Purpose of Review:

This article reviews the common behavioral and cognitive features of frontotemporal dementia (FTD) and related disorders as well as the distinguishing clinical, genetic, and pathologic features of the most common subtypes.

Recent Findings:

Advances in clinical phenotyping, genetics, and biomarkers have enabled improved predictions of the specific underlying molecular pathology associated with different presentations of FTD. Evaluation of large international cohorts has led to recent refinements in diagnostic criteria for several of the FTD subtypes.

Summary:

The FTDs are a group of neurodegenerative disorders featuring progressive deterioration of behavior or language and associated pathology in the frontal or temporal lobes. Based on anatomic, genetic, and neuropathologic categorizations, the six clinical subtypes of FTD or related disorders are: (1) behavioral variant of FTD, (2) semantic variant primary progressive aphasia, (3) nonfluent agrammatic variant primary progressive aphasia, (4) corticobasal syndrome, (5) progressive supranuclear palsy, and (6) FTD associated with motor neuron disease. Recognition and accurate diagnoses of FTD subtypes will aid the neurologist in the management of patients with FTD.

Table 5-1.

Symptoms

Disinhibition may manifest in a variety of ways, including increased disclosure of personal information to strangers or acquaintances (eg, medical information, finances), increased sexual interest or comments, loss of manners (such as belching in public), new use of derogatory or racist language in reference to others (eg, calling someone fat or bald in public), and impulsivity (eg, inappropriate spending). Apathy is a common early feature and may present as a loss of interest in usual social and nonsocial activities. Patients may be noted to spend hours sitting on the couch staring at the television or wall. Some patients will develop simple or complex repetitive behaviors such as touching items in a room, counting figures on patterned wallpaper, or picking up scraps of paper in public places. Hyperorality typically involves increased consumption, particularly of sweets, and in the extreme, can include consumption of spoiled foods and inedible objects. Some patients will begin to use tobacco or alcohol for the first time or increase their use of such substances. Although not included in the core criteria, patients with FTD, particularly those withC9ORF72 expanded repeat mutations, may also exhibit psychotic features early in the disease course, including visual or auditory hallucinations and bizarre or somatic delusions.5

Neurologic Examination

Evidence of the above behavioral changes may be observed during the course of the neurologic examination. Patients with bvFTD may show evidence of poor grooming and hygiene on presentation and loss of manners, such as belching during the examination. Either a flat affect may be observed, or conversely, a silly, childlike affect may be seen and manifested by a patient hugging the examiner or giggling after being instructed to stick out his or her tongue or during the testing of the reflexes. Patients with bvFTD may appear obviously restless, standing up and even attempting to leave the room midexamination. Patients with a flat affect may appear apathetic and lack spontaneous speech, giving only brief one- to two-word responses to questions despite preserved language abilities. Although such abnormal behaviors typically increase over the course of the disease, at early stages patient’s conduct may be generally appropriate for the limited time of the examination. Positive snout or grasp reflex may be present, although these frontal release signs are not sensitive or specific for FTD.6 Cranial nerve, motor, sensory, and the remainder of reflex examinations are typically normal.

Neuropsychological Testing in Behavioral Variant of Frontotemporal Dementia

Standard neurocognitive testing in patients with bvFTD classically demonstrates deficits in executive function tasks, with relative sparing in memory and visuospatial domains. However, many patients with early-stage disease may still perform well on executive tasks, particularly those patients with right temporal predominant atrophy. It is now appreciated that some patients with bvFTD have significant episodic memory deficits.7 While specific standardized tests of social cognition are in validation stages for bvFTD, patients with bvFTD generally show poor performance on tasks of facial expression recognition, particularly for negative emotions, as well as on theory of mind tasks, such as visual cartoons in which they must understand the mental state of others. Consideration of qualitative aspects of performance during neurocognitive testing including behaviors and error types may be more helpful than raw scores in detecting bvFTD. Specifically, during testing, patients with bvFTD may appear restless, apathetic, perseverative, confabulatory, and impulsive, failing to wait for the examiner to finish task instructions and including expletives in phonemic fluency tests.8

Neuroimaging Characteristics

Atrophy or hypometabolism of the right frontal or right temporal lobe is the hallmark neuroimaging finding in patients with bvFTD (Case 5-1). Bilateral frontal lobe involvement may also be seen, although when atrophy is observed in the dominant hemisphere, language symptoms are typically also present (see later discussion of semantic variant PPA and nonfluent agrammatic variant PPA). Patterns of atrophy in other brain regions vary according to mutation type. Patients withC9ORF72 expanded repeats demonstrate atrophy predominantly in the frontal lobes, with some atrophy also observed in the anterior temporal lobes, parietal lobes, occipital lobes, and cerebellum and thalamus; inMAPT mutations, atrophy is greatest in the anteromedial temporal lobes; patients with bvFTD andGRN mutations show temporal, insular, and parietal lobe atrophy.10,11 On fluorodeoxyglucose positron emission tomography (FDG-PET) imaging, hypometabolism in the right temporal or right or bilateral frontal lobes is suggestive of FTD (Figure 5-212). Patterns of frontal or anterior temporal hypoperfusion with preserved parietal signal on SPECT can distinguish FTD from AD with a sensitivity and specificity of approximately 80%.13 Similar patterns of hypometabolism on FDG-PET imaging show approximately 90% diagnostic accuracy when distinguishing FTD from AD.14 PET amyloid imaging shows a similarly high accuracy of distinguishing FTD from AD, with patients with FTD typically showing low levels of amyloid binding on PET (amyloid negative), while patients with AD show elevated amyloid binding (amyloid positive).12 Several PET tau ligands are currently under investigation in FTD but are not validated to date.

Diagnostic Challenges in Behavioral Variant of Frontotemporal Dementia

Making and confirming a diagnosis of bvFTD can be challenging as the personality or behavioral changes are insidious, and diagnosis in the early stages is highly reliant on caregiver reports of behavioral changes. Furthermore, the degree of frontal atrophy can overlap with that observed in normal controls.15 The termbvFTD phenocopy syndrome has been used to characterize patients who present with a history obtained from a caregiver that meets symptom-based criteria for possible FTD but who lack focal atrophy on neuroimaging and who do not progress to demonstrate objective behavioral or cognitive deficits.16 Patients with bvFTD phenocopy syndrome who fail to progress have increased rates of mood disorders, substance abuse, obsessive-compulsive personality traits, Asperger syndrome traits, or recent intense life events that likely contribute to the observed behaviors.17 Thus, careful consideration of the patient’s baseline personality, life events, and relationship factors that may influence behavior, and the caregiver’s perspective on behaviors, is necessary.18

Table 5-2.

Case 5-2

A 69-year-old right-handed retired secretary was referred for a neurologic consultation for difficulties with “memory” and behavior. She had a long history of anxiety and depression that had been managed by medications until 2 years prior to presentation, when she was dismissed from her volunteer job for “lacking control.” Her family noted trouble with word comprehension, as the patient would ask, “What is a screwdriver?” and “What is a buffet?” Circumlocutions were noted in her descriptions, such as describing a pizza as a “round thing.” This was followed by lack of recognition of objects. For example, when her husband handed her an ice cream cone, she grabbed at the ice cream on top rather than from the cone. Recently, she had not recognized her niece and nephew or herself in photographs. The patient stopped initiating household chores, such as doing the dishes or laundry, and appeared confused when attempting such tasks. According to her husband, she was “always walking, pacing, or standing.” She became very self-centered and seemed to lack appreciation of others’ needs. She became fixated on daily routines even if inconvenient to others. Her personal hygiene declined. Family history was notable for multiple family members on her mother’s side with anxiety and depression. There was no known history of neurodegenerative dementia or amyotrophic lateral sclerosis in any family members.

On examination, while her speech rate was generally high, she used frequent fillers, such as “thing” or “da da da.” Her responses to direct questions were tangential. The remainder of her neurologic examination was normal, including the absence of frontal release signs. On further cognitive testing, she scored 8 out of 30 on the Mini-Mental State Examination (MMSE), typically not understanding the question being asked. Her clock drawing skills were reasonably preserved. Semantic fluency was severely impaired with only two animals named in 1 minute. In contrast, phonemic fluency was only mildly impaired with a total of 20 F-A-S Test words named over the 3 minutes (patient was given 1 minute to list words beginning with the letterF, followed by 1 minute to list words beginning withA, and then 1 minute to list words beginning with the letterS). Naming on the Western Aphasia Battery was impaired, with only 11 out of 20 items correct and some evidence of visual object agnosia, including nonrecognition of a pipe. Deficits in semantic association were also demonstrated on the Pyramid and Palm Trees Test. Trail Making B test was normal at the 50th percentile.

Review of a recently performed brain MRI demonstrated severe anterior left temporal lobe atrophy and moderate atrophy of the right temporal pole (Figure 5-3). A diagnosis of semantic variant primary progressive aphasia was made.

Comment. This patient demonstrates a classic presentation of semantic variant primary progressive aphasia. Often, the family members may identify the chief complaint as memory deficits, but with careful assessment, it is clear that loss of word meaning and comprehension deficits underlie the observed changes. Behavioral features are usually present early on and progress with increasing atrophy of the right temporal lobe.

Table 5-3.

Case 5-3

A 66-year-old woman presented for a neurologic consultation because of difficulty speaking. She reported 2 to 3 years of gradually increasing deficits in “getting the words out.” She stated, “I know what I want to say, but the words get stuck at the tip of my tongue.” Her spouse noticed that at times she would get part of the sound of the word correct, and part wrong, such as calling a “fork” a “fort.” She had also developed a mild stutter. Her husband noticed she was often able to describe the meaning of the word, even when she could not say the word itself.

On examination, she demonstrated halting, hesitant speech although she could generally answer questions appropriately. She correctly named a chair and key, but could not name the glove, instead gesturing to her hand. She could not name cactus, but said “it is a thing that grows…desert…ouch.” During repetition she omitted small words and made paraphasic errors. She followed all verbal and written commands. When asked to write a sentence, she wrote, “Today very sunny outside.” When asked to describe the picnic scene from the Western Aphasia Battery, she demonstrated word-finding deficits, paraphasic errors, and hesitations (item she was pointing to in parentheses): “The carpet, and man, and woman…on their black (blanket). Man’s food…food there (sandals). The man…bag…bark(book). The man glass (glasses). Bag (basket). Boy has a kite…a gags…(dog). Girl…song…sand…make (rake), sarvs (shovels), cake…cast (castle). Man on dark (dock) and fish. Sailboat and two babli (people)Ithere. A house there. A carI garange (garage) there and flangs (flag). Tree.” The remainder of her neurologic examination was unremarkable. Neuroimaging demonstrated atrophy in the leftinferior frontal lobe (Figure 5-4).

One year later, the patient presented with further deficits in articulatory speech consistent with verbal apraxia. She also demonstrated worsening short-term verbal memory deficits and new difficulty with dressing (despite normal strength). On examination, mild rigidity and odd involuntary posturing of her right arm were noted, with ideomotor apraxia and deterioration of handwriting (Figure 5-5).

Comment. This patient initially presented with symptoms meeting criteria for nonfluent agrammatic variant primary progressive aphasia and indicative of dominant frontal lobe pathology. Over time, her symptoms progressed to include apraxia and alien limb phenomenon, consistent with evolution to corticobasal syndrome. In addition to progression to corticobasal syndrome, patients presenting with nonfluent agrammatic variant primary progressive aphasia may also develop symptoms consistent with behavioral variant of frontotemporal dementia or progressive supranuclear palsy.

Neurologic Examination

Nonfluent speech with word-finding difficulties, circumlocutions, stuttering, and grammatical errors with relative preservation of comprehension is typically observed, although deficits may be mild at first. Subtle right-side motor deficits (slower fine motor movements, pronator drift) may be observed in some patients with more widespread pathology in the left (or dominant) frontal lobe.

Neuroimaging

Nonfluent agrammatic variant PPA is associated with atrophy of the dominant inferior frontal lobe (Figure 5-4).

PROGRESSIVE SUPRANUCLEAR PALSY

Although originally classified as a Parkinson-plus syndrome, PSP is now also included as an FTD-related disorder based on the presence of frontal lobe involvement and tau pathology. Prior to the onset of hallmark features including early postural instability and vertical gaze impairments, approximately 20% of patients with PSP first present with FTD symptoms, including behavioral changes or progressive language deficits (Table 5-4). The most common behavioral symptoms in patients with PSP include apathy, disinhibition, anxiety, dysphoria, stereotypic or repetitive behaviors, and up to 30% of patients with PSP will meet criteria for bvFTD.26,27 Patients with PSP may also present with primary apraxia of speech, combined apraxia of speech and progressive nonfluent aphasia, or develop these symptoms during the disease course.25 In patients presenting with primary apraxia of speech, atrophy or hypometabolism is found in the superior premotor cortex and supplementary motor area, and PSP is the most common underlying pathology.28

Neurologic Examination

In the most common subtype of PSP, Richardson syndrome, increased axial rigidity of the neck and trunk, slowed vertical saccades, dysarthria, apathy or depression, and general slowing of speech and thought are observed.26 Gait is often narrow based in early stages of the disease despite a history of falls and imbalance. As the disease progresses, patients often develop ophthalmoplegia particularly of vertical gaze, akinetic rigid parkinsonism, dystonia, verbal apraxia, pseudobulbar palsy, and frontal release signs.

Neuropsychological Testing

Cognitive deficits are found in the majority of patients with PSP. Most commonly, patients with PSP demonstrate cognitive slowing and poorer performance on timed tests of executive function and verbal fluency.27 Comprehension and memory are generally preserved.

Neuroimaging

Structural imaging in PSP may reveal midbrain atrophy referred to as the hummingbird sign on sagittal images (Figure 5-629), as well as hypometabolism in frontal, caudate, midbrain, and thalamic regions on FDG-PET.30

CORTICOBASAL DEGENERATION

Corticobasal degeneration (CBD) is a progressive neurodegenerative disorder affecting the frontal and parietal cortices and basal ganglia associated with abnormal 4-repeat tau isoform pathology. The termcorticobasal syndrome (CBS) is used to describe patients presenting with the clinical features associated with CBD but who lack histologic confirmation, as CBS presentations may be associated with a variety of underlying neuropathologies including AD, FTD, and CBD. CBD is typically sporadic, although occasionally CBS is the presenting phenotype for patients withMAPT,GRN, orC9ORF72 mutations. Classic features of CBS include apraxia and alien limb phenomenon, frontal deficits, and extrapyramidal motor symptoms such as myoclonus or rigidity. Five phenotypic presentations of CBD have recently been proposed (Table 5-5).31 As in PSP, patients with CBD may first present with behavioral changes, executive function deficits, or language features consistent with early frontal lobe pathology. Behavioral changes include those described for bvFTD. Language presentations of CBS are most commonly agrammatic nonfluent aphasia or apraxia of speech. Symptoms referable to the parietal lobes, including apraxias and visuospatial deficits, may also be a presenting feature.32 Motor abnormalities may be absent in as many as approximately 50% of patients at the time of presentation with cognitive deficits, although during the course of the disease the majority of patients will show motor features. Approximately 30% of patients with CBS will develop alien limb syndrome, in which one arm may levitate or assume involuntary postures or movements, and 25% will have cortical sensory deficits.31

FRONTOTEMPORAL DEMENTIA–MOTOR NEURON DISEASE

Frontotemporal dementia symptoms are found in approximately 30% of patients diagnosed with amyotrophic lateral sclerosis (ALS). Patients with FTD-ALS may present with behavioral changes consistent with bvFTD or a milder dysexecutive profile including verbal fluency deficits.34 Hallucinations and delusions are more common in patients with FTD-ALS, in particular in patients withC9ORF72 expanded repeat mutations (see the following section on genetic risk factors), the most common genetic cause of familial FTD-ALS.35,36

PROGNOSIS

The average survival for patients diagnosed with FTD is approximately 7 to 10 years. Estimates differ somewhat according to FTD subtype, with survival in FTD-MND averaging just 2 to 3 years, approximately 6 to 8 years in PSP, approximately 9 to 10 years in bvFTD and nonfluent agrammatic variant PPA, and the longest median survival in patients with semantic variant PPA of approximately 12 years.2 Common proximate causes of death in patients with FTD related to the disease include pneumonia or complications of falls.

RISK FACTORS

Although approximately 50% to 60% of FTD is considered to be sporadic in etiology, genetic mutations account for the majority of risk factors identified for developing FTD.

CONCLUSION

The FTDs can be recognized based on careful parsing of clinical features and neuroimaging characteristics. Consideration of referral for genetic counseling and genetic testing is indicated for most patients given the high incidence of hereditary FTD. Although not yet widely available for clinical use, molecular-specific diagnostic tools (eg, tau PET imaging, TDP-43 and tau biomarkers) and treatments are under development, making accurate recognition and diagnosis of FTD and FTD subtype essential for appropriate counseling and management.

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