Arnold Pick was the first to notice, on autopsy, these protein aggregations, which he called Pick bodies. Later, researchers discovered that quite a few different proteins, including phosphorylated tau, TDP-43, and/or fused-in-sarcoma, were implicated in the various subtypes of frontotemporal dementia. The longstanding eponym Pick disease recently has been replaced in favor of the more depictive term frontotemporal dementia or the umbrella term frontotemporal lobar degeneration, which encompasses all the clinical phenotypes.2,5
Frontotemporal dementia also may have strong genetic components. A recent study showed that 10% to 25% of patients have an identifiable autosomal dominant inheritance pattern.6,7 The genetic links involve specific mutations in the C9ORF72, MAPT, and/or GRN genes, which lead to the pathologic protein buildup that triggers the degenerative process.2,8
Frontotemporal dementia is a fairly uncommon dementia with lower prevalence than Alzheimer disease, vascular dementia, and dementia with Lewy bodies. However, the prevalence is skewed in terms of age groups because frontotemporal dementia is a more common diagnosis in younger patients. The mean age of onset is about 58 years, with the most frequent presentation between ages 40 and 75 years. In comparison, early-onset Alzheimer disease (onset of symptoms before age 65 years) is unusual.4 When these patients under age 65 years are taken into account, frontotemporal dementia has an equal prevalence to Alzheimer disease.2 The prevalence of frontotemporal dementia also may be underestimated because its behavioral symptoms can be misdiagnosed as psychiatric conditions.5 Unfortunately, frontotemporal dementia is a steadily progressive disease that causes a faster decline than Alzheimer disease, with the average patient surviving only 4 to 8 years after diagnosis.
Behavioral variant frontotemporal dementia is the most common subtype of frontotemporal dementia, accounting for over half of cases.9 This subtype is characterized by often subtle changes in behavior, personality, and/or social conduct that precede obvious cognitive decline. An impulsive job change or a new childlike sense of humor may be the first indication of pathology. As more of the patient's frontal lobe is affected, behavioral disinhibition worsens. Patients begin to exhibit socially inappropriate behavior and fail to recognize social cues.4,9 This lack of social awareness often causes embarrassment for family members. One study even suggests that new criminal behavior in previously law-abiding citizens could be a warning sign. The researchers found that up to one-third of patients had criminal records for offenses such as violent behavior, theft, public indecency, and inappropriate sexual advances.10
The disease tends to affect demeanor as well. Patients may become either more impulsive or more withdrawn than their norms. Outright apathy and disinterest can develop, which are understandably often misdiagnosed as depression.11 The loss of sympathy and empathy is one of the most difficult symptoms of behavioral variant frontotemporal dementia for family members to understand. Patients will become uncaring toward family members and even pets. They may lash out, say hurtful things, and detach themselves emotionally.4,9 Decreased libido is a frequent symptom.11 Interviewing the caregiver separately from the patient usually is the best way to elicit these subtle changes.
Other common findings include compulsive behavior and hyperorality. Patients may exhibit binge eating; eating to excess at meals; and increased consumption of sweets, alcohol, or tobacco. Other frequent symptoms are placing inedible objects in the mouth, eating only one type of food, or scratching or picking at the skin or lips. Later in the disease, repetitive movements and speech patterns also can develop.4
The most important part of the patient encounter is a close observation of the patient's behavior. Depending on the severity of the disease, the patient may already have significant disinhibition and fail to recognize normal social cues during the encounter. Repetitious or compulsive behavior may be obvious. Some patients may even make inappropriate sexual advances.9
As part of the routine physical, check for the presence of frontal release signs, defined as the reemergence of certain primitive reflexes normally seen only in infants. The most commonly found reflexes in patients with advanced behavioral variant frontotemporal dementia are the palmar grasp and rooting reflex, which are elicited by stroking the palm and cheek, respectively.4 Although these reflexes also are found in patients with advanced Alzheimer disease, they are noticeable at a much earlier stage of disease in patients with frontotemporal dementia.4
Because behavioral variant frontotemporal dementia has such a varied presentation, a framework to recognize and organize the symptoms clinically has been devised. In 2010, a multinational group called the International Behavioural Variant FTD Criteria Consortium created the newest set of criteria to standardize the diagnosis of frontotemporal dementia. The criteria are broken down into three levels of diagnostic certainty—possible, probable, and definite (Table 1).1 A diagnosis of possible frontotemporal dementia is made clinically; probable and definite diagnoses require additional concrete findings.
PRIMARY PROGRESSIVE APHASIA
This subtype is further delineated into three variants: progressive nonfluent aphasia, semantic dementia, and logopenic phonological aphasia.4 Although these categories are described discretely in this section, patients' symptoms often overlap in true clinical presentation. Behavioral changes may still be apparent, but typically are more subtle, such as apathy, irritability, or depression.12
Progressive nonfluent aphasia is the most common variant of primary progressive aphasia and manifests as anomia, or trouble finding words and naming objects. Patients often have halting speech with pronunciation and grammar errors.4,13 Patients whose disease is mild usually can compensate by using alternative words or simplifying their speech. Although comprehension and repetition are spared early on, these abilities begin to deteriorate as the disease progresses.4,13
Semantic dementia presents as more of a difficulty in language comprehension with a relatively normal fluency. These patients also have trouble finding words and naming objects. They have additional problems with remembering meanings of words, and often compensate by using vague language.13 They may also have visual agnosia, or trouble finding words for visual images.4 Visual agnosia can be tested by showing patients pictures of commonly recognized animals, such as lions or giraffes, and asking them to identify the animal.
Because progressive nonfluent aphasia and semantic dementia tend to overlap in clinical presentation, a verbal fluency test can help tease out true impairments. Verbal fluency testing includes two main subtypes: category fluency (sometimes called semantic fluency) and letter fluency (sometimes called phonetic fluency). Listing animals, fruits, or vegetables tests category fluency; listing words that begin with a certain letter tests letter fluency.14 A normally functioning adult at age 65 years should be able to list 15 words in 60 seconds for each category. In general, patients with progressive nonfluent aphasia perform equally poorly on both types of verbal fluency. However, patients with semantic dementia often perform significantly worse on category fluency than letter fluency.4
Logopenic phonological aphasia is a rare subtype of primary progressive aphasia. These patients have significant impairments in speech quality, talking slowly and having difficulties with word retrieval. Unlike patients with other subtypes, these patients have significant trouble with sentence repetition.4
An MRI is necessary to rule out a focal lesion in anyone presenting with word-finding and comprehension difficulty, decreased fluency, and/or motor speech difficulty. However, if an MRI reveals focal atrophy rather than a lesion, consider primary progressive aphasia.5
The four most commonly diagnosed dementias—Alzheimer disease, vascular dementia, dementia with Lewy bodies, and frontotemporal dementia—together account for more than 90% of all cases of dementia.15 Although Alzheimer disease continues to dominate in terms of prevalence, a recent study discovered that the less-prevalent dementias are actually mislabeled as Alzheimer disease up to one-third of the time.16 Simply recognizing key symptoms not consistent with Alzheimer disease can increase accurate diagnosis and patient care.
Perform a thorough review of the patient's history, soliciting input from others who know the patient well. The most meaningful warning sign for Alzheimer disease is significant memory impairment that precedes other symptoms.9 Misplacing keys, getting lost driving, and forgetting appointments or anniversaries can be the earliest signs of memory loss in a patient with Alzheimer disease.17
Mental status screening tests, such as the Montreal Cognitive Assessment or the Mini Mental State Examination, should be administered early in the evaluation of a patient with possible dementia. Compared with patients with Alzheimer disease, many patients with behavioral variant frontotemporal dementia continue to score normally on these screening tests even in advanced disease.13
In patients with frontotemporal dementia, family or caregivers are less concerned with memory loss than with reporting changes in the patient's routine behavior, relationships, preferences, and even appetite. Ask family members if the patient seems more withdrawn or more outgoing than usual. Has he or she been embarrassing in public? Has he or she had trouble finding words or speaking clearly? Any positive answers should raise suspicions of an alternate diagnosis to Alzheimer disease. Table 2 provides a side-by-side comparison of differences between frontotemporal dementia and Alzheimer disease. If any of the patient's history or symptoms raise red flags, do not ignore them.
CONFIRMING THE DIAGNOSIS
Once the clinician suspects a diagnosis of frontotemporal dementia based on patient history and symptoms, a neurology referral is indicated. A neurologist can repeat mental status screening tests and perform more detailed testing to confirm the diagnosis as well as determine its severity. Depending on the patient's initial symptoms, collaboration with a neuropsychologist may also be considered.
Comprehensive neuropsychologic tests that assess many different domains of cognition (memory, attention, language, visuospatial ability, and executive function) are most effective for diagnosing frontotemporal dementia. The main impairment is seen in executive functioning—tasks that require planning, problem-solving, or abstract reasoning.13 Examples include making a trail that alternates between numbers and letters in ascending order or explaining the meaning behind a common saying such as “people in glass houses shouldn't throw stones.” A patient lacking executive function may only connect numbers and ignore letters on trail drawing or answer that people in glass houses shouldn't throw stones because the windows would break. However, other areas of functioning, particularly memory, tend to remain relatively intact.4,13 Patients with primary progressive aphasia are an exception, as they will understandably score poorly on the language portions of the tests. The specific language impairment (naming, verbal fluency, comprehension, repetition) can distinguish between the subtypes of primary progressive aphasia.13
If neuroimaging was not already obtained in the primary care setting, a neurologist can order it for diagnosis and to rule out organic causes of the patient's symptoms.4 MRI is the ideal initial imaging test. As expected, patients with frontotemporal dementia have localized brain atrophy of the frontal and temporal lobes. In those with the behavioral variant, the atrophy is asymmetric and varies in severity among patients (Table 3). Primary progressive aphasia shows a predominately left-sided atrophy. If MRI is normal but frontotemporal dementia is still strongly suspected, a positron emission tomography (PET) or a single photon emission CT (SPECT) may reveal localized areas of hypometabolism in the frontotemporal region.4,9 Positive MRI or PET scan results combined with clinically apparent disease warrant a probable diagnosis of frontotemporal dementia.1
The only way to make a definitive diagnosis is direct visualization of neuronal protein accumulations on brain examination done at an autopsy.1 Talk to the family about whether they want an autopsy and definitive diagnosis. Genetic testing for isolation of one of the specific mutations of the C9ORF72, MAPT, and/or GRN genes is not done in routine clinical care.
Frontotemporal dementia has no FDA-approved treatments. The key to management is early diagnosis so that sufficient support services can be put in place. This disease course is particularly hard on family members and caregivers as it disrupts the patient's entire personality. Therefore, having a plan in place early on can help ease the burden on the family, as the patient will inevitably deteriorate into complete dependence. Daytime care, financial planning, and safety assessments are just some of the resources to be considered. Keeping the patient on a routine and encouraging frequent social interaction can reduce behavioral instability. As the patient's motor function deteriorates, occupational and speech therapists can help evaluate the need for assistive devices, swallowing assessments, and communication aids.4,9 The burden on family members and caregivers should not be overlooked, and they should be provided ample counseling and psychologic services. A publication by the National Institutes of Health/National Institute on Aging: “Frontotemporal Disorders: Information for Patients, Families, and Caregivers” provides practical advice on managing these devastating conditions as well as a list of resources. This publication is available online at https://www.nia.nih.gov/alzheimers/publication/frontotemporal-disorders/introduction. The Association for Frontotemporal Degeneration (www.theaftd.org) is also a good source of information and support for patients and families.
Unfortunately, standard medications used to treat Alzheimer disease have proven ineffective in treating frontotemporal dementia. The acetylcholinesterase inhibitors, such as donepezil and rivastigmine, showed no benefit in clinical trials.18-20 Another study of the NMDA receptor antagonist, memantine, actually showed detrimental adverse reactions, including exacerbation of behavioral disturbances.21 These medications are not recommended for treating patients with frontotemporal dementia. Other medications have been tested in small clinical trials but had no statistically significant disease-modifying effects.18
For now, pharmacologic treatment is reserved for managing behavioral symptoms. Selective serotonin reuptake inhibitors have been the most effective for decreasing impulsivity, repetitious behaviors, and sexual disinhibition.18,20 Trazodone and some antipsychotics also may be beneficial for aggressive or easily agitated patients, though the antipsychotics must be prescribed with caution due to the increased incidence of extrapyramidal adverse reactions in patients with frontotemporal dementia.19 Use of these medications in patients with frontotemporal dementia is off-label and should be prescribed thoughtfully for targeted symptoms, with ongoing reevaluation, dose adjustment, or discontinuation as indicated by patient response. Open communication between clinicians and caregivers works best to attain each patient's ideal medication regimen.
Research is focused on fully understanding the molecular pathophysiology of frontotemporal dementia. The ultimate goal is to determine specific targets for disease-modifying therapy. A promising target is in genetic therapies of the progranulin gene (GRN). Between 10% and 40% of genetically linked patients with frontotemporal dementia have abnormalities in this gene, causing underproduction of a necessary neural protein. Replacing this protein in patients who have the gene abnormality could reverse the disease.22
The other issue plaguing clinicians is definitively diagnosing frontotemporal dementia in its early stages instead of at autopsy. A recent breakthrough in a new form of PET imaging may significantly improve these diagnostic issues for patients with frontotemporal dementia as well as for those with Alzheimer disease. The new technology uses tagged tau protein biomarkers to map the extent of pathologic tau aggregates in the brain. The amount of aggregates correlates to the type and extent of neurodegenerative disease. This emerging technology, in combination with clinical presentation and standard imaging, may replace the need for autopsy in order to confirm a diagnosis.23
Researchers also are exploring other options for treating symptomatic frontotemporal dementia. For example, a small randomized controlled study showed short-term improvement of emotional blunting in patients using intranasal oxytocin; however, further research is needed before this treatment becomes clinically relevant.24 Other limited data from a 2015 trial suggested potential benefit of a medical liquid nutrition formulation.25 The supplement provided a statistically significant reduction in negative behavioral symptoms of patients with behavioral variant frontotemporal dementia. This may prove to be a future adjunct to pharmacologic treatment.25
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Keywords:Copyright © 2017 American Academy of Physician Assistants
frontotemporal dementia; Alzheimer disease; neurodegenerative; cognition; brain; behavior disturbance