FTLD: a family of syndromes

FTLD is associated with several clinical syndromes involving behavior, language, and motor function. Until recently, the main syndromes encompassed by the clinical term FTD were bvFTD, nfvPPA, and svPPA. Recent discoveries revealed overlap at a clinical, genetic, and pathologic level between these syndromes and 3 other syndromes: FTD with motor neuron disease (FTD-MND), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). The clinical expression of these syndromes is markedly different, reflecting selective injury of specific areas of the brain, which leads to the diverse signs and symptoms.

Recent clinical-pathologic studies all emphasize that proper clinical assessments are paramount to clinicopathologic prediction. Accurate diagnosis is the first step in the determination of the pathologic substrate because different syndromes are associated with different pathologies. In an effort to improve diagnosis, new criteria have been developed in the last year for bvFTD and the PPAs (semantic variant and nonfluent variant).

bvFTD is characterized by dramatic personality and behavioral changes with prominent loss of social cognition. New international research criteria have been established for bvFTD and focus on the behavioral/executive deficits ( Box 1 ).

As its name implies, bvFTD begins with prominent changes in social cognition, emotion, and behavior. Typical early symptoms include apathy, disinhibition, repetitive and compulsive behaviors, and progressive inability to represent the self and others, manifesting as shallow insight and lack of empathy. Disinhibition can lead to sociopathic behaviors such as being overly familiar with strangers, unsolicited sexual approaches, public urination, traffic violations, and shoplifting. There can be dramatic personality changes, such as change in religious beliefs, political conviction, dress, and social style. In bvFTD, overeating, weight gain, overstuffing the mouth, and idiosyncratic food fads occur. Patients often display utilization behavior, manifested by grasping at items in view or repeatedly switching lights on and off. Cognitive complaints, unlike in Alzheimer’s disease (AD), are typically less dramatic than the behavioral changes, and the main deficits are in executive function. bvFTD is the most common of the 3 main clinical subtypes of FTD, accounting for 56% of cases. It shows a male predominance (2:1), has the earliest age of onset (58 years at diagnosis), and progresses the most rapidly (3.4 years from diagnosis to death). bvFTD has the highest genetic susceptibility and is strongly associated with MND.

nfvPPA (previously known as progressive nonfluent aphasia) is a disorder of expressive language and speech production. New international criteria for PPA were recently published and highlight the expressive language deficits with relative sparing of single sentence or word comprehension ( Boxes 2–4 ). nfvPPA accounts for 25% of FTD and has an intermediate rate of progression (4.3 years from diagnosis) and genetic cause. Nonfluent speech is often accompanied by agrammatism, phonemic paraphasias, anomia, and speech apraxia. Speech is slow, effortful, and telegraphic, and in contrast to bvFTD, personal and interpersonal conduct, behavior, and insight are preserved early on.

svPPA, previously known as semantic dementia or temporal variant FTD, is a disorder with loss of semantic knowledge for words. It presents differently depending on which hemisphere is the site of pathology. Left-sided atrophy produces progressive loss of meaning for words, objects, and emotions. In contrast, right-sided pathology is associated with behavioral changes. svPPA accounts for less than 20% of all FTD cases and shares an earlier age of onset with bvFTD but shows the slowest rate of progression (5.2 years from diagnosis to death). svPPA has fewer cases of autosomal-dominant inheritance.

Although the term FTD was established to include only bvFTD, nfvPPA, and svPPA, it is now known that there are strong links and considerable overlap between FTD clinical syndromes and other conditions including PSP and CBS. Many patients begin with an nfvPPA syndrome and later evolve into a clinical disorder suggestive of CBS or PSP.

There are no consensus clinical research criteria for CBS but previous studies have described a progressive, asymmetric, akinetic-rigid syndrome that does not respond to levodopa treatment. Individuals have a combination of deficits attributable to cortical dysfunction, such as apraxia, language difficulties, and cortical sensory loss or neglect as well as symptoms attributable to basal ganglia dysfunction such as rigidity or dystonia. Cognitively, planning and other aspects of executive function are impaired in CBS. In October 2009, a group of corticobasal degeneration (CBD)/CBS researchers met to determine consensus clinical research criteria for CBS. The new criteria (Litvan and colleagues, manuscript in preparation) will be similar to the previous criteria but will also include dementia syndromes that have been associated with CBD.

Consensus research criteria have been developed for PSP and have been reported to have excellent predictive power for underlying PSP pathology. PSP is named for its characteristic eye movement abnormalities, and a diagnosis of probable PSP requires a slowly progressive disorder with onset after age 40 years and a vertical supranuclear gaze palsy of eye movements and falls within the first year of diagnosis. Other supportive criteria include prominent axial rigidity, early dysphagia and dysarthria, apathy, and cognitive impairments consisting mainly of executive dysfunction. Significant behavioral changes including impulsivity, perseveration, and diminished judgment also feature in PSP.

MND may co-occur with bvFTD-like symptoms, or, less commonly, with svPPA or nfvPPA, and the term FTD-MND has been applied to these cases. FTD-MND most commonly affects lower motor neurons to the bulbar and upper limb musculature. The close relationship between dementia and MND (also known as amyotrophic lateral sclerosis) surfaced with the discovery of overlapping genetics, including a recent discovery that the expanded hexanucleotide repeat in a noncoding region of chromosome 9 is associated with MND and FTD. In addition, common neuropathologic substrates exist between the 2 syndromes, suggesting a strong connection between them. In prospective studies, up to 50% of patients with FTD had possible or probable MND, and 50% of patients with MND who underwent behavioral and neuropsychological evaluation had measurable (mainly frontal/executive and behavioral) cognitive deficits, and many met criteria for an FTD syndrome.

FTLD: understanding the syndrome-pathology relationship

The underlying pathology of FTLD has proved more complex than anticipated. It is now known that at least 3 different molecular pathologies exist consisting of abnormal protein aggregation: tau, TDP-43, and FUS.

Abnormal tau deposition or aggregation was the first pathologic substrate described and, until recently, it was believed to be the main cause of FTLD. Tau is a protein that binds to and stabilizes microtubules that are necessary for maintaining neuronal shape and for transport of cellular cargo. The abnormal tau can be seen in neurons, glia, or both. The syndromes that associate with abnormal tau deposition are known as tauopathies. PSP is associated exclusively with tau pathology, whereas in the case of CBS, although most cases are caused by abnormal tau aggregation, there is recognition that other diseases can cause the syndrome such as TDP-43 or AD. Nonfluent variant PPA is also primarily a tauopathy but can also be associated with TDP-43 or AD. A variety of mutations have been identified in the microtubule-associated protein tau (MAPT) gene that lead to bvFTD, nfvPPA, PSP, and CBS.

Tau-negative cases of FTLD stain for ubiquitin, an integral part of the degradative system. Most ubiquitin-positive inclusions observed in FTLD result from the accumulation of inclusions that stain for TDP-43, a widely expressed nuclear protein with presumed functions in transcription regulation and exon skipping. These neuronal or cytoplasmic ubiquitinated inclusions are usually seen in affected cortex, dentate granule cells, and primary motor cortex, spinal cord, or brain stem motor neurons in FTD-MND.

Four distinct patterns of pathologic features and regional variability were observed in cases of TDP-43 proteinopathy, and these patterns have clinical relevance, because they are specific to some, although not all, of the syndromes. FTLD-TDP A, which features many neuronal cytoplasmic inclusions and short dystrophic neurites in layer 2 of the cortex, is seen in bvFTD, nfvPPA, and nearly all patients with granulin (GRN) mutations. Patients with FTLD-TDP and a GRN polymorphism of the T-allele of rs5848 often show an FTLD-TDP A pathologic pattern. FTLD-TDP B is transcortical and features some neuronal cytoplasmic inclusions and few dystrophic neurites and is seen in bvFTD and FTD-MND. FTLD-TDP C is also predominantly in layer 2, features many, long, dystrophic neurites and few neuronal cytoplasmic inclusions, and is seen in svPPA and bvFTD. A fourth subtype, FTLD-TDP D, is seen only in valosin-containing protein (VCP) mutations and consists of many short dystrophic neurites, many lentiform neuronal intranuclear inclusions, and few neuronal cytoplasmic inclusions. The pathology are seen in all layers. The clinical phenotype associated with the VCP mutations is inclusion body myopathy with Paget disease of bone and FTD.

The inclusions in ubiquitin-positive, TDP-43–negative cases of FTLD were recently discovered to stain for the FUS protein. FUS is a ubiquitously expressed DNA/RNA-binding protein involved in multiple aspects of gene expression, transcription regulation, RNA splicing, transport, and translation. FUS pathology is reportedly associated with a distinct clinical phenotype that includes young onset, prominent obsessionality, repetitive behaviors and rituals, social withdrawal and lack of engagement, hyperorality with pica, and marked stimulus-bound behavior including use behavior. In addition, FUS cases show severe caudate atrophy. This pathologic subtype may be the easiest to disentangle from the other FTLD pathologic substrates.

Clinicopathologic correlations have shown that certain FTLD syndromes are reliably associated with specific proteinopathies: FTD-MND is associated almost uniquely with FTLD-TDP, with only a few cases ascribed to FUS. svPPA also is almost always associated with FTLD-TDP, with only rare cases of FTLD-tau described. PSP is exclusively a tauopathy. However, the rest of the syndromes are difficult to predict because nfvPPA is most often associated with a tauopathy, but FTLD-TDP and AD pathology can cause this clinical syndrome in some cases. bvFTD is difficult to predict, because it can be associated with FTLD-tau, FTLD-TDP, FTLD-FUS, or AD. CBS is similarly difficult to predict, because although most cases are associated with FTLD-tau, there are reports of FTLD-TDP and AD as the pathologic substrate of CBS.

FTLD: understanding the syndrome-pathology relationship

The underlying pathology of FTLD has proved more complex than anticipated. It is now known that at least 3 different molecular pathologies exist consisting of abnormal protein aggregation: tau, TDP-43, and FUS.

Abnormal tau deposition or aggregation was the first pathologic substrate described and, until recently, it was believed to be the main cause of FTLD. Tau is a protein that binds to and stabilizes microtubules that are necessary for maintaining neuronal shape and for transport of cellular cargo. The abnormal tau can be seen in neurons, glia, or both. The syndromes that associate with abnormal tau deposition are known as tauopathies. PSP is associated exclusively with tau pathology, whereas in the case of CBS, although most cases are caused by abnormal tau aggregation, there is recognition that other diseases can cause the syndrome such as TDP-43 or AD. Nonfluent variant PPA is also primarily a tauopathy but can also be associated with TDP-43 or AD. A variety of mutations have been identified in the microtubule-associated protein tau (MAPT) gene that lead to bvFTD, nfvPPA, PSP, and CBS.

Tau-negative cases of FTLD stain for ubiquitin, an integral part of the degradative system. Most ubiquitin-positive inclusions observed in FTLD result from the accumulation of inclusions that stain for TDP-43, a widely expressed nuclear protein with presumed functions in transcription regulation and exon skipping. These neuronal or cytoplasmic ubiquitinated inclusions are usually seen in affected cortex, dentate granule cells, and primary motor cortex, spinal cord, or brain stem motor neurons in FTD-MND.

Four distinct patterns of pathologic features and regional variability were observed in cases of TDP-43 proteinopathy, and these patterns have clinical relevance, because they are specific to some, although not all, of the syndromes. FTLD-TDP A, which features many neuronal cytoplasmic inclusions and short dystrophic neurites in layer 2 of the cortex, is seen in bvFTD, nfvPPA, and nearly all patients with granulin (GRN) mutations. Patients with FTLD-TDP and a GRN polymorphism of the T-allele of rs5848 often show an FTLD-TDP A pathologic pattern. FTLD-TDP B is transcortical and features some neuronal cytoplasmic inclusions and few dystrophic neurites and is seen in bvFTD and FTD-MND. FTLD-TDP C is also predominantly in layer 2, features many, long, dystrophic neurites and few neuronal cytoplasmic inclusions, and is seen in svPPA and bvFTD. A fourth subtype, FTLD-TDP D, is seen only in valosin-containing protein (VCP) mutations and consists of many short dystrophic neurites, many lentiform neuronal intranuclear inclusions, and few neuronal cytoplasmic inclusions. The pathology are seen in all layers. The clinical phenotype associated with the VCP mutations is inclusion body myopathy with Paget disease of bone and FTD.

The inclusions in ubiquitin-positive, TDP-43–negative cases of FTLD were recently discovered to stain for the FUS protein. FUS is a ubiquitously expressed DNA/RNA-binding protein involved in multiple aspects of gene expression, transcription regulation, RNA splicing, transport, and translation. FUS pathology is reportedly associated with a distinct clinical phenotype that includes young onset, prominent obsessionality, repetitive behaviors and rituals, social withdrawal and lack of engagement, hyperorality with pica, and marked stimulus-bound behavior including use behavior. In addition, FUS cases show severe caudate atrophy. This pathologic subtype may be the easiest to disentangle from the other FTLD pathologic substrates.

Clinicopathologic correlations have shown that certain FTLD syndromes are reliably associated with specific proteinopathies: FTD-MND is associated almost uniquely with FTLD-TDP, with only a few cases ascribed to FUS. svPPA also is almost always associated with FTLD-TDP, with only rare cases of FTLD-tau described. PSP is exclusively a tauopathy. However, the rest of the syndromes are difficult to predict because nfvPPA is most often associated with a tauopathy, but FTLD-TDP and AD pathology can cause this clinical syndrome in some cases. bvFTD is difficult to predict, because it can be associated with FTLD-tau, FTLD-TDP, FTLD-FUS, or AD. CBS is similarly difficult to predict, because although most cases are associated with FTLD-tau, there are reports of FTLD-TDP and AD as the pathologic substrate of CBS.

Genetics of FTLD

Although most FTLD cases are sporadic, unlike the other dementing illnesses, FTLD has a strong familial component because up to 40% to 50% of cases are diagnosed as familial and 10% show an autosomal-dominant pattern of inheritance. Multiple genes have been implicated in FTLD, including MAPT (chromosome 17), GRN (chromosome 17), VCP (chromosome 9), chromatin-modifying protein 2B (also known as charged multivesicular body protein 2B gene) CHMP2B (chromosome 3), and FUS gene (chromosome 16). Recently, a novel mutation has been discovered as the most common cause of familial FTD and MND; it consists of an expanded hexanucleotide repeat in a noncoding region of chromosome 9 open reading frame 72. The gene encodes an uncharacterized protein with no known domains or function, but which is highly conserved across species.

These genetic abnormalities are associated with specific proteinopathies so that MAPT mutation leads to a tauopathy, VCP and GRN mutations and expanded hexanucleotide repeat to TDP-43 proteinopathy, and FUS mutation to a FUSopathy. The abnormal protein in CMP2B mutations remains elusive to date; no specific protein has been discovered to identify the inclusions.

FTLD was first linked to chromosome 17 (MAPT gene) by Wilhelmsen and colleagues. MAPT mutations are associated with tau pathology, and more than 40 different mutations in the MAPT gene have been reported in association with familial FTD syndromes. Humans carry an equal ratio of 3R and 4R tau, but mutations in the tau intron lead to increases in the ratio of 4R to 3R tau. A wide spectrum of disorders has been reported with tau inclusions, including bvFTD, nfvPPA, CBD, and PSP.

Although MAPT mutations were the first discovered, epidemiologic studies have identified GRN mutations in 5% to 11% of all FTD and 11% to 26% of patients with a family history, making it the most common cause of genetic FTLD. This mutation is also on chromosome 17 but at 17q21 in the progranulin ( GRN ) gene. More than 50 progranulin mutations have been found since it was discovered in 2006, and these mutations lead to deficient protein levels of progranulin. The role of progranulin in neurodegeneration is still unknown, although progranulin is a trophic factor, and is implicated in wound healing, tumor growth, inflammation, and brain development in mice; it promotes neuronal survival and stimulates neuritic outgrowth in cultures of rat motor and cortical neurons. Progranulin mutations are associated with phenotypic heterogeneity, even within family members with the same mutation. bvFTD is the most common presentation of GRN mutation followed by nfvPPA and svPPA although parkinsonian and AD syndromes are also seen. The ubiquitinated inclusions associated with progranulin mutations stain for TDP-43.

The likelihood of a genetic mutation associated with the FTLD syndrome varies across the different subtypes. bvFTD and FTD-MND are the most strongly familial of the FTLD syndromes. Semantic variant is the least familial, whereas nfvPPA lies in between bvFTD and svPPA. As a risk for FTD, the role of apolipoprotein E4 seems to be small, although E4 may expand the pathologic damage in frontal regions in FTD.

Polymorphisms, in the absence of mutation, have gained attention as possible contributors to pathology. Rademakers and colleagues showed a significant reduction in progranulin protein level in homozygous GRN T-allele carriers in vivo, and the neuropathology of homozygous GRN rs5848 T-allele carriers frequently resembled the pathologic FTLD-ubiquitin subtype of GRN mutation carriers. Structural differences in brain areas important for social cognition (ie, left medial orbital white matter [WM], right fusiform WM, and right supramarginal total volume) were observed between normal controls with homozygous T-alleles of a common genetic variant rs5848 in the GRN gene compared with the CT and CC polymorphisms. The MAPT H1H1 haplotype is overly represented in patients with CBS and PSP; healthy white controls show between 60% and 70% homozygosity for H1, approximately 90% of patients with CBS and PSP are H1H1. How polymorphisms interact with the molecular pathology to determine the specific pathology as well as its distribution is unknown.

The ubiquitinated inclusions associated with progranulin mutations stain not for progranulin but instead for TDP-43. In contrast to sporadic cases of FTD with ubiquitin-TDP-43 pathology, in which the inclusions occur in the cytoplasm, with progranulin mutations, TDP-43 is found in the nucleus. This naturally occurring protein is found in the nucleus and is implicated in exon skipping and transcription regulation. Mutations in the TARDBP-43 gene localized on chromosome 1 have recently been identified in a few families with autosomal-dominant MND, which supports the role of TDP-43 in the pathophysiology of MND.