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The term Frontotemporal lobar degeneration describes a pathological process that selectively affects the frontal and temporal cortices, while the different clinical syndromes that result from this neurodegenerative process is now often referred to as Frontotemporal Dementia or FTD (Josephs 2008, Seelaar et al. 2011).
FTD can be divided in two main groups according to the predominant clinical features at the onset of the disease: a behavioural variant (bv-FTD) characterised by early, prominent behavioural and personality changes, and a variant characterised by a progressive language disorder often referred to as Primary Progressive Aphasia or PPA (Mesulam 2003; Grossman 2010). The latter have been traditionally subdivided in two clinical syndromes: Semantic Dementia (SD) and Progressive Non-Fluent Aphasia (PFNA). In recent years, a third subcategory has been described, termed Logopenic Progressive Aphasia or LPA (Gorno-Tempini et al. 2008).
In contrast to other neurodegenerative disorders, such as Alzheimer's disease (AD), the neuropathology of FTLD is heterogeneous. There is also a considerable overlap with extrapyramidal disorders, especially Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD), and with Motor neuron disorders such as Amyotrophic Lateral Sclerosis (Kövari 2009).
The first section will give a general framework of the current understandings of the pathology and genetics of FTLD, followed by the clinical and imaging findings of each of the clinical syndromes. Finally, the correlations between the neuropathological data and the latter syndromes will be reviewed.
Pathology and Genetics of FTLD - Overview
The pathology of FTLD is characterised by focal atrophy of the frontal and temporal lobes macroscopically; and neuronal loss, gliosis and spongiosis on microscopic examination (Cairns et al. 2007; Kövari 2009). Progress made in the fields of molecular pathology and genetics have helped in the understanding and pathological classification of FTLD. The current classification divides it into three main groups according to the type of proteins found as intracellular inclusions in neuronal cells (Cairns et al. 2007, Seelaar et al. 2011):
FTLD-Tau: Tau-positive inclusions (inclusions containing the microtubule-associated protein Tau). Tau deposits contain either a three-repeat variant (3R-Tau), a four-repeat (4R-Tau) or a mixture of both (3R/4R-Tau); different neuropathological entities are associated with each of this three subtypes (Figure 2):
3R-Tau: Pick's disease (i.e. FTLD with intraneuronal argyrophilic inclusions or "Pick bodies").
4R-Tau: PSP, CBD, and much rarer Argyrophilic Grain Disease (AGD) and Multiple System Tauopathy with Dementia (MSTD).
3R/4R-Tau: Neurofibrillary tangle dementia
MAPT mutations: Mutations in the Microtubule-Associated Protein Tau (MAPT) gene have been linked to any of the above variants.
FTLD-U: Ubiquitin positive (Tau negative) inclusions. These inclusions are composed of different proteins, of which the major component is one called TDP-43, which stands for TAR DNA-binding Protein 43 (Cairns et al. 2007). This group is therefore divided in two subcategories:
TDP-43 (+): positive for TDP-43, and classified into four groups (Sampathu et al. 2006) according to the pattern of distribution of the inclusions and the morphological changes in neurons (Fig 2).
TDP-43 (-): represents only 5-20% of FTLD-U, and the major constituent of these cases is a protein called Fused in Sarcoma or FUS (Urwin et al. 2010).
A subgroup that is negative for both TDP-43 and FUS has been recently described, and labelled as FTLD-UPS (Seelaar et al. 2011). The latter has been so far associated in the vast majority of cases with mutations in the CHMBP2B gene (Urwin et al. 2010).
Dementia Lacking Distinctive Histology (DLDH): is a descriptive term used when there is evidence of frontal and temporal lobe atrophy without lesions in hematoxylin-eosin, silver stain and all immunohistochemistry (Josephs 2008).
The realisation that between 10-20% of cases have a strong hereditary component led to the discovery of genetic mutations associated with the development of FTD (Leyton & Hodges 2010). The relationship is stronger for certain clinical subtypes such as bv-FTD and FTD-MND. For practical purposes, around half of the familiar cases are due to mutations in two genes, both located on chromosome 17:
Microtubule associated protein tau (MAPT): Mutations in MAPT can give rise either a clinical picture resembling extrapyramidal disorders i.e. FTD with parkinsonism linked to chromosome 17 (FTDP-17), or bv-FTD (Seelaar et al. 2011).
Progranulin (PGRN): Mutations in PGRN are relatively frequent, and are associated with the clinical phenotypes of bv-FTD, PNFA, LPA and CBD (Pickering-Brown 2010).
Other genes have been associated, albeit less frequently, with hereditary forms of FTD (Seelaar et al. 2011):
Valosin containing protein (VCP) - chromosome 9
Charged multivesicular body protein 2 B (CHMBP2B) - chromosome 3
TAR-DNA binding protein (TARDP) - chromosome 1
Fused in Sarcoma (FUS) - chromosome 16
Ubiquitin (+), Tau (-)
Type 1: abundant dystrophic neurites (SD)
Type 2: neuronal cytoplasmic inclusions (FTD-MND)
Type 3: neuronal intranuclear and cytoplasmic inclusions (PGRN)
Type 4: intranuclear inclusions (VCP)
(PSP, CBD, AGD, MSTD)
Figure 2. Pathological classification of Frontotemporal lobar degeneration (FTLD). The two major catagories are those Ubiquitin-positive (FTLD-U) and Tau-positive (FTLD-Tau). Each subcategory is associated with certain clinical syndromes (shown in brackets). TDP-43 = TAR DNA-binding protein 43, PSP = Progressive supranuclear palsy, CBD = Corticobasal degeneration, AGD = Argyrophilic grain disease, MSTD = Multiple system tauopathy with dementia, MAPT = Microtubule associated protein Tau gene, SD = Semantic Dementia, MND = Motor neuron disease, PGRN = Progranulin gene, VCP = Valosin containing protein gene, FUS = Fused in Sarcoma, CHMP2B = Charged multivesicular body protein 2B.
Frontotemporal lobar degeneration - Clinical Syndromes
Behavioural variant of FTD (Bv-FTD)
The behavioural variant of FTD is characterised by marked changes in personality and behaviour, leading to a profound disruption in social functioning and interpersonal relationships (Piguet et al. 2011a; Seelar et al. 2011). These changes are sometimes so profound that relatives and friends describe that the patient "is not himself anymore". The onset is often insidious and, since cognitive deficits are subtle, the clinical picture can be at first mistaken with neuropsychiatric disorders (Leyton & Hodges 2010). Although many of the clinical features are not specific for bv-FTD, it is their predominance in early stages of the disease what helps to distinguish this entity from other types of dementia, such as AD (Piguet et al. 2011a). Other cognitive functions e.g. visuospatial abilities and language are relatively preserved (Piguet et al. 2011a); sparing of episodic memory remains controversial in light of recent evidence (Hornberger et al. 2010; Pennington, Hodges & Hornberger 2011).
The clinical picture is dominated by a constellation of behavioural and cognitive disturbances which mainly reflect impairment of different frontal lobe functions, such as social cognition, emotion processing, motivation and executive functions:
Apathy: this is a frequent finding, and is usually manifested as loss of interest in previous activities, hobbies and social activities, reduced verbal and motor output, loss of motivation and volitional drive, lack of personal hygiene.
Disinhibition: this is also a very common symptom and usually coexists with apathy (Rabinovici & Miller 2010). It is manifested by inappropriate comments and/or sexual remarks, childish behaviour, rudeness, irritability and even aggressiveness.
Impulsivity: pathological gambling, excessive spending, reckless behaviour (e.g. while driving), shoplifiting, or even physical assault.
Repetitive/stereotyped behaviours, reflected by perseveration, ritualistic behaviours, wandering, compulsions, hoarding and utilisation behaviour.
Emotional blunting/lack of empathy: problems in emotion processing and recognition (especially for negative emotions), disinterest in interpersonal relationships, selfishness, and impaired perception of others' thoughts or emotional states (i.e. theory of mind).
Changes in eating behaviour: compulsive food intake, increased preference for sweets ("sweet tooth"). These changes are thought to be related not only with orbitofrontal circuits (Seelaar et al. 2011) but also with hypothalamic dysregulation (Piguet et al. 2011b).
Impaired insight: regarding the nature of the disease, its behavioural symptoms and their consequences in their global functioning.
Cognitive dysfunction: rigidity of thought, planning difficulties, deficits in attention and working memory, concrete thinking,
The presence of hallucinations and other symptoms of psychosis are relatively rare in bv-FTD, except in those cases associated with Motor Neurone Disease (bv-FTD/MND) and cases linked to mutations in the FUS gene (Piguet et al. 2011a).
A set of clinical criteria has been developed which emphasise the core clinical aspects of the disease (Table 1) as well as imaging and genetic biomarkers (Rascovsky, Hodges & Kipps 2007; Seelaar et al. 2011); further research is needed to determine their validity in the clinical setting (Piguet et al. 2011a).
The imaging findings in bv-FTD include initially atrophy of the frontal lobe, especially the orbitofrontal and medial regions, insular and anterior cingulate cortex (Piguet et al. 2011a, Seelaar et al. 2011). Other regions involved are the hippocampus, amygdalar complex, thalamus and basal ganglia (Piguet et al. 2011a). These changes may be subtle at presentation, and hence normal structural imaging does not rule out the diagnosis. As the disease progresses, atrophy extends to other areas such as the lateral portion of the frontal cortex, the temporal lobe and anterior parietal regions (Seelaar et al. 2011). There are some radiological patterns suggestive of the likely underlying pathology: bilateral involvement of the dorsolateral prefrontal cortex (DLPC) suggests Pick's disease (Whitewell et al. 2005), while prominent caudate atrophy has been correlated with FUS pathology (Seelaar et al. 2011). In addition, there seems to be a correlation between predominant right temporal atrophy and Tau pathology, and left temporal atrophy and TDP histopathology (Whitwell et al. 2005). Functional studies such as Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT)
Table 1- Proposed International consensus criteria for bv-FTD
Three of these features must be present throughout the course of the disease:
Early (3 years) disinhibition
Early (3 years) apathy or inertia
Early (3 years) loss of sympathy or empathy
Early (3 years) perseverative, stereotyped, or compulsive/ritualistic behaviour
Hyperorality and dietary changes
Neuropsychological profile: executive function deficits with relative sparing of memory and visuospatial functions
All the following criteria must be present to meet diagnosis:
Meets criteria for possible bv-FTD
Significant functional decline
Imaging results consistent with bv-FTD (frontal and/or anterior temporal atrophy on CT or MRI or frontal hypoperfusion or hypometabolism on SPECT or PET)
Criteria A and either B or C must be present to meet diagnosis:
Meets criteria for possible or probable bv-FTD
Histopathological evidence of FTLD on biopsy at post-mortem
Presence of a known pathogenic mutation
Exclusion criteria for bv-FTD
Criteria A and B must be absent; C can be positive only for possible bv-FTD:
Pattern of deficits is better accounted for by other non-degenerative nervous system or medical disorders
Behavioural disturbance is better accounted for by a psychiatric diagnosis
Biomarkers strongly indicative of Alzheimer's disease or other neurodegenerative process
Adapted from (Piguet et al. 2011a)
Semantic Dementia (SD)
Semantic dementia is characterised by a loss of knowledge or meaning of words, objects, facts and people, and thus differs from other disorders in which the deficit is in lexical retrieval or motor speech (Leyton & Hodges 2010). The latter process leads to a progressive impoverishment in vocabulary, especially for low frequency words, as well as a tendency to apply more familiar and broader terms for naming objects (e.g. "thing" or "animal"). The first problems noticed by patients are word finding difficulties and naming, and therefore they tend to complain initially of "memory difficulties". There is an increased reliance on circumlocutions to account for these deficits (Hodges & Patterson 2007; Seelaar et al. 2011). The loss of semantic knowledge is also reflected by a diminished performance in single-word comprehension tests (Kertesz et al. 2010; Seelaar et al. 2011). Semantic deficits are not restricted to language and can affect other modalities, e.g. visual and (Gorno-Tempini et al. 2011). A striking feature of SD, which is also very useful in clinical assessment, is the presence of "surface dyslexia" i.e. the words are read by general rules of pronunciation and not by their meaning (Leyton & Hodges 2010). Speech fluency, articulation, prosody, repetition and syntax are preserved as well as executive and visuospatial skills (Rabinovici & Miller 2010). Patients with also SD tend to have behavioural symptoms similar to bv-FTD (Seelaar et al. 2011), particularly those cases with predominant right temporal atrophy (Rabinovici & Miller 2010). The latter group are also prone to develop prosopagnosia, altered eating preferences and sleep disorders (Josephs et al. 2009; Rabinovici & Miller 2010).
MRI Imaging shows bilateral atrophy of the anterior pole of the temporal lobe (usually left more than right), anterior hippocampus and amygdala (Hodges & Patterson 2007). Other areas frequently affected include the entorhinal cortex, the inferior temporal and fusiform gyri (Seelaar et al. 2011). The atrophy of the anterior part of the left temporal lobe seems to be more marked in cases with Ubiquitin positive pathology (Rohrer et al. 2009), while prominent hippocampal atrophy is usually associated with AD pathology (Rohrer & Fox 2009). As with other language variants, these changes spread to frontal lobe structures with increase severity of the disease. There is also a correlation between the changes seen in structural imaging and regions of hypometabolism in functional studies such as PET (Hodges & Patterson 2007).
Progressive Non-Fluent Aphasia (PNFA)
This variant has a less homogeneous clinical picture than SD, although some features are quite typical. In contrast to SD, patients with PNFA have marked impairment in speech articulation and initiation (speech apraxia) and deficits in sentence construction and correct use of grammatical rules (agrammatism), with relative preservation of single word comprehension and semantic knowledge. Speech output is slow, non-fluent, hesitant and disprosodic; these alterations are particularly evident during spontaneous speech (Grossman 2010, Rabinovici & Miller 2010). Agrammatism is reflected by inappropriate syntax, incorrect use of tenses and omission of articles, auxiliary verbs and prepositions i.e. "telegraphic speech"(Henry & Gorno-Tempini 2010). Both speech apraxia and agrammatism are also evident during reading and writing, respectively. Other deficits include phonemic errors, anomia (with preserved semantic knowledge) and impaired repetition. Behavioural disturbances and cognitive deficits (especially in multitasking and working memory) might also develop, though less often than bv-FTD and SD (Grossman 2010).
There is often an overlap with extrapyramidal disorders such as Progressive Supranuclear Palsy (PSP) and Cortico-Basal Degeneration (CBD); therefore the neurological examination might reveal features consistent with these entities, such as apraxia, myoclonus, or supranuclear gaze palsy (Josephs 2008). As with other FTD variants, there is also increased association with Motor Neurone Disease.
PNFA - Imaging
Imaging initially reveals atrophy of the anterior perisylvian area of the left hemisphere; the anterior insular cortex and left inferior frontal lobe are also particularly affected (Seelaar et al. 2011). As the disease progresses, changes extend to other areas, such as the DLPC, mesial frontal lobe structures, anterior parietal lobe, and superior/middle temporal gyri (Grossman 2010). Although case series with pathological and radiological correlation are scant, there seems to be a link between some imaging patterns and pathology. PFNA cases with inferior frontal and superior temporal atrophy have been linked to tau pathology (Rohrer et al. 2009), and
Logopenic Progressive Aphasia (LPA)
This category was initially devised to describe those patients with a progressive language disorder who did not fit one either SD or PNFA (Leyton & Hodges 2010). The most salient clinical features are: slowness and reduction of speech output, word finding pauses and naming deficits, impaired repetition and phonemic errors (Henry & Gorno-Tempini 2010; Seelar et al. 2011). LPA differs from PNFA in that motor aspects of speech and grammar are preserved; whereas the major distinction from SD is that single-word comprehension is spared (Gorno-Tempini et al. 2011). Nevertheless, patients usually have problems to understand long, complex sentences and commands; this has been linked to deficits in the working memory system (Gorno-Tempini et al. 2008). There are also descriptions of difficulties in praxis, calculation and episodic memory (Gorno-Tempini et al. 2011)
The most prominent changes occur in the left hemisphere, especially the posterior aspects of temporal lobe, and the inferior parietal lobe (Henry & Gorno-Tempini 2010). The superior and middle temporal gyri are particularly affected (Leyton & Hodges 2010). These abnormalities in the temporo-parietal junction have been emphasised in the latest diagnostic criteria (Gorno-Tempini et al. 2011). Other areas that can also be involved, particularly in later stages, are: inferior and medial aspects of the temporal lobe (Grossman 2010), inferior frontal lobe and contralateral temporo-parietal cortex (Henry & Gorno-Tempini 2010). Functional imaging studies (PET and SPECT) show perfusion abnormalities that parallel the main structural changes i.e. left temporo-parietal junction (Gorno-Tempini et al. 2011).
Figure 3. Approximate anatomical location of each of the language syndromes in Primary Progressive Aphasia. PNFA= Progressive Non-Fluent Aphasia, SD = Semantic Dementia, LPA = Logopenic Progressive Aphasia. Adapted from (Grossman 2010).
Significant developments made in last years in the fields of pathology and genetics fostered interest in establishing correlations between the different clinical syndromes and neuropathological findings. These data, along with the use of imaging and other biomarkers, could be of great value in the prediction of the underlying pathology. An important point worth to remember is that the clinical syndrome of FTD is associated in the vast majority of cases with FTLD pathology (Seelaar et al. 2011), but other specific patterns such as AD and LBD pathology are sometimes present ( ). For instance, nearly 50% of patients with LPA have AD pathology (Henry & Gorno-Tempini 2010). As mentioned before, the delineation of hereditary forms and their respective gene mutations added further insight to the characterisation of the FTLD spectrum. A summary of the current view regarding clinicopathological associations is shown in Table 2.
The degenerative changes involve nearly symmetrical atrophy of both frontal and temporal lobes (Piguet et al. 2011). The selective degeneration of different brain areas has been associated with each of the main symptoms in bv-FTD (Seelaar et al. 2011): orbitofrontal cortex and right anterior temporal cortex (disinhibition), right anterior cingulate cortex and superior frontal gyrus (apathy), orbitofrontal-striatal circuit (stereotypic behaviours) and DLPFC (executive dysfunction).
Regarding histopathology, studies have shown that both Tau and TDP-43 represent approximately half of bv-FTD cases (Leyton & Hodges 2010), while the remainder are associated with FUS pathology (Seelaar et al. 2010). The latter group appears to have a distinct phenotype consisting of early age of onset, prominent behavioural and psychiatric symptoms, and atrophy of the caudate on MRI (Rohrer et al. 2010). Finally, patients with bv-FTD and coexistent MND are nearly always positive for TDP-43 (Hu & Grossman 2009) making this one of the strongest clinicopathological associations in FTLD.
In SD there is a preferential involvement of the ventral and lateral aspects of both anterior temporal cortices (Figure 3), usually more in the left (Grossman 2010). The overwhelming majority of cases are associated with TDP-43 pathology, especially the type 1 (i.e. abundant dystrophic neuritis), although there are case reports of Tau and AD type pathology as well (Seelaar et al. 2011).
Progressive Non-Fluent Aphasia
The major macroscopical changes occur primarily in the left inferior frontal lobe and the anterior insula (Rohrer & Fox 2009). These two areas have also been linked to aphasic symptoms and apraxia of speech respectively (Ratnavalli 2010; Seeley 2010). Despite the variability in the data from the different case series, the neuropathology is most often FTLD-Tau (Seelaar et al. 2011), followed by TDP-43 and other types such as AD and LBD (Grossman 2010). Interestingly, the presence of speech apraxia is highly suggestive of Tau pathology at postmortem (Rohrer & Fox 2009, Deramecourt et al. 2010).
Logopenic Progressive Aphasia
LPA degenerative changes involve mainly the left temporoparietal region and inferior parietal cortex (Gorno-Tempini et al. 2008; Rohrer et al. 2010); this coincides with the notion that deficits in the phonological loop and posterior language networks (Bonner, Ash & Grossman 2010; Rohrer et al. 2010). The most common neuropathological finding LPA cases is AD pathology (Henry & Gorno-Tempini 2010), followed by variable degrees of Tau and TDP-43 cases (Mesulam et al. 2008).
Table 2 - Clinical and pathological correlations in FTLD
Behavioural variant-FTD + MND
Tau (~50%), TDP-43 (~50%), FUS
TDP-43 (~100%) - especially type 1
Some reports of AD pathology and Pick's bodies
Progressive Non-Fluent Aphasia
Tau (70%), TDP-43 (30%)
Some reports of LBD, AD and DLDH pathology
Also TDP-43 and Tau
TDP-43 = TAR DNA-binding protein 43, FUS = Fused in Sarcoma, AD = Alzheimer's Disease, LBD = Lewy body disease, DLDH = Dementia lacking distinctive pathology.