Easy To Miss, Hard to Treat: Notes on Frontotemporal Dementia

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NEUROPSYCHIATRY

The term frontotemporal dementia (FTD) describes a group of neurodegenerative disorders that are characterized by the clinical syndrome of progressive dysfunction in executive functioning, behaviors, and language.¹ FTD is thought to be the third most common type of dementia after Alzheimer disease (AD) and dementia with Lewy bodies.FTD is also a common type of early-onset dementia (occurring among individuals 65 years or younger).²

FTD was noted in 1892 by Arnold Pick, MD, when he described an individual who presented with aphasia, temporal lobar atrophy, and presenile dementia.² In 1911 the association between Pick bodies and FTD was described by Alois Alzheimer, MD, PhD, who named the disorder “Pick’s disease.” The term Pick’s disease became synonymous with FTD, referring to both the clinical syndrome and the pathological diagnosis. Currently, “Pick’s disease” is used only to describe the pathological diagnosis. In 1982, M. Marsel Mesulam, MD, identified the language subtype of FTD: primary progressive aphasia (PPA).

Available evidence indicates that FTD is the second most common cause of dementia among individuals 65 years or younger.¹ The prevalence of FTD among individuals with early-onset dementia is between 3% and 26%. The population prevalence of FTD varies between 1 to 26 per 100,000.² These numbers probably underestimate the true prevalence, as the disorder is often missed or misdiagnosed.

Subtypes

FTD has 2 main subtypes, based on their predominating presentations: the behavioral variant of FTD (bvFTD), and the language variant, ie, PPA.³ Based on the localizations and underlying cerebral dysfunction, the language variant can be further subdivided into the nonfluent variant of PPA (nfvPPA) and the semantic variant of PPA (svPPA). Male predominance has been noted in the bvFTD and svPPA variants and female predominance in the nfvPPA variant. Table 1 details the diagnostic criteria of FTD’s 3 variants.^4,5

Table 1. Diagnostic Criteria for the FTD Variants

A third variant of PPA has been described as logopenic PPA (lvPPA),in which individuals exhibit specific impairment with confrontation naming or word-finding difficulties and impaired sentence repetition.^1,6 Neuroimaging studies among these individuals demonstrate predominant left posterior perisylvian or parietal atrophy/hypoperfusion/hypometabolism. Definite histopathologic evidence or the presence of a known pathogenic mutation allow for a definite diagnosis of FTD.

Evidence indicates that approximately 12.5% of individuals with bvFTD have concomitant motor neuron disease.⁷ In addition, 27.3% of individuals have features of minor motor system dysfunction, including occasional fasciculations and mild muscle wasting or weakness. As the disease evolves, the clinical presentation of the 3 variants overlap with each other and with syndromes of atypical parkinsonism, including progressive supranuclear palsy (PSP) and corticobasal degeneration syndrome (CBS).⁸

Compared with AD, patients with FTD tend to have a shorter duration of survival from diagnosis and more rapid decline of cognition and function.³ The average survival time with FTD depends on the subtype; the average survival time is approximately 3 years for bvFTD and motor neuron disease and 12 years for with svPPA.

Neurobiology

Current evidence indicates that FTD is a highly heritable disorder, with familial FTD accounting for approximately one-third to half of cases.¹ Most cases of familial FTD present as the bvFTD variant. A family history of dementia is found in 25% to 50% of FTD cases, and about 10% have a clear autosomal-dominant inheritance.⁹ Mutations in the microtubule-associated protein tau (τ), progranulin, and chromosome 9 open reading frame 72 expansion are the most common causes of familial FTD. These mutations result in the variable clinical presentations of FTD.

Table 2. Differentiating Clinical Features: 4 Types of Dementia

The major variants of FTD are classified based on their respective protein-based inclusions and underlying molecular pathologies.¹ The current neuropathological classification allows most cases of FTD to be placed into 1 of 3 broad molecular subgroups: frontotemporal lobar degeneration (FTLD)-τ subtype; the FTLD-TDP subtype associated with TDP-43; or FET protein accumulation.¹⁰ The FTLD-τ variant accounts for approximately 40% of all FTD cases. Approximately half the postmortem cases of FTD have abnormal deposition of transactive response DNA-binding protein 43 (TDP-43).

Diagnosis

FTD may be misdiagnosed as other psychiatric disorders, including schizophrenia, bipolar disorder, depression, or obsessive-compulsive disorder.² The bvFTD variant is most likely to be misdiagnosed as another psychiatric disorder; FTD may be misdiagnosed as AD or another type of dementia. Table 2 describes the differentiating clinical features of the dementias.¹¹

Given the high risk for misdiagnosis, suspected cases of FTD should be carefully evaluated. A thorough history from the individual and a reliable collateral source that tracks the progression of behavioral and cognitive symptoms are essential. A focused physical examination that identifies parkinsonian and/or upper motor neuron signs will assist in the diagnosis. Laboratory testing (including complete metabolic panel, complete blood count, thyroid function tests, liver function tests, vitamin B12 levels, and urine drug screen) should be done to rule out reversible causes of cognitive and behavioral impairments. Among atypical cases, toxicology for heavy metals, inflammatory biomarkers for autoimmune and paraneoplastic syndromes, and testing for infectious etiologies including syphilis and HIV should be considered.

Table 3. Neuroimaging Findings in FTD

Table 4. Neuropsychological Profile: 4 Dementias

Neuroimaging studies including magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), and single photon emission computed tomography (SPECT) scans can also assist in diagnosing FTD. Table 3 describes the neuroimaging findings in FTD.¹² Cerebrospinal fluid (CSF) assessment will help rule out AD when the patient has low β-amyloid concentrations and high τ protein concentration. Neuropsychological testing will help rule out other causes of cognitive and functional changes. Table 4 provides neuropsychological profiles of various types of dementias.¹³ Among individuals with a family history of dementia, movement disorders, and/or psychotic disorders, genetic counseling and a search for genes that cause FTD are both recommended.²

Treatments

Currently there are no US Food and Drug Administration (FDA) approved disease-modifying drugs for the treatment of FTD.¹⁴ In a systematic review, Nardell and Tampi found a total of 9 randomized, controlled, double-blinded clinical trials that evaluated various drugs for the treatment of FTD.¹⁵ These included 2 trials of the selective serotonin reuptake inhibitor paroxetine, 1 trial of trazodone, 2 trials of stimulants (methylphenidate and dextroamphetamine), 1 trial of the acetylcholinesterase inhibitor galantamine, 2 trials of the N-methyl-d-aspartate (NMDA) antagonist memantine, and 1 trial of the neuropeptide oxytocin. The investigators concluded that SSRIs, trazodone, and the amphetamines may be effective in reducing some behavioral symptoms. None of these medications, however, improved cognition among individuals with FTD. Available data also indicated that these medications were well tolerated.

The evidence for the use of antipsychotics for the treatment of behavioral symptoms in FTD comes mainly from case reports and uncontrolled studies.¹⁶ In addition, the use of antipsychotics can worsen the risk of extrapyramidal adverse effects, to which individuals with FTD are especially vulnerable. Furthermore, the boxed warning for the risk for death with the use of antipsychotics among individuals with dementia holds true also for individuals with FTD. For the treatment of behavioral symptoms in FTD, the evidence for the use of anticonvulsants—including valproic acid, topiramate, and carbamazepine—is limited to case reports. Evidence indicates that individuals with FTD and parkinsonism often do not respond to dopaminergic drugs, including levodopa/carbidopa, although some case reports indicate some benefits with these agents. Table 5 summarizes the pharmacotherapy for FTD.^15,16

Table 5. Pharmacotherapy for FTD

Trials of τ aggregation inhibitors, τ acetylation inhibitors, anti-τ active vaccine, anti-τ monoclonal antibodies, anti-human sortilin monoclonal antibody, microtubule-stabilizing drugs, and progranulin expression activators have been completed or are currently in various phases of trials.¹⁷ Unfortunately, available results indicate that none of these drugs have yet been found to be beneficial.

Available evidence indicates that nonpharmacological management techniques are helpful among individuals with FTD.¹⁸ These interventions include environmental approaches that assist individuals who struggle to accurately interpret, understand, and react to their environment. In addition, behavioral modification techniques and providing familiar activities appear to reduce different types of behaviors. Evidence indicates that educational services and coping strategies that are focused on problem-solving are effective in managing behavioral symptoms and reduce caregiver burden. The development of individualized regimens incorporating environmental and behavioral strategies have been proven to be highly beneficial in assisting individuals with FTD. The family caregivers who use these strategies become more competent in managing patients’ challenging behaviors. Speech therapy has been found to be beneficial among individuals with PPA.¹⁹

Concluding thoughts

The clinical syndrome of FTD is characterized by executive dysfunction, behavioral disturbances, and language impairment. FTD is often misdiagnosed or underdiagnosed due to the heterogeneity of its clinical presentation and the overlap of its clinical symptoms with those of other common neuropsychiatric disorders. Although there are no FDA-approved medications for the treating FTD, some agents have shown modest efficacy in improving behavioral but not cognitive symptoms. Nonpharmacological techniques can be beneficial in managing behavioral symptoms. Many newer therapies are currently under trial, although their benefits are not yet certain.

Dr Tampi is chairman, Department of Psychiatry & Behavioral Sciences, Cleveland Clinic Akron General, Akron, OH; chief, Section for Geriatric Psychiatry, Cleveland Clinic, Cleveland, OH; and professor of medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH. Ms Tampi is executive vice president, Diamond Healthcare, Richmond, VA. Dr Parish is with the Behavioral Advisory Group, Strongsville, OH. The authors report no conflicts of interest concerning the subject matter of this article.

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