Frontotemporal Dementia and Related Disorders: Deciphering the Enigma

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1 NEUROLOGICAL PROGRESS Frontotemporal Dementia and Related Disorders: Deciphering the Enigma Keith A. Josephs, MST, MD In the past century, particularly the last decade, there has been enormous progress in our understanding of frontotemporal dementia, a non-alzheimer s type dementia. Large clinicopathological series have been published that have clearly demonstrated an overlap between the clinical syndromes subsumed under the term frontotemporal dementia and the progressive supranuclear palsy syndrome, corticobasal syndrome, and motor neuron disease. There have also been significant advancements in brain imaging, neuropathology, and molecular genetics that have led to different approaches to classification. Unfortunately, the field is complicated by a barrage of overlapping clinical syndromes and histopathological diagnoses that does not allow one to easily identify relations between individual clinical syndromic presentations and underlying neuropathology. This review deciphers this web of terminology and highlights consistent, and hence important, associations between individual clinical syndromes and neuropathology. These associations could ultimately allow the identification of appropriate patient phenotypes for future targeted treatments. Ann Neurol 2008;64:4 14 The clinical diagnosis of frontotemporal dementia (FTD) refers to a group of progressive overlapping clinical syndromes characterized by the insidious onset of behavioral changes, loss of word and object knowledge, and aphasia. 1 Recent large clinicopathological studies have demonstrated an overlap among the FTD syndromes, some extrapyramidal syndromes, and motor neuron disease (MND). 2 5 Furthermore, FTD and these related disorders show overlapping histopathological and biochemical abnormalities that have led to the recommendation by some researchers to lump FTD and related disorders under one large umbrella term, Pick s complex. 6 Parallel to the publications of clinicopathological series, neuroimaging and molecular genetic studies have published important findings that have been shown to be useful in refining clinicopathological associations. Unfortunately, the exponential number of publications of clinical, neuropathological, neuroimaging, and molecular genetic research on FTD and related disorders has complicated the field with the reporting of a barrage of overlapping diagnoses and interpretations of histopathological classifications. This has led to a complex lattice of associations between clinical and neuropathological diagnoses, some of which are clearly minor associations whereas others are more significant. Therefore, one cannot easily identify important relations between individual clinical syndromic presentations and underlying histopathologies. This review deciphers this web and highlights consistent, and hence important, associations between the more common individual syndromes and neuropathology. Fine-tuning these associations with better understanding of imaging characteristics, environmental and genetic causes, and biochemical alterations will ultimately allow the identification of appropriate patient phenotypes for targeted treatments currently in development. In this review, the term FTD is applied as an umbrella term for the clinical syndromes of behavioral variant FTD (bvftd), semantic dementia (SD), and progressive nonfluent aphasia (PNFA), whereas the term frontotemporal lobar degeneration (FTLD) will be used as an umbrella term for the spectrum of FTDrelated pathologies. 7 Similarly, the term extrapyramidal syndromes is used as an umbrella term for the clinical syndromes of corticobasal syndrome (CBS) and the progressive supranuclear palsy syndrome (PSP-S), whereas the terms corticobasal degeneration and progressive supranuclear palsy (PSP) are used only in the context of pathological diagnosis. Clinical Syndromes FTD is an umbrella term that includes a number of different syndromic variants, all characterized by the From the Department of Neurology, Behavioral Neurology and Movement Disorders, Mayo Clinic, Rochester, MN. Received Jan 29, 2008, and in revised form Apr 22, Accepted for publication Apr 25, Published online in Wiley InterScience ( DOI: /ana Address correspondence to Dr Josephs, Mayo Clinic, Department of Neurology, 200 1st Street SW, Rochester, MN josephs.keith@mayo.edu American Neurological Association Published by Wiley-Liss, Inc., through Wiley Subscription Services

2 Table 1. Different Terminologies Associated with Progressive Aphasias Terminology Description of Terminology Semantic dementia Progressive nonfluent aphasia Apraxia of speech Logopenic aphasia Aphasic dementia PPA subtypes 21 Agrammatic/ dysfluent PPA Semantic variant PPA Logopenic variant PPA PPA primary progressive aphasia. Characterized by a loss of word meaning (single words) and comprehension difficulties Nonfluent speech output with agrammatic and telegraphic speech (such as writing a telegram) Characterized by slow speaking rate, abnormal prosody, and distorted sound substitutions, sometimes accompanied by groping and trial-and-error articulatory movements Characterized by slow speech and impaired syntactic comprehension and naming Characterized by prominent speech and language deficits but accompanied by mild behavioral or cognitive deficits such as loss of episodic memory or visuospatial/ perceptual deficits Equivalent to progressive nonfluent aphasia and is characterized by poor syntax and fluency but good comprehension Equivalent to the nonagnostic form of semantic dementia and is characterized by poor comprehension but good syntax and fluency Equivalent to logopenic aphasia and is characterized by good syntax and comprehension but frequent word-finding pauses presence of behavioral and personality changes and aphasia. 1 The consensus criteria published in 1998 identifies three variants of FTD that are now referred to as bvftd, SD, and PNFA. 1 These syndromes have overlapping features but are each characterized by the predominant feature. Hence, bvftd is diagnosed when the dominant presenting feature is a change in personality or behavior associated with executive dysfunction. Language impairment can also occur in bvftd but is overwhelmingly overshadowed by the change in personality. A small subset of patients with bvftd has been noted to have bizarre visual hallucinations and prominent Parkinsonism, although the pathology underlying these patients is unclear. It also appears that a small proportion of patients fulfilling criteria for bvftd show little progression in their symptoms over time. 8,9 These are referred to as slowly progressive FTD. SD is characterized by loss of word and object knowledge and comprehension deficits that can be associated with varying degrees of prosopagnosia (loss of facial recognition). 1 Behavioral changes are also noted in SD but tend to be somewhat distinct from the behavioral changes seen in bvftd. 10,11 Some researchers have further divided SD into right and left temporal variants based on which temporal lobe shows the greater amount of atrophy. Behavioral changes rather than prosopagnosia, as originally reported, are the typical presenting feature of the right temporal variant. 12,13 The third syndrome, known as PNFA, is characterized by a nonfluent speech output, agrammatism, and telegraphic speech. Unlike bvftd and SD, behavioral and personality changes are less common in PNFA. More commonly seen in PNFA, particularly later on in the disease course, is the development of extrapyramidal features, sometimes leading to a change in the diagnosis from PNFA to CBS. 4,14 A parallel development to PNFA and SD was primary progressive aphasia (PPA), 15 a term coined by Mesulam, 16 who first reported a series of six patients with progressive aphasia. A diagnosis of PPA can be made in any patient with a progressive neurodegenerative disease in which language impairment is the most salient feature, 15 and hence the term PPA subsumes PNFA, and overlaps with SD. Other terminologies have also been described in relation to progressive aphasias, and a recent publication suggested dividing PPA into three clinical variants (Table 1). 21 It remains controversial, however, whether a semantic variant of PPA exists in which a visual associative agnosia (loss of the meaning of objects when viewed) is truly absent, or whether semantic PPA is simply SD dominated by a verbal associative agnosia. 22 Although bvftd, SD, and PNFA are syndromes dominated by behavioral and language changes, extrapyramidal features, especially in PNFA, can be prominent. Over the past decade, many case reports, as well as large clinicopathological series, have recognized an overlap among these three syndromes and PSP-S, CBS, and MND. 2 5 PSP-S is typically characterized by akinesia and rigidity, vertical supranuclear gaze palsy, and early falls. 23,24 Behavioral and personality changes and executive dysfunction can occur in PSP-S but tend to Josephs: Deciphering the FTD Enigma 5

3 be mild, whereas apathy can be a prominent feature, hence the overlap with bvftd. The CBS is also characterized by akinesia and rigidity, but this tends to be asymmetric. 25 A combination of limb apraxia and myoclonus, and alien limb phenomenon can be prominent. Behavioral and personality changes and nonfluent speech can also be prominent, hence the overlap with the FTD syndromes. In some cases of FTD, features of MND are observed, suggesting that FTD and MND may be on the same disease spectrum. 26 Features of MND may include bulbar symptoms such as difficulty speaking and swallowing, weakness, spasticity, fasciculations, hyperactive reflexes, clonus, and a Babinski sign. The features of MND tend to be mixed upper and predominantly lower but can be predominantly upper. MND is rare in SD, PNFA, PSP-S, and CBS, but it has been described. 17,27,28 MND is more commonly associated with features of bvftd, hence the term FTD-MND, although many patients diagnosed with FTD-MND do not meet strict criteria for bvftd. 1 In FTD-MND, disease progression is rapid, with death occurring after an illness duration of approximately 2 years. 29 Behavioral and cognitive deficits usually precede clinical features of MND, although a sizable proportion of patients with MND have, or can later develop, features suggestive of FTD. 30 Imaging In clinical practice, routine imaging is performed primarily to rule out other nondegenerative processes that can mimic the FTD syndromes and related disorders. However, imaging can also be useful to aid in the clinical diagnosis based on the identification of specific patterns of atrophy that are best observed on head magnetic resonance imaging scans. It is important to note that many of the findings reported on magnetic resonance imaging do not have pathological confirmation and, therefore, represent the clinical syndrome and not the pathology. The three main FTD syndromes, bvftd, SD and PNFA, have somewhat distinct patterns of atrophy. The bvftd is associated with atrophy affecting bilateral frontal lobes, particularly the medial frontal lobes, and anterior temporal lobes, whereas SD is associated with bilateral, although usually asymmetric, middle, inferior, and medial anterior temporal lobe atrophy. In contrast, PNFA shows left perisylvian atrophy. In the related disorders, atrophy of the midbrain tegmentum and superior cerebellar peduncle is characteristic of the PSP-S, whereas frontoparietal atrophy is associated with the CBS. Functional imaging studies such as single-photon computed tomography and positron emission tomography have found similar patterns of neocortical hypoperfusion and hypometabolism in these clinical syndromes. In addition, some patients may also show changes in basal ganglia and thalamus. A recent study showed that on first presentation, bvftd disproportionately had right frontal hypoperfusion on single-photon computed tomography, although the temporal lobes were also involved and were associated with specific clinical features. 31 A number of group studies using an automated technique called voxel-based morphometry have assessed the patterns of atrophy in the different clinical variants of FTD. This technique performs statistical comparisons across groups of subjects to identify regions that show significant atrophy. Studies have largely confirmed the patterns observed in observational case studies, although they have also provided further insight into the extent of brain loss in these disorders. For example, voxel-based morphometry studies that examine bvftd, SD, PNFA, PSP-S, and CBS have been published. 18,19,32 34 Interestingly, one group of researchers demonstrated that a distinct pattern of atrophy affecting posterior temporal and parietal regions was associated with logopenic aphasia. 18 This same pattern of atrophy was also reported to be associated with aphasic dementia 20 and with PPA patients with impaired word finding but intact comprehension on conversational speech. 35 Atrophy of the supplemental motor cortex and superior premotor cortex extending into the motor cortex has been shown to be associated with apraxia of speech, 19 and posterior frontal lobe atrophy has been observed in FTD-MND. 36 Histopathology With the advent of immunohistochemistry it became clear that many different pathologies underlie the FTD syndromes, and that these same pathologies were associated with the FTD-related disorders, such as PSP-S, CBS, and MND. It is now well established in the field that more than 15 different pathologies can underlie FTD and related disorders. 7,37 The most common pathology associated with FTD was thought to be dementia lacking distinctive histology (DLDH), 38 a diagnosis made when there was gross evidence of frontal and temporal lobe atrophy and histological findings of neuronal loss and gliosis affecting superficial cortical lamina of these same cortical regions and absence of the typical pathological findings of Alzheimer s disease. It was also recognized that many cases with DLDH had evidence of neuronal loss and gliosis affecting the CA1 and subicular regions of the hippocampus, that is, hippocampal sclerosis. 39 With the advent of ubiquitin immunohistochemistry, many cases of DLDH were observed to have ubiquitinated inclusions and dystrophic neurites in lamina II of the frontal and temporal cortices, as well as in the dentate granule cells of the hippocampus Hence, the majority of DLDH cases were renamed frontotemporal lobar degeneration with ubiquitin-only immunoreactive changes (FTLD-U), although rare cases of FTLD-U 6 Annals of Neurology Vol 64 No 1 July 2008

4 Fig 1. Classification scheme demonstrating the subdivision of the spectrum of frontotemporal lobar degeneration (FTLD) pathologies into tauopathies versus TAR DNA-binding protein 43 (TDP-43) proteinopathies. Some cases, however, are neither a tauopathy nor a TDP-43 proteinopathy and are therefore classified as Others. AGD argyrophilic grain disease; ALS-PDC amyotrophic lateral sclerosis-parkinsonism complex of Guam; BIBD basophilic inclusion body disease; CBD corticobasal degeneration; DLDH dementia lacking distinctive histology; DNTC diffuse neurofibrillary tangle dementia with calcifications; FTLD-U frontotemporal lobar degeneration with ubiquitin-only immunoreactive changes; MST sporadic multisystem tauopathy; MBD neurofilament inclusion body disease; PiD Pick s disease; PSP progressive supranuclear palsy; TDD tangle dominate dementia. without lobar atrophy have also been described. 8 It was also observed that, in addition to the ubiquitinated neocortical lesions and those in the dentate granule cells of the hippocampus, some cases of DLDH also had evidence of motor neuron degeneration or descending corticospinal tract degeneration. Those cases have been separated from FTLD-U and were called FTLD-MND. 40 Further subclassification of FTLD- MND has been recently suggested, based on the findings of isolated upper MND in some cases for which the term FTLD with primary lateral sclerosis was proposed. 43 The separation of FTLD-U from FTLD- MND is supported by the fact that hippocampal sclerosis is common in FTLD-U but uncommon in FTLD-MND. 43,44 The diagnosis of true DLDH is now extremely rare and is reserved only for cases in which there is evidence of frontal and temporal lobar atrophy but absent lesions on hematoxylin and eosin, silver, and all immunohistochemistry. Molecular Pathology In 2006, researchers from the University of Pennsylvania and from Japan identified one of the major ubiquitinated proteins in FTLD-U, FTLD-MND, as well as amyotrophic lateral sclerosis (ALS) as the TAR DNAbinding protein 43 (TDP-43). 45,46 These diseases therefore became known as TDP-43 proteinopathies (Fig 1). TDP-43 is a highly conserved nuclear protein that functions in the regulation of transcription and alternative splicing. Consensus criteria were published using TDP-43, and data generated from two previous studies, 47,48 suggesting that FTLD-U be further subclassified into three variants based on the morphology, distribution, and ratio of TDP-43 positive neuronal cytoplasmic inclusions to dystrophic neurites: FTLD-U types 1, 2, and 3 37 (Fig 1: Table 2). FTLD-MND essentially was subsumed under FTLD-U type 2. It has also been suggested that these three variants show an association with the FTD syndromes: type 1 was associated with SD, type 2 with FTD-MND and bvftd, and type 3 with bvftd and PNFA Further studies, however, are needed to confirm this observation. Recent studies have demonstrated that abnormal TDP-43 immunoreactivity also occurs in Alzheimer s disease, 51 Pick s disease (PiD), 46,52 pure hippocampal sclerosis (no evidence of lobar atrophy), 51 Lewy body disease, 53 and the ALS-parkinsonism complex of Guam, 54,55 and one study demonstrated alterations in the Alzheimer s disease phenotype when TDP-43 was copresent. 56 Rare cases of FTLD-U without abnormal TDP-43 immunoreactivity have also been published. 57 Although the majority of FTLD cases are TDP-43 proteinopathies, a significant number of FTLD and related disorders are characterized by the accumu- Josephs: Deciphering the FTD Enigma 7

5 Table 2. Histological Features and Genetic Associations of the Different Frontotemporal Lobar Degeneration with Ubiquitin-Only Immunoreactive Changes Subtypes FTLD-U Subtype Description of Histological Features Genetic Associations Type 1 Type 2 Type 3 Type 4 Type 5 Frontotemporal neuronal loss and gliosis with a predominance of TDP-43/ubiquitin/P62-positive elongated dystrophic neurites with few neuronal cytoplasmic inclusions Frontotemporal neuronal loss and gliosis with a predominance of TDP-43/ubiquitin/P62-positive neuronal cytoplasmic inclusions with few short dystrophic neurites Frontotemporal neuronal loss and gliosis with TDP-43/ ubiquitin/p62-immunoreactive neuronal cytoplasmic inclusions, short dystrophic neurites, and intranuclear inclusions Frontotemporal neuronal loss and gliosis with TDP-43/ ubiquitin/p62 neuronal intranuclear inclusions and dystrophic neurites with scant neuronal cytoplasmic inclusions Frontotemporal neuronal loss and gliosis with ubiquitin/p62 but without TDP-43 positive neuronal cytoplasmic inclusions and dystrophic neurites No associations yet identified Intraflagellar transport 74 (IFT74) mutation Progranulin (PGRN) mutations Valosin-containing protein (VCP) mutations Charged multivesicular body protein 2B (CHMP2B) mutations FTLD-U frontotemporal lobar degeneration with ubiquitin-only immunoreactive changes; TDP-43 TAR DNA-binding protein 43. lation of another abnormal protein, the microtubuleassociated protein tau (MAPT). 58,59 This group of diseases became known as the tauopathies (see Fig 1). Tau is a microtubule-associated protein that functions to stabilize microtubule and promote microtubule assembly by binding to tubulin. 60 Tau has six different isoforms that are generated by alternative splicing of exons 2, 3, and 10. Alternative splicing of exons 2 and 3 results in tau isoforms that differ by the presence of one or two amino-terminal inserts, whereas alternative splicing of exon 10 affects the number of carboxylterminal repeats. 61,62 Inclusion of exon 10 results in four-repeat () tau, whereas exclusion of exon 10 results in three-repeat (3R) tau. Each tauopathy has distinct morphological characteristics of neuronal and glial lesions, differ in the anatomic distribution of the lesions, and may differ by the molecular pathology (Table 3). Some tauopathies, such as progressive supranuclear palsy and corticobasal degeneration, are much more common than others, such as PiD, whereas some tauopathies are extremely rare, such as diffuse neurofibrillary tangle dementia with calcifications 63 and diffuse argyrophilic grain disease. 64 Although more than 90% of cases of FTD and related disorders can be classified as a TDP-43 proteinopathy or a tauopathy (see Fig 1), a small proportion of FTD cases is associated with additional rare pathologies that are not characterized by either abnormal TDP-43 or tau (see Fig 1). One such pathology is known as neurofilament inclusion body disease 65 or neuronal intermediate filament inclusion dementia, 66 which is characterized by the accumulation of intraneuronal inclusions that are immunoreactive to neurofilament and -internexin. 65,67 Another rare pathology is characterized by the identification of basophilic round neuronal inclusions that show variable immunoreactivity to ubiquitin but are negative to all other routine stains, silver stains, and immunostains. 68 This disease now known as basophilic inclusion body disease tends to be associated with MND, 69 although initial descriptions of this pathology were associated with bvftd where the pathology was called generalized variant of PiD. 70 Inclusions in neurofilament inclusion body disease and basophilic inclusion body disease are not immunoreactive to either TDP-43 or tau. Molecular Genetics Parallel to the discoveries in molecular pathology, and refinement of clinical and histopathological features of FTLD and related disorders, there have been major discoveries in the molecular genetics of FTLD. Four major genes and one confirmed genetic locus for FTLD have been reported. The first major discovery was the identification of mutations in the MAPT gene, 71 which was identified in 9 of 13 families with varying degrees of behavioral and personality changes and extrapyramidal features that had been linked to chromosome By the end of 2007, 41 different potential pathogenic MAPT mutations had been reported. 73 These include 27 missense 8 Annals of Neurology Vol 64 No 1 July 2008

6 Table 3. Tauopathies Associated with Frontotemporal Dementia and the Related Disorders Diseases Brief Description of the Key Histological Features Dominant Tau-Isoform Pick s disease Progressive supranuclear palsy Progressive supranuclear palsy with corticospinal tract degeneration Corticobasal degeneration ALS-parkinsonismdementia complex of Guam Tangle dominant dementia Neurofibrillary tangle dementia with calcifications Argyrophilic grain disease Diffuse argyrophilic grain disease Sporadic multiple system tauopathy Tau- and silver-positive rounded inclusions visible on hematoxylin and eosin and balloon neurons (Pick cells) Tau-positive neuronal and glial lesions especially globose neurofibrillary tangles and tufted astrocytes in cardinal nuclei Prominent tau-positive globular cytoplasmic inclusions in oligodendrocytes in motor cortex, subjacent white matter, and corticospinal tract Tau-positive neuronal and glial lesions, especially astrocytic plaques and threadlike lesions in cardinal regions Widespread tau-positive neurofibrillary tangles in neocortex, absentsparse senile plaques, and substantia nigra degeneration Tau-positive neurofibrillary tangles, frequent ghost tangles, and threads almost limited to limbic areas, and absent neuritic plaques Tau-positive neurofibrillary tangles, absent neuritic plaques, and prominent basal ganglia and cerebellar calcification Tau-positive spindle- or comma-shaped argyrophilic grains and coiled bodies limited to limbic regions Tau-positive spindle- or comma-shaped argyrophilic grains and coiled bodies in neocortical, subcortical, and brainstem regions Tau-positive globular neuronal and glial tau-positive inclusions in both gray and white matter of the neocortex 3R three repeat; four repeat; ALS amyotrophic lateral sclerosis. 3R 3R 3R 3R mutations, 4 silent mutations, 2 in-frame single codon deletions, and 8 intronic mutations. MAPT mutation frequencies in FTLD populations have been shown to vary from 0 to 50% depending on the study design. 74 The pathology identified in patients with mutations in the MAPT gene is invariable tau, although the tau isoform deposition is heterogeneous. 75 Patients with mutations in exon or intron 10 most commonly show tau deposition, whereas missense mutations outside of exon 10 usually produce 3R tauopathy. There has been no reproducible association between clinical phenotypes and the position of a mutation within the MAPT gene. The majority of patients with an identified mutation in the MAPT gene have behavioral and personality changes; however, the clinical features widely vary and at times even mimic Alzheimer s disease. Clinical features can even vary widely in the same family. 74 Of the remaining four families who had been linked to chromosome 17, 72 no mutations in the MAPT gene could be identified. In 2006, however, two groups of researchers reported the identification of mutations in the progranulin (PGRN) gene that were associated with FTD and more specifically FTLD-U pathology. 76,77 All but one of the remaining four families has been proved to have PGRN mutations. By the end of 2007, 44 different pathogenetic PGRN mutations have been reported. 73 The mutations have been found scattered over the gene, most commonly being small insertions and deletions. All PGRN mutations identified so far result in functional null alleles or haploinsufficiency by producing a premature termination codon that leads to degradation of mutant RNA by nonsense-mediated decay. 77,78 Progranulin mutation frequencies in FTLD populations have ranged from 5 to 10%, although a frequency of 13 to 25% has been reported in the subset of FTLD population in which a positive family history is identified. 76,78,79 The pathology associated with PGRN mutations has been FTLD-U, specifically FTLD-U type 3. 80,81 There have been no reported cases of FTLD-MND. Similar to MAPT mutations, the majority of patients with an identified mutation in the PGRN gene have behavioral and personality changes; however, the clinical features vary widely and also may mimic Alzheimer s disease. 82 Aphasia, best characterized as PPA because it does not always fit nicely into the PNFA or SD criteria, 1 has been described, and parkinsonism is a common feature. 36,80,82 Rare presentations of Parkinson s disease and PSP-S Josephs: Deciphering the FTD Enigma 9

7 Fig 2. Schematic plot illustrating the most prominent associations between clinical syndromes, patterns of atrophy, pathological diagnoses, and protein biochemistry for sporadic frontotemporal dementia (FTD). TDP-43 TAR DNA-binding protein 43. Clinical syndromes: AOS apraxia of speech present; AOS apraxia of speech absent; bvftd behavioral variant FTD; CBS corticobasal syndrome; EP extrapyramidal; FTD-MND FTD with motor neuron disease; PNFA progressive nonfluent aphasia; PSP-S progressive supranuclear palsy syndrome; SD semantic dementia. Pathological diagnoses: CBD corticobasal degeneration; FTLD-U frontotemporal lobar degeneration with ubiquitin-only immunoreactive changes; FTLD-MND frontotemporal lobar degeneration with motor neuron disease; PiD Pick s disease; PSP progressive supranuclear palsy. have been reported, 80 and CBS has been emphasized Unlike MAPT and PGRN, the other two major genes account for a small subset of FTD cases. Mutations in the charged multivesicular body protein 2B (CHMP2B) were identified in a large Danish family originating for the Jutlan region of Denmark. 86 Subsequently, other mutations have been identified, although some are of uncertain pathogenicity. Clinical features are most typical of the bvftd in CHMP2B mutations. Initial pathological studies were consistent with DLDH; however, recent reanalysis has demonstrated the presence of ubiquitinated inclusions that are not immunoreactive to TDP It has been proposed that FTLD with CHMP2B mutations (see Fig 1; see Table 1) be designated as FTLD-U type An association between FTD, inclusion body myopathy, and Paget s disease of the bone with an autosomal dominant pattern of inheritance has been described. 88 Mutations in the valosin-containing protein (VCP) were subsequently identified. 89 Histological analyses in patients with VCP mutations show widespread ubiquitin- and TDP-43 positive intranuclear inclusions 90 ; hence, FTLD with VCP mutation (see Fig 1; see Table 1) has been designated FTLD-U type Several families in which FTD and ALS cooccur have now been linked to chromosome 9p In addition, a group of researchers reported a nonsense mutation in the intraflagellar transport 74 (IFT74) gene in one family 94 ; however, no causal mutations were conclusively identified in other FTD-ALS families. Mutations in the gene encoding for TDP-43 have now been identified in familial ALS 95,96 but not in FTD-MND families. Clinical, Pathological, and Genetic Correlations It is clear that there are many different clinical, pathological, and genetic variants of FTD and related disorders. It is important to attempt to link these different aspects of FTD. Over the last few years four large clinicopathological studies representative of different regions of the United States, as well as Europe and Canada, have been published. 2 5 In three of these studies, early clinical syndromic diagnoses were matched with the associated pathological diagnoses. 2 4 What became clear from these three studies is that there appears to be trends for certain early clinical syndromes to be associated with certain pathologies and biochemistry (Fig 2), 10 Annals of Neurology Vol 64 No 1 July 2008

8 even though clinical syndromes may change over time. 4 In addition, voxel-based morphometry studies in autopsy-confirmed cohorts have identified regional patterns of atrophy that further link these clinical syndromes and the underlying biochemistries 19,20,36,97,98 (see Fig 2). One of the observed trends is that a clinical syndrome dominated by extrapyramidal features (akinesia, rigidity, postural instability, less likely tremor) more likely predicts an underlying tauopathy. 2 4 For example, of 69 patients with a diagnosis of PSP-S or CBS in the three clinicopathological studies, 97% had a tauopathy. 2 4 It has also been shown that the presence of apraxia of speech accompanying PNFA is suggestive of a tauopathy. 19 Another observation is that SD is more likely to be a TDP-43 proteinopathy. 99 A strong association occurs when MND coexists with bvftd, that is, FTD-MND, 2,3 where 100% of cases have a TDP-43 proteinopathy. 2 4 Although bvftd may be more commonly associated with a TDP-43 proteinopathy, it may also be associated with PiD, a tauopathy. 3 Of 74 bvftd patients reported in the United States and Canadian pathological series, 55% were associated with a TDP-43 proteinopathy, with only 16% having PiD. 2,4 However, the proportion of patients with PiD appears significantly greater in the European series of bvftd patients (42%). 3 Finally, aphasic dementia is associated with underlying Alzheimer s disease, and logopenic aphasia has been suggested to also be associated with Alzheimer s disease, although clinicopathological series have not yet been reported. Unlike in the sporadic variants of FTD, no clear trends have been demonstrated for familial FTD. One study suggested subtle clinical differences between patients with MAPT and PGRN mutations, 100 whereas another found differences in atrophy patterns. 101 Hence, in situations of familial FTD, it would be advisable to begin by screening for mutations in both PGRN and MAPT. Voxel-based morphometry studies have also identified patterns of atrophy in the different pathological diagnoses. Patterns of atrophy vary across the different tau variants, with the anterior frontal lobe particularly involved in PiD, 98 whereas the posterior frontal and parietal lobes are involved more in PSP and corticobasal degeneration 97 (Fig 3). Atrophy of the superior cerebellar peduncle is associated with PSP. 97 In contrast, the TDP-43 proteinopathies show atrophy of the frontal and temporal lobes, with FTLD-MND restricted primarily to the midposterior frontal lobe 36,98 (see Fig 3). Prominent medial frontal lobe atrophy also occurs in the TDP-43 proteinopathies and the tauopathies. Although not shown, an interesting subset of patients with slowly progressive FTD has been reported Fig 3. Three-dimensional surface (top) and midsagittal renders (bottom) of the brain showing the most prominent regions of cortical and brainstem atrophy associated with tauopathy and TAR DNA-binding protein 43 (TDP-43) proteinopathy, as well as their specific pathologies, identified from voxel-based morphometry (VBM) group studies. These figures are strictly schematic, designed to highlight the main regions of atrophy in these groups, and do not attempt to exactly duplicate actual VBM output. Yellow sections indicate corticobasal degeneration/progressive supranuclear palsy; checkered yellow sections indicate Pick s disease; partial green sections and checkered green sections indicate frontotemporal lobar degeneration with ubiquitin-only immunoreactive changes; checkered green sections indicate frontotemporal lobar degeneration with motor neuron degeneration. by two different groups. 8,9 A common theme across both series is that the majority of patients have features characteristic of bvftd; however, unlike in typical bvftd, there appears to be absent-minimal lobar atrophy on serial imaging and even at autopsy. One suggestion is that these patients may not have a neurodegenerative process 9 ; however, FTLD-U pathology has been reported. 8 In summary, although many different syndromes and pathologies underlie FTD and related disorders, there are many trends between presenting and progressive clinical syndromes and underlying biochemistry. Some of these trends appear particularly strong, such as a sporadic syndrome dominated by extrapyramidal features suggesting an underlying tauopathy and the presence of MND suggesting a TDP-43 proteinopathy. Other trends appear less strong but nevertheless are important to recognize if future treatments aim to target specific proteins, such as tau. Josephs: Deciphering the FTD Enigma 11

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