Psychiatry, Division of Geriatric Psychiatry, at the University of Toronto; Dr. Freedman is also affiliated with the Division of Neurology and Rotman Research Institute, at Baycrest, and with the Departments of Medicine, Division of Neurology, at Mount Sinai Hospital, at the University Health Network, and at the University of Toronto. Address correspondence to Mr. Edward Kaye, Baycrest, Kunin-Lunenfeld Applied Research Unit, Brain Health Complex, 7th Floor, Room 726, 3560 Bathurst Street, Toronto, Ontario M6A2E1, Canada; tkaye@klaru-baycrest.on.ca (e-mail).

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Abstract

Frontotemporal lobar degeneration is comprised of three syndromes: frontotemporal dementia (FTD), semantic dementia, and progressive nonfluent aphasia, with FTD being the most prevalent. FTD is characterized predominantly by character change and disordered social conduct. A variety of pathologies may underlie these syndromes, yet it is the location of the pathology rather than the type that dictates the clinical features of the disease. Several medications have been investigated to measure efficacy of treatment in FTD, often with mixed results. The authors review these findings and comment on future directions.

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Frontotemporal lobar degeneration presents as one of three major clinical syndromes¹: frontal-variant frontotemporal dementia (fvFTD),² semantic dementia (sometimes referred to as primary progressive fluent aphasia or temporal-variant FTD), and progressive nonfluent aphasia. Despite frontotemporal lobar degeneration being the cause of 12.5—16.5% of all degenerative-type dementias,³ there is a shortage of research to elucidate its underlying mechanisms, and there are few studies that have evaluated the effectiveness of pharmacological treatments to improve the symptoms of frontotemporal lobar degeneration. There is currently no standard pharmacological intervention for the treatment of frontotemporal lobar degeneration and no known treatment to delay its progression; however, there are various prescribed medications that are commonly used to help alleviate some symptoms.

Due to the heterogeneity in the clinical presentation of the syndromes comprising frontotemporal lobar degeneration, this article will focus on fvFTD. We will first characterize the clinical presentation of fvFTD, followed by an overview of the underlying neuropathology. We shall then review the research literature on the pharmacological agents that have been studied to ameliorate the behavioral and cognitive changes associated with FTD, as well as explore future directions.

Clinical Presentation

Each of the major syndromes constituting frontotemporal lobar degeneration has its own common clinical presentation.⁴ Although semantic dementia and progressive nonfluent aphasia present with prominent language abnormalities at the onset of the disease course, fvFTD initially presents with a personality change and behavioral abnormalities. The behavioral features, which are seen early in fvFTD, may include the loss of personal and social awareness, disinhibition, poor insight, impulsivity, stereotypies, and hyperorality. Furthermore, the inability to recognize emotion—in particular anger and disgust—the inability to empathize with others, and the impaired moral reasoning that are observed in fvFTD patients closely resemble the profile of persons with antisocial personality disorder.⁵ These patients may exhibit psychosis,³ increased risk-taking behavior,⁶ compulsions,⁷—¹² and apathy.¹³ Although the behavioral abnormalities worsen with disease progression, many of the behavioral deficits lessen with increased apathy and withdrawal. Moreover, as the disease progresses, these patients are at risk for developing changes to the motor system, such as motor neuron disease, parkinsonism, and dysphagia, although motor neuron disease can precede the manifestations of fvFTD.¹⁴

In addition to behavioral abnormalities, fvFTD is associated with cognitive deficits. For instance, patients may display great impairment in executive function¹⁵,¹⁶ and at varying points in the disease course may¹⁵,¹⁷,¹⁸ or may not¹⁹ present with memory impairments. Furthermore, prominent attentional deficits may be present.¹⁵,¹⁶

Importantly, the symptoms of fvFTD are more related to the affected areas of the brain than to specific neuropathological factors.⁴ Consequently, the degree of frontal versus temporal compromise can account for much of the variability in the clinical presentations of the disorder.²⁰ In addition, patients with greater right hemispheric compromise show more pronounced impairment in social cognition. Moreover, although patients may initially present with features that are consistent with one particular frontotemporal lobar degeneration subtype, as the disease progresses, their clinical profile may be more consistent with a different subtype.²¹ This is not to say that the profile switches from one subtype to another; rather, the new profile is an add-on to the initial one. However, the new profile may still be more prominent than the initial one. For example, a patient may initially be diagnosed with fvFTD but may later present with semantic dementia as his or her condition progresses. Therefore, the clinical presentation of fvFTD is heterogeneous within a population of patients and may vary within a particular patient.

Neurotransmitter and Receptor Alterations

Research evidence suggests that there are significant neurotransmitter system abnormalities in fvFTD, and the cholinergic, serotonergic, dopaminergic, noradrenergic, and glutamatergic systems are thought to be implicated. The following discussion will provide a general overview of the restricted findings of the involvement of neurotransmitter system abnormalities in fvFTD. However, although the scope of the research is moderate at present, significant venues for pharmacological intervention are implied.

Cholinergic System

Given the significance of an impaired cholinergic system in Alzheimer’s disease, the most common form of dementia, it is understandable why investigators explored this system in FTD patients. The literature is mixed in terms of the integrity of the cholinergic system in FTD. Most studies show normal or higher levels of cortical choline acetyltransferase,²²—²⁴ as well as normal levels of acetylcholinesterase.²⁵ One study reports that postsynaptic muscarinic receptor binding is intact in the brains of FTD patients,²³ yet others report a decrease in binding.²⁶,²⁷ Lastly, studies have demonstrated that the neurons in the nucleus basalis of Meynert are preserved,²²,²⁸ except for one study that found a decrease in the density of these neurons at autopsy.²⁹

Serotonergic System

Investigators have often found a dysfunctional serotonergic system in FTD patients. This is further supported by the clinical presentation of this illness, which closely corresponds to serotonergic dysfunction.⁴ Researchers have identified a significant reduction in postsynaptic 5-HT1 and 5-HT2 serotonin receptors, particularly in the frontal cortex, including orbitofrontal and medial frontal regions, as well as in the temporal, cingulate, and hypothalamic regions.²³,²⁴,³⁰ Others have observed presynaptic serotonergic deficits²⁴,³¹ and neuronal loss by 40% in the raphe nuclei in FTD.³² This evidence of serotonergic dysfunction in FTD lends support for therapeutic trials with medications that act to increase serotonergic tone in the brain.

Dopaminergic System

There is some evidence supporting a dysfunctional dopaminergic system in FTD. This includes observations of reduced D2 ligand uptake in the frontal cortex³³and fewer presynaptic dopamine transporters in the striatum,³⁴ and in the syndrome frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), there are also reduced presynaptic striatal dopaminergic nerve terminals.³⁵ However, other studies did not find evidence of dopaminergic dysfunction in FTD.³⁶,³⁷

Noradrenergic System

Similarly, there is conflicting evidence for a dysfunctional noradrenergic system in FTD. For instance, one group found that the density of neurons in the locus coeruleus is preserved,³² whereas another group found that it is decreased.³⁸ Further research is required to ascertain the involvement of the noradrenergic system in FTD.

Glutamatergic System

Finally, the glutamatergic system may play a role in FTD. There are indications that the frontal and temporal cortices of FTD patients have reduced levels of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors,²³ as well as reduced numbers of glutamatergic pyramidal cells.³⁹ Further examination of the role of the glutamatergic system in FTD should be undertaken.

Symptomatic Treatments of fvFTD

There is a dearth of clinical trials testing the efficacy of medications to treat the symptoms of FTD. The clinical trials that have been conducted include evaluations of cholinesterase inhibitors, antidepressants, an NMDA receptor antagonist, antipsychotics, and a stimulant in the treatment of FTD symptoms.

Cholinesterase Inhibitors

Cholinesterase inhibitors, with their relative efficacy in treating Alzheimer’s disease, were an intuitive pharmacologic intervention to undergo evaluation in the treatment of fvFTD. However, cholinesterase inhibitors do not consistently improve cognitive and behavioral symptoms of this disease. According to a review, such treatment is associated with increased aggressiveness and agitation.³¹ Similarly, donepezil treatment was associated with an exacerbation of disinhibition and compulsions.⁴⁰

Some studies suggest positive effects from treatment with cholinesterase inhibitors while others do not. An open-label study compared a group treated with rivastigmine, an inhibitor of both acetylcholinesterase and butyrylcholinesterase, with comparison groups receiving an antipsychotic, a benzodiazepine, or selegiline. Rivastigmine treatment was associated with less behavioral impairment and less caregiver burden, though it did not improve cognition.⁴¹ However, another study consisted of an open-label phase followed by a double-blind, randomized placebo-controlled phase comparing the effects of galantamine in patients with FTD versus those with progressive nonfluent aphasia and semantic dementia.⁴² Galantamine improved word production in the progressive nonfluent aphasia and semantic dementia group, but it was ineffective at improving scores on the Clinical Global Impression Severity Scale in the FTD group. Furthermore, the Frontal Behavioral Inventory (the FBI) displayed a worsening, albeit nonsignificant, effect in the treatment group compared to the stable placebo group. Therefore, due to the strength in the design of this study, it may be suggested that galantamine is ineffective in treating FTD, although the strength of this conclusion is limited by the smaller size of this study (36 and 34 participants, respectively, in the open-label and placebo-controlled phases).

In a randomized comparison trial, nine FTD patients were treated immediately after diagnosis with either donepezil or rivastigmine.⁴³ All four men in the study showed clinically significant cognitive improvement, as evaluated by the Mini-Mental State Examination (MMSE) and the Clock Drawing Test, and three of the four men showed positive changes in their single photon emission computed tomography (SPECT) scans after 6 months. Three of the five women only improved slightly after 3 months, and two of the five women continued to deteriorate. It appears from this study that donepezil and rivastigmine may be effective in treating cognitive impairments in FTD, particularly in afflicted men, but it is worth noting that only nine participants were tested and that the males were younger than the females (64.2±2.2 years old versus 71.6±2.9 years old, respectively). This potential age effect may underlie the apparent gender difference.

Antidepressants

The medications most commonly studied to treat FTD are the class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs). SSRIs such as sertraline, fluvoxamine, fluoxetine, and paroxetine are commonly used as the first line of treatment for the management of disinhibition, stereotypies, sexually inappropriate behaviors, and dietary changes (i.e., food cravings) in fvFTD.⁴⁴—⁴⁶ Unfortunately, most evaluations of SSRIs in the treatment of fvFTD have used open-label or case series designs, with only a few randomized, placebo-controlled trials.¹⁴ The latter have produced mixed results for the efficacy of SSRIs in the treatment of fvFTD.

In an open-label study, sertraline appeared to decrease the stereotypical movements in a group of 18 FTD patients.⁴⁷ Similarly, fluvoxamine appeared to reduce stereotypies and compulsive complaints of pain in two cases of FTD.⁴⁸

In an uncontrolled study,⁴⁶ 11 FTD patients were randomly assigned to receive fluoxetine, sertraline, or paroxetine for 3 months. The patients showed improved behavioral symptoms, including disinhibition, depressive symptoms, carbohydrate craving, and compulsions; however, cognition did not improve.

A meta-analysis⁴⁹ examined the combined effects of four different antidepressants (trazodone, selegiline, fluvoxamine, and paroxetine). The results show a considerable combined mean reduction (improvement) of 15.4 points on the Neuropsychiatric Inventory (NPI), a caregiver interview that assesses recent changes in particular behaviors. It should be noted that the authors of this study admit that the effect of these medications may be an overestimation as these studies had small sample sizes, only two of the six studies were placebo-controlled, and there may have been a publication bias toward positive trials. Additionally, the fluvoxamine trial included in the meta-analysis⁵⁰ tested 10 patients with fvFTD as well as five patients with semantic dementia. Because these two subgroups were not separated in the analysis, we cannot conclude how well the fvFTD subgroup truly responded to the treatment, yet the cohort as a whole, relative to baseline, showed significant improvement on total NPI scores and on each of the subscales of the Stereotypy Rating Inventory.

It should also be noted that the two studies evaluating paroxetine⁴⁵,⁵¹ found opposing results in terms of its efficacy. Both are randomized, controlled studies, yet they differ greatly in their methodologies, namely in study length, treatment dosage and inclusion criteria. Specifically, the investigators in the randomized, double-blind, placebo-controlled study⁵¹ treated FTD and semantic dementia patients for 9 weeks and found that relative to placebo, paroxetine, 40 mg/day, failed to improve behavioral symptoms and impaired cognition. However, the investigators in the other study,⁴⁶ which used an open-label design, treated both FTD and semantic dementia patients with paroxetine, 20 mg/day (treatment), or piracetam, 1,200 mg/day (comparison), for 14 months. They found a significant behavioral improvement with no effect on cognition in the treatment group relative to the comparison group. Because these two studies were small, testing 10 and 16 patients, respectively, and due to the methodological differences described above, we cannot accurately compare the results of these studies, although the studies do suggest that paroxetine may only be efficacious in the treatment of FTD when given over a longer period of time. Trazodone, a low affinity serotonin reuptake inhibitor that increases extracellular levels of 5-HT in frontal cortex, also has a high affinity for 5-HT2A receptors and acts as an antagonist at alpha-1 and alpha-2 adrenergic receptors. Considering the aforementioned neurotransmitter aberrations in FTD, trazodone may be a useful treatment option. A randomized, double-blind, placebo-controlled cross-over trial⁵² and an open-label trial⁵³ both had similar findings: trazodone is well-tolerated and can significantly improve behavioral disturbances as measured by the NPI but does not improve cognition as measured by the MMSE.

Researchers have also evaluated treating fvFTD with monoamine oxidase inhibitors (MAOIs), a class of antidepressants with a different pharmacodynamic action than SSRIs. Unlike SSRIs, MAOIs increase the availability of norepinephrine, serotonin, and dopamine, which is of particular interest because there is evidence supporting the disruption of each of these three neurotransmitter systems in FTD (refer to previous section). Furthermore, MAO-A and MAO-B, enzymes targeted by MAOIs, show regional specificity to neuroanatomical areas that are associated with fvFTD. For example, MAO-A and MAO-B displayed significantly increased activity in the hypothalamus and decreased activity in the nucleus basalis of Meynert, while MAO-A also displayed decreased activity in the temporal pole.⁵⁴ Moclobemide, a well-tolerated MAO-A inhibitor, appeared to improve behavior, affect, and speech in six FTD patients after a 4-week treatment period.⁵⁵ Additionally, selegiline, a well-tolerated MAO-B inhibitor, may be useful in the treatment of FTD as it may have neuroprotective effects by reducing free radical production and by saving dying neurons.⁵⁶,⁵⁷ A 3-month treatment with selegiline was associated with significantly improved neuropsychiatric symptoms as well as attention in three FTD patients.⁵⁸ Despite the positive results obtained in these case report studies, MAOIs need to be evaluated in larger randomized, double-blind, placebo-controlled studies in order to ascertain their efficacy in treating FTD.

Memantine

At present, only a few studies have examined the effects of memantine, an NMDA-receptor antagonist. In a case series report,⁵⁹ three FTD patients (ages 52, 57, and 64 years old) were treated for 3 months with the therapeutic dose of 20 mg/day of memantine. All three showed significant improvement in total NPI score, specifically in the subscales of apathy, agitation, and anxiety, and all showed good tolerance for memantine. However, a case study found that a 73-year-old man’s clinical state continually deteriorated while his treatment with sertraline was augmented with memantine for a period of 6 months.⁶⁰ The latter case study not only used memantine as an adjunct treatment but also used a lower dose of the medication at 10 mg/day. Thus, there may have been a dose effect as well as a potential interaction between the two medications.

Recently, a 26-week Phase IV nonrandomized, uncontrolled, open-label trial evaluating the efficacy of memantine in treating frontotemporal lobar degeneration was conducted on 21 patients with FTD, 13 with semantic dementia, and nine with progressive nonfluent aphasia.⁶¹ The target dose of 20 mg daily was well-tolerated by most patients. Treatment was associated with a transient improvement in total NPI scores primarily in the FTD group, though variable declines were observed on numerous cognitive and behavioral measures, specifically, the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-cog), Executive Interview (EXIT25), the FBI, the NPI, the Texas Functional Living Scale, and the Unified Parkinson's Disease Rating Scale-motor scale (UPDRS). The FTD and semantic dementia groups declined on most of these measures, but remained stable on the UPDRS, whereas the progressive nonfluent aphasia group remained relatively stable on the ADAS-cog, NPI, and Texas Functional Living Scale, but declined on the UPDRS. The researchers suggest that future placebo-controlled trials of memantine in frontotemporal lobar degeneration are warranted and may have greater power to detect behavioral and cognitive effects if focused on FTD and semantic dementia. It is clear from these reports that more research must be conducted to ascertain whether memantine is an effective treatment in frontotemporal lobar degeneration syndromes.

Antipsychotics

Numerous studies have investigated the efficacy of typical and atypical antipsychotics for the treatment of FTD. Considering the impairment observed in the dopaminergic and serotonergic systems in FTD patients, aripiprazole, an atypical antipsychotic that has dopaminergic and 5-HT1A partial agonistic effects, is a theoretically viable option for treatment, and clinicians evaluated it in a case study examining the 73-year-old man discussed in the memantine section.⁶⁰ Under consecutive treatment with this medication, the patient’s clinical symptoms significantly improved. The patient showed improvement in cognition, as measured by the MMSE, and a marked clinical improvement in the negative symptom score of the Positive and Negative Syndrome Scale. Additionally, prior to aripiprazole administration the patient had a decrease in frontal glucose metabolism, which showed partial normalization after only 5 weeks of treatment. This case study provides very limited support for the use of aripiprazole to improve cognition and negative symptoms in FTD patients. Aripiprazole must be more rigorously tested before deeming it an appropriate treatment option.

In another case study, the treating physicians monitored the effects of risperidone on a 42-year-old woman thought to have a "frontal dementia of a non-Alzheimer’s type, possibly Pick’s disease."⁶² After 1 week her psychotic features began to be allayed, and after 3 to 4 months she was free from delusions and hallucinations, she had increased insight and motivation, and her declining cognition had stabilized. However, she became depressed and was treated with paroxetine. She also began to display extrapyramidal symptoms of akathisia and parkinsonism, requiring treatment with clonazepam.

Additional potential support for the use of antipsychotics to treat FTD is observed in a study that reports reduction in agitation in all of the three patients treated with quetiapine, and in one of the three patients treated with risperidone.¹³ However, this study combined patients with FTD, semantic dementia and progressive nonfluent aphasia, and we do not know how many people in these two groups were FTD patients, if any.

Investigators examined the effects of olanzapine on the neuropsychiatric manifestations of FTD in a group of 17 patients with some success.⁶³ This 24-month follow-up study found that olanzapine was well-tolerated and significantly improved scores on all of the behavioral and mood outcomes measured: Clinical Insight Rating Scale, NPI, Behavioral Pathology in Alzheimer’s Disease Rating Scale, and the Cornell Scale for Depression in Dementia. Although cognitive test scores did not significantly differ from baseline, they displayed a worsening trend. This is a noteworthy result because it is plausible that the observed worsening trend could reach significance if a future study were to employ a larger sample size. Therefore, a medication such as olanzapine that improves behavior but potentially worsens or fails to stabilize cognition would not be an ideal FTD treatment option.

Furthermore, symptoms such as delusions, euphoric symptoms, and disinhibited outbursts, which are commonly refractory to treatment with SSRIs, usually can be controlled with the use of atypical antipsychotics.¹⁴ However, great caution must be taken when prescribing antipsychotics to FTD patients. Unfortunately, both typical and atypical antipsychotics may cause extrapyramidal side effects⁶²,⁶⁴,⁶⁵ and FTD patients may be particularly susceptible to these effects.⁶⁴ In addition, treating behavioral symptoms in elderly dementia patients with typical and atypical antipsychotics may increase mortality compared with placebo.⁶⁴,⁶⁵

Methylphenidate

Frontotemporal dementia patients may display an increased tendency toward compulsive and risk-taking behaviors, and in order to reduce these behaviors, a treatment should target the underlying neural substrates. Methylphenidate may be an effective treatment because deficits in the dopaminergic and noradrenergic systems exist in FTD, and methylphenidate likely affects risk-taking behavior observed in FTD through its effects on the orbitofrontal cortex and the striatum and the connections between these two regions. The dopamine transporters that methylphenidate is believed to target are primarily found in the striatum. The purpose of the dopaminergic projections from the midbrain to the striatum is to signal reward-related information. This circuit is likely hyperactive in FTD and, coupled with the hypoactivity found in the orbitofrontal cortex, leads to the expression of reward-dependent behavior. The increases in orbitofrontal cortex metabolism observed due to methylphenidate administration may ultimately modulate the activity of the dopaminergic projections from the midbrain to the striatum.⁶⁶ Moreover, disrupted circuitry in the orbitofrontal cortex correlates with increased disinhibition,⁶⁷ which may be ameliorated with the increase in orbitofrontal cortex metabolism that occurs from treatment with methylphenidate.

One group of investigators⁶⁶ administered methylphenidate to eight FTD patients. Despite not finding any significant changes in cognition, notably memory and executive function, as well as not finding significant improvements in mood, the medication significantly decreased risk-taking behavior. Similarly, one case study reports that methylphenidate was associated with returning the patient’s personality to near-normal levels.⁶⁸

Pathological Indicators of FTD and Disease-Modifying Interventions

To date, medications used to treat FTD do not delay the progression of the disease. However, several neuropathological features of the various forms of FTD are identified and implicate possible targets for disease-modifying therapies. These features include ubiquitin inclusions, progranulin mutations, and tau mutations.

FTD with ubiquinated inclusions (FTD-U, also referred to as FTLD-U), including FTD with motor neuron disease, constitutes the most common neuropathologies in frontotemporal lobar degeneration. Ubiquinated inclusions consist primarily of a protein called TAR DNA-binding protein 43 kDA (TDP-43).⁶⁹ Less common are tauopathies, such as Pick’s disease, corticobasal degeneration, and progressive supranuclear palsy.²¹

Frontotemporal dementia with motor neuron disease is highly heritable⁷⁰ and appears to be associated with an unidentified gene on chromosome 9p.⁷¹,⁷² Therefore, this gene and its protein product(s) are potential disease-modifying targets, as are the genetic and biochemical pathways involving TDP-43.

Another pathological correlate of FTD that occurs in most cases without motor neuron disease is the result of genetic mutations that cause a loss of function in the progranulin (PRGN) gene,⁷³,⁷⁴ where progranulin is a pleiotropic protein involved in mediating neuronal development and inflammation.⁷⁵ Postmortem, these patients have FTD with ubiquinated inclusions/TDP-43 pathology, which implicates the potential efficacy of PRGN-altering therapies. Such treatments may act by normalizing PRGN gene expression, by enhancing progranulin posttranslational modification, or by introducing exogenous progranulin into the brains of FTD patients with PRGN mutations. These therapies may even be useful for patients without such mutations.¹⁴

Lastly, according to a review paper on FTD,⁷⁶ the most common histological feature of the disease, in cases that meet the strict clinical criteria for fvFTD,¹ is tauopathy, where the microtubule-associated protein tau aggregates in a hyperphosphorylated form. Mutant forms of tau have been found to exist in 30%—42% of FTD cases at autopsy.⁷⁷—⁷⁹ These aggregates disrupt normal cellular function and lead to cell death and loss of synapses. The altered levels of tau and its deposition may result from alterations in splicing, tau expression levels, and posttranslational processing.⁸⁰

To study the mechanisms of neurodegeneration in diseases with abnormal changes in tau, a group of investigators generated several cell models of tauopathy.⁸¹ They created neuroblastoma cell lines that could inducibly express different variants of the repeat domain of tau (tauRD), including a repeat domain with the deletion mutation ΔK280. This mutation is known to exist in FTD and is very prone to spontaneously aggregate. The researchers confirmed that the tauRD is toxic to cells and observed that fragmentation of the tauRD precedes aggregation, suggesting that fragmentation, rather than phosphorylation, is important for aggregation. Fragmentation can be inhibited by treating the cells with various inhibitors, thereby preventing aggregation. Importantly, preventing tau aggregation, even without altering its expression, can reduce toxicity to cells.

The findings from this study⁸¹ have important clinical implications, despite its limitations. The results suggest the viability of incorporating inhibitors in pharmacological agents to prevent the toxic aggregation of tau in FTD. However, before attempting to apply these results clinically, it is important to remember that the tauopathy that underlies fvFTD is heterogeneous, which may limit the utility of disease-modifying treatments directed at tau.¹⁴ Additionally, this study was conducted on cells in vitro, therefore, these results may not necessarily be observed in vivo. Of course, one must also take into consideration obstacles such as the blood-brain barrier and selectivity and specificity for the target when designing a disease-modifying agent. Medications like the anticancer drug paclitaxel, which is designed to stabilize microtubules, are currently being evaluated.⁸² A randomized, double-blind, placebo-controlled trial evaluated methylthioninium chloride, a tau aggregation inhibitor, and found that it stabilized the progression of Alzheimer’s disease in mild and moderate Alzheimer’s disease patients.⁸³ Perhaps FTD patients would benefit from methylthioninium chloride treatment as well. Other inhibitors and microtubule tau stabilizers are showing positive results in in vitro and animal studies.⁸⁴—⁸⁶

Conclusions, Limitations, and Future Directions

Frontotemporal dementia is a relatively common cause of dementia and accounts for most of the dementia cases in late middle-aged adults. At the time of disease onset, many people are in the middle of their working years,⁸⁷ and the rapid decline in their functioning puts great burden on both their families and the health care system, as many people with FTD are institutionalized 1 year following the diagnosis.⁸⁸ Despite the relative lack of cognitive treatments for FTD, there are several options for treating some of the behavioral manifestations of the disease. Given the evidence, SSRIs and trazodone appear to be the best first options for treatment. Nevertheless, more research must be completed to ensure that those with FTD are diagnosed and treated early in their disease course in the hopes of delaying the progression of the disease and to delay institutionalization.

An essential element for the early detection of FTD is the use of standardized assessment tools, as there are currently none specific to this disease. One study demonstrated that early in the course of the disease, the brains of FTD patients contain lesions in the orbitofrontal cortex, superior medial frontal cortex, and the hippocampus.⁸⁹ Dysfunctions in the orbitofrontal cortex and in the medial frontal cortex underlie social cognitive deficits,⁹⁰,⁹¹ yet most neuropsychological tests are primarily sensitive to dorsolateral frontal dysfunction and have low sensitivity to early FTD. This illustrates the need for behavioral and neuropsychological measures that are sensitive to lesions in the orbitofrontal and medial frontal cortices, as well as tests of social cognition such as measures of Theory of Mind.⁹²

Another factor involved in the early detection of FTD is the initial difficulty clinicians may have in distinguishing it from other forms of dementia. Fortunately, various forms of dementia may be reliably differentiated from one another when various behavioral rating scales are employed, such as the Cambridge Behavioral Inventory⁹³ and the FBI.⁹⁴,⁹⁵ There are mixed results regarding the utility of the NPI in discriminating various forms of dementia.⁹⁴,⁹⁵ Additionally, behavioral measures have been demonstrated to have superior sensitivity over cognitive measures in diagnosing FTD.⁹⁶

Furthermore, early diagnosis may be possible with the use of neuroimaging technology. For example, positron emission tomography (PET) research illustrates the ubiquitous dysfunction in the ventromedial frontal cortex of FTD patients,⁹⁷ a region highly implicated in the clinical presentation of FTD.

It is interesting to note that while patients with frontotemporal lobar degeneration are diagnosed based on clinical criteria that suggest which region of the brain is most affected, neuroimaging data may suggest primary dysfunction in a different region. This occurs due to lack of an exclusive relation between the syndrome and the distribution of pathological change, which is generally measured as atrophy.⁹⁸ For example, patients with semantic dementia invariably have temporal lobe atrophy, but such atrophy does not guarantee neuropsychological findings of language dysfunction. Similarly, patients with fvFTD invariably possess frontal-lobe atrophy and temporal-lobe atrophy, yet the atrophy in the temporal lobe may be greater than in the frontal lobe, and the patients may not display obvious semantic impairment. Therefore, these examples demonstrate the importance of recognizing that despite the usefulness of neuroimaging as a diagnostic aid, it could lead to an incorrect clinical diagnosis if the results were given undue weight in differential diagnosis.

An issue that has created inconsistencies in the FTD literature is the operational definition as to which patients classify as FTD. This varies from study to study. Some studies use the term FTD as the broad superordinate term to encompass the three major syndromes (FTD, semantic dementia, and progressive nonfluent aphasia), while others use the term frontotemporal lobar degeneration. Although the authors clearly define their classification system, it is not always mentioned how many patients comprise each subtype. This makes it difficult, for example, to ascertain the potential use of a particular treatment for a patient with a particular frontotemporal lobar degeneration syndrome.

Researchers choose from a plethora of outcome measures to determine whether a particular intervention is successful. This creates the challenge of accurately comparing various studies’ results to one another. Some of the measures used in FTD treatment studies are the MMSE, the NPI, the FBI, and the FTD Inventory (see Freedman⁹⁹ for a review). Interestingly, the studies discussed throughout this article rarely observed any changes in cognition and have made the argument that the cognitive impairment may be refractory to treatment. However, noting that the MMSE, a measure commonly utilized to evaluate cognitive change in FTD studies, is not sensitive to the prominent executive impairment found in FTD patients, any changes in cognition that may have occurred as a result of treatment may be undetected.

Another issue is that there is variability in what constitutes a significant change or improvement. For instance, a statistically significant improvement has been defined as being a total score reduction of 50% on the NPI,⁵² whereas elsewhere, improvement on the NPI has been defined as posttreatment scores being significantly different from baseline.⁴¹ Clearly, in order to properly compare the results of individual studies and, in turn, accurately evaluate therapeutic effectiveness, investigators should be consistent in their choices of outcome measures and should standardize what constitutes a statistically significant and clinically relevant improvement on any given measure.

Finally, given the considerable prevalence of FTD, and the relative paucity of pharmacological trials for it, funding agencies should give high priority to financing research aimed at improving early FTD detection and at evaluating the most appropriate forms of treatment. Future studies need to have rigorous experimental designs, include a sufficient sample size, and employ an intent-to-treat analysis to account for participants who fail to complete the protocol. This would strengthen the conclusions from these studies, thereby improving the ability of physicians and other caregivers to provide optimal care for patients living with FTD.

Acknowledgments

Abstract | Acknowledgments | References

During the preparation of this article, Mr. E.D. Kaye was supported by the Scace Graduate Fellowship for Research in Alzheimer’s, Finkler Graduate Student Fellowship, Harry C. Sharpe Fellowship, and University of Toronto Institute of Medical Science Fellowship; Dr. M. Freedman held a research grant from the Canadian Institute of Health Research and was supported by the Saul A. Silverman Family Foundation, Toronto, Ontario, Canada, as part of a Canada International Scientific Exchange Program (CISEPO) project, and has received support from Eli Lilly (Research Funds), Pfizer Canada (Advisory Board, CME Speaker, Research Funds), Janssen-Ortho Inc. (Advisory Board, CME Speaker), Lundbeck Canada (CME Speaker), Novartis (Advisory Board, CME Speaker), and Wyeth Canada (Advisory Panel); and Dr. N.P.L.G. Verhoeff held a New Investigator Research Grant from the Alzheimer’s Association (NIRG-04-1181) and has received an honorarium from Janssen-Ortho Inc. (Advisory Board).

References

Abstract | Acknowledgments | References

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