INTRODUCTION — Frontotemporal dementias (FTDs) are a group of clinically and neuropathologically heterogeneous neurodegenerative disorders characterized by prominent changes in social behavior and personality or aphasia accompanied by degeneration of the frontal and/or temporal lobes. Some patients with FTD also develop a concomitant motor syndrome such as parkinsonism or motor neuron disease (MND). FTD is one of the more common causes of early-onset dementia, with an average age of symptom onset in the sixth decade.
This topic will review the clinical features and diagnosis of the main clinical syndromes of FTD. The treatment of FTD and the genetics, pathology, and pathogenesis of FTD are discussed separately. (See "Frontotemporal dementia: Treatment" and "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis".)
TERMINOLOGY — Terminology for FTD has evolved over time. In 1892, Arnold Pick first described a patient with progressive aphasia and focal frontotemporal atrophy . Alois Alzheimer later characterized the disorder as "Pick disease," defined by distinctive round, silver-staining inclusions called Pick bodies . Subsequent clinicopathologic studies determined that many patients diagnosed clinically with Pick disease did not have Pick neuropathology at autopsy, and thus Pick disease now designates the pathologic diagnosis, rather than a clinical syndrome.
The term "FTD" serves as an umbrella term for three clinical presentations: behavioral variant FTD (bvFTD) and two forms of primary progressive aphasia (PPA), the nonfluent and semantic variants. Historically, bvFTD has also been called "FTD" or "frontal variant FTD," while semantic variant PPA has been called "temporal variant FTD" and "semantic dementia." Nonfluent variant PPA is also referred to as "agrammatic PPA." The third variant of PPA, the logopenic variant, is typically associated with Alzheimer pathology and is not included as one of the three clinical FTD syndromes.
The pathology underlying clinically defined FTD is heterogeneous. The term "frontotemporal lobar degeneration" (FTLD) refers to this group of neuropathologic diagnoses, further categorized by abnormal protein inclusions due to tau, TDP-43, and other proteins. Distinguishing between clinical and neuropathologic disease definitions is important, since clinicopathologic series have revealed that clinical syndromes often fail to predict underlying pathology. The pathologic features of FTD are discussed in detail separately. (See "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis".)
BEHAVIORAL VARIANT FTD — Behavioral variant FTD (bvFTD) is the most common clinical subtype, comprising approximately half of all cases of FTD. The hallmark of bvFTD is progressive changes in personality and behavior early in the disease course . These behavioral symptoms represent a significant and persistent shift from the premorbid personality.
Disease onset usually occurs during the sixth decade but has been reported as early as the second decade and as late as the ninth. Because of their overlap with psychiatric disorders, symptoms in bvFTD often precede the correct diagnosis by several years . (See "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis", section on 'Epidemiology'.)
Clinical presentation — Early behavioral changes of bvFTD include the following:
●Disinhibition – Examples of disinhibition or socially inappropriate behavior include touching or kissing strangers, public urination, and flatulence without concern. Patients may make offensive remarks or invade others' personal space. Patients with FTD may exhibit utilization behaviors, such as playing with objects in their surroundings or taking others' personal items.
●Apathy and loss of empathy – Apathy manifests as losing interest and/or motivation for activities and social relationships. Patients may participate less in conversations and grow passive. Apathy is mistaken frequently for depression, and patients are often referred for psychiatric treatment early in the disease course.
As patients lose empathy, caregivers may describe patients as cold or unfeeling towards others' emotions. Degeneration of right orbitofrontal and anterior temporal regions is associated with the loss of sympathy and empathy [5,6].
●Hyperorality – Hyperorality and dietary changes manifest as altered food preferences, such as carbohydrate cravings, particularly for sweet foods, and binge eating. Increased consumption of alcohol or tobacco may occur. Patients may eat beyond satiety or put excessive amounts of food in their mouths that cannot be chewed properly. They may attempt to consume inedible objects. This behavior correlates with right orbitofrontal, insular, striatal and hypothalamic degeneration [7-9].
●Compulsive behaviors – Perseverative, stereotyped, or compulsive ritualistic behaviors include stereotyped speech, simple repetitive movements, and complex ritualistic behaviors such as hoarding, checking, or cleaning. Some patients develop new hobbies or interests, particularly those with a religious aspect, which are pursued obsessively. Other behaviors traditionally associated with obsessive compulsive disorder, such as handwashing and germ phobias, are generally absent. Patients with FTD can develop a rigid personality, rigid food preferences, and inflexibility to changes in routine.
Most patients lack insight into their behavioral changes and the distress experienced by their family members . To probe for a history of subtle behavioral changes, it may be useful to ask caregivers about the following :
●Has the patient said or done anything in public that has embarrassed others?
●Does the patient appear to have a lack of disgust?
●Does the patient seem indifferent or oblivious to others' feelings and less warm or affectionate, especially toward grandchildren or pets?
●Have food preferences changed or table manners declined?
●Does the patient seem more concerned with timekeeping or tend to watch the clock?
●Has there been a change in the patient's sense of humor?
●Has the patient developed new hobbies or interests pursued obsessively, especially with a religious or spiritual bent?
Patients with bvFTD generally lack cranial nerve, sensory, cerebellar, pyramidal, and extrapyramidal motor findings, at least initially. Frontal release signs may be seen, but the diagnostic utility of these signs is low, as they are not specific to FTD. In later stages of bvFTD, disinhibition and compulsive behaviors often wane as patients grow more apathetic, reflecting further degeneration in the medial frontal cortex . Parkinsonism may also emerge in advanced stages of the disease.
Approximately 15 to 20 percent of patients with bvFTD develop concomitant motor neuron disease (MND); less frequently they may exhibit clinical features of either corticobasal syndrome (CBS) or progressive supranuclear palsy (PSP). (See 'Motor syndromes associated with FTD' below.)
Neuropsychologic testing — Patients with bvFTD typically score well on neuropsychologic testing early in the course of the disease. Neuropsychologic measures of executive function largely test frontal lobe functions referable to the dorsolateral prefrontal cortex, a region that is spared in early stages of bvFTD.
In early bvFTD, damage to medial frontal and orbitofrontal regions is associated with apathy and disinhibition. Measures of social cognition include impairments in recognizing affect, emotions, and sarcasm  and difficulty understanding another person's perspective .
As the disease involves dorsolateral prefrontal regions, executive functions such as set-shifting and verbal fluency decline. Memory and visuospatial functions are usually spared in bvFTD, although frontal lobe dysfunction can make it appear to families that patients have memory problems. Memory impairment, when present, has been associated with an increased rate of progression in several studies [14,15]. Apathy and poor attention and planning make it challenging to interpret neuropsychologic test results in many patients with bvFTD.
Neuroimaging — Structural and functional imaging provides supportive but not diagnostic evidence for bvFTD [16-18], as neuroimaging may appear normal upon visual inspection early in the disease course [19,20]. As the disease progresses, focal frontal or temporal atrophy manifests in 50 to 65 percent of patients [21-23] and targets the anterior insula, anterior cingulate cortex, and amygdala [24-27]. Atrophy may affect one brain hemisphere more than the other; over time, homologous regions in the other hemisphere degenerate.
The earliest regions of damage in bvFTD are usually (but not always) right hemispheric and include the anterior insula, pregenual anterior cingulate, and orbitofrontal cortex. Neuroanatomic-behavior correlation studies reveal that medial frontal and anterior cingulate damage correlates with apathy, while right anterior temporal and right medial frontal atrophy correlates with loss of empathy [6,28]. Damage to orbitofrontal, right insula and striatum correlates with changes in eating behavior [7-9]. Simple motor stereotypies correlate with striatal atrophy, while complex ritualistic compulsions are related to atrophy in orbitofrontal, caudate, and temporal lobe atrophy [29,30]. In patients with bvFTD and MND, magnetic resonance imaging (MRI) may demonstrate atrophy in premotor regions and precentral gyri .
The magnitude of frontotemporal atrophy not only varies with respect to disease duration but may also vary with respect to the age of symptom onset. In an autopsy series of over 100 cases of pathology-confirmed frontotemporal lobar degeneration (FTLD), the majority of cases with an age of onset <65 years had evidence of moderate to severe frontotemporal atrophy and ventricular dilation at autopsy, while only 40 percent of the late-onset cases had severe frontotemporal atrophy .
Functional neuroimaging studies (single-photon emission computed tomography [SPECT], perfusion MRI, or positron emission tomography [PET]) demonstrating frontal or frontotemporal hypoperfusion or hypometabolism may be more sensitive than MRI in the early stages of disease, but are not in themselves diagnostic [16,17,33]. Diffusion tensor imaging shows abnormal diffusivity in gray matter in these regions . In contrast with amyloid PET tracers, which show promise for distinguishing Alzheimer disease (AD) dementia from non-Alzheimer neurodegenerative disorders, tau PET tracers appear to have less specificity [35,36], but new tau PET tracers are currently being researched for specificity and sensitivity to FTLD-tau pathologies.
Evaluation — The diagnosis of bvFTD is made primarily by clinical assessment. Patients are generally not reliable informants of behavioral problems (because of their lack of insight), and interviewing family members is crucial . The presence of abnormal social conduct, eating disorders, stereotyped behaviors, and akinesia/apathy along with the absence of significant memory or visual spatial deficits are very specific (close to 99 percent) and moderately sensitive (80 to 85 percent) for the diagnosis of bvFTD [21,24,38-44].
Computed tomography (CT) or MRI brain scans are required to exclude structural pathology; atrophy patterns found on such scans may support the diagnosis. Neuropsychologic testing may be helpful in distinguishing bvFTD from other neurodegenerative syndromes and psychiatric disorders, but similar to structural brain imaging, findings on neuropsychologic testing are supportive rather than diagnostic. Other laboratory tests are typically performed to exclude potentially reversible contributors or causes of cognitive impairment. (See "Evaluation of cognitive impairment and dementia".)
Clinicopathologic studies suggest that bvFTD can be diagnosed fairly reliably in life, although occasionally Alzheimer pathology manifests as bvFTD .
Diagnostic criteria for bvFTD — In 2011, the International Behavioral Variant FTD Criteria Consortium (FTDC) published new criteria for bvFTD, building upon the 1998 Neary criteria . The FTDC criteria synthesize clinical features, neuroimaging, neuropathology, and genetic testing [16,17]. A diagnosis of possible bvFTD is based solely on the clinical syndrome and aims to identify patients at the mildest stages of disease.
Possible bvFTD requires a combination of three of six clinical features:
●Loss of sympathy/empathy
●Dysexecutive neuropsychologic profile
Probable FTD requires the same clinical criteria, plus demonstrable functional decline and imaging findings that reflect the principal anatomic location of neurodegeneration in bvFTD (ie, frontal and/or temporal lobe atrophy, hypometabolism, or hypoperfusion).
Both possible and probable bvFTD require the exclusion of other neurologic, medical, and psychiatric disorders that would better account for the pattern of deficits and behavioral disturbance.
A third diagnostic category, bvFTD with definite FTLD pathology, is satisfied when cases of possible or probable bvFTD are accompanied by either biopsy or postmortem histopathologic evidence of FTLD or evidence of a known pathogenic mutation. (See "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis", section on 'Genetic factors'.)
Using pathologically confirmed cases of FTLD as a gold standard, the FTDC criteria for possible and probable bvFTD have a sensitivity of 85 and 75 percent, respectively .
Differential diagnosis — Once systemic medical illness, substance abuse, and non-neurodegenerative neurologic illnesses have been excluded, the main entities considered in the differential diagnosis for bvFTD are psychiatric disorders and other neurodegenerative disorders such as dementia with Lewy bodies and AD. In general, neuroimaging will reliably exclude non-neurodegenerative neurologic diseases affecting the frontal lobes, such as infarction, tumors, abscess, and trauma.
●Psychiatric disorders – Depression, obsessive compulsive disorder, and bipolar disorder are often considered in an individual presenting with behavioral or personality changes; in particular, apathy associated with bvFTD is mistaken commonly for depression.
Clues that such changes are early signs of bvFTD rather than depression may include lack of any prior psychiatric history and the emergence of certain specific behaviors such as changes in eating (as opposed to simply decreased appetite) or social faux pas. Occasionally, patients with bvFTD can appear euphoric . While the usual age of onset of bvFTD is somewhat older than is typical for a first presentation of major psychiatric disease, there is substantial overlap. Changes are insidious in some, and therefore longitudinal clinical follow-up helps to establish the diagnosis of bvFTD versus psychiatric disease.
●Dementia with Lewy bodies – In the setting of neurodegenerative disease, delusions and hallucinations are more suggestive of dementia with Lewy bodies . Psychosis, including hallucinations and delusions, is atypical for FTD , although psychosis may occur in 20 to 50 percent of bvFTD patients who carry the C9orf72 hexanucleotide expansion, the most common genetic cause of sporadic and familial FTD and amyotrophic lateral sclerosis (ALS) [47,48]. (See "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis", section on 'C9orf72 expansion'.)
●Alzheimer disease – Patients with early-onset AD are frequently misdiagnosed with bvFTD and vice versa. Usually, patients with AD perform more poorly on measures of cognitive function referable to the medial temporal lobes (ie, episodic memory) and parietal lobes (ie, visuospatial skills and apraxia) than those with bvFTD. Patients with AD often perform poorly on measures of executive function and do not exhibit prominent loss of social cognition as an early feature of disease.
Structural imaging can help elucidate focal atrophy patterns that differ between bvFTD (frontal and temporal cortices) and AD (medial temporal and parietal cortices) . Biomarkers that strongly suggest AD include low beta amyloid and high phospho-tau in the cerebrospinal fluid. (See "Clinical features and diagnosis of Alzheimer disease", section on 'Role of biomarkers'.)
In addition to cerebrospinal fluid AD biomarkers, amyloid-binding PET ligands (florbetapir, flutemetamol, florbetaben) and tau-PET (flortaucipir) are useful for identifying AD pathology. PET scans do not yet have the capability to confirm FTLD pathology. Amyloid PET scans are not yet covered by most third-party payers, rendering them prohibitively expensive for most patients. Clinically, amyloid PET is most helpful in diagnosing early-onset AD. (See "Early-onset dementia in adults".)
PRIMARY PROGRESSIVE APHASIA — Primary progressive aphasia (PPA) is a clinical syndrome characterized by the insidious onset and gradual progression of a speech or language impairment manifested by deficits in speech apraxia, word finding, word usage, word comprehension, or sentence construction [50,51]. PPA arises when the language-dominant hemisphere is the principal target of neurodegeneration. PPA is characterized by isolated language deficits during early stages of the disease.
Three variants of PPA have been described based on the type of language impairment: nonfluent, semantic, and logopenic . These patterns of language impairment in PPA reflect the anatomic distribution of peak atrophy sites. As neurodegeneration progresses in later stages of PPA, language remains the most affected cognitive domain, but other cognitive domains also decline.
Clinical presentation — The hallmark of PPA is early, progressive language disturbance leading to functional impairment with relative preservation of episodic memory and other cognitive domains. Language dysfunction is apparent during routine conversation and/or through speech and language assessments. Activities of daily living are maintained except those relating to language (eg, difficulty using the telephone) . While other cognitive functions may be affected later in the course, language dysfunction remains the most impaired domain throughout the disease course.
Nonfluent variant PPA — The core feature of nonfluent variant PPA is a motor speech deficit characterized by effortful production of the linguistic units of sound (phonemes). Although word finding is a common complaint across all PPA subtypes, the characteristic that distinguishes the nonfluent variant from other forms of PPA is articulatory difficulty. This is characterized by effortful, halting speech with inconsistent speech-sound errors and distortions and agrammatism in language production .
At the bedside, apraxia of speech can be tested by having the patient repeat a word such as "caterpillar" or "artillery" rapidly and repeatedly, since these words are particularly challenging to articulate. Sound distortions and difficulty pronouncing such words iteratively are characteristic of speech apraxia. These deficits correspond anatomically with atrophy within the left inferior frontal gyrus and posterior fronto-insula.
While comprehension is typically spared for single words and simple sentences, patients often have difficulty with complex sentences, particularly those with complex syntax, such as using the passive voice or multiple dependent clauses .
Social comportment, memory, visual spatial skills, and other cognitive abilities are typically preserved at the time of presentation [53-56]. While patients usually retain some insight, they may seem inappropriately unconcerned .
Deficits may be restricted to expressive language function for a few to several years before a more global dementia supervenes [56,58]. Some patients go on to develop behavioral alterations or symptoms of motor neuron disease (MND) or corticobasal syndrome (CBS) [53,56,58-61]. (See 'Motor syndromes associated with FTD' below.)
Semantic variant PPA — The core features of semantic variant PPA are impaired single-word comprehension and object naming in the setting of preserved fluency, repetition, and grammar.
Word-finding difficulty, especially for low-frequency items, is the earliest symptom, and there is progressive loss of knowledge of the characteristics of objects. Early on, patients may exhibit a marked discrepancy between the ability to understand complete sentences, which tends to be preserved, and the ability to understand single object words, which is impaired . As the disease progresses, language comprehension becomes more globally impaired.
Patients may also exhibit surface dyslexia or dysgraphia, in which words with irregular spellings (eg, yacht, colonel, tissue) are mispronounced or misspelled because the correct pronunciation or spelling relies on semantic knowledge.
At the bedside, the clinician can ask the patient to draw animals such as a turtle, dog, and bird; those with semantic variant PPA frequently make drawings of animals lacking defining features (eg, no shell for a turtle), demonstrating loss of semantic detail around a given animal. In patients with right greater than left temporal pole involvement, facial recognition of famous people may be impaired in the early stages of the disease .
Although asymmetric atrophy of the temporal poles is typical in the early stages of semantic variant PPA, eventually the disease spreads to the contralateral side. With bilateral involvement, there is emergence of behavioral symptoms such as behavioral rigidity, parsimony of speech, loss of empathy, and hypergraphia. As disease spreads from anterior temporal lobes to mesial temporal cortices, episodic memory may decline, while visuospatial skills and executive function remain relatively intact .
Logopenic variant PPA — The logopenic variant of PPA is typically associated with Alzheimer pathology and is not included as one of the three clinical FTD syndromes.
The logopenic variant of PPA features impaired single-word retrieval and repetition with errors in speech and naming, but with spared single-word comprehension and object knowledge, spared motor speech, and absence of agrammatism . Like the nonfluent variant, speech can have a slow rate with frequent word-finding pauses and paraphasic errors. With logopenic variant PPA, however, slow rate is primarily due to word-finding pauses, rather than difficulties with word production, articulation, or apraxia of speech.
The speech of logopenic variant PPA has been described as "empty," in the sense that a patient might tell a story vaguely or with words that profoundly lack descriptive detail.
Phonological short-term memory deficits in logopenic variant PPA manifest as difficulty with long, grammatically complex sentences, although single-word repetition is spared.
The logopenic variant of PPA is typically associated with Alzheimer pathology and is not included as one of the three clinical FTD syndromes.
Neuropsychologic testing — Neuropsychologic testing can help to discern a pattern of language deficits characteristic of one of the three clinical variants of PPA.
Patients with PPA typically perform well on tests of episodic memory, executive function, and visuospatial function in early stages of the disease . Patients with nonfluent and logopenic PPA perform well on measures of social cognition, such as recognition of sarcasm, empathy, and the ability to understand others' perspectives. In semantic variant PPA, degeneration of right anterior temporal lobe often emerges, leading to decline in empathy and the emergence of coldness in personality profiles, increased rigidity, and interrupting others .
The language examination, including evaluation of articulation, grammar, fluency, and speech praxis, helps to differentiate among the nonfluent, semantic, and logopenic variants. In nonfluent variant PPA, testing reveals nonfluent speech, agrammatism, and apraxia of speech along with impaired naming and verbal fluency. In semantic variant PPA, testing reveals loss of word and object knowledge and surface dyslexia or dysgraphia. Speech errors and impairments in single-word retrieval and sentence repetition, with spared grammar, motor speech, and single-word comprehension, distinguish the logopenic variant from the nonfluent and semantic variants. A brief 30-point test has been developed for detecting PPA in speakers of French .
Neuroimaging — As with behavioral variant FTD (bvFTD), structural and functional imaging in patients with PPA may demonstrate atrophy, hypometabolism, and/or hypoperfusion in the frontal and/or temporal lobes, in a pattern specific to the clinical variant.
In nonfluent variant PPA, atrophy emerges in left posterior fronto-insular cortex . Functional imaging such as single-photon emission computed tomography (SPECT) or 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) may demonstrate predominant hypoperfusion or hypometabolism in left posterior fronto-insula [52,59,64]. Tau PET tracers are being studied in the evaluation of patients with neurodegenerative dementia. (See 'Neuroimaging' above.)
In semantic variant PPA, striking anterior temporal atrophy emerges, which is usually asymmetric . Hypoperfusion or hypometabolism on SPECT or FDG-PET in anterior temporal lobes may also be present.
In logopenic variant PPA, structural imaging often shows predominant left posterior temporal cortex and parietal atrophy . FDG-PET and SPECT may highlight hypometabolism or hypoperfusion in these brain regions. Amyloid PET imaging studies suggest that patients with logopenic variant PPA are likely to have Alzheimer pathology .
Evaluation — PPA is a clinical diagnosis, made primarily by detailed history and neurologic examination in a patient presenting with progressive language dysfunction with sparing of other cognitive domains early in the disease course.
A structural neuroimaging study is required to exclude lesions that may cause progressive aphasia. While not diagnostic on their own, atrophy patterns are included as supportive criteria for PPA. For example, left posterior frontal atrophy is associated with nonfluent variant PPA, while left anterior temporal atrophy is characteristic in semantic variant PPA (and left parietal atrophy in logopenic variant PPA). Neuropsychologic testing can identify vulnerable linguistic features for speech therapy and also contributes to understanding possible neuropathologic diagnoses. As in other progressive cognitive syndromes, laboratory tests are typically performed to exclude potentially reversible contributors or causes of cognitive impairment. (See "Evaluation of cognitive impairment and dementia".)
Diagnostic criteria for PPA — Clinical criteria for the diagnosis of PPA and its three clinical variants were established by international expert consensus in 2011 (table 1) . These criteria incorporate clinical, imaging, and biomarker data and have replaced the older Neary criteria .
A diagnosis of PPA requires all of the following features :
●The most prominent clinical feature is difficulty with language
●The language deficits are the principal cause of impaired activities of daily living
●Aphasia is the most prominent deficit at symptom onset and for the initial phases of disease
In addition, the following four criteria must be answered negatively :
●Pattern of deficits is better accounted for by other non-neurodegenerative nervous system or medical disorders
●Cognitive disturbance is better accounted for by a psychiatric diagnosis
●There are prominent initial episodic memory, visual memory, and visuoperceptual impairments
●There is a prominent initial behavioral disturbance
Once a PPA diagnosis is established by these criteria, the aphasia is subclassified further as nonfluent variant (table 2), semantic variant (table 3), or logopenic variant (table 4). This schema includes purely clinical diagnostic criteria as well as clinical diagnoses supported by neuroimaging findings such as atrophy (structural imaging), hypoperfusion (SPECT), hypometabolism (PET), or pathologic and genetic data.
Differential diagnosis — The majority of PPA cases are due to frontotemporal lobar degeneration (FTLD) or Alzheimer disease (AD) pathology.
Other considerations include cerebrovascular disease and a slowly growing mass lesion such as a brain tumor [53,58,68-71]. Thus, a neuroimaging study, usually brain computed tomography (CT) or magnetic resonance imaging (MRI), is important to exclude mass lesions and other structural pathology in patients with primary aphasia. (See "Approach to the patient with aphasia".)
Clinicopathologic correlations — At a group level, the three clinical variants of PPA correspond to different underlying neuropathologies, although prediction of an individual patient's underlying pathologic diagnosis remains challenging. Being able to determine the underlying pathologic diagnosis is important for enrollment in drug trials that are testing disease-modifying treatments and will become critical once such treatments may be available in the future.
●Most cases of nonfluent variant PPA are associated with tau-positive FTLD (FTLD-tau) , with 88 percent of patients showing FTLD-tau in one series , but FTLD with TDP43-positive inclusions (FTLD-TDP) type A pathology has also been reported .
●Most cases of logopenic variant PPA are due to underlying Alzheimer pathology, although hemispheric asymmetry in the distribution of neurofibrillary tangles distinguishes logopenic variant PPA from typical AD [72-74].
The heterogeneous pathologies underlying PPA suggest that the PPA clinical syndrome is determined not by the histopathology of the neurodegeneration but rather by its anatomic predilection for the language network of the brain . (See "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis".)
MOTOR SYNDROMES ASSOCIATED WITH FTD — Most patients with FTD (behavioral variant [bvFTD] or the primary progressive aphasias [PPAs]) do not manifest prominent motor features early in the disease course. However, there are three clinical syndromes that manifest with motor symptoms in addition to cognitive and behavioral symptoms, which may be caused by frontotemporal lobar degeneration (FTLD) pathology.
Behavioral variant FTD with motor neuron disease — Motor neuron disease (MND) may precede or follow the development of FTD, which is usually the bvFTD subtype [41,75-81]. In patients with classic amyotrophic lateral sclerosis (ALS) presenting to neuromuscular clinics, 15 to 20 percent have cognitive and behavioral symptoms consistent with bvFTD , while up to 50 percent have subtle deficits on neuropsychologic testing [82,83]. The true incidence of subsequent MND in patients who present initially with FTD is less certain. (See "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Cognitive symptoms'.)
The MND associated with bvFTD is generally similar to that seen in classic ALS, with a few exceptions. As in classic ALS, there is involvement of both upper motor neurons (resulting in pyramidal signs such as spasticity and hyperreflexia) and lower motor neurons (resulting in weakness, atrophy, and fasciculations). Bulbar involvement resulting in facial or tongue weakness or dysphagia is more common in patients with FTD-MND than classic ALS. Pseudobulbar affect, or uncontrolled bouts of laughter or crying that are sometimes inconsistent with the patient's actual mood, is commonly seen .
The behavioral symptoms of FTD-MND are generally similar to those of typical bvFTD. (See 'Clinical presentation' above.)
However, psychotic symptoms are more common in FTD-MND than in bvFTD without MND . This appears to be particularly true in carriers of the C9orf72 repeat expansion, the most commonly identified genetic cause of FTD-MND [47,48,86]. (See "Familial amyotrophic lateral sclerosis", section on 'C9ORF72 gene'.)
There are rare reports of nonfluent variant PPA or semantic variant PPA co-occurring with MND [87,88].
Patients with FTD-MND have shorter survival than those with FTD without MND .
Corticobasal syndrome — Historically, corticobasal degeneration (CBD) was described as a progressive neurodegenerative disorder characterized by asymmetric parkinsonism, apraxia, myoclonus, dystonia, and alien limb syndrome [90-92]. Over time, clinicopathologic correlation studies have demonstrated that this classical clinical syndrome is poorly predictive of underlying CBD pathology , which is a tauopathy characterized by tau-positive neuronal and glial inclusions, achromatic ballooned neurons, and neurodegeneration involving the frontal lobes, basal ganglia, and brainstem [94,95].
Other pathologies associated with the clinical corticobasal syndrome (CBS) include Alzheimer pathology, the pathology of progressive supranuclear palsy (PSP; also a tauopathy), FTLD with TDP43-positive inclusions (FTLD-TDP), and Creutzfeldt-Jakob disease. (See "Corticobasal degeneration", section on 'Antemortem versus postmortem diagnosis'.)
Autopsy-proven CBD is a frontal lobe predominant disease [95,96], with motor symptoms sometimes emerging only in advanced stages of disease [95,97-100]. The initial clinical syndrome may take the form of bvFTD, nonfluent variant PPA, executive dysfunction with motor features as identified in the early clinical descriptions of CBS, or PSP [95,97,99,101-105].
A lack of early motor findings therefore does not exclude CBD in patients presenting with a clinical syndrome suggestive of FTD. Moreover, CBD manifests with substantial clinical heterogeneity, such that features of bvFTD, nonfluent variant PPA, and CBS may overlap or evolve within patients during their disease course [98,106].
CBD syndrome is discussed in more detail separately. (See "Corticobasal degeneration".)
Progressive supranuclear palsy — PSP is a neurodegenerative syndrome consisting of supranuclear gaze palsy, axial dystonia with a hypererect posture, bradykinesia, rigidity, and falls early in the clinical course [107,108].
Most patients with PSP also have changes in cognition and behavior that overlap with bvFTD [109-111]. Apathy and disinhibition are the most common behavioral symptoms and may even precede motor symptoms [110,112,113]. Aggression, hyperorality, and stereotypical motor behavior as seen in patients with bvFTD are not as common in PSP .
PSP is discussed in greater detail separately. (See "Progressive supranuclear palsy (PSP): Clinical features and diagnosis".)
GENETIC TESTING — In FTD, an autosomal dominant pattern of inheritance is observed in the families of approximately 10 to 25 percent of patients [53,115-119]. An additional 40 percent of patients report a family history of dementia or psychiatric conditions, but without a clear inheritance pattern.
The most common genetic mutations causing familial FTD include microtubule-associated protein tau (MAPT), progranulin (GRN), and C9orf72 hexanucleotide repeat expansion. Patients with behavioral variant FTD (bvFTD), particularly when associated with motor neuron disease (MND), are most likely to have an inherited condition; in one series, more than half of such patients demonstrated a family history consistent with autosomal dominant inheritance . (See "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis", section on 'Genetic factors'.)
The family history, the results of pathologic studies (if available) in the patient or family member, and the clinical syndrome can guide appropriateness for genetic testing . Clinical genetics consultation is encouraged in patients considering genetic testing given the implications of test results to family members and uncertainties about penetrance, particularly in the absence of a family history .
Clinical trials for anti-tau drugs, progranulin-elevating therapies, and compounds that reduce or eliminate the suspected abnormalities derived from the C9orf72 repeat expansion are underway.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cognitive impairment and dementia".)
SUMMARY AND RECOMMENDATIONS
●Terminology – Frontotemporal dementia (FTD) is a common cause of early-onset dementia. Disease onset usually occurs in the sixth decade but can range from the second decade to the ninth.
"FTD" is an umbrella term for several clinical presentations: behavioral variant FTD (bvFTD) and two forms of primary progressive aphasia (PPA), nonfluent variant PPA and semantic variant PPA. The underlying pathology of FTD is heterogeneous; each clinical variant is associated with a distinct cluster of neuropathologies. (See 'Terminology' above.)
●Behavioral variant FTD – BvFTD is the most common clinical subtype and is characterized by progressive personality and behavior changes, including disinhibition, apathy and loss of empathy, hyperorality, and compulsive behaviors. Approximately 15 to 20 percent of patients with bvFTD develop concomitant motor neuron disease (MND). (See 'Clinical presentation' above and 'Behavioral variant FTD with motor neuron disease' above.)
On neuropsychologic tests, patients typically score well in executive function and episodic memory early in the disease course. Impairments in emotion and sarcasm recognition and inability to understand another person's perspective may be evident. Apathy and inattention in patients can make the interpretation of neuropsychologic testing challenging. (See 'Neuropsychologic testing' above.)
Neuroimaging often reveals unilateral focal frontal and temporal atrophy that may progress to involve both hemispheres as the disease progresses. (See 'Neuroimaging' above.)
Diagnostic criteria developed by an international consortium synthesize clinical features, neuroimaging, neuropathology, and genetic testing. (See 'Diagnostic criteria for bvFTD' above.)
Other disorders in the differential diagnosis should be excluded including primary psychiatric disorders, structural pathology in the frontal or temporal lobes, and other neurodegenerative disorders such as Alzheimer disease (AD) or dementia with Lewy bodies. (See 'Differential diagnosis' above.)
●Primary progressive aphasia – The hallmark of PPA is progressive language disturbance leading to functional impairment with relative preservation of episodic memory and other cognitive domains. Three variants of PPA have been described:
•In nonfluent variant PPA, patients present with a motor speech deficit characterized by effortful production of the linguistic units of sound (phonemes). The nonfluent variant is frequently associated with frontotemporal lobar degeneration (FTLD)-tau pathology. (See 'Nonfluent variant PPA' above.)
•In semantic variant PPA, patients have impaired single-word comprehension and object naming and preserved fluency, repetition, and grammar. The semantic variant is frequently associated with FTLD with TDP43-positive inclusions (FTLD-TDP) type C pathology. (See 'Semantic variant PPA' above.)
•The logopenic variant is characterized by impaired word retrieval and sentence repetition, resulting in slow, spontaneous speech with frequent word-finding problems. The logopenic variant is typically associated with Alzheimer pathology. (See 'Logopenic variant PPA' above.)
Neuroimaging in patients with PPA may demonstrate atrophy in the frontal and/or temporal lobes, in patterns specific to each clinical variant. (See 'Neuroimaging' above.)
Diagnostic criteria for PPA require progressive language dysfunction with relative sparing of other cognitive domains. (See 'Diagnostic criteria for PPA' above.)
●Motor syndromes – Motor syndromes associated with FTD include MND, corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP). (See 'Motor syndromes associated with FTD' above.)
●Genetic testing – Genetic testing is available for several mutations that are known to cause familial FTD syndromes. In the absence of a clinical imperative for diagnosis, however, such testing should be done selectively. (See 'Genetic testing' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Bruce L Miller, MD, who contributed to an earlier version of this topic review.
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