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Frontotemporal Dementia David C. Perry, MD1
Bruce L. Miller, MD1
1 Department of Neurology, University of California, San Francisco,
California
Address for correspondence David C. Perry, MD, UCSF Memory and Aging Center MC: 1207, 675 Nelson Rising Lane, Suite 190, San Francisco, CA 94158 (e-mail: [email protected]).
Abstract
Keywords
► frontotemporal dementia ► motor neuron disease ► Pick’s disease ► neurodegenerative disease
Frontotemporal dementia (FTD) encompasses several clinical syndromes that involve a progressive change in behavior and/or language; it is more common than Alzheimer’s disease in early-onset dementia under the age of 60 years. In the behavioral variant of FTD (bvFTD) patients have social and emotional changes with prominent disinhibition, apathy, lack of empathy, changes in diet, and repetitive behaviors. Motor neuron disease or parkinsonism are seen in association with bvFTD. Frontal and/or temporal atrophy are often seen on structural brain imaging. Several pathological entities can cause bvFTD, and they are defined by the presence of specific abnormal protein accumulations. Most cases are characterized by accumulation of the proteins tau, TAR-DNA-binding protein43 (TDP-43), and fused in sarcoma (FUS). Though most cases are sporadic, a variety of genes have been identified that cause autosomal dominant forms of FTD. The most common mutations occur in C9ORF72, MAPT, and GRN. No disease-modifying treatments have been currently identified, but limited evidence supports the use of antidepressants or neuroleptics in symptomatic management, and education regarding nonpharmacologic methods may be helpful to caregivers.
The existence of a degenerative dementia affecting the frontal and temporal lobes of the brain has been known since 1892 when Arnold Pick first described a patient with progressive changes in behavior and language.1 Alois Alzheimer subsequently defined the pathological features thought to accompany this illness.2 Pick’s students Onari and Spatz suggested the term Pick’s disease for this condition in 1926. Awareness and detailed study of this disease waned as Alzheimer’s disease (AD) became the main focus of dementia research. New interest in frontotemporal dementia (FTD) has occurred; it is now recognized as a significant cause of early age of onset dementia. The nomenclature surrounding this illness has changed over time and is inconsistently used. Frontotemporal dementia encompasses three clinical syndromes that result in progressive changes in behavior and/or language. The behavioral variant of FTD (bvFTD) makes up about half of all FTD cases3 and is the focus of this review. The two types of primary progressive aphasia (PPA) that comprise the other half of FTD cases include a semantic variant (svPPA) and a nonfluent variant (nfvPPA). The term frontotemporal lobar degeneration (FTLD) refers to the underlying pathological entities that cause FTD.
Issue Theme Neurodegenerative Dementias; Guest Editor, Brandy R. Matthews, MD
Epidemiology Among those younger than 60 years old, FTD is the most common neurodegenerative cause of dementia4 and is equally as common as AD among those with dementia younger than 65.5 The overall prevalence is 2.7 per 100,000 in the Netherlands6 and among 45- to 64-year-olds in Cambridge is 15 per 100,000.5 The age of onset ranges from the third to ninth decade, but is most common in the sixth decade.6,7 Men tend to be affected more than women.3,5 The average time from symptom onset to death in bvFTD is 8.7 years,8 but there is considerable variability, with the most rapid course occurring in those with coexisting motor neuron disease, and some slowly progressive forms that can evolve over decades.
Clinical Features Patients with bvFTD undergo a progressive change in personality, as well as social, emotional, and cognitive function. Depending on the underlying neuropathology, signs of motor neuron disease or extrapyramidal features may develop, particularly late in the illness. Disinhibition, apathy, loss of
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DOI http://dx.doi.org/ 10.1055/s-0033-1359316. ISSN 0271-8235.
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Semin Neurol 2013;33:336–341.
Frontotemporal Dementia
Frontotemporal Dementia with Motor Neuron Disease Approximately 15% of patients with bvFTD also develop signs and symptoms of motor neuron disease consistent with amyotrophic lateral sclerosis (ALS),14 including weakness, atrophy, fasciculations, upper motor neuron signs (increased deep tendon reflexes, extensor plantar response, or spasticity), and bulbar symptoms (dysarthria and dysphagia). As in ALS, pseudobulbar affect can also be seen. These cases are referred to as FTD with motor neuron disease (FTD-MND), or alternatively FTD-ALS. There is increasing appreciation of the clinical and pathological overlap between FTD and ALS as up to 50% of patients with ALS show signs of executive dysfunction on testing.15,16
Overlap with Corticobasal Syndrome and Progressive Supranuclear Palsy There is substantial clinical and pathological overlap between FTD and two parkinsonian spectrum disorders, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS; often referred to by the pathological term corticobasal degeneration [CBD]). Progressive supranuclear palsy typically involves extrapyramidal features with early loss of postural reflexes and falls, axial and limb rigidity, and a supranuclear gaze restriction with prominent limitation of vertical gaze and decreased velocity of saccadic eye movements. The behavioral changes of bvFTD can be seen as well, particularly apathy, impulsivity, and executive dysfunction. Corticobasal syndrome, as the name implies, involves cortical features (e.g., cortical sensory deficits, apraxia, or alien limb phenomenon) and basal ganglia features (e.g., rigidity, bradykinesia, or dystonia). As with PSP, cognitive and behavioral changes can accompany the motor findings. bvFTD without an associated movement disorder can be a syndromic presentation of both PSP and CBD pathology.
Neuroimaging Dramatic frontal and/or temporal atrophy on computed tomography (CT) or magnetic resonance imaging (MRI) are the hallmark neuroimaging features of bvFTD (►Fig. 1) with the earliest involved regions including the anterior insula, anterior cingulate, and orbitofrontal cortex.20 Hypometabolism of these brain regions can also be seen on positron emission tomography with fluorodeoxyglucose (FDG-PET).21 More specific correlations have also been found between regional brain atrophy and the presence of specific FTD symptoms, including disinhibition with the orbitofrontal cortex,22 apathy with medial frontal and anterior cingulate cortices,23 eating behavior changes with right insula, striatum, and orbitofrontal cortex,24,25 and compulsive behaviors with putamen, globus pallidus, and temporal lobe.26
Diagnosis The diagnosis of bvFTD was previously made with criteria published in 199427 and 1998.28 Due to limitations that
Right Temporal Variant of Frontotemporal Dementia When FTD affects the left anterior temporal lobe, the progressive aphasic syndrome of svPPA is typically seen. In approximately one-fourth of anterior temporal predominant cases the right side is affected first.17 These patients often begin with a behavioral syndrome and may meet diagnostic criteria for bvFTD. Right temporal lobe variant FTD patients are often described as cold, aloof, indifferent, and lacking empathy. Compulsive behaviors, particularly those involving word games and puns can be present.18 Prosopagnosia, or inability to recognize faces, is a frequently observed feature19 as the illness spreads from the anterior temporal lobe to inferior temporal areas involved in face processing, such as fusiform gyrus. Regardless of which hemisphere is affected first, the contralateral anterior temporal lobe becomes involved with disease progression.18
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Fig. 1 Brain magnetic resonance imaging of a patient with behavioral variant frontotemporal dementia, showing left greater than right frontal atrophy. The right side of the brain is on the left of axial and coronal images. Seminars in Neurology
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sympathy or empathy, eating behavior changes, and stereotyped or compulsive behaviors are characteristic. Patients typically lack insight into their symptoms. Disinhibited behavior may include inappropriate touching of strangers, offensive remarks, lack of respect for personal space, inappropriate response to social cues, and impulsive actions. Patients may become apathetic with low motivation or decreased initiation of behavior. Lack of empathy is manifest by disregard for the feelings of others or coldness in social engagement. Repetitive behaviors can either be simple, such as picking or tapping, or complex, such as repetitive hand washing, counting, or collecting. Dietary changes often involve overeating, carbohydrate craving, adopting rigid preferences or food fads, or in some cases putting inedible objects in the mouth. Patients in the early stages of the disease may do well on many traditional cognitive tests.9 The classic neuropsychological profile of bvFTD involves impairment in executive function (e.g., set shifting tasks such as Trails B and generation tasks such as letter fluency) with relative preservation of memory and visuospatial function in relation to the degree of executive dysfunction, although memory performance varies.10,11 A subset of patients have been described who do not seem to progress over time, who lack the hallmark atrophy on imaging, and who may be relatively more preserved on cognitive testing.12 They have been referred to as FTD phenocopy patients, and some do not suffer from a neurodegenerative disease. Recently, it has been reported that some harbor a disease-causing mutation.13
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rendered these at times too restrictive to capture all bvFTD patients,29 an international consortium proposed new criteria in 2011. These most recent diagnostic criteria for bvFTD30 are displayed in ►Table 1. The criteria establish three levels of diagnostic certainty: possible, probable, and definite. To meet criteria for possible bvFTD a patient must have a progressive deterioration of behavior with three out of six core features (disinhibition, apathy, loss of sympathy/ empathy, eating behavior changes, compulsive behaviors, and an executive predominant pattern of dysfunction on cognitive testing). In addition, functional decline and imaging consistent with bvFTD are necessary for a probable bvFTD diagnosis. Definite bvFTD requires a bvFTD clinical syndrome with genetic or pathological confirmation of FTLD. These criteria have been found to be more sensitive 30 compared with prior diagnostic criteria and to have good interrater reliability.31
Table 1 International consensus criteria for bvFTD30 I. Required criterion – progressive deterioration of behavior and/or cognition by observation or history II. Possible bvFTD – 3 of 6 required A. Early behavioral disinhibition B. Early apathy or inertia C. Early loss of sympathy or empathy D. Early perseverative, stereotyped, or compulsive/ritualistic behavior E. Hyperorality and dietary changes F. Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions III. Probable bvFTD (all of the following required) A. Meets criteria for possible bvFTD B. Significant functional decline
Pathology The pathology described by Arnold Pick, subsequently referred to as Pick’s disease, is only one of many underlying etiologies that can cause bvFTD. In all FTLD pathologies, there are signs of neurodegeneration involving frontal and/or temporal lobes with neuronal loss, gliosis, and microvacuolation.32 The majority of cases are either caused by abnormal accumulations of the protein tau, referred to as FTLD-TAU or the 43-kD TAR-DNA-binding protein (TDP-43), referred to as FTLD-TDP.33 Most of the remaining 10% of cases have pathology associated with the protein Fused in Sarcoma, referred to as FTLD-FUS.34 Recognition of these three pathologies has all but eliminated the prior classification of DLDH, or dementia lacking distinctive histopathology.35 Of note, underlying AD pathology is identified at autopsy in some patients with a bvFTD syndrome.
IV. bvFTD with definite FTLD pathology (A and either B or C required) A. Meets criteria for possible or probable bvFTD B. Histopathological evidence of FTLD on biopsy or at postmortem C. Presence of a known pathogenic mutation V. Exclusion criteria for bvFTD – Criteria A and B must both be answered negatively; criterion C can be positive for possible bvFTD but must be negative for probable bvFTD A. Pattern of deficits is better accounted for by other nervous system or medical disorders B. Behavioral disturbance is better accounted for by a psychiatric diagnosis
FTLD-TAU Tauopathies associated with bvFTD are defined by alternative splicing of the microtubule associated protein tau (MAPT) into a three amino acid repeat (3R) and a four repeat (4R) form. The presence of 3R or 4R tau, among other pathological features, defines the tau-related diseases.36 Pick’s disease is a 3R tauopathy characterized by Pick bodies (round, neuronal, cytoplasmic inclusions that stain with Bielschowsky, but not Gallyas silver staining) and achromatic, balloon neurons referred to as Pick cells. Progressive supranuclear palsy, CBD, argyrophilic grain disease (AGD), and the rare multiple system tauopathy with dementia are 4R tau diseases. Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is a subtype associated with mutations in the tau gene (MAPT) and contains both 3R and 4R tau, as do the uncommon tangle dominant dementia (TDD) and Guam ALS Parkinson’s dementia complex.
FTLD-TDP There are four recognized types of FTLD-TDP, referred to under a harmonized classification system as types A–D,37 ranked in order of frequency of occurrence. Seminars in Neurology
C. Imaging results consistent with bvFTD (frontal and/or anterior temporal atrophy on CT or MRI or frontal hypoperfusion or hypometabolism on SPECT or PET)
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C. Biomarkers strongly indicative of Alzheimer’s disease or other neurodegenerative process Abbreviations: bvFTD, behavioral variant frontotemporal dementia; CT, computed tomography; FTLD, frontotemporal lobar degeneration; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single photon emission computed tomography.
FTLD-FUS Three subtypes of FTLD-FUS include atypical frontotemporal lobar degeneration with ubiquitin positive inclusions (aFTLD-U),38 basophilic inclusion body disease (BIBD),39 and neuronal intermediate filament inclusion disease (NIFID).40
Genetics A family history of dementia is found in 40% of cases of FTD and 10% have clear autosomal dominant inheritance.41 The most common genes resulting in autosomal dominant inheritance of FTD are MAPT, progranulin (GRN), and C9ORF72. MAPT mutation carriers develop symptoms younger than patients with other known genetic causes,42 and may have
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benefit. Quetiapine may be a more appealing initial choice because it has less D2 antagonism than other medications in its class and may, therefore, result in fewer extrapyramidal side effects. Cholinesterase inhibitors should be avoided, given evidence of behavioral worsening in FTD and lack of cognitive improvement.57 Though there was some early indication of behavior improvement with memantine, subsequent large studies have demonstrated no benefit.58,59 Caregiver stress is higher in bvFTD than AD; therefore, education about the illness, available support services, and regarding non-pharmacologic behavioral strategies is helpful.60
Conclusions The personality, social, and emotional changes of bvFTD are debilitating to patients and devastating to families. As knowledge of the molecular and genetic causes of FTLD continues to expand, treatments will be directed at the underlying cause of disease, providing hope for modification of the disease course of this leading cause of early-onset dementia.
Acknowledgments David C. Perry, MD reports no conflicts of interest. Bruce L. Miller, MD, receives grant support from the NIH/NIA (FTLD Program Project Grant “Genes, Images Emotions,” Alzheimer’s Disease Research Center, T32 & K08/23 Training Grants) and has nothing to disclose related to this paper. Dr. Miller serves as a consultant for TauRx, Allon Therapeutics, Bristol-Myers Squibb, Neurology Scientific and Eli Lilly US. He receives philanthropic support from the Consortium for Frontotemporal Dementia Research, Tau Consortium and the Hellman Family Foundation. He is on the Board of Directors for the John Douglas French Foundation for Alzheimer’s Research and The Larry L. Hillblom Foundation.
Clinicopathological Correlations Predicting the underlying molecular pathology in bvFTD is challenging, but accuracy may be improved by identifying the presence of specific examination features or family history. FTLD-TAU may have features of parkinsonism or eye-movement abnormalities, particularly slow and hypometric saccades, if PSP pathology is present. FTD-MND is typically associated with TDP type B neuropathology. SvPPA and the right temporal variant of frontotemporal dementia are associated with TDP type C neuropathology. TDP type D neuropathology is found in carriers of VCP mutations. Patients with FTLD-FUS tend to have a younger age of onset than those with sporadic bvFTD.34
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Treatment There are no U.S. Food and Drug Administration approved treatments for FTD. Though no disease-modifying treatments are available, increasing understanding of the various molecular and genetic causes of FTD have improved the focus of current research, and clinical trials of agents targeting these pathologies are expected in the near future. The evidence for effective symptomatic therapies is limited. Neuroleptics and antidepressants may have some efficacy. Antidepressants may be a safer initial choice due to the more favorable side-effect profile. Several selective serotonin reuptake inhibitors50–52 and trazodone53 have been shown to improve behavior in small studies. The use of neuroleptics must be weighed against side effects, particularly the exacerbation of extrapyramidal symptoms. Olanzapine,54 risperidone,55 and aripiprazole56 have shown
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more symmetric atrophy with predilection for the temporal lobes comparatively.43 In addition to bvFTD, GRN mutation carriers can develop other clinical syndromes, including nfvPPA, CBS, and AD.44 The most common cause of inherited FTD and ALS is a hexanucleotide expansion in C9ORF72. Amyotrophic lateral sclerosis, bvFTD, and FTD-MND are the most common syndromes associated with this change on chromosome 9, with PPA subtypes being seen more rarely. Psychotic features are more common in these patients than in noncarriers.45 Additional ubiquitin-positive, p62 positive inclusions that are TDP-43 negative have been found in patients with C9ORF72 mutations.46 Recent studies would suggest that these inclusions contain dipeptide repeats made from nonstart codon dependent translation of the mutation’s hexanucleotide repeat expansion.47 Mutations in TARDBP (the gene that encodes TDP-43) and FUS typically cause familial ALS, but can cause FTD in some cases. Less common causes of inherited FTD include mutations in the charged multivesicular body protein 2B (CHMP2B) on chromosome 3 and valosin-containing protein (VCP) on chromosome 9. CHMP2B mutations are found in few families, including Danish48 and Belgian kindreds, and cause pathology without tau, TDP-43, or FUS staining, referred to as FTD-3. VCP mutations can cause Paget’s disease of bone and inclusion body myositis in addition to bvFTD.49
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Frontotemporal Dementia
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Frontotemporal Dementia David C. Perry, MD1
Bruce L. Miller, MD1
1 Department of Neurology, University of California, San Francisco,
California
Address for correspondence David C. Perry, MD, UCSF Memory and Aging Center MC: 1207, 675 Nelson Rising Lane, Suite 190, San Francisco, CA 94158 (e-mail: [email protected]).
Abstract
Keywords
► frontotemporal dementia ► motor neuron disease ► Pick’s disease ► neurodegenerative disease
Frontotemporal dementia (FTD) encompasses several clinical syndromes that involve a progressive change in behavior and/or language; it is more common than Alzheimer’s disease in early-onset dementia under the age of 60 years. In the behavioral variant of FTD (bvFTD) patients have social and emotional changes with prominent disinhibition, apathy, lack of empathy, changes in diet, and repetitive behaviors. Motor neuron disease or parkinsonism are seen in association with bvFTD. Frontal and/or temporal atrophy are often seen on structural brain imaging. Several pathological entities can cause bvFTD, and they are defined by the presence of specific abnormal protein accumulations. Most cases are characterized by accumulation of the proteins tau, TAR-DNA-binding protein43 (TDP-43), and fused in sarcoma (FUS). Though most cases are sporadic, a variety of genes have been identified that cause autosomal dominant forms of FTD. The most common mutations occur in C9ORF72, MAPT, and GRN. No disease-modifying treatments have been currently identified, but limited evidence supports the use of antidepressants or neuroleptics in symptomatic management, and education regarding nonpharmacologic methods may be helpful to caregivers.
The existence of a degenerative dementia affecting the frontal and temporal lobes of the brain has been known since 1892 when Arnold Pick first described a patient with progressive changes in behavior and language.1 Alois Alzheimer subsequently defined the pathological features thought to accompany this illness.2 Pick’s students Onari and Spatz suggested the term Pick’s disease for this condition in 1926. Awareness and detailed study of this disease waned as Alzheimer’s disease (AD) became the main focus of dementia research. New interest in frontotemporal dementia (FTD) has occurred; it is now recognized as a significant cause of early age of onset dementia. The nomenclature surrounding this illness has changed over time and is inconsistently used. Frontotemporal dementia encompasses three clinical syndromes that result in progressive changes in behavior and/or language. The behavioral variant of FTD (bvFTD) makes up about half of all FTD cases3 and is the focus of this review. The two types of primary progressive aphasia (PPA) that comprise the other half of FTD cases include a semantic variant (svPPA) and a nonfluent variant (nfvPPA). The term frontotemporal lobar degeneration (FTLD) refers to the underlying pathological entities that cause FTD.
Issue Theme Neurodegenerative Dementias; Guest Editor, Brandy R. Matthews, MD
Epidemiology Among those younger than 60 years old, FTD is the most common neurodegenerative cause of dementia4 and is equally as common as AD among those with dementia younger than 65.5 The overall prevalence is 2.7 per 100,000 in the Netherlands6 and among 45- to 64-year-olds in Cambridge is 15 per 100,000.5 The age of onset ranges from the third to ninth decade, but is most common in the sixth decade.6,7 Men tend to be affected more than women.3,5 The average time from symptom onset to death in bvFTD is 8.7 years,8 but there is considerable variability, with the most rapid course occurring in those with coexisting motor neuron disease, and some slowly progressive forms that can evolve over decades.
Clinical Features Patients with bvFTD undergo a progressive change in personality, as well as social, emotional, and cognitive function. Depending on the underlying neuropathology, signs of motor neuron disease or extrapyramidal features may develop, particularly late in the illness. Disinhibition, apathy, loss of
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DOI http://dx.doi.org/ 10.1055/s-0033-1359316. ISSN 0271-8235.
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Semin Neurol 2013;33:336–341.
Frontotemporal Dementia
Frontotemporal Dementia with Motor Neuron Disease Approximately 15% of patients with bvFTD also develop signs and symptoms of motor neuron disease consistent with amyotrophic lateral sclerosis (ALS),14 including weakness, atrophy, fasciculations, upper motor neuron signs (increased deep tendon reflexes, extensor plantar response, or spasticity), and bulbar symptoms (dysarthria and dysphagia). As in ALS, pseudobulbar affect can also be seen. These cases are referred to as FTD with motor neuron disease (FTD-MND), or alternatively FTD-ALS. There is increasing appreciation of the clinical and pathological overlap between FTD and ALS as up to 50% of patients with ALS show signs of executive dysfunction on testing.15,16
Overlap with Corticobasal Syndrome and Progressive Supranuclear Palsy There is substantial clinical and pathological overlap between FTD and two parkinsonian spectrum disorders, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS; often referred to by the pathological term corticobasal degeneration [CBD]). Progressive supranuclear palsy typically involves extrapyramidal features with early loss of postural reflexes and falls, axial and limb rigidity, and a supranuclear gaze restriction with prominent limitation of vertical gaze and decreased velocity of saccadic eye movements. The behavioral changes of bvFTD can be seen as well, particularly apathy, impulsivity, and executive dysfunction. Corticobasal syndrome, as the name implies, involves cortical features (e.g., cortical sensory deficits, apraxia, or alien limb phenomenon) and basal ganglia features (e.g., rigidity, bradykinesia, or dystonia). As with PSP, cognitive and behavioral changes can accompany the motor findings. bvFTD without an associated movement disorder can be a syndromic presentation of both PSP and CBD pathology.
Neuroimaging Dramatic frontal and/or temporal atrophy on computed tomography (CT) or magnetic resonance imaging (MRI) are the hallmark neuroimaging features of bvFTD (►Fig. 1) with the earliest involved regions including the anterior insula, anterior cingulate, and orbitofrontal cortex.20 Hypometabolism of these brain regions can also be seen on positron emission tomography with fluorodeoxyglucose (FDG-PET).21 More specific correlations have also been found between regional brain atrophy and the presence of specific FTD symptoms, including disinhibition with the orbitofrontal cortex,22 apathy with medial frontal and anterior cingulate cortices,23 eating behavior changes with right insula, striatum, and orbitofrontal cortex,24,25 and compulsive behaviors with putamen, globus pallidus, and temporal lobe.26
Diagnosis The diagnosis of bvFTD was previously made with criteria published in 199427 and 1998.28 Due to limitations that
Right Temporal Variant of Frontotemporal Dementia When FTD affects the left anterior temporal lobe, the progressive aphasic syndrome of svPPA is typically seen. In approximately one-fourth of anterior temporal predominant cases the right side is affected first.17 These patients often begin with a behavioral syndrome and may meet diagnostic criteria for bvFTD. Right temporal lobe variant FTD patients are often described as cold, aloof, indifferent, and lacking empathy. Compulsive behaviors, particularly those involving word games and puns can be present.18 Prosopagnosia, or inability to recognize faces, is a frequently observed feature19 as the illness spreads from the anterior temporal lobe to inferior temporal areas involved in face processing, such as fusiform gyrus. Regardless of which hemisphere is affected first, the contralateral anterior temporal lobe becomes involved with disease progression.18
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Fig. 1 Brain magnetic resonance imaging of a patient with behavioral variant frontotemporal dementia, showing left greater than right frontal atrophy. The right side of the brain is on the left of axial and coronal images. Seminars in Neurology
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sympathy or empathy, eating behavior changes, and stereotyped or compulsive behaviors are characteristic. Patients typically lack insight into their symptoms. Disinhibited behavior may include inappropriate touching of strangers, offensive remarks, lack of respect for personal space, inappropriate response to social cues, and impulsive actions. Patients may become apathetic with low motivation or decreased initiation of behavior. Lack of empathy is manifest by disregard for the feelings of others or coldness in social engagement. Repetitive behaviors can either be simple, such as picking or tapping, or complex, such as repetitive hand washing, counting, or collecting. Dietary changes often involve overeating, carbohydrate craving, adopting rigid preferences or food fads, or in some cases putting inedible objects in the mouth. Patients in the early stages of the disease may do well on many traditional cognitive tests.9 The classic neuropsychological profile of bvFTD involves impairment in executive function (e.g., set shifting tasks such as Trails B and generation tasks such as letter fluency) with relative preservation of memory and visuospatial function in relation to the degree of executive dysfunction, although memory performance varies.10,11 A subset of patients have been described who do not seem to progress over time, who lack the hallmark atrophy on imaging, and who may be relatively more preserved on cognitive testing.12 They have been referred to as FTD phenocopy patients, and some do not suffer from a neurodegenerative disease. Recently, it has been reported that some harbor a disease-causing mutation.13
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rendered these at times too restrictive to capture all bvFTD patients,29 an international consortium proposed new criteria in 2011. These most recent diagnostic criteria for bvFTD30 are displayed in ►Table 1. The criteria establish three levels of diagnostic certainty: possible, probable, and definite. To meet criteria for possible bvFTD a patient must have a progressive deterioration of behavior with three out of six core features (disinhibition, apathy, loss of sympathy/ empathy, eating behavior changes, compulsive behaviors, and an executive predominant pattern of dysfunction on cognitive testing). In addition, functional decline and imaging consistent with bvFTD are necessary for a probable bvFTD diagnosis. Definite bvFTD requires a bvFTD clinical syndrome with genetic or pathological confirmation of FTLD. These criteria have been found to be more sensitive 30 compared with prior diagnostic criteria and to have good interrater reliability.31
Table 1 International consensus criteria for bvFTD30 I. Required criterion – progressive deterioration of behavior and/or cognition by observation or history II. Possible bvFTD – 3 of 6 required A. Early behavioral disinhibition B. Early apathy or inertia C. Early loss of sympathy or empathy D. Early perseverative, stereotyped, or compulsive/ritualistic behavior E. Hyperorality and dietary changes F. Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions III. Probable bvFTD (all of the following required) A. Meets criteria for possible bvFTD B. Significant functional decline
Pathology The pathology described by Arnold Pick, subsequently referred to as Pick’s disease, is only one of many underlying etiologies that can cause bvFTD. In all FTLD pathologies, there are signs of neurodegeneration involving frontal and/or temporal lobes with neuronal loss, gliosis, and microvacuolation.32 The majority of cases are either caused by abnormal accumulations of the protein tau, referred to as FTLD-TAU or the 43-kD TAR-DNA-binding protein (TDP-43), referred to as FTLD-TDP.33 Most of the remaining 10% of cases have pathology associated with the protein Fused in Sarcoma, referred to as FTLD-FUS.34 Recognition of these three pathologies has all but eliminated the prior classification of DLDH, or dementia lacking distinctive histopathology.35 Of note, underlying AD pathology is identified at autopsy in some patients with a bvFTD syndrome.
IV. bvFTD with definite FTLD pathology (A and either B or C required) A. Meets criteria for possible or probable bvFTD B. Histopathological evidence of FTLD on biopsy or at postmortem C. Presence of a known pathogenic mutation V. Exclusion criteria for bvFTD – Criteria A and B must both be answered negatively; criterion C can be positive for possible bvFTD but must be negative for probable bvFTD A. Pattern of deficits is better accounted for by other nervous system or medical disorders B. Behavioral disturbance is better accounted for by a psychiatric diagnosis
FTLD-TAU Tauopathies associated with bvFTD are defined by alternative splicing of the microtubule associated protein tau (MAPT) into a three amino acid repeat (3R) and a four repeat (4R) form. The presence of 3R or 4R tau, among other pathological features, defines the tau-related diseases.36 Pick’s disease is a 3R tauopathy characterized by Pick bodies (round, neuronal, cytoplasmic inclusions that stain with Bielschowsky, but not Gallyas silver staining) and achromatic, balloon neurons referred to as Pick cells. Progressive supranuclear palsy, CBD, argyrophilic grain disease (AGD), and the rare multiple system tauopathy with dementia are 4R tau diseases. Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is a subtype associated with mutations in the tau gene (MAPT) and contains both 3R and 4R tau, as do the uncommon tangle dominant dementia (TDD) and Guam ALS Parkinson’s dementia complex.
FTLD-TDP There are four recognized types of FTLD-TDP, referred to under a harmonized classification system as types A–D,37 ranked in order of frequency of occurrence. Seminars in Neurology
C. Imaging results consistent with bvFTD (frontal and/or anterior temporal atrophy on CT or MRI or frontal hypoperfusion or hypometabolism on SPECT or PET)
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C. Biomarkers strongly indicative of Alzheimer’s disease or other neurodegenerative process Abbreviations: bvFTD, behavioral variant frontotemporal dementia; CT, computed tomography; FTLD, frontotemporal lobar degeneration; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single photon emission computed tomography.
FTLD-FUS Three subtypes of FTLD-FUS include atypical frontotemporal lobar degeneration with ubiquitin positive inclusions (aFTLD-U),38 basophilic inclusion body disease (BIBD),39 and neuronal intermediate filament inclusion disease (NIFID).40
Genetics A family history of dementia is found in 40% of cases of FTD and 10% have clear autosomal dominant inheritance.41 The most common genes resulting in autosomal dominant inheritance of FTD are MAPT, progranulin (GRN), and C9ORF72. MAPT mutation carriers develop symptoms younger than patients with other known genetic causes,42 and may have
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benefit. Quetiapine may be a more appealing initial choice because it has less D2 antagonism than other medications in its class and may, therefore, result in fewer extrapyramidal side effects. Cholinesterase inhibitors should be avoided, given evidence of behavioral worsening in FTD and lack of cognitive improvement.57 Though there was some early indication of behavior improvement with memantine, subsequent large studies have demonstrated no benefit.58,59 Caregiver stress is higher in bvFTD than AD; therefore, education about the illness, available support services, and regarding non-pharmacologic behavioral strategies is helpful.60
Conclusions The personality, social, and emotional changes of bvFTD are debilitating to patients and devastating to families. As knowledge of the molecular and genetic causes of FTLD continues to expand, treatments will be directed at the underlying cause of disease, providing hope for modification of the disease course of this leading cause of early-onset dementia.
Acknowledgments David C. Perry, MD reports no conflicts of interest. Bruce L. Miller, MD, receives grant support from the NIH/NIA (FTLD Program Project Grant “Genes, Images Emotions,” Alzheimer’s Disease Research Center, T32 & K08/23 Training Grants) and has nothing to disclose related to this paper. Dr. Miller serves as a consultant for TauRx, Allon Therapeutics, Bristol-Myers Squibb, Neurology Scientific and Eli Lilly US. He receives philanthropic support from the Consortium for Frontotemporal Dementia Research, Tau Consortium and the Hellman Family Foundation. He is on the Board of Directors for the John Douglas French Foundation for Alzheimer’s Research and The Larry L. Hillblom Foundation.
Clinicopathological Correlations Predicting the underlying molecular pathology in bvFTD is challenging, but accuracy may be improved by identifying the presence of specific examination features or family history. FTLD-TAU may have features of parkinsonism or eye-movement abnormalities, particularly slow and hypometric saccades, if PSP pathology is present. FTD-MND is typically associated with TDP type B neuropathology. SvPPA and the right temporal variant of frontotemporal dementia are associated with TDP type C neuropathology. TDP type D neuropathology is found in carriers of VCP mutations. Patients with FTLD-FUS tend to have a younger age of onset than those with sporadic bvFTD.34
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Treatment There are no U.S. Food and Drug Administration approved treatments for FTD. Though no disease-modifying treatments are available, increasing understanding of the various molecular and genetic causes of FTD have improved the focus of current research, and clinical trials of agents targeting these pathologies are expected in the near future. The evidence for effective symptomatic therapies is limited. Neuroleptics and antidepressants may have some efficacy. Antidepressants may be a safer initial choice due to the more favorable side-effect profile. Several selective serotonin reuptake inhibitors50–52 and trazodone53 have been shown to improve behavior in small studies. The use of neuroleptics must be weighed against side effects, particularly the exacerbation of extrapyramidal symptoms. Olanzapine,54 risperidone,55 and aripiprazole56 have shown
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more symmetric atrophy with predilection for the temporal lobes comparatively.43 In addition to bvFTD, GRN mutation carriers can develop other clinical syndromes, including nfvPPA, CBS, and AD.44 The most common cause of inherited FTD and ALS is a hexanucleotide expansion in C9ORF72. Amyotrophic lateral sclerosis, bvFTD, and FTD-MND are the most common syndromes associated with this change on chromosome 9, with PPA subtypes being seen more rarely. Psychotic features are more common in these patients than in noncarriers.45 Additional ubiquitin-positive, p62 positive inclusions that are TDP-43 negative have been found in patients with C9ORF72 mutations.46 Recent studies would suggest that these inclusions contain dipeptide repeats made from nonstart codon dependent translation of the mutation’s hexanucleotide repeat expansion.47 Mutations in TARDBP (the gene that encodes TDP-43) and FUS typically cause familial ALS, but can cause FTD in some cases. Less common causes of inherited FTD include mutations in the charged multivesicular body protein 2B (CHMP2B) on chromosome 3 and valosin-containing protein (VCP) on chromosome 9. CHMP2B mutations are found in few families, including Danish48 and Belgian kindreds, and cause pathology without tau, TDP-43, or FUS staining, referred to as FTD-3. VCP mutations can cause Paget’s disease of bone and inclusion body myositis in addition to bvFTD.49
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Frontotemporal Dementia
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