Geoffrey A. Kerchner, M.D., Ph.D.
Michael H. Rosenbloom, M.D.
Frontotemporal dementia (FTD) is a common cause of young-onset dementia, affecting 20,000–30,000 individuals nationwide (Knopman and Roberts 2011), and is the third most common neurodegenerative cause of dementia after Alzheimer’s disease (AD) and dementia with Lewy bodies (Snowden et al. 2002). In contrast to AD, FTD manifests with behavioral changes, language impairment, and executive dysfunction with relative sparing of memory and visuospatial function. Furthermore, these conditions may progress to involve motor systems of the brain, resulting in motor neuron disease and parkinsonism.
AD is associated with a discrete neuropathological signature, namely, amyloid plaques and neurofibrillary tangles; FTD, however, is more variable and may be characterized by the aggregation of one of several possible proteins in the affected frontal or temporal cortices. The microtubule-associated protein tau, transactive response DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS) (Karageorgiou and Miller 2014) are the most commonly encountered protein deposits; other, less common pathologies have been described. Frontotemporal lobar degeneration (FTLD) is the term for the pathological process underlying a clinical FTD syndrome. There is no straightforward one-to-one association between clinical phenotypes (e.g., behavioral-variant FTD, semantic-variant primary progressive aphasia, or nonfluent-variant primary progressive aphasia; see section “Clinical Features” below) and the underlying neuropathology (FTLD-tau, FTLD-TDP, or FTLD-FUS). For example, behavioral-variant FTD patients with different molecular pathologies may exhibit similar clinical phenotypes.
FTD may be further distinguished from AD by the strong genetic association that is found in 40% of patients (Rabinovici et al. 2010). Often, patients may report an extensive history of family members reeceiving what is, in retrospect, a misdiagnosis of AD or a psychiatric condition such as bipolar disorder or schizoaffective disorder. Mutations in genes for tau (MAPT) or progranulin (GRN) account for many cases of familial FTD (Karageorgiou and Miller 2014). More recently, a hexanucleotide repeat expansion on chromosome 9 (C9ORF72) was identified as a cause of many cases of frontotemporal degeneration with amyotrophic lateral sclerosis. Whereas MAPT mutations result in FTLD-tau pathology, GRN and C9ORF72 mutations associate with FTLD-TDP (Karageorgiou and Miller 2014).
Although the current treatment for FTD is supportive care, the varied pathological targets associated with these neurodegenerative processes present opportunities for future molecular-targeted or genetic treatments. However, such treatment strategies first require an appreciation of the clinical phenotypes and the characteristics of the three FTD syndromes (Table 23–1).
FTD syndrome |
Symptoms |
Cognitive exam findings |
Neuroimaging |
Motor findings |
Neuropathology |
Behavioral-variant FTD |
Behavioral disinhibition Apathy or inertia Loss of sympathy or empathy Early perseverative, stereotyped, or compulsive ritualistic behaviors Hyperorality |
Deficits in executive tasks Relative preservation of memory and visuospatial function |
Right-hemispheric frontal and/or anterior temporal atrophy, particularly involving the orbitofrontal, insular, and anterior cingulate cortices |
Motor neuron disease (10%–15%) Parkinsonism (20%) or supranuclear gaze disturbance (less common) |
FTLD-tau FTLD-TDP FTLD-FUS Others |
Nonfluent/agrammatic- variant primary progressive aphasia |
Progressive expressive aphasia characterized by slow, effortful speech with decreased output; dysarthria; and progression to mutism |
Agrammatism Inconsistent speech sound errors and distortions and apraxia of speech Impaired comprehension of syntactically complex sentences Spared single-word comprehension and object knowledge Relative preservation of memory and visuospatial function |
Left posterior fronto- insular atrophy on structural MRI Left posterior fronto- insular SPECT hypoperfusion or PET hypometabolism |
Right hemibody apraxia, parkinsonism, dystonia, alien limb Progression to corticobasal syndrome or progressive supranuclear palsy |
FTLD-tau in most cases |
Semantic-variant primary progressive aphasia |
Left predominant Word-finding difficulties Comprehension difficulties Right predominant Prosopagnosia Poor emotional recognition Disinhibition Mental rigidity Food fads Compulsions |
Left predominant Impaired confrontational naming Impaired single-word comprehension Impaired object knowledge Surface dyslexia Spared repetition, grammar, and motor speech production Relative preservation of memory and visuospatial function Right predominant Prosopagnosia Impaired affect recognition |
Asymmetric left and/or right anterior and lateral temporal atrophy on structural MRI |
Less common |
FTLD-TDP in most cases |
Note. FTLD-FUS= frontotemporal lobar degeneration–fused in sarcoma; FTLD-tau=frontotemporal lobar degeneration–tau; FTLD-TDP=frontotemporal lobar degeneration–transactive response DNA-binding protein 43; MRI=magnetic resonance imaging; PET=positron emission tomography; SPECT=single-proton emission computed tomography.
FTD comprises three distinct clinical syndromes: behavioral-variant frontotemporal dementia (bvFTD) and two language variants, semantic-variant primary progressive aphasia (svPPA) and nonfluent/agrammatic-variant primary progressive aphasia (nfvPPA). In 2011, revised consensus criteria incorporating clinical symptoms, neuropsychological testing, and neuroimaging were published to guide the diagnosis of bvFTD (Rascovsky et al. 2011).
bvFTD is the most common type of FTD, responsible for slightly more than half of cases and more commonly found in men (Rabinovici et al. 2010). Early onset at ages <65, impaired executive performance on neuropsychological testing, and focal frontal or temporal lobe cerebral atrophy on neuroimaging are key elements in distinguishing bvFTD from other neurodegenerative conditions. The six major clinical features associated with bvFTD are early behavioral disinhibition; early apathy or inertia; early loss of sympathy or empathy; early perseverative, stereotyped, or compulsive/ritualistic behavior; hyperorality or dietary changes; and neuropsychological deficits that are predominantly executive in nature, sparing episodic memory and visuospatial function. Almost universally, there is a lack of insight on the part of the patient into the behavioral and cognitive changes that are observed by others.
Behavioral disinhibition is the most widely recognized clinical characteristic of bvFTD and may be manifested by overspending, sexually inappropriate remarks, and socially embarrassing behavior (Rabinovici et al. 2010). Apathy, which may appear simultaneously with disinhibition early in the disease or over time, is associated with decreased motivation, social isolation, and reduced emotional range. Loss of empathy and sympathy is equally disturbing to caregivers, who complain about a lack of response to grief or sadness experienced by loved ones. An increased predilection for sweets occurs frequently, but it is nonspecific and is frequently observed in other neurodegenerative disorders such as AD. In bvFTD, there is a pathological shift in feeding behaviors with the development of impaired satiety and hyperphagia. These symptoms develop as a result of atrophy involving feeding centers within the right ventral insula, striatum, and orbitofrontal cortex (Woolley et al. 2007). bvFTD leads to progressive dysfunction of the frontal networks that regulate repetitive behaviors, producing compulsive motor symptoms such as throat clearing, rubbing, picking, pacing, or wandering (Rabinovici et al. 2010). Compulsive collecting, hoarding, shoplifting, and rummaging are also common.
Cognitive symptoms reflect prominent executive dysfunction with relative sparing of memory and visuospatial function (Rascovsky et al. 2007). Specific cognitive deficits are found on frontal-based tasks such as attention, working memory, set shifting, mental flexibility, response inhibition, and abstract reasoning (Rabinovici et al. 2010). Poor attention often manifests as distractibility and impulsiveness. While sparing of memory function is typical, 10%–15% of patients may present with episodic memory deficits (Graham et al. 2005). Together, this spectrum of cognitive deficits renders a typical patient unable to solve problems or to engage in complex tasks.
M.-Marsel Mesulam offered the initial description of primary progressive aphasia (PPA) in 1982, a condition characterized by progressive language decline over 2 years with relative preservation of memory and visuospatial function (Mesulam 1982). Recent clinical observations have demonstrated that PPA is a disorder with heterogeneous pathologies inclusive of both FTLD- and AD-specific findings (Gorno-Tempini et al. 2004). PPA cases due to FTLD pathology include two distinct clinical phenotypes: nfvPPA and svPPA. Of note, Gorno-Tempini and colleagues (2011) have published proposed criteria for nfvPPA and svPPA as well as for logopenic aphasia caused by AD.
nfvPPA is a progressive, primary language disorder resulting from motor speech dysfunction and characterized by effortful, nonfluent speech. Patients initially exhibit shortened phrase length, dysarthria, phonemic paraphasias, and speech apraxia, with subsequent progression to mutism over time. In addition to effortful speech, the other key clinical feature is agrammatism, with omissions of articles and other syntactic words, leading to speech sometimes described as telegraphic (Gorno-Tempini et al. 2011). Comprehension is relatively spared compared with speech production, yet patients may struggle to decode syntactically complex sentences (Gorno-Tempini et al. 2011). This condition localizes within the left hemisphere prefrontal-perisylvian region of the cerebral cortex (Gorno-Tempini et al. 2004). There is a female predominance for nfvPPA (Johnson et al. 2005). In contrast to bvFTD, social decorum remains intact throughout the course of the disease. Neuropsychological testing reveals primary expressive language impairment but may also show minor working memory and executive deficits (Gorno-Tempini et al. 2004). At autopsy, nfvPPA is frequently associated with FTLD-tau pathology.
svPPA is distinct from nfvPPA, sparing speech fluency and instead resulting in impairments in naming, object knowledge, and single-word comprehension. Patients with svPPA struggle with word finding, particularly for nouns, leading to speech that is empty and impoverished, yet more fluent than that seen in nfvPPA. Unlike a patient with AD, for whom a word may be at the tip of the tongue and readily recognized from a list, a patient with svPPA loses not only the word itself but also the semantic knowledge surrounding the noun in question. For example, the svPPA patient confronted with a picture of a dog will neither generate the correct word nor succeed in choosing the word from a list; when told that it is a dog, they may respond, “Dog...dog...what is a dog?” These deficits localize to the anterior temporal lobes, which exhibit asymmetric atrophy that is worse in the left hemisphere in about three-quarters of cases (Thompson et al. 2003). Particularly when the right temporal lobe is affected, svPPA may involve behavioral symptoms, including strict routines, food fads, clock watching, and dieting (Rabinovici et al. 2010). Prosopagnosia may be detected on evaluation. At autopsy, svPPA is frequently associated with FTLD-TDP pathology (Davies et al. 2005).
In addition to cognitive and behavioral impairment, FTD may result in progressive deterioration in motor function. Approximately 10%–15% of patients with bvFTD will develop motor neuron disease (amyotrophic lateral sclerosis) and experience dysphagia, dysarthria, limb weakness, or loss of dexterity (Lomen-Hoerth et al. 2002). Respiratory weakness and impaired swallowing are frequently life-limiting manifestations. In addition, 20% of patients with FTD will develop parkinsonian symptoms, including tremor, rigidity, slowness, or imbalance. Followed longitudinally, nfvPPA may evolve into either a progressive supranuclear palsy or corticobasal syndrome manifestation. Progressive supranuclear palsy is characterized by the presence of axial rigidity, pseudobulbar affect, and supranuclear gaze palsy, whereas corticobasal syndrome includes features of apraxia, myoclonus, limb dystonia, and alien limb phenomenon.
The nosology of the FTD clinical syndromes has evolved rapidly, reflecting in part a rapidly growing understanding of these diseases and their interrelationships. Terms such as Pick’s disease, semantic dementia, and progressive nonfluent aphasia are still actively used in the literature. In addition, the DSM criteria were recently updated, in DSM-5 (American Psychiatric Association 2013), to include FTD as a disorder, but the entity is referred to as frontotemporal neurocognitive disorder, designated as major or mild, which comprises behavioral and language variants. (svPPA and nfvPPA are not differentiated according to DSM-5.)
In FTD, there are two general approaches to treatment: interventions that treat symptoms and those that slow disease progression. While a symptomatic therapy may alleviate some disease manifestations, it will have no impact on disease progression or mortality. When a symptomatic therapy is discontinued, it is expected that the patient’s subsequent clinical course will reflect the natural history of the illness, thus demonstrating the absence of any lasting treatment effect. By contrast, disease-modifying therapy is an important and separate treatment goal, often targeting the very molecules that drive disease pathogenesis. Such a therapy alters the fundamental course of the disease, offering lasting benefits for the future. The ideal treatment approach to FTD would be two-pronged, combining both symptomatic and disease-modifying drugs to address the mixture of cognitive and behavioral deficits as well as the responsible molecular process.
Unfortunately, current treatment is limited to symptomatic therapy, as no disease-modifying agent for FTD has yet emerged. Major challenges to identifying disease-modifying FTD treatments include not only the complex and incompletely understood molecular underpinnings of the various FTD subtypes (e.g., bvFTD, nfvPPA, svPPA) but also the difficulty in identifying the particular histopathological process affecting a given patient. Essentially, the molecular steps leading to accumulation of tau, TDP-43, or FUS are distinct and demand individual pharmacological approaches. For instance, a treatment directed against FTLD-tau may be effective for the nfvPPA patient with a tau-driven disease process but will be a fruitless strategy for svPPA patients with FTLD-TDP pathology. On the other hand, disease-modifying drugs impacting a shared, common final pathway, such as cell death, may be effective for multiple neurodegenerative diseases. Importantly, tau is implicated in both AD and some forms of FTD, and new AD drugs targeting tau may be useful in diseases characterized by FTLD-tau pathology. In the coming years, clinical trials of such tau-directed agents as well as of drugs targeting TDP-43 or other pathways are expected to emerge (see section “Future Directions” below).
Nonpharmacological and pharmacological treatments may ameliorate FTD-associated symptoms. Importantly, symptomatic treatment decisions should be based on which symptoms the clinician wishes to treat, and the approach does not depend on whether the patient has bvFTD, nfvPPA, or svPPA.
Limitations in pharmacological therapy for FTD underscore the importance of optimizing patient and caregiver quality of life through nonpharmacological interventions. These treatments have a supportive quality and are similar to those commonly recommended for other neurodegenerative conditions such as AD.
FTD is a devastating disease that dramatically impacts lifestyle not only for the diagnosed individual but also for the caregiver and family. Any new diagnosis should be accompanied by a formal family meeting in which questions related to diagnosis, prognosis, and treatment can be addressed by the health care professional. In certain cases, a referral to community resources such as the Alzheimer’s Association may be helpful to reinforce the diagnosis and provide access to supportive resources. There is evidence that the caregiver burden associated with FTD is greater than that associated with AD (Wong et al. 2012), and providing access to regional caregiver support groups is highly recommended.
Social disinhibition is one of the most striking and debilitating symptoms associated with bvFTD. Such behaviors may complicate public outings. Strategies to avoid embarrassing experiences include visiting places where the patient is well known or establishments that are not crowded (Merrilees et al. 2010). Families may carry a small business-size card that explains the patient’s diagnosis to strangers. Individuals with FTD may be prone to agitation. Caregivers are encouraged to avoid triggers and when confronted with an outburst not to escalate the situation but to remain calm and to acknowledge the patient’s emotions. An effort should be made to limit potentially activating stimuli at home, such as loud music or television (Merrilees et al. 2010).
As noted earlier, the epidemiology of FTD demonstrates several patterns of heritability. Given the heritable nature of FTD, genetic counseling addressing the utility as well as consequences of genetic testing should be offered to patients and their families.
Longitudinal cohort studies in healthy aging populations have shown that routine cognitive and physical activity reduces the future risk of dementia. The majority of this research has been performed with respect to development of AD and vascular dementia, but the same principles may be generalized to other neurodegenerative diseases, including FTD.
Patients should be encouraged to remain physically active. Research suggests that moderate physical activity positively impacts mood, sleep, functional ability, and cognition (Lautenschlager et al. 2008). The majority of beneficial activities studied in the literature are aerobic in nature (brisk walking, hiking, aerobics, strength training, swimming, tennis doubles, yoga, martial arts, weight lifting, golfing without a golf cart, and moderate use of exercise machines [e.g., exercise bike, treadmill, elliptical]). Exercise at least three times a week in middle and late life has been shown to result in decreased risk for dementia in longitudinal cohort studies (Laurin et al. 2001). Other research suggests that similar levels of exercise may reduce the rate of decline among patients already diagnosed with dementia.
Participation in mentally engaging activities in late life is thought to maximize cognitive reserve by enhancing neurogenesis and synaptogenesis. Observational studies have suggested that cognitively intense leisure activities in the elderly, such as reading, writing, doing crossword puzzles, playing board/card games, playing musical instruments, participating in group discussions, and dancing, are associated with a decreased risk of dementia (Verghese et al. 2003). Furthermore, these activities appear to reduce decline in global cognition, perceptual speed, and working memory (Wilson et al. 2002) and may help patients who already exhibit cognitive decline.
Patients with PPA, especially nfvPPA, may benefit from a course of speech therapy to optimize expressive language. Therapists may be able to equip patients with a speech assist device. Recently developed, affordable electronic devices with preprogrammed phrases and voice simulation have been helpful in providing alternative means of communication for patients with nfvPPA.
FTD often produces motor impairments, typically weakness or parkinsonism. When motor impairments are present and functionally limiting, physical, occupational, and/or speech therapy may be helpful.
Establishing safety in the homes of persons with FTD and their families is critically important. A home safety evaluation is recommended for patients with FTD to avoid potential accidents relating to appliances and wandering behavior (Rabinovici et al. 2010). In addition, executive dysfunction has specific implications in terms of medication compliance and chronic disease management. Medication management support either through an individual’s caregiver or from a community-based support organization (e.g., public health nurse, home care) should be established.
As a result of FTD-associated executive dysfunction, the provider should address transfer of responsibility for cognitively demanding activities such as driving and finances. Consultation with financial advisors and legal counsel, and discussion of conservatorship, may be appropriate. Individuals should be encouraged to execute a durable power of attorney as appropriate. Another common safety concern in FTD is reckless driving that places the patient, family members, and others at risk. All patients should have their driving ability evaluated in an objective manner through a formal driving evaluation. In more severe cases, car keys may be kept safely away from the patient (Merrilees et al. 2010).
End-of-life treatment options and decisions need to take into account effective pain management and the goals of the individual with dementia via advance directive. Decisions about resuscitation and intubation in case of emergency should ideally be made during the earliest stages of the condition. Clinical providers should refer individuals with FTD to advance care–planning resources to assure that patients have tools and can execute documents that will guide their care when they are no longer capable of doing so.
There is no treatment approved by the U.S. Food and Drug Administration to treat symptoms or modify disease progression in FTD. Rather, clinicians make use of the existing arsenal of psychoactive drugs to treat a patient’s particular symptoms and improve quality of life to the extent possible, prescribing drugs off-label in an attempt to provide relief to patients. Such drugs and the evidence to support their use are considered here by drug class. Unfortunately, the level of evidence supporting the use of most of the medications discussed below is modest, and most of what is discussed here is limited to published case series and open-label studies. While most of the research outlined here has involved patients with bvFTD (except as indicated), recommendations can reasonably be expected to extend to patients with other FTD variants who exhibit the types of symptoms that these drugs are meant to target.
There are profound serotonergic abnormalities in FTD (Huey et al. 2006). Consequently, selective serotonin reuptake inhibitors (SSRIs), which have a favorable side-effect profile with low risk of harm, are widely used to treat a variety of behavioral symptoms in patients with FTD (Pasquier et al. 2003). In an open-label study of 11 FTD patients treated with fluoxetine, sertraline, or paroxetine, most patients experienced a reduction in disinhibition, depressive symptoms, carbohydrate craving, or compulsions, and no subject worsened on these measures (Swartz et al. 1997).
Citalopram was studied in a 6-week open-label, uncontrolled study of 15 patients with FTD and severe behavioral symptoms (Herrmann et al. 2012). Treatment was associated with a significant reduction in disinhibition, irritability, depression, and other behavioral disturbances. Hermann et al. attempted to document the degree of endogenous serotonin deficiency in subjects using a citalopram challenge test; they found that greater citalopram efficacy correlated with greater endogenous neurotransmitter deficiency. Citalopram can cause QT prolongation and risk for cardiac arrhythmia, and dosing above 20 mg/day in elderly patients is discouraged.
Paroxetine may reduce repetitive, ritualistic behavior (Chow and Mendez 2002). In a randomized, open-label study of 16 FTD patients comparing paroxetine with piracetam, improvements in behavioral symptoms occurred in the paroxetine group (Moretti et al. 2003a). However, no effect of paroxetine emerged from a randomized, double-blind, placebo-controlled trial of 10 FTD patients treated with paroxetine at a higher dose (40 mg/day vs. 20 mg/day) (Deakin et al. 2004).
Sertraline has received less attention than paroxetine, but one open-label, uncontrolled study of the drug suggests that it may be effective at reducing the compulsive, stereotypical motor behaviors that can occur in bvFTD (Mendez et al. 2005). Other drugs that have shown possible benefits include fluvoxamine (Ikeda et al. 2004) and trazodone (Lebert and Pasquier 1999).
Given the scant evidence currently available, there is no specific treatment recommendation regarding the use of SSRIs to treat behavioral and psychological symptoms in FTD. These agents appear safe, and the limited evidence reviewed above suggests possible efficacy.
Antipsychotic medications have also been used to treat the behavioral symptoms of FTD, especially agitation and disinhibition, although there is a general lack of supporting literature. Case reports with risperidone (Curtis and Resch 2000) and aripiprazole (Fellgiebel et al. 2007; Reeves and Perry 2013), as well as an open-label uncontrolled study of olanzapine (Moretti et al. 2003b), provide some very limited support for their use. Importantly, patients with FTD may be exceptionally sensitive to the motor side effects of antipsychotic medications, exhibiting high rates of extrapyramidal symptoms. In addition, antipsychotic medications are associated with a risk of death in elderly patients. For these reasons, until better evidence is available to reject the concern that risks outweigh benefits, antipsychotic drugs should not be recommended for routine use in patients with FTD. Paradoxically, there is evidence that dopamine agonists such as selegiline, a monoamine oxidase–B inhibitor that slows the metabolism of dopamine, may reduce neuropsychiatric symptoms in FTD (Moretti et al. 2002).
In part because of the pervasive apathy that occurs among many patients with FTD, some clinicians have considered the use of psychostimulants. A single dose of methylphenidate appeared to reduce risky decision making on a laboratory-based gambling task in a small, double-blind, placebo-controlled experiment involving eight patients (Rahman et al. 2006). In another double-blind crossover trial of eight patients with bvFTD alternately given quetiapine and dextroamphetamine, there was a significant reduction in apathy and disinhibition associated with dextroamphetamine (Huey et al. 2008). Given this limited research, and the possibility of adverse reactions to stimulant medications, no recommendation can be made at this point regarding their use in the treatment of FTD.
Cholinesterase inhibitors, including donepezil, rivastigmine, and galantamine, are first-line symptomatic therapies for AD. Their use in AD is scientifically rational, reflecting a profound cholinergic deficit arising from the early demise of neurons in the nucleus basalis of Meynert. In FTD, there is a relative preservation of cholinergic neurons in the brain and no a priori reason to expect a benefit from cholinesterase inhibition (Huey et al. 2006).
Data regarding the efficacy of cholinesterase inhibitors in FTD are mixed and difficult to interpret because of a lack of placebo-controlled studies. In one small open-label study (Lampl et al. 2004), nine patients with bvFTD were given either donepezil or rivastigmine, and modest cognitive benefits were observed, possibly more so among the four men in the study. In another 12-month open-label study, 20 bvFTD patients were given either rivastigmine or no cholinesterase inhibitor (Moretti et al. 2004), and treatment-associated improvements in behavior, caregiver burden, and executive cognitive function emerged for patients taking rivastigmine.
A study of galantamine in 40 patients with bvFTD or PPA revealed no evidence of benefit (Kertesz et al. 2008). These patients were given escalating doses of galantamine during an 18-week open-label phase and then randomly assigned to receive drug or placebo during an 8-week double-blind phase. Galantamine produced no improvement in behavioral or language symptoms. A global severity score trended better in the treatment group among the subset of patients with PPA. This is the largest and only double-blind study of a cholinesterase inhibitor in FTD, and the results were negative.
Donepezil may worsen behavior in bvFTD. In a 12-patient open-label study of donepezil (Mendez et al. 2007), the treated bvFTD group at 6 months exhibited no change in Mini-Mental State Examination scores or in a measure of overall functioning relative to 12 matched, untreated bvFTD patients. However, caregivers of the treated patients did endorse a higher level of disinhibition and compulsiveness that reversed upon discontinuation of donepezil. In another study, discontinuation of previously prescribed donepezil among patients with FTD led to improved neuropsychiatric symptoms and reduced caregiver burden (Kimura and Takamatsu 2013).
Taken together with the lack of compelling evidence for a benefit of galantamine or rivastigmine, these observations with donepezil have prompted a general recommendation to avoid cholinesterase inhibitors in FTD. A further potential harm of cholinesterase inhibition is the risk of increasing oral secretions and contributing to aspiration in the subset of FTD patients with associated motor neuron disease. Finally, it is worth noting that in clinical cases in which AD and FTD are equal differential considerations, a cholinesterase inhibitor cannot be used as a “litmus test” to aid in the diagnostic construct because any beneficial response in a patient with AD is modest and evident only over time.
Memantine in moderate to severe AD results in modest symptomatic improvements in cognition, function, and behavior. Whereas this drug was designed as a low-affinity, use-dependent N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, its overall mechanism of action is not straightforward (Parsons et al. 2007). Two randomized, placebo-controlled trials of memantine in FTD showed no benefit on cognitive or neuropsychiatric endpoints (Boxer et al. 2013b; Vercelletto et al. 2011) and a trend toward worsening cognition in one study (Boxer et al. 2013b). Therefore, memantine is not recommended for the treatment of FTD.
Treatment options for FTD will become increasingly sophisticated as clinical trials identify candidate disease-modifying therapies. Such therapies will likely be protein-specific, growing directly out of basic science studies of FTLD-tau, FTLD-TDP, and FTLD-FUS.
One exciting current example is the introduction of drugs aimed at preventing tau aggregation. Such therapy could potentially offer disease-modifying benefits both in AD and in a subset of FTD syndromes, including some cases of bvFTD and most cases of nfvPPA. Davunetide was initially promising for this indication but failed to help patients with progressive supranuclear palsy, an FTD-related tauopathy (Boxer et al. 2014). Methylene blue is another agent that has been investigated for its potential to reduce tau aggregation and slow AD progression, but a clinical trial of a second-generation version of this compound was negative. Other potential therapeutic interventions include inhibition of enzymes that contribute to tau phosphorylation (glycogen synthase kinase–3β [GSK3β] or cyclin-dependent kinase–5), manipulation of tau-processing pathways (e.g., ubiquitination), reduction of tau expression, and other approaches. There has been limited investigation into lithium and valproic acid, inhibitors of GSK3β, for treatment of tauopathies.
FTLD-TDP neuropathology results in some cases from low levels of another protein, progranulin. Loss-of-function mutations in progranulin result in a haploinsufficiency of the protein and cause familial, autosomal dominant FTD with FTLD-TDP pathology (Baker et al. 2006; Cruts et al. 2006). Although the exact function of progranulin is unknown, normalizing protein levels could be a potential therapeutic strategy. A pilot study of amiodarone for this indication was negative (Alberici et al. 2014), and trials of novel histone deacetylase inhibitors are under way.
As protein-specific therapies emerge, accurate in vivo diagnosis will be essential. Specifically, tools that can differentiate FTLD-tau from FTLD-TDP are needed because most future disease-modifying agents are likely to be targeted toward one pathway or the other. Neuroimaging will play a critical role in this effort. Two large longitudinal studies patterned after and complementary to the Alzheimer’s Disease Neuroimaging Initiative began recruiting patients with FTD to undergo sophisticated neuroimaging, with a goal of characterizing the brain functionally and structurally over time and developing spinal fluid biomarkers that may correspond to the underlying molecular pathogenesis (Boxer et al. 2013a). The hope is that this study will yield not only new information on brain-behavior correlates but also strategies for identifying the underlying proteinopathy in a specific patient and for monitoring the response to emerging treatments.
Patients with FTD should be treated supportively and conservatively. Because of the absence of disease-modifying pharmacological therapy or compelling evidence supporting drug efficacy for reducing neuropsychiatric symptoms, nonpharmacological approaches should take priority. In a patient with a neurodegenerative disease, the capacity to regain lost functions or to learn new behaviors is fundamentally compromised. For this reason, the emphasis must be on tolerance of odd behaviors, compensatory strategies for deficits, and modification of the environment to cope with new caregiving realities.
In situations where neuropsychiatric symptoms interfere with safe caregiving or quality of life despite optimal nonpharmacological interventions, a medication may be considered. Mood dysregulation, obsessions, or compulsive behaviors may respond to SSRIs. There is no role for prescribing cholinesterase inhibitors or memantine in FTD. There should be a conscious effort to avoid sedative medications like antipsychotics, benzodiazepines, and anticholinergic medications, among others, given the risk of worsening cognition and precipitating delirium. However, atypical antipsychotics may be considered as a temporary measure when agitation interferes with safety.
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