INTRODUCTION AND TERMINOLOGY — Frontotemporal dementia (FTD) is a clinically and neuropathologically heterogeneous disorder characterized by disturbances in behavior, personality, and language accompanied by focal degeneration of the frontal and/or temporal lobes.
FTD serves as an umbrella term for several clinical syndromes, including behavioral variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA), and nonfluent variant primary progressive aphasia (nfvPPA).
The term "frontotemporal lobar degeneration" (FTLD) applies to the pathological diagnoses associated with the clinical FTD spectrum. This pathologic entity can be subdivided according to the nature of the characteristic cytoplasmic or nuclear protein inclusions that are observed histopathologically and believed to be neurotoxic.
Each clinical FTD syndrome may be associated with different neuropathologies, which poses a significant challenge to the development and testing of therapies designed to target specific protein dysfunction in neurodegeneration. Moreover, studies reveal the significant neuropathological and genetic overlap between motor neuron disease and FTD.
This topic will review the epidemiology, pathogenesis, and pathology of FTD. The clinical manifestations, diagnosis, and treatment of FTD are discussed separately. (See "Frontotemporal dementia: Clinical features and diagnosis" and "Frontotemporal dementia: Treatment".)
EPIDEMIOLOGY — FTD is one of the more common causes of early-onset dementia and occurs at similar frequency to Alzheimer disease (AD) in patients younger than 65 years. A systematic review of 26 studies spanning Europe, Asia, North America, and South America found that, on average, FTD accounted for 2.7 percent of diagnoses among patients with dementia 65 years and older. For patients with dementia younger than 65 years, FTD accounted for 10.2 percent of diagnoses [1]. It has been suggested that the estimated incidence and prevalence of FTD are underreported, since many patients present with behavioral changes and are likely to be referred to psychiatric services [2].
The mean age of onset of FTD is approximately 58 years [3-8]. The reported age of onset has ranged from 20 to 80 years, although onset before 40 or after 75 years of age is unusual.
In most case series, the proportion of males and females with FTD is roughly equal [1], but some series have reported a male preponderance [2-5,8,9].
GENETIC FACTORS — FTD is highly heritable. Studies suggest that 30 to 50 percent of patients with FTD have at least one relative with dementia [10-12], with an autosomal-dominant inheritance pattern observed in approximately 10 to 25 percent of patients with FTD [4,5,7,8,10,13].
Patients with behavioral variant FTD (bvFTD), particularly when associated with motor neuron disease, 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 [10].
The most common disease-causing genetic mutations include those in microtubule-associated protein tau (MAPT), the granulin precursor (GRN) gene, and a hexanucleotide expansion in chromosome 9 open reading frame 72 (C9orf72). Among patients with FTD who carry a genetic mutation, over 80 percent have a mutation in one of these three genes [14]. Mutations in these three genes account for approximately 15 percent of patients with a family history of dementia [15,16].
Mutations in other genes, including valosin-containing protein (VCP), charged multivesicular body protein 2B (CHMP2B), and TANK binding kinase 1 (TBK1), are rare [15,16]. The co-occurrence of two evidently pathogenic mutations in the same patient (eg, C9orf72 expansion plus a mutation in either GRN or MAPT) [17] and homozygous MAPT [18,19], GRN [20], and C9orf72 [21] expansion carriers have been reported.
MAPT mutations — Over 60 pathogenic autosomal-dominant mutations in MAPT have been identified [22]. MAPT mutations typically cause bvFTD with or without parkinsonism [23]. Some MAPT mutation carriers with parkinsonism also meet criteria for progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) [24]. Patients with semantic variant primary progressive aphasia (svPPA), PSP, and CBD have been reported but are less common. Mutations that do not affect the splicing of exon 10 in MAPT are typically associated with the bvFTD syndrome, while mutations that affect exon 10 splicing and increase the ratio of four repeat (4R) tau to three repeat (3R) tau more frequently cause bvFTD with PSP or parkinsonism [25-27]. The R406W mutation may present with an amnestic Alzheimer disease (AD)-like syndrome. (See 'FTLD-tau' below and 'Clinicopathological correlations' below.)
Compared with other frontotemporal lobar degeneration (FTLD) genetic mutations, MAPT mutation carriers have an earlier age of symptom onset, typically between the ages of 40 and 60 years [22]. In contrast to sporadic bvFTD, MAPT mutation carriers also may show early memory impairment with corresponding mesial temporal lobe atrophy [28,29].
At autopsy, patients with FTLD due to MAPT mutations invariably feature FTLD-tau pathology, yet the mechanism by which MAPT gene mutations result in FTLD is not well understood.
GRN mutations — Like MAPT, the gene encoding progranulin (GRN) also lies on chromosome 17. The function of progranulin is complex, with important roles as a growth factor in development, wound repair, neuroinflammation, autophagy, and lysosomal function [30], but its role in neurodegeneration remains unclear [31-34].
The age of symptom onset ranges widely (35 to 87 years), but on average, disease onset occurs later than in MAPT carriers [31,35,36].
Over 100 autosomal-dominant mutations in GRN have been associated with FTLD [22]. All known mutations result in a truncated progranulin mRNA that undergoes nonsense-mediated decay via the nonsense-mediated surveillance system, which results in a haploinsufficiency of functional progranulin protein [37,38]. Progranulin haploinsufficiency results in FTLD-TDP pathology, but the mechanism by which this occurs remains unknown.
GRN mutation carriers typically develop bvFTD, nonfluent variant primary progressive aphasia (nfvPPA), or CBD, and patients with an amnestic AD-like syndrome have been described [39]. In some patients with GRN-associated FTLD, structural magnetic resonance imaging (MRI) brain scans demonstrate extensive white matter lesions, in addition to the more typical pattern of focal frontal, temporal, and parietal lobe atrophy [40,41]. (See 'FTLD-TDP' below and 'Clinicopathological correlations' below.)
C9orf72 expansion — A noncoding hexanucleotide repeat on chromosome 9 within C9orf72 is the most common genetic cause of familial FTD and amyotrophic lateral sclerosis (ALS), representing approximately 12 and 25 percent of familial cases, respectively [42,43]. The C9orf72 expansion has also been identified in patients with sporadic ALS and FTD. Compared with sporadic ALS, ALS due to C9orf72 is associated with earlier disease onset, bulbar disease, higher frequency of comorbid FTD, and shorter age-matched median survival. (See "Familial amyotrophic lateral sclerosis", section on 'C9ORF72 gene'.)
While the predominant clinical presentation of C9orf72 expansion carriers is bvFTD, ALS, or both (FTD-MND), patients with svPPA and nfvPPA have been reported [44-46].
Possible pathophysiologic mechanisms include haploinsufficiency of C9orf72 protein, the development of repeat RNA foci translated from the expanded repeat, and abnormal dipeptide-repeat (DPR) proteins translated from the repeat mRNA [47]. Defects in nucleocytoplasmic transport through the nuclear pore may also contribute to disease [48-51]. Repeat length appears highly variable across brain regions and other tissues, including blood, even within an individual [52,53]. Studies are mixed, with most showing no clear associations of repeat length with cognitive impairment [53], clinical syndrome (eg, FTD versus ALS), age of onset [52], or age at death [54], although longer repeats may be associated with longer disease duration in FTD, but not ALS [54], or shorter survival [52]. C9orf72 expansions result in FTLD-TDP pathology. (See 'FTLD-TDP' below.)
Other genetic mutations — Rare genetic variants associated with FTD include mutations in VCP, CHMP2B, TBK1, TAR DNA-binding protein (TARDBP; the gene that encodes TDP-43), sequestosome 1 (SQSTM1), triggering receptor expressed on myeloid cells 2 (TREM2), and coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) [55,56]. VCP is associated with bvFTD, inclusion body myositis, Paget bone disease, and familial ALS [57-59]. Mutations in TARDBP, fused in sarcoma (FUS), and ubiquilin 2 (UBQLN2) are linked to familial ALS but are rarely associated with FTD clinical presentations. (See "Familial amyotrophic lateral sclerosis", section on 'ALS14 (VCP gene)' and "Familial amyotrophic lateral sclerosis", section on 'ALS10 (TARDBP gene)' and "Familial amyotrophic lateral sclerosis", section on 'ALS6 (FUS gene)'.)
SHARED PATHOLOGICAL FEATURES — The gross pathology of all frontotemporal lobar degeneration (FTLD) subtypes reveals degeneration in the frontal and/or temporal lobes. Cortical and/or basal ganglia atrophy may be symmetric or asymmetric, and substantia nigra depigmentation emerges in a subset of cases. While behavioral variant FTD (bvFTD) typically targets the fronto-insula and the anterior cingulate cortex, specific atrophy patterns may be associated with underlying neuropathology [60], although the prediction of an individual's underlying pathology based on atrophy patterns generally remains tenuous.
Microscopically, most FTLD cases demonstrate microvacuolation and neuronal loss accompanied by swollen neurons, loss of myelin, and astrocytic gliosis. In addition, abnormal protein inclusions are seen in the cytoplasm and/or nuclei of neuronal and/or glial cells. The constituents of these abnormal protein inclusions are known in most cases and are used to classify FTLD pathology into distinct subtypes. (See 'Pathological subtypes' below and 'Clinicopathological correlations' below.)
PATHOLOGICAL SUBTYPES — Nearly all frontotemporal lobar degeneration (FTLD) cases are classified into three major subtypes based on the composition of the protein inclusions and their morphology and anatomic distribution. These major categories of protein inclusions are tau, the TAR DNA-binding protein 43 (TDP-43), and FET proteins.
Together, FTLD-tau and FTLD-TDP account for approximately 90 percent of FTLD cases [61]. Approximately 50 percent of FTLD cases feature FTLD-tau pathology, while FTLD-TDP accounts for approximately 40 percent, and FTLD-FET accounts for 5 to 10 percent. FTLD in which inclusions are labeled only by the markers of the ubiquitin-proteasome system (UPS) is rare (<1 percent) and is found in patients carrying the rare CHMP2B mutation [62].
FTLD-tau — Tau protein is encoded by the MAPT gene on chromosome 17. Tau stabilizes microtubules, promotes microtubule assembly, and regulates axonal transport [63-65].
Tau protein is alternatively spliced into six isoforms, among which are a three amino acid sequence repeat isoform (3R) and a four repeat isoform (4R). In normal cells, 3R and 4R tau occur in equal proportions. In FTLD-tau pathology, the ratio of hyperphosphorylated 3R and 4R tau varies amongst pathological subtypes. FTLD-tau neuropathologies are thus subclassified by whether tau inclusions are predominantly composed of 3R or 4R tau, or a mixture of both. Pick disease is classified as a 3R tauopathy. FTLD due to a MAPT mutation and chronic traumatic encephalopathy feature both 3R and 4R tau inclusions. Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and less common pathologies such as argyrophilic grain disease and globular glial tauopathy (GGT) predominantly feature inclusions with the 4R species. Chronic traumatic encephalopathy, CBD, and PSP are discussed separately. (See "Sequelae of mild traumatic brain injury", section on 'Chronic traumatic encephalopathy' and "Corticobasal degeneration" and "Progressive supranuclear palsy (PSP): Clinical features and diagnosis".)
The earliest report of FTLD pathology described distinctive round, silver-staining inclusions named Pick bodies [66,67]. While the term "Pick disease" historically referred to both the clinical and pathological diagnosis, current FTLD nomenclature uses "Pick disease" to refer to the pathological diagnosis only. In Pick disease, Pick bodies develop in the granule cells of the dentate gyrus, the pyramidal neurons in the CA1 region of the hippocampus, and the pyramidal neurons in the frontal and temporal lobes. Pick bodies are spherical tau-positive neuronal cytoplasmic inclusions (NCIs) composed primarily of 3R tau and occur in association with achromatic ballooned neurons, or Pick cells [68]. Tau deposition in Pick disease progresses sequentially, beginning in the frontotemporal limbic/paralimbic and neocortical regions, then involving subcortical structures (eg, basal ganglia, locus ceruleus, raphe nuclei), primary motor cortex and precerebellar nuclei, and finally visual cortex [69]. Pick disease presents more commonly as behavioral variant FTD (bvFTD), although nonfluent variant primary progressive aphasia (nfvPPA), semantic variant primary progressive aphasia (svPPA), and CBD are also associated clinical syndromes [60,69,70].
Rare FTLD-tau pathologies include the pathology associated with MAPT mutation carriers, argyrophilic grain disease, and GGT.
●FTLD caused by a MAPT mutation, also known as FTD with parkinsonism linked to chromosome 17 (FTDP-17), exhibits hyperphosphorylated tau inclusions in neurons and glia in cortical and subcortical regions. The characteristics of tau pathology vary between MAPT families, with some correlation between the specific MAPT mutation and pathological features [24]. Mutations that affect the splicing of exon 10 and increase the ratio of 4R to 3R tau result in a pathology reminiscent of PSP and CBD [25-27,71]. Mutations in other exons may lead to a predominance of either Pick bodies (3R tau) or Alzheimer disease (AD)-like neurofibrillary tangles with a mixture of 3R and 4R [71]. (See 'Genetic factors' above.)
●Argyrophilic grain disease was first described as a pathological finding with small, spindle-shaped argyrophilic inclusions or "grains" consisting of 4R tau within medial temporal lobes and limbic regions, which may also be seen in other cortical regions and the lateral hypothalamus [72]. Argyrophilic grain disease may arise alone or along with other neuropathologies and has been seen in association with aging, amnestic mild cognitive impairment (MCI), AD-like dementia, and slowly progressive bvFTD [73-78]. Aside from slower disease progression, clinical features that may distinguish MCI due to argyrophilic grain disease versus AD have yet to be determined.
●GGT (also reported as "sporadic multiple system tauopathy with dementia") is a rare 4R tau pathology characterized by widespread globular neuronal and glial tau-positive inclusions in gray and white matter [79]. The clinical presentations of GGT include bvFTD with or without parkinsonism, primary lateral sclerosis, or a combination of these two syndromes [80].
FTLD-TDP — TDP-43 protein is an RNA binding protein present in the nucleus of normal cells and involved in transcription regulation [81-84]. In FTLD-TDP, abnormally phosphorylated and ubiquitinated TDP-43 appears in various abnormal morphologies, including NCIs, neuronal intranuclear inclusions, dystrophic neurites, and glial cytoplasmic inclusions [81,83-85]. Based on the types of inclusions and their distribution throughout the brain, FTLD-TDP can be further subdivided into four types [62,86]:
●Type A, with many compact NCIs and many short, thick dystrophic neurites, predominantly in layer 2 of the cortex
●Type B, with moderate diffuse granular NCIs and few dystrophic neurites, in all layers of cortex
●Type C, with few NCIs and many long, thick dystrophic neurites, in all layers of cortex
●Type D, with few NCIs; many short, thick dystrophic neurites; and many lentiform neuronal intranuclear inclusions, in all layers of cortex
Type A is the most common subtype, accounting for approximately 40 to 50 percent of FTLD-TDP cases, followed by type B (approximately 30 percent), type C (up to 25 percent), and type D, which is rare [83,87]. The mechanisms through which TDP-43 protein abnormalities lead to neurodegeneration are a focus of intense research but are not yet understood.
Several autosomal-dominant FTLD mutations result in FTLD-TDP pathology:
●FTLD caused by mutations in GRN [37,88] is typically associated with FTLD-TDP type A pathology. (See 'GRN mutations' above.)
●FTLD and amyotrophic lateral sclerosis (ALS) caused by the C9orf72 repeat expansion is associated with variable degrees of FTLD-TDP pathology [43,89] and also inclusions of dipeptide-repeat (DPR) proteins directly derived from the expanded repeat [90]. Most patients show TDP type B neuropathology, though some show features more consistent with type A or a mixture between types A and B. (See 'C9orf72 expansion' above.)
●Inclusion body myositis with Paget disease of bone and FTD, caused by VCP gene mutations [91], results in type D pathology.
TDP-43 inclusions are also seen in most cases of ALS, in patients with and without clinical FTD symptomatology [92,93]. Based on the significant clinical and pathologic overlap among FTLD-TDP with or without motor neuron disease and TDP-positive ALS with or without dementia, it has been suggested that TDP-43 proteinopathies exist along a clinicopathologic spectrum of multisystem neurodegenerative diseases [94]. (See "Epidemiology and pathogenesis of amyotrophic lateral sclerosis", section on 'Pathology'.)
FTLD-FET — Mutations in the gene coding for FUS protein were originally identified as a cause of familial ALS. (See "Familial amyotrophic lateral sclerosis", section on 'ALS6 (FUS gene)'.)
Given the overlap between motor neuron disease and FTD, and FUS protein's functional homology with TDP-43, the involvement of FUS in FTD was explored, and most cases of FTLD with inclusions that were tau and TDP negative were found to stain positively for FUS protein [95]. FUS is a member of the FET protein family, which consists of other RNA- and DNA-binding proteins in Ewing sarcoma (EWS) and TATA-box binding protein associated factor 15 (TAF15) [96]. In addition to FUS, these pathological inclusions were also found to harbor EWS and TAF15 proteins [97]. FET proteins are also found in basophilic inclusion body disease (BIBD) and neuronal intermediate filament inclusion disease (NIFID) [98,99]. Together, FTLD-FET is estimated to account for 5 to 10 percent of all FTLD cases.
FTLD-UPS — FTLD cases that only label for markers of UPS are rare. Most FTLD-UPS cases are associated with FTD linked to chromosome 3 caused by mutations in CHMP2B. The neuropathology includes ubiquitin- and p62-positive granular neurocytoplasmic inclusions (that are negative for tau, TDP-43, and FUS proteins) [100,101].
CLINICOPATHOLOGICAL CORRELATIONS — Predicting the underlying pathology remains challenging for behavioral variant FTD (bvFTD), yet the specific primary progressive aphasia (PPA) subtypes do show stronger clinicopathological correlations.
●In one series of bvFTD, 29 percent had FTLD-tau, 47 percent had FTLD-TDP, and 7 percent had FTLD-FUS (with 13 percent showing a primary diagnosis of Alzheimer disease [AD] and 3 percent with amyotrophic lateral sclerosis [ALS]) [60].
●Semantic variant PPA (svPPA) is nearly always associated with FTLD-TDP type C (ranging from 75 to 100 percent across various cohorts) [102].
●Nonfluent variant PPA (nfvPPA) is most commonly associated with a four repeat (4R) tau pathology, with some reports describing an association with TDP type A [102].
●Logopenic variant PPA is usually caused by AD pathology, reported in up to 95 percent in one series [103].
Viewed from the pathological-clinical perspective:
●FTLD-tau pathology is most commonly associated with bvFTD, nfvPPA, and corticobasal degeneration (CBD).
●Within FTLD-TDP, common clinical syndromes for type A include bvFTD, nfvPPA, and CBD [86,104]. Type B mostly commonly appears as bvFTD with or without motor neuron disease. Type C nearly always presents as svPPA, and much less commonly bvFTD [104]. Type D, the rarest subtype, has only been identified in VCP mutation carriers. In one series, hallucinations in the initial years of the disease were related to TDP-43 pathology, including but not limited to C9orf72 repeat expansion carriers [105]. The presence of perseverative or compulsive behavior was more common in the type B and C histotypes.
●FTLD-FUS is the most common of the FTLD-FET pathologies and is strongly associated with the bvFTD phenotype, usually in association with ALS.
SUMMARY
●Terminology – Frontotemporal dementia (FTD) is a clinically and neuropathologically heterogeneous disorder characterized by disturbances in behavior, personality, and language accompanied by focal degeneration of the frontal and/or temporal lobes.
Frontotemporal lobar degeneration (FTLD) denotes the pathological diagnoses associated with the clinical FTD spectrum. In addition to behavioral variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and semantic variant primary progressive aphasia (svPPA), FTLD neuropathology is found in patients with motor neuron disease, corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). (See 'Introduction and terminology' above.)
●Epidemiology – FTD is a common cause of early-onset dementia and occurs at a similar frequency to Alzheimer disease (AD) in patients younger than 65 years. The mean age of onset is 58 years. (See 'Epidemiology' above.)
●Genetic factors – Thirty to 50 percent of patients with FTD have at least one relative with dementia. The most common pathogenic genetic mutations include variants in MAPT, GRN, and the C9orf72 repeat expansion. (See 'Genetic factors' above.)
●Pathology – The gross pathology of FTLD includes symmetric or asymmetric atrophy in the frontal and/or temporal lobes. Characteristic microscopic findings include microvacuolation and neuronal loss, accompanied by swollen neurons, loss of myelin, and astrocytic gliosis. In addition, abnormal protein inclusions are seen in the cytoplasm and/or nuclei of neuronal and/or glial cells. (See 'Shared pathological features' above.)
FTLD is subdivided according to the properties of the neuropathological inclusions. The majority of FTLD cases are found to harbor inclusions composed of hyperphosphorylated tau protein or the TDP-43 protein. FTLD-FET pathology is less common, accounting for only 5 to 10 percent of FTLD cases. (See 'Pathological subtypes' above.)
•FTLD-tau includes several different pathological subtypes, including Pick disease, chronic traumatic encephalopathy, CBD, PSP, the pathology of MAPT mutation carriers, argyrophilic grain disease, and global glial tauopathy. (See 'FTLD-tau' above.)
•In FTLD-TDP, abnormally phosphorylated and ubiquitinated TDP-43 appears as various morphologies. FTLD-TDP pathology is also found in patients with genetic mutations in GRN and VCP and the C9orf72 repeat expansion. (See 'FTLD-TDP' above.)
●Clinicopathological correlations – Predicting the underlying pathology remains challenging for bvFTD; most show either FTLD-tau or FTLD-TDP neuropathology.
Specific variants of primary progressive aphasia (PPA) show strong associations with neuropathology. svPPA is nearly always associated with TDP type C. nfvPPA is most commonly associated with a four repeat (4R) tau pathology. The logopenic variant of PPA is usually caused by AD. (See 'Clinicopathological correlations' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Bruce L Miller, MD, who contributed to an earlier version of this topic review.
