Harro Seelaar

Jonathan D Rohrer

Yolande A L Pijnenburg

Nick C Fox

MD John C Van Swieten
email: j.c.vanswieten@erasmusmc.nl

Clinical, genetic, and pathological heterogeneity of frontotemporal dementia: a review

Keywords: Frontotemporal dementia, frontotemporal lobar degeneration, tau, TDP-43, FUS, MAPT, Progranulin FTD, frontotemporal dementia, FTLD, frontotemporal lobar degeneration, MAPT, microtubule associated protein tau, GRN, progranulin, FUS, fused in sarcoma, FTLD-tau, FTLD with tau-positive inclusions, FTLD-TDP, FTLD

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Introduction

Frontotemporal dementia (FTD) is the second most common early-onset dementia and is characterized clinically by progressive behavioural changes and frontal executive deficits and/or selective language difficulties. Although recognised over a century ago the last few years have seen rapid advances in our understanding of FTD, its genetic causes and pathological substrates. [START_REF]Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups[END_REF][START_REF] Neary | Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria[END_REF][START_REF] Mckhann | Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease[END_REF][START_REF] Ratnavalli | The prevalence of frontotemporal dementia[END_REF][START_REF] Harvey | The prevalence and causes of dementia in people under the age of 65 years[END_REF] In 1892 Arnold Pick described a patient with progressive aphasia and lobar atrophy, [START_REF] Pick | Über die Beziehungen der senilen Hirnatropie zur Aphasie[END_REF] and in 1911 the presence of argyrophilic neuronal inclusions at neuropathological examination, later known as 'Pick bodies', was reported by Alois Alzheimer. [START_REF] Alzheimer | Über eigenartige Krankheitsfälle des späteren Alters[END_REF] The selective involvement of the frontal and/or temporal cortices with relative preservation of more posterior cerebral regions determines the presentation, and gives rise to the terms FTD as a clinical syndrome with distinct subtypes, and the term frontotemporal lobar degeneration (FTLD) to describe the pathological syndrome. The disease progresses from an insidious onset of behavioural change or language impairment and cognitive decline to a severe and more generalised dementia, accompanied by progressive cerebral hypometabolism and atrophy of frontal and temporal lobes preferentially.

The clinical spectrum of FTD encompasses distinct canonical syndromes: the behavioural variant of FTD (bvFTD) and the language variants, semantic dementia (SD) and progressive non-fluent aphasia (PNFA). There is also overlap of FTD with motor neuron disease (FTD-MND or FTD-ALS), as well as the parkinsonian syndromes, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). [START_REF] Kertesz | The evolution and pathology of frontotemporal dementia[END_REF] Recent advances in FTD have identified novel genetic defects and a chromosomal locus in hereditary forms of FTLD, [START_REF] Seelaar | Distinct genetic forms of frontotemporal dementia[END_REF][START_REF] Chow | Inheritance of frontotemporal dementia[END_REF][START_REF] Goldman | Comparison of family histories in FTLD subtypes and related tauopathies[END_REF][START_REF] Hutton | Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17[END_REF][START_REF] Baker | Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17[END_REF][START_REF] Cruts | Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21[END_REF] as well as novel neuropathological associations, e.g. the proteins TAR DNA binding protein of and fused in sarcoma (FUS) are now recognized in the pathological classification of FTLD. [START_REF] Sampathu | Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies[END_REF][START_REF] Mackenzie | Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype[END_REF][START_REF] Cairns | Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration[END_REF][START_REF] Mackenzie | Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update[END_REF][START_REF] Neumann | Frontotemporal lobar degeneration with FUS pathology[END_REF] In this review we will discuss the different clinical variants, neuropsychological aspects, neuroimaging, hereditary forms, pathological subtypes and the clinicopathological associations of FTD with the focus on recent developments.

Epidemiology

The exact prevalence of FTD remains uncertain, as there have been only a few studies and these have produced a wide range of estimates. The highest prevalences have been reported from two independent studies in the UK and one Italian study with an estimated prevalence of FTD of 15 -22 per 100,000 inhabitants aged 45 -64 years,(4-5, 20) which was almost half the prevalence of AD in this age group.( 5) However, a study from the Netherlands estimated the prevalence of FTD to be significantly lower (9.4 per 100,000 in the age group of 60 -69 years). [START_REF] Rosso | Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study[END_REF] The lower prevalence relative to AD in that series is consistent with some pathological series. [START_REF] Brun | Frontal lobe degeneration of non-Alzheimer type. I. Neuropathology[END_REF][START_REF] Ikeda | Epidemiology of frontotemporal lobar degeneration. Dementia and geriatric cognitive disorders[END_REF] The estimated prevalence in a Swedish population-based sample of 85-year-olds was 3.1 per 100 inhabitants. [START_REF] Gislason | The prevalence of frontal variant frontotemporal dementia and the frontal lobe syndrome in a population based sample of 85 year olds[END_REF] Two reported incidence studies of FTD were remarkably consistent; 3.5 and 4.1 cases per 100,000 person-years in the age-group of 45 -64 years. [START_REF] Knopman | The incidence of frontotemporal lobar degeneration in Rochester, Minnesota, 1990 through 1994[END_REF][START_REF] Mercy | Incidence of early-onset dementias in Cambridgeshire, United Kingdom[END_REF] There do not appear to be clear gender differences in susceptibility. [START_REF] Rosso | Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study[END_REF][START_REF] Ikeda | Epidemiology of frontotemporal lobar degeneration. Dementia and geriatric cognitive disorders[END_REF][START_REF] Mercy | Incidence of early-onset dementias in Cambridgeshire, United Kingdom[END_REF][START_REF] Hou | Frequency of dementia etiologies in four ethnic groups. Dementia and geriatric cognitive disorders[END_REF] The average age at onset is around 50 -60 years, although approximately 10 percent have an age at onset over 70 years (up to 89 years). [START_REF] Seelaar | Distinct genetic forms of frontotemporal dementia[END_REF] There is a wide range in durations of illness (2 -20 years) partly reflecting different underlying pathologies. Patients with FTD-MND have the shortest survival with a mean of three years. [START_REF] Seelaar | Distinct genetic forms of frontotemporal dementia[END_REF][START_REF] Hodges | Survival in frontotemporal dementia[END_REF]

Clinical presentation

BvFTD, SD and PNFA all share an insidious onset and inexorably progressive but variable decline. Each clinical syndrome is associated with topographically distinct cerebral involvement: with bvFTD associated with symmetrical (or right-sided) frontal and anterior temporal dysfunction, PNFA left frontotemporal dysfunction and SD anterior temporal (typically left more than right) deficits. BvFTD is the most common of these subtypes and accounts for about half of all cases [START_REF] Seelaar | Distinct genetic forms of frontotemporal dementia[END_REF][START_REF] Johnson | Frontotemporal lobar degeneration: demographic characteristics of 353 patients[END_REF] without any clear differences in presentation between sporadic and familial bvFTD, or between late and early onset bvFTD. [START_REF] Ber | Demographic, neurological and behavioural characteristics and brain perfusion SPECT in frontal variant of frontotemporal dementia[END_REF] While all of the subtypes can occur in conjunction with motor neuron disease (FTD-MND), it is most commonly seen with bvFTD, occasionally with PNFA and only very rarely with SD.

Emotional blunting, loss of empathy, apathy, selfishness and neglect of personal hygiene are typical of bvFTD, but may be seen in all subtypes. [START_REF] Bathgate | Behaviour in frontotemporal dementia, Alzheimer's disease and vascular dementia[END_REF] Other frequently reported symptoms are disinhibition, irritability, gluttony, altered preference for foods (particularly for sweets), wandering, pacing, motor and verbal stereotypies, and hoarding. [START_REF] Bathgate | Behaviour in frontotemporal dementia, Alzheimer's disease and vascular dementia[END_REF] It has been suggested that bvFTD can be subdivided into apathetic and disinhibited variants depending on initial presentation, [START_REF] Snowden | Distinct behavioural profiles in frontotemporal dementia and semantic dementia[END_REF] however these symptoms frequently co-occur and the usefulness of this distinction is questionable.(30) A stereotyped-compulsive syndrome has been recognized as a third variant. [START_REF] Snowden | Fronto-temporal lobar degeneration: frontotemporal dementia, progressive aphasia, semantic dementia[END_REF] A significant correlation with specific topographic patterns of atrophy, hypoperfusion or hypometabolism has been found for several of these symptoms. Apathy is associated with atrophy and dysfunction of the right anterior cingulate cortex and superior frontal gyrus, [START_REF] Zamboni | Apathy and disinhibition in frontotemporal dementia: Insights into their neural correlates[END_REF] disinhibition with the right subgenual cingulate cortex and orbitofrontal cortex, [START_REF] Zamboni | Apathy and disinhibition in frontotemporal dementia: Insights into their neural correlates[END_REF][START_REF] Mcmurtray | Variations in regional SPECT hypoperfusion and clinical features in frontotemporal dementia[END_REF][START_REF] Peters | Orbitofrontal dysfunction related to both apathy and disinhibition in frontotemporal dementia[END_REF] overeating with an orbitofrontal-striatal circuit, [START_REF] Woolley | Binge eating is associated with right orbitofrontal-insular-striatal atrophy in frontotemporal dementia[END_REF] and executive dysfunction with the dorsolateral and prefrontal cortex. [START_REF] Huey | Executive dysfunction in frontotemporal dementia and corticobasal syndrome[END_REF] The core features of current clinical criteria for bvFTD encompass an insidious onset and gradually progressive course, early disruption of social and personal conduct, early emotional blunting and lack of insight. [START_REF] Neary | Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria[END_REF][START_REF] Mckhann | Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease[END_REF] Stereotypic behaviour, alterations in eating behaviour, and loss of social awareness particularly support a diagnosis of FTD, while more posterior symptoms such as difficulty with spatial orientation and locating objects suggest Alzheimer's disease (AD). [START_REF] Bathgate | Behaviour in frontotemporal dementia, Alzheimer's disease and vascular dementia[END_REF][START_REF] Bozeat | Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer's disease?[END_REF][START_REF] Miller | A study of the Lund-Manchester research criteria for frontotemporal dementia: clinical and single-photon emission CT correlations[END_REF] Apathy, mood changes, and dysexecutive symptoms occur in both and have not been found to be effective discriminators of FTD from AD. [START_REF] Bozeat | Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer's disease?[END_REF][START_REF] Marra | Clusters of cognitive and behavioral disorders clearly distinguish primary progressive aphasia from frontal lobe dementia, and Alzheimer's disease. Dementia and geriatric cognitive disorders[END_REF][START_REF] Chow | Apathy symptom profile and behavioral associations in frontotemporal dementia vs dementia of Alzheimer type[END_REF] The clinical criteria focus on behavioural changes rather than cognitive disturbances, and therefore might equally apply to a number of psychiatric syndromes, including (late-onset) depression and schizophrenia. However, virtually no studies have focussed on the differentiation of bvFTD from psychiatric disorders. With this in mind, an interesting group of patients is the "non-progressive", "benign" or "slow" bvFTD, who do not (or only slowly) progress over time, and do not show definite structural atrophy or hypometabolism many years from symptom onset. [START_REF] Davies | Progression in frontotemporal dementia: identifying a benign behavioral variant by magnetic resonance imaging[END_REF][START_REF] Kipps | Understanding social dysfunction in the behavioural variant of frontotemporal dementia: the role of emotion and sarcasm processing[END_REF][START_REF] Kipps | Behavioural variant frontotemporal dementia: not all it seems?[END_REF] Behavioural symptoms may appear to progress according to carer description but without measurable cognitive change. [START_REF] Kipps | Behavioural variant frontotemporal dementia: not all it seems?[END_REF] As these patients with a non-progressive bvFTD appear to have a normal life expectancy and seldom come to autopsy, the underlying pathology is still unknown. [START_REF] Kipps | Understanding social dysfunction in the behavioural variant of frontotemporal dementia: the role of emotion and sarcasm processing[END_REF][START_REF] Kipps | Behavioural variant frontotemporal dementia: not all it seems?[END_REF] Possible diagnoses that have been suggested include decompensated Asperger syndrome or personality disorder, mild bipolar syndrome, or an otherwise previously undescribed neuropsychiatric syndrome with functional disruption of the same orbitofrontal-amygdala-polar network. [START_REF] Kipps | Understanding social dysfunction in the behavioural variant of frontotemporal dementia: the role of emotion and sarcasm processing[END_REF] Autopsy-proven studies have shown that the current clinical criteria correctly classify approximately 80-90 percent of bvFTD cases, whereas 3 to 17 percent are pathologicallyproven AD. [START_REF] Rosen | Utility of clinical criteria in differentiating frontotemporal lobar degeneration (FTLD) from AD[END_REF][START_REF] Knopman | Antemortem diagnosis of frontotemporal lobar degeneration[END_REF][START_REF] Forman | Frontotemporal dementia: clinicopathological correlations[END_REF][START_REF] Alladi | Focal cortical presentations of Alzheimer's disease[END_REF] However, the criteria lack sensitivity (37 percent) in the early phase of bvFTD.( 50) Therefore, revised criteria for bvFTD have been proposed in light of recent advances. [START_REF] Rascovsky | Diagnostic criteria for the behavioral variant of frontotemporal dementia (bvFTD): current limitations and future directions[END_REF] The most important revisions are the incorporation of neuroimaging and genetic findings within the criteria and expansion of the role of supportive behavioural features for the diagnosis of bvFTD. [START_REF] Rascovsky | Diagnostic criteria for the behavioral variant of frontotemporal dementia (bvFTD): current limitations and future directions[END_REF] The nosology of the language variants of FTD remains controversial. PNFA and SD are the canonical subtypes of what is collectively often termed primary progressive aphasia (PPA).

Fluent speech, progressive impairment of single-word comprehension, preserved articulatory abilities, and a multimodal breakdown of semantic memory are the characteristic features of SD. [START_REF] Gorno-Tempini | Cognition and anatomy in three variants of primary progressive aphasia[END_REF] Patients with SD may show behavioural changes in the course of the disease similar to bvFTD. [START_REF] Rosen | Behavioral features in semantic dementia vs other forms of progressive aphasias[END_REF] In particular they may become egocentric and develop fixed daily routines. [START_REF] Rosen | Behavioral features in semantic dementia vs other forms of progressive aphasias[END_REF] PNFA patients present with apraxia of speech and/or expressive agrammatism: single-word comprehension and object knowledge are relatively preserved and behavioural symptoms are less common. However, there are patients with progressive language impairment who do not fit into the SD and PNFA: a third, more recently defined, subtype of PPA is the logopenic or phonological variant (LPA) which is characterized by a slow rate of speech output, wordfinding difficulties, deficits in sentence repetition, and occasional phonemic errors in spontaneous speech and naming, whereas motor speech, expressive grammar and single-word comprehension are relatively spared. [START_REF] Gorno-Tempini | Cognition and anatomy in three variants of primary progressive aphasia[END_REF][START_REF] Gorno-Tempini | The logopenic/phonological variant of primary progressive aphasia[END_REF] It remains unclear whether there are further subtypes of PPA although there is some evidence that patients with GRN mutations have a non-fluent PPA syndrome distinct to either PNFA or LPA. [START_REF] Rohrer | Progranulin-associated primary progressive aphasia: a distinct phenotype?[END_REF] PPA subtypes have an association with different types of underlying pathology. SD is associated most commonly with FTLD-TDP type 1 [START_REF] Cairns | Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration[END_REF] pathology and only rarely with FTLD-tau or AD pathology. [START_REF] Alladi | Focal cortical presentations of Alzheimer's disease[END_REF][START_REF] Davies | The pathological basis of semantic dementia[END_REF][START_REF] Grossman | Primary progressive aphasia: clinicopathological correlations[END_REF] PNFA is commonly associated with FTLD-tau, [START_REF] Davies | The pathological basis of semantic dementia[END_REF][START_REF] Mesulam | Alzheimer and frontotemporal pathology in subsets of primary progressive aphasia[END_REF][START_REF] Deramecourt | Prediction of pathology in primary progressive language and speech disorders[END_REF], although AD and to a lesser extent FTLD-TDP pathology have also been described. [START_REF] Alladi | Focal cortical presentations of Alzheimer's disease[END_REF][START_REF] Grossman | Primary progressive aphasia: clinicopathological correlations[END_REF][START_REF] Mesulam | Alzheimer and frontotemporal pathology in subsets of primary progressive aphasia[END_REF] Finally, LPA is predominantly associated with AD pathology. [START_REF] Mesulam | Alzheimer and frontotemporal pathology in subsets of primary progressive aphasia[END_REF][START_REF] Deramecourt | Prediction of pathology in primary progressive language and speech disorders[END_REF] Although these are relatively strong associations, they are not absolute, and it is currently not possible to predict with certainty the underlying pathology of specific PPA syndromes. [START_REF] Grossman | Primary progressive aphasia: clinicopathological correlations[END_REF] However, using multimodal predictors including qualitative clinical features, neuropsychological test scores, and atrophy on MRI improve the noninvasive prediction of the underlying pathology in non-fluent PPA.( 60) [START_REF] Gorno-Tempini | Cognition and anatomy in three variants of primary progressive aphasia[END_REF][START_REF] Rohrer | Progranulin-associated primary progressive aphasia: a distinct phenotype?[END_REF][START_REF] Amici | An overview on Primary Progressive Aphasia and its variants[END_REF][START_REF] Brambati | Reading disorders in primary progressive aphasia: a behavioral and neuroimaging study[END_REF][START_REF] Rohrer | Progressive logopenic/phonological aphasia: Erosion of the language network[END_REF][START_REF] Wilson | Connected speech production in three variants of primary progressive aphasia[END_REF]

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Neuropsychology and social cognition

Impairment of executive function including planning, organisation, judgement, problem solving and mental flexibility, is characteristic of FTD,( 69) whereas memory, visual perception, and spatial skills are usually relatively well-preserved. [START_REF] Mendez | Accuracy of the clinical evaluation for frontotemporal dementia[END_REF][START_REF] Diehl-Schmid | Behavioral disturbances in the course of frontotemporal dementia. Dementia and geriatric cognitive disorders[END_REF][START_REF] Hodges | The differentiation of semantic dementia and frontal lobe dementia (temporal and frontal variants of frontotemporal dementia) from early Alzheimer's disease: a comparative neuropsychological study[END_REF][START_REF] Kramer | Distinctive neuropsychological patterns in frontotemporal dementia, semantic dementia, and Alzheimer disease[END_REF][START_REF] Libon | Neuropsychological decline in frontotemporal lobar degeneration: a longitudinal analysis[END_REF][START_REF] Wittenberg | The early neuropsychological and behavioral characteristics of frontotemporal dementia[END_REF]. However, executive dysfunction may be absent or overshadowed by pronounced behavioural changes in early disease, and may also be seen in AD. [START_REF] Snowden | Social cognition in frontotemporal dementia and Huntington's disease[END_REF] Verbal fluency (letter and categorical) is usually impaired in bvFTD and PNFA, but to a lesser degree also in AD. [START_REF] Rogers | Semantic memory in Alzheimer's disease and the frontotemporal dementias: a longitudinal study of 236 patients[END_REF][START_REF] Rascovsky | Disparate letter and semantic category fluency deficits in autopsy-confirmed frontotemporal dementia and Alzheimer's disease[END_REF][START_REF] Libon | Neurocognitive contributions to verbal fluency deficits in frontotemporal lobar degeneration[END_REF] In SD patients, semantic fluency is more impaired than letter fluency. [START_REF] Rogers | Semantic memory in Alzheimer's disease and the frontotemporal dementias: a longitudinal study of 236 patients[END_REF][START_REF] Libon | Neurocognitive contributions to verbal fluency deficits in frontotemporal lobar degeneration[END_REF] Early episodic memory impairment, a characteristic feature of AD, has also been reported in pathologically-proven bvFTD cases, and in patients with GRN gene mutations. [START_REF] Hodges | Clinicopathological correlates in frontotemporal dementia[END_REF][START_REF] Van Swieten | Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia[END_REF] Though orientation in time and place, delayed free recall and delayed recognition are more often impaired in AD than in FTD at initial assessment, it still remains difficult to differentiate FTD from AD in the early phase using standard neuropsychological tests. [START_REF] Hornberger | How preserved is episodic memory in behavioral variant frontotemporal dementia?[END_REF] As standard neuropsychological tests cannot reliably differentiate bvFTD from AD, [START_REF] Nedjam | Confabulation, but not executive dysfunction discriminate AD from frontotemporal dementia[END_REF][START_REF] Hutchinson | Neuropsychological deficits in frontotemporal dementia and Alzheimer's disease: A meta-analytic review[END_REF][START_REF] Collette | Comparison of inhibitory functioning in mild Alzheimer's disease and frontotemporal dementia. Cortex; a journal devoted to the study of the nervous system and behavior[END_REF] several investigators have explored the utility of emotional processing and social recognition tasks in the clinical diagnosis of FTD over recent years. Social dysfunction and emotional blunting commonly occur in FTD. [START_REF] Kipps | Understanding social dysfunction in the behavioural variant of frontotemporal dementia: the role of emotion and sarcasm processing[END_REF][START_REF] Snowden | Social cognition in frontotemporal dementia and Huntington's disease[END_REF][START_REF] Lough | Social reasoning, emotion and empathy in frontotemporal dementia[END_REF][START_REF] Rosen | Neuroanatomical correlates of impaired recognition of emotion in dementia[END_REF][START_REF] Lavenu | Perception of emotion on faces in frontotemporal dementia and Alzheimer's disease: a longitudinal study[END_REF][START_REF] Fernandez-Duque | Impaired recognition of negative facial emotions in patients with frontotemporal dementia[END_REF][START_REF] Keane | Face and emotion processing in frontal variant frontotemporal dementia[END_REF][START_REF] Kipps | Emotion, social functioning and activities of daily living in frontotemporal dementia[END_REF][START_REF] Mendez | The scale for emotional blunting in patients with frontotemporal dementia[END_REF] Theory of Mind (ToM) tests require the interpretation of social situations and ascribing mental state to oneself and others, and may reveal subtle deficits not detected with standard neuropsychological testing. [START_REF] Snowden | Social cognition in frontotemporal dementia and Huntington's disease[END_REF] Recent reports suggest that the neural basis for ToM tasks, social cognition and empathy lies within the medio-and/or orbitofrontal cortex, which is affected early in bvFTD.( 92) Patients with bvFTD have impaired scores on these tests of social judgments and cognitive flexibility, and express concrete, literal interpretations. [START_REF] Snowden | Social cognition in frontotemporal dementia and Huntington's disease[END_REF][START_REF] Eslinger | Oops! Resolving social dilemmas in frontotemporal dementia[END_REF] Performances in ToM tests do not correlate with executive functioning on standard neuropsychological testing in the early phase. [START_REF] Lough | Social reasoning, emotion and empathy in frontotemporal dementia[END_REF][START_REF] Adenzato | Theory of mind ability in the behavioural variant of frontotemporal dementia: an analysis of the neural, cognitive, and social levels[END_REF][START_REF] Gregory | Theory of mind in patients with frontal variant frontotemporal dementia and Alzheimer's disease: theoretical and practical implications[END_REF] However, in a more advanced stage, when atrophy spreads to dorsolateral frontal structures, the ToM ability and executive functioning become strongly related. [START_REF] Snowden | Social cognition in frontotemporal dementia and Huntington's disease[END_REF][START_REF] Eslinger | Oops! Resolving social dilemmas in frontotemporal dementia[END_REF][START_REF] Adenzato | Theory of mind ability in the behavioural variant of frontotemporal dementia: an analysis of the neural, cognitive, and social levels[END_REF] Empathy as rated by caregivers is clearly impaired in bvFTD and SD patients and correlates with ToM tasks. [START_REF] Lough | Social reasoning, emotion and empathy in frontotemporal dementia[END_REF][START_REF] Rankin | Patterns of cognitive and emotional empathy in frontotemporal lobar degeneration[END_REF] In line with these observations, recognition of facial emotions is impaired in patients with bvFTD, in particular for negative emotions (anger, fear, sadness and disgust). [START_REF] Lough | Social reasoning, emotion and empathy in frontotemporal dementia[END_REF][START_REF] Lavenu | Perception of emotion on faces in frontotemporal dementia and Alzheimer's disease: a longitudinal study[END_REF][START_REF] Fernandez-Duque | Impaired recognition of negative facial emotions in patients with frontotemporal dementia[END_REF][START_REF] Keane | Face and emotion processing in frontal variant frontotemporal dementia[END_REF][START_REF] Kipps | Emotion, social functioning and activities of daily living in frontotemporal dementia[END_REF][START_REF] Mendez | The scale for emotional blunting in patients with frontotemporal dementia[END_REF][START_REF] Lavenu | Perception of emotion in frontotemporal dementia and Alzheimer disease[END_REF] The same applies for the recognition of vocal emotions, in particular for anger and sad voices.( 89) Interpretation of sarcastic statements is impaired in FTD, and is correlated with the ability to recognize negative emotions.( 44) Self-conscious emotions, such as embarrassment and amusement, are another important aspect of emotion functioning which may be disrupted in FTD. [START_REF] Sturm | Self-conscious emotion deficits in frontotemporal lobar degeneration[END_REF][START_REF] Sturm | Diminished self-conscious emotional responding in frontotemporal lobar degeneration patients[END_REF] Social cognition tests also seem to help to differentiate bvFTD patients with imaging abnormalities from the non-progressive bvFTD with normal neuroimaging. [START_REF] Lough | Social reasoning, emotion and empathy in frontotemporal dementia[END_REF][START_REF] Rankin | Patterns of cognitive and emotional empathy in frontotemporal lobar degeneration[END_REF] It will be interesting to investigate further whether impaired social cognition is a very early feature of familial FTD as has already been described in a single case study of a presymptomatic mutation carrier; studying presymptomatic mutation carriers may allow identification of sensitive (even preclinical) cognitive predictors of decline and its neural substrate.(100)

Neuroimaging

Patients with FTD classically have frontal and temporal atrophy and hypometabolism which is often asymmetric. In the clinical setting this is often best seen using volumetric structural MRI scans (with coronal T1 images being particularly useful for assessing asymmetry) or with functional imaging using either FDG-PET or, less commonly, HMPAO-SPECT. More recently, however, neuroimaging studies have aimed to refine these initial findings, mostly in clinical cohorts, but also in pathologically and genetically-confirmed FTD.

Studies of mild bvFTD in clinically-defined cohorts show involvement particularly of frontal and paralimbic areas,(101) namely the anterior cingulate cortex and frontal insula as well as medial frontal and orbitofrontal cortices, hippocampus, striatum and thalamus, more in the right than left hemisphere. With increasing disease severity, more diffuse atrophy in similar areas is seen with involvement of more lateral frontal areas and subsequently more posterior temporal and anterior parietal atrophy.( 102 although one small study suggests there may be a difference between patients with MAPT mutations that affect splicing of exon 10 (more medial temporal lobe atrophy) compared with mutations that do not affect splicing of exon 10 (more lateral temporal lobe atrophy).( 109) Bringing these findings together, one study that used a cluster analysis to investigate bvFTD suggested there may be four types of bvFTD anatomically: a temporal-dominant subtype associated with MAPT mutations; a temporofrontoparietal subtype that can be associated with GRN mutations but also with other pathologies such as corticobasal degeneration (CBD); as well as frontal-dominant and frontotemporal subtypes.( 110) Larger studies of pathologicallyproven patients are needed to confirm these findings.

Early voxel-based morphometry (VBM) studies of SD showed asymmetrical atrophy of the anterior and inferior temporal lobes,(111-112) usually affecting the left more than the right hemisphere. These findings were supported by subsequent region of interest (R OI) studies of the temporal lobe, which identified involvement particularly of the temporal pole and anterior parts of the entorhinal cortex, fusiform gyrus, inferior temporal gyrus, amygdala and hippocampus with relative sparing of the superior temporal gyrus.(113-114) Most studies have used clinically-defined cohorts but one study looking at measurement of cortical thickness in patients with left greater than right temporal lobe atrophy showed a similar pattern of involvement in a pathologically-confirmed cohort of patients, all with FTLD-TDP.( 115). This study also showed that areas within the left hemisphere outside the temporal lobe are involved with increasing disease severity, namely orbitofrontal, inferior frontal, insular, and anterior cingulate cortices.(115) Increasing involvement of the temporal lobe in the right hemisphere is seen with disease progression.(115-116) A mirror-image pattern of initial atrophy and disease progression seems to occur in those with right greater than left temporal lobe involvement (RTLA).(117) Although SD is characteristically FTLD-TDP pathologically, in a small number of cases, Pick's disease (FTLD-tau) and occasionally AD pathology can be seen. One small study showed similar patterns of atrophy in the FTLD-TDP and FTLD-tau but with a qualitatively different pattern in those with AD who had mostly hippocampal involvement, lack of the knife-edge anterior temporal atrophy seen in the other groups and without the sparing of the superior temporal gyrus.( 118) Studies of PNFA are fewer and more heterogeneous, which reflects the clinical heterogeneity of this group. As with SD, there is asymmetrical involvement with more atrophy in the left hemisphere and most significant involvement of the inferior frontal lobe and anterior insula. [START_REF] Gorno-Tempini | Cognition and anatomy in three variants of primary progressive aphasia[END_REF]116,(119)(120) With increasing severity there is involvement of left superior temporal, middle and superior frontal and anterior parietal lobes.( 116 A different neuroimaging tool that accurately differentiates FTLD from AD is arterial spin labeling (ASL) perfusion MRI, which reveals noninvasive quantification of cerebral blood blow, without the use of ionizing radiation as in SPECT or PET.( 130) Patients with AD pathologically can also be defined using amyloid molecular imaging (e.g. PIB-PET) (131) but the availability of such scans is currently limited to a few large research centres.

One of the more novel concepts to emerge from recent neuroimaging studies of FTD using the technique of resting-state fMRI is the idea that FTD is caused by degeneration within specific intrinsic functional connectivity networks that are selectively vulnerable to FTLD pathologies.(132) Consistent with earlier VBM findings in structural MRI studies of bvFTD, resting-state fMRI studies show attenuated connectivity within an anterior 'salience' network of dorsal anterior cingulate and frontoinsular cortices which has connectivity to subcortical and limbic structures.(133) In contrast there appears to be enhanced connectivity in the more posterior 'default' network which has been shown to be affected in AD.(133) These findings have been linked to specific neuropathological findings (early involvement of von Economo neurons in FTD),(134) and further work will be needed to look at whether specific pathological subtypes can be linked to specific and distinct neural network degeneration.

Cerebrospinal fluid and plasma biomarkers

Currently cerebrospinal fluid (CSF) biomarkers have limited ability to identify FTD reliably. This might be explained by both the pathological heterogeneity and the large variation in neurodegenerative severity. Levels of CSF tau in FTD are normal, increased or even decreased.( 135

Genetics

A positive family history has been found in 30 -50 percent of patients with bvFTD, whereas patients with SD or PNFA have a much lower frequency. (9-11, 21, 145-146) The heritability in FTD-MND differs between studies from 10 -60 percent. [START_REF] Seelaar | Distinct genetic forms of frontotemporal dementia[END_REF][START_REF] Goldman | Comparison of family histories in FTLD subtypes and related tauopathies[END_REF]146) An autosomal dominant mode of inheritance is found in 10 -27 percent of all FTD patients. (9-11, 21, 145-146).

Genetic heterogeneity of FTLD is reflected by the identification of mutations in the microtubule associated protein tau (MAPT) and progranulin (GRN) genes in approximately 50 percent of the familial cases, whereas mutations in the valosin containing protein (VCP), charged multivesicular body protein 2B (CHMP2B), TAR-DNA binding protein (TARDP), and fused in sarcoma (FUS) genes are found in less than five percent. Familial FTD-MND has been linked to chromosome 9, but the causative gene defect has yet to be discovered. FTD patients, and up to 22 percent in familial FTD. [START_REF] Seelaar | Distinct genetic forms of frontotemporal dementia[END_REF][START_REF] Baker | Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17[END_REF][START_REF] Cruts | Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21[END_REF](151)(152)(153) Its frequency is similar to that of MAPT gene mutations in hereditary FTD. [START_REF] Seelaar | Distinct genetic forms of frontotemporal dementia[END_REF]146) GRN gene mutations are occasionally reported in sporadic cases. [START_REF] Seelaar | Distinct genetic forms of frontotemporal dementia[END_REF](151)(152)(153) Whether this is due to a low penetrance of the GRN mutation in one of the parents or to a spontaneous mutation in the patient is unknown.

MAPT

GRN encodes the progranulin protein, which is a growth factor implicated in wound healing and tumour growth inflammation, and is abundantly expressed in specific neuronal subsets.( 154 Extrapyramidal features are frequently seen, and include CBS with limb apraxia, asymmetric parkinsonism, and dystonia.(157-158, 163-165) ALS is only a very rare part of the clinical spectrum within GRN families, [START_REF] Seelaar | Distinct genetic forms of frontotemporal dementia[END_REF]151,161,163,166) e.g. it has been reported in a single patient of a large Canadian family. [START_REF] Baker | Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17[END_REF]167)

Other hereditary forms

The genetic heterogeneity of FTD is further emphasized by the rare occurrence of mutations in the VCP, CHMP2B, TARDP and FUS genes. There still remains a subgroup of FTD patients with a positive family history without known gene mutations. These patients usually have bvFTD and memory problems with or without MND, TDP-43 pathology and neuronal loss and gliosis of the cornu ammonis 1 and subiculum of the hippocampus (hippocampal sclerosis) at neuropathological examination.( 9)

Genetic risk factors

Several investigators have tried to identify genetic risk factors for FTD. Homozygosity for the T allele of the SNP rs5848 was found to have a 3.2 fold increased risk for developing FTLD-TDP,(194) but this observation could not be replicated in other studies. (195)(196) The same is true for three other SNPs of the GRN gene, which were initially found to be associated with younger onset age or shorter survival in FTLD or ALS. [START_REF] Seelaar | Distinct genetic forms of frontotemporal dementia[END_REF]194)

Genetic screening in clinical practice

The benefit of genetic screening in FTD depends on the strength of the family history and the clinical subtype. Genetic defects, either MAPT or GRN, are most often found in patients with an autosomal dominant form of bvFTD. [START_REF] Seelaar | Distinct genetic forms of frontotemporal dementia[END_REF]146) Genetic screening in SD is unlikely to be useful, although patients who develop semantic impairment later in the illness may have a MAPT gene mutation, [START_REF] Seelaar | Distinct genetic forms of frontotemporal dementia[END_REF]146) whereas a GRN mutation can be found in a familial form of PNFA. [START_REF] Seelaar | Distinct genetic forms of frontotemporal dementia[END_REF]146,156) Current gene defects are very rare in FTD-MND, and genetic screening is therefore likely not to be useful at present. [START_REF] Seelaar | Distinct genetic forms of frontotemporal dementia[END_REF]146) Screening in sporadic patients will be of little value as a very few mutations have been found in sporadic patients, except for those with a concealed or incomplete family history. In this latter group, careful consideration is necessary before embarking on and genetic screening.( 146)

Pathology

FTLD is the common underlying pathology of clinical FTD subtypes, and also includes ALS, PSP, and CBD. The major pathological hallmark of FTLD is selective atrophy of the frontal and temporal cortex, with neuronal loss, gliosis and spongiosis of the superficial layers, especially of layer II. The nomenclature has been changed several times since it was first described by Arnold Pick over a hundred years ago. [START_REF] Pick | Über die Beziehungen der senilen Hirnatropie zur Aphasie[END_REF] The term Pick's disease is now reserved for cases of FTLD with intraneuronal argyrophilic inclusions, the so-called Pick bodies, which consist of abnormal three-repeat tau protein (FTLD-tau).

FTLD is a neuropathologically heterogeneous disorder, which can be divided into two major subtypes; FTLD with tau-positive inclusions (FTLD-tau), and FTLD with ubiquitin-positive and TDP-43-positive, but tau-negative inclusions (FTLD-TDP).( 18) FTLD-tau includes patients with MAPT mutations, Pick's disease, PSP, CBD, argyrophilic grain disease (AGD), and multiple system tauopathy with dementia (MSTD).( 18

  , SEE PAGE 41 *** Motor neuron disease (MND) may occur early or late in the disease course in a subset of FTD patients.(65-66) Muscle atrophy, weakness, and fasciculations are often most prominent in the upper extremities and the tongue. The disease has a rapidly progressive course with a mean survival of three years. It is now accepted that FTD and MND are part of the same clinicopathological spectrum. A third of all FTD-MND cases have a positive family history for dementia, FTD, MND, or FTD-MND. The causative gene defect in FTD-MND has yet to be discovered. Some patients with predominantly right temporal lobe atrophy (RTLA) present with prominent behavioural changes, episodic memory disturbances, topographical disorientation and prosopagnosia.(67-68) Patients with RTLA are usually diagnosed clinically with either bvFTD or SD.(68) It has been suggested that patients with bvFTD and RTLA have FTLD-tau pathology, whereas patients with SD and RTLA have FTLD-TDP pathology.[START_REF] Josephs | Two distinct subtypes of right temporal variant frontotemporal dementia[END_REF]

  ) It remains unclear whether this pattern of atrophy is a feature of bvFTD independent of the underlying pathology (which is heterogeneous) or whether different pathologies have distinct patterns of atrophy. Unfortunately, there are currently no studies which directly compare all of the pathological subtypes. Patients with FUS pathology seem to have a similar pattern of frontal paralimbic atrophy to that described above but in addition have severe caudate involvement compared to FTLD-tau or FTLD-TDP.(103-105) Studies comparing genetically-defined FTD patients with either GRN or MAPT mutations (106-107) have described different patterns between the two groups: GRN mutations are associated with asymmetrical frontal, temporal and inferior parietal lobe atrophy whereas MAPT mutations are associated with relatively symmetrical anteromedial temporal lobe and orbitofrontal grey matter atrophy.(106-107) The presence of early parietal lobe atrophy in GRN mutations, a feature which may distinguish such cases from other FTD patients, has been shown in studies of presymptomatic mutation carriers.(100, 108) Whether patients with different mutations in the same gene have distinct patterns of atrophy is unclear

  ) ROI studies have also shown involvement of the caudate in PNFA.(121) There are few pathologically-confirmed studies of PNFA and these are usually in mixed pathological groups but they show similar findings to the clinical cohort studies.(116, 122) Some small studies suggest there may be different patterns of atrophy in PNFA patients with PSP clinically (and therefore likely pathologically) compared to those without PSP,(123) and also in those with GRN mutations (FTLD-TDP pathologically) compared to those without.(63) More detailed studies of PNFA subgroups will be needed to confirm these findings. *** INSERT FIGURE 1 HERE*** Being able to distinguish FTD from AD is important clinically and recent studies have suggested that atrophy or cortical thinning of precuneus, posterior cingulate, posterior temporal and parietal areas is characteristic of AD pathology independent of clinical diagnosis and is therefore helpful in distinguishing those with atypical AD presentations (which may include bvFTD or a progressive aphasia) from those with FTLD pathology.(124-126) Clinically, however, VBM or cortical thickness studies are unlikely to be available and simpler techniques such as visual rating scales have been developed which can help to differentiate FTD from AD.(127) More sophisticated methods using techniques such as support vector machines are being developed which allow automatic classification of patients into FTD or AD groups with little user input necessary, although currently these are computationally demanding.(128) Another possibility is to use support vector machine-based MRI analyses that integrate gray matter and diffuse tensor imaging (DTI), which has shown accurate pathological or CSF-defined categorization of FTLD and AD.(129)

  ) Levels of CSF phosphorylated tau are essentially normal in FTD, in contrast with AD. Levels of CSF amyloid beta have been found to be either decreased or in the normal range. An indication of lower amyloid beta levels in FTD compared with AD and control subjects, might particularly be useful to distinguish FTD patients from subjects without a neurodegenerative disorder.(135) Decreased levels of progranulin protein are found in plasma, serum and cerebrospinal fluid (CSF) by enzyme-linked immunosorbent assay (ELISA), and may reliably differentiate GRN mutations carriers from non-carriers.(136-140) It remains to be investigated if measurement of plasma or CSF levels of TDP-43 is useful diagnostically, as plasma phosphorylated TDP-43 levels have been found to be correlated with the extent of TDP-43 pathology in FTLD.(141-142)Recent biomarker studies on CSF are using multi-analyte profiling to derive novel biomarkers for neurodegenerative disorders and have delivered some promising neuropeptides (agoutirelated peptide (AgRP), adrenocortotrophic hormone (ACTH), which are useful in distinguishing FTLD-TDP from FTLD-tau patients.(143)(144)

  More than 40 mutations in the MAPT gene have been identified in families with FTD and parkinsonism linked to chromosome 17q (FTDP-17) with accumulation //www.molgen.ua.ac.be/FTDmutations).(12) Alternative splicing of exons 2, 3 and 10 of the MAPT gene gives rise to six isoforms: three isoforms containing three amino-acid repeats (3R), and three isoforms with four repeats (4R).(147) Mutations can be distinguished into missense mutations in exon 9 -13 affecting the normal function of the tau protein to stabilize microtubules, and intronic and some coding mutations affecting the splicing of exon 10 at the mRNA level, resulting in a change of the ratio of 3R to 4R tau isoforms.(148)The mean age at onset is 55 years and usually shows a small intrafamilial variation between 45 and 65 years, although the disease may present before the age of 40 years or after 70 years in a few mutations.(149) The mean duration of illness is approximately nine years, but varies between five and twenty years. There exists a dementia-dominant phenotype with prominent behavioural changes including disinhibition and obsessive-compulsive behaviour,(149) and a parkinsonism-dominant phenotype with CBS or PSP-like syndromes.(80) Patients may develop language problems e.g. mild semantic impairment during the illness.(150) Progranulin More than 60 mutations in the GRN gene on chromosome 17 (1.7 Mb centromeric to the MAPT gene) have been identified to date, and account for approximately 5 -10 percent of all

  ) The neuropathology of patients with GRN mutations is characterized by The mean age at onset is around 60 years ranging from 35 to 89 years, with a penetrance of 90 percent by the age of 70 years.[START_REF] Van Swieten | Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia[END_REF] 151) Within families, the onset age shows considerable variation with a difference of up to 20 years between consecutive generations.[START_REF] Seelaar | Distinct genetic forms of frontotemporal dementia[END_REF][START_REF] Van Swieten | Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia[END_REF] The mean duration is eight years (range 3 -22 years).Apathy and social withdrawal are the most common behavioural changes. Twenty-five percent of patients presents with early isolated language dysfunction, suggestive of an anomic non-fluent type (without motor speech impairment) and with relatively early single word comprehension impairment.(156) Hallucinations and delusions are frequently reported.(157-159) Episodic memory deficits occur in 10 -30 percent, and may lead to the clinical diagnosis of amnestic variant of MCI or together with parietal deficits, like dyscalculia, visuospatial dysfunction, and limb apraxia to AD.(157)(158)(160)(161)(162)

  (168)(169)(170)(171) VCP gene mutations are associated with inclusion body myopathy (90%), Paget's disease of the bone (45%) and FTD (38%) (IBMPFD), presenting between the age of40 and 60 years.(168, 172) The clinical presentation of CHMP2B gene mutations consists of a frontal lobe syndrome and a more global cognitive impairment, with parkinsonism, dystonia, pyramidal signs, and myoclonus later in the course of the disease.(173) ALS has been reported in only two patients.(174) TARDBP gene mutations on chromosome 1 are found in five percent of familial ALS,(170, 175-182) and occasionally in FTD or FTD-MND cases.(170-171) Also FUS gene mutations are found in five percent of the familial ALS cases,(183-186) and in one clinical bvFTD patient, but not in FTD-MND.(187) However, for the majority of the FTD-MND families, the genetic defect has yet to be identified. A number of these families have been linked to a locus on chromosome 9p13.2-21.3, but at time of writing an exhaustive sequencing of all genes in this region has not revealed any coding or splice-donor site mutations.(188)(189)(190)(191)(192)(193)

  Also, an association of the Cystatin C gene (CST3) haplotype B, the ε4 allele of the apolipoprotein E gene (APOE), and heterozygosity of the codon 129 polymorphism of the prion protein gene (PNRP) could not be confirmed in further studies.(197-201) Finally, SNPs in the Ubiquitin associated protein 1 (UBAP1) gene have been associated with FTD,(202) which was supported by a reduced mRNA expression from the disease-associated haplotype in a quantitative analysis.(202) Recently, an international genome wide association study (GWAS) with pathologically proven FTLD-TDP patients has demonstrated a significant association with three SNPs within the TMEM106B gene on chromosome 7p21.(203) TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with GRN gene mutations.(203) TMEM106B encodes an uncharacterized transmembrane protein of 274 amino acids.(203) Expression data showed increased TMEM106B expression in the frontal cortex of FTLD-TDP than in controls, suggesting that increased TMEM106B expression in the brain might be linked to mechanisms of disease in FTLD-TDP and that risk alleles at TMEM106B confer genetic susceptibility by increasing gene expression.(203)

)

  MAPT mutations are associated with different types of tau inclusions (Pick bodies, neurofibrillary tangles and pretangles) in the frontal and temporal cortex, hippocampus and subcortical nuclei, and sometimes in midbrain, brainstem, cerebellum and spinal cord.(149) Glial tangles and coiled bodies in white matter are found in a few MAPT mutations and consist predominantly of four-repeat tau isoforms.(149) FTLD-TDP is the second major subtype of FTLD, with ubiquitin-positive inclusions, which have the TDP-43 protein as major constituent.(204) The further classification into four different FTLD-TDP subtypes according to the morphology and distribution of the inclusions (15-16) can be predicted to some extent by the clinical picture: SD is strongly associated with abundant dystrophic neurites (type 1), FTD-MND with numerous neuronal cytoplasmatic inclusions in both superficial and deep cortical laminae (type 2), GRN mutations are characterized by numerous cytoplasmatic inclusions, dystrophic neurites and neuronal intranuclear inclusions (type 3), and VCP mutations are characterized by numerous intranuclear and infrequent number of neuronal cytoplasmatic inclusions and dystrophic neurites (type 4).(15, 17) It remains unclear what differences in underlying pathophysiology determine the distinction between these TDP-43 subtypes. A small number of FTLD cases with ubiquitin-positive, TDP-43 negative pathology,(205-208) have recently shown immunoreactivity with the FUS antibody.(19, 103) None of these FTLD-FUS cases had FUS gene mutations.(208) FTLD-FUS cases are characterized by a young age at onset, bvFTD, a negative family history, and caudate atrophy on MRI.(103-104) FUS-positive inclusions are also found in patients with neuronal filament inclusion disease (NIFID).(209) NIFID patients mostly present with bvFTD symptoms, a negative family history, and pyramidal and/or extrapyramidal movement disorder.(209) The FUS protein contains 526 amino-acids and is as nuclear protein involved in DNA repair and the regulation of RNA splicing.(183-184) Mutations in the FUS gene on chromosome 16 have emphasized its pathogenetic role in the clinicopathological spectrum of FTD and ALS.(187) Finally, the pathological heterogeneity of FTLD has been further emphasized by cases with ubiquitin-positive, TDP-43 and FUS-negative inclusions, termed FTLD-UPS. Most of the FTLD-UPS cases carry a CHMP2B mutation,(210) but there remains a few without CHMP2B mutations.(208). Further research on FTLD-UPS is necessary to elucidate the full complement of FTLD pathologies.(208) Future clinicopathological studies, including neuroimaging and genetics are necessary to improve the prediction of the underlying pathology. Especially the prediction of the underlying pathology in (sporadic) bvFTD will be important, as tau-, TDP-43-, or FUSpathology could be the disease-modifying protein in these patients. *** INSERT FIGURE 2 HERE *** Future directions Important advances in the field research on FTD over the last decade have led to an impressive change in the clinical recognition of this disease. Future scientific efforts should focus on three major lines of research: 1. to improve the early detection of the disease 2. to develop reliable markers in predicting the underlying pathology, and 3. to unravel its pathophysiology in order to develop therapeutic strategies preventing or delaying the disease process. Concerning the clinical diagnosis, an international study has been initiated to revise the clinical criteria based on a large sample of pathologically-proven cases. The aim is that neuroimaging and genetic data, and the most salient clinical features should be incorporated in a revised set of simplified criteria of bvFTD. A second clinical issue will be to monitor the progression of the disease in individual patients, which has now become available by the recent introduction of FTD rating scale (FRS)(211) characterizing the features of different severity stages. Finally, the use of social cognition tasks will help in the early detection of bvFTD and discrimination from non-progressive bvFTD. Their use offers us the opportunity to investigate the relative contributions of individual brain regions to social cognition in FTD.Although relatively specific atrophy patterns have been found in clinical FTD subtypes, neuroimaging features as biomarkers for underlying pathology in bvFTD have yet to be determined. Support vector machines and arterial spin labeling are new neuroimaging tools to accurately differentiate FTD from AD. Another novel and promising neuroimaging technique is resting-state fMRI, which has shown changes in the salience network in FTD. An interesting question will be whether the early (or even presymptomatic) MAPT or GRN mutation carriers can be detected using this technique.The differentiation of PPA into SD, PNFA, and LPA has proven to be an important step in predicting underlying pathology in these groups: TDP-43 pathology is most commonly found in SD, tau-pathology in PNFA, and AD-pathology in LPA. Multimodal predictors, including clinical parameters, neuropsychological test scores, and atrophy patterns, will improve the prediction of the underlying pathology in clinical PPA syndromes. However, radioactive compounds to detect tau or TDP-43 pathology in the brain with PET scanning would be of great help to differentiate bvFTD into its two major pathological subtypes during life. The recent recognition of the FUS protein as a pathological component of neuronal inclusions in a specific subtype of FTLD emphasizes the existence of different pathways, and will also contribute to further understanding of the underlying pathophysiology. Another strategy would be the development of new CSF biomarkers, which could be derived by large-scale proteomics analysis.Several common (MAPT, GRN) and rare (VCP, CHMP2B, TARDBP, FUS), genetic factors have been found in hereditary FTD over recent years. However, we still have to identify one or more gene defects in familial FTD with and without MND. Whole exome sequencing as innovative genetic technique might reveal new genetic defects in small families with FTD and for pathologically well-characterized FTLD subtypes (like FTLD-FUS). Identification of novel genetic defect(s) will help to understand the pathophysiology of TDP-43 in hereditary and probably also of the sporadic FTLD-TDP. A large genome-wide association study of more than 3000 DNA samples is currently underway and may hopefully reveal additional genetic factors with a small effect on the disease process.All these small steps in unravelling the pathophysiology should finally lead to the development of therapeutic interventions for FTD.

Figure 1 :Figure 2 :

 12 Figure 1: Clinical, genetic and pathological spectrum of FTLD

Table 1 : Language characteristics in PPA variants (52, 55, 61-64)

 1

		Spontaneous Speech	Motor speech Single word	Grammar / Sentence	Sentence	Naming/	Fluency	Reading
				comprehension	comprehension	Repetition	word retrieval
	SD	Fluent	Spared	Impaired	Initially spared, becomes	Spared	Anomia	Impaired	Surface
		Grammatically correct			impaired as single word		(nouns > verbs)	(categorical > letter)	dyslexia
		Empty and circumlocutory			comprehension deteriorates
		Semantic errors
	PNFA	Decreased fluency	Impaired	Initially spared,	Impaired for complex	Can be impaired Spared initially but	Impaired	Phonological
		Articulatory errors		becomes affected in	sentences		anomic as disease	(letter > categorical)	dyslexia
		Apraxia of speech and/or		late disease			progresses
		Agrammatism					(verbs > nouns)
	LPA	Slow output with word-	Spared	Relatively spared	Impaired for simple and	Impaired	Impaired	Impaired	Phonological
		finding pauses			complex sentences			(letter ≈ categorical)	dyslexia
		Phonemic paraphasias

Acknowledgements

Harro Seelaar and John C. van Swieten are funded by Stichting Dioraphte and Hersenstichting. The Dementia Research Centre is an Alzheimer's Research Trust Co-ordinating centre and receives support from the NIHR Biomedical Research Centres scheme. Nick C. Fox is funded by the Medical Research Council and is an NIHR Senior Investigator.

Competing Interest:

None Declared


Robert Klinc

Andreja Istenič Starčič

The comparative study of the ICT collaborative environments in master courses

Keywords: engineering education, computer supported collaborative learning, distance learning, problem based learning, ITC Euromaster

ICT collaborative environments surpasses old practices with drawing learning closer to a real life with interactivity and authenticity of real world problems in learning and consequently reducing de-contextualization in the learning process. Contemporary educational ICT usage in learning processes is student-centred. In 1993 University of Stanford (USA) started an ICT supported distance learning course named Architecture/Engineering/Construction Computer Integrated Global Teamwork Course (AEC Global Teamwork). The mission of the program is to educate the professionals to be able to work in multi discipline collaborative environments and to take advantage of information technologies to produce high quality products in faster and more economic way. In autumn 2001, nine European universities started the project in order to develop an inter university postgraduate programme in information technology in construction (ITC Euromaster). The paper presents a comparative study of both distance learning master courses with the focus on the ICT collaborative environments.

Introduction

Even though advances in information and communication technologies (ICT) significantly changed the way professionals in building and construction (BC) industry work, the dominant training method is still the traditional classroom lecture with all its drawbacks. Rebolj and. [START_REF] Rebolj | Another step towards a virtual university in construction IT[END_REF] argue that this is an important reason why IT is not used in construction projects more often, even though the demand coming from the industry is clear.

During the last years the advances in technology and changed organizational infrastructure of the industry magnified the importance of teamwork. [START_REF] Serce | A Web-Based Synchronous Collaborative Review Tool: A Case Study of an On-line Graduate Course[END_REF] emphasized that employees (in every industry) have to be able to think creatively, solve problems and most important -they have to be able to take decisions as a team. Therefore Serce and Yildirim pointed out that institutions of higher education should focus on educating graduates who are not only flexible and have market related skills but also have enhanced collaborative skills especially in the interdisciplinary teams. Since the year 1999 in Europe major activities within the Bologna reform are the definition of the graduates' competences. One of major projects is Tuning with its focus on generic competences and subject specific competences. The survey conducted in the field of civil, building and structural engineering among European employers in 2005 showed that employers ranked the competence "ability to work in an interdisciplinary team" on the 4 th rank from 17 generic competences. It was ranked after "capacity for applying knowledge in practice", "basic knowledge of the profession", "capacity for analysis and synthesis" (Šubic Kovač, Istenič Starčič 2006).

In addition, [START_REF] Turk | Construction IT: Definition, Framework and Research Issues[END_REF] stated that major problem in the implementation of technology is the varying IT capability of team members.

In response to the demands of the AEC sector for improvement and broadening of the competence of engineering students in using new technologies while solving specific problems, in 1993 University of Stanford (USA) started an ICT supported distance learning course named Architecture/Engineering/Construction Computer Integrated Global Teamwork Course (AEC Global Teamwork), also known as PBL (Problem-Project-Product-Process-People-Based Learning). The mission of the programme has been to educate the next generation of professionals to be able to work in multi-discipline collaborative environments and to take advantage of information technologies to produce high quality products in a faster and more economic way. It is aimed at undergraduate, graduate and postgraduate students from all over the world.

Positive feedback from the AEC Global Teamwork encouraged other institutions to introduce their own BC oriented distance learning courses. One of them is ITC Euromaster. In autumn 2001, nine European universities started the project in order to develop an inter-university postgraduate programme in information technology in construction (ITC). The objective has been to provide students with the ability to extend their knowledge in the application of ICT in BC and related industries [START_REF] Dado | Towards establishing a distant learning environment for a European Master in Construction IT[END_REF]. The project was realised in the academic year 2004/2005 when the first generation of students started the Socrates/Erasmus European Masters course in construction information technology, ITC Euromaster.

In this paper both programmes are briefly described and major observations and differences are presented. This is followed by the survey carried out among participants in order to compare both courses. Finally, results are presented, key findings are discussed, and conclusions summarized.

The comparative study the ICT collaborative environments

ICT collaborative environments surpasses old practices with drawing learning closer to a real life with interactivity and authenticity of real world problems in learning and consequently reducing decontextualization in the learning process. Contemporary educational ICT usage in learning processes is student-centred. This demands readiness for active learning methods, self-directed learning, and reflection of one's own learning progress, learn to learn skills, collaboration skills and digital literacy. Deployment of ICT collaborative environments can foster quality of teaching and learning but in the process of the sustainable implementation in study programmes many obstacles are faced such as curriculum development, interoperability standards and staff development (Istenič [START_REF] Starčič | The Development of the Collaborative Model of ICT Learning Systems for Lifelong Learning[END_REF]). The conditions for computer supported collaborative learning according to Johnson & Johnson: positive interdependence, individual and group responsibility, face-to-face promotive interaction, interpersonal and small group skills, group processing (1996).

ICT collaborative environments support many students who would not be able to attend courses in other departments and programmes than those they are currently studying. [START_REF] Fruchter | Computer Integrated Architecture/Engineering/Construction Project-centred Learning Environment[END_REF] addressed two critical problems of the practices in the A/E/C industry and education: (1) fragmentation and (2) discipline-based education. Poor communication among the professionals together with the fact that every professional involved in the project (architect, structural engineer, contractor ...) sees the final product in a different way can result in a missed deadline or exceeded budget. Some of the problems could be addressed by new technologies, but without an improved team effort even the technology can fail. That is why in 1993 the Architecture/Engineering/Construction Computer Integrated Global Teamwork Course (AEC Global Teamwork) at Stanford University has been launched. The course was carried out in response to the needs of the industry to improve and broaden the competence of students. They are expected to become familiar with project performance, collaboration technologies, to improve their ability to work as a team, and to understand management concepts [START_REF] Fruchter | Computer Integrated Architecture/Engineering/Construction Project-centred Learning Environment[END_REF]).

In the AEC Global Teamwork course a number of teams (usually 4-5) of students are facing the challenge to complete the assigned project from the start to the successful finish. Teams are working on different projects with some unique constraints. All teams have an architect, several structural engineers and construction managers. Each team also has at least one 'owner' or 'investor'.

The goal of the course is to educate participating students in (1) how different disciplines (architecture, engineering, construction) impact each other, (2) using up-to-date technologies for collaboration and daily work, (3) how to build a team and be able to take decisions as a team over the internet and (4) how to simulate concurrent engineering and collaboration technology from the organizational point of view [START_REF] Fruchter | Computer Integrated Architecture/Engineering/Construction Project-centred Learning Environment[END_REF].

Project is being done almost exclusively over the internet, using available technological solutions. Team members are coming from different countries and are dispersed all over the world. They are forced to employ technology to overcome the limitations and problems caused by different geographical location and time zones. In that way knowledge and resource sharing among programmes and universities is guaranteed.

Cooperation instead of competition was the primary driver of the ITC Euromaster initiative too. [START_REF] Rebolj | Another step towards a virtual university in construction IT[END_REF] stated that from the beginning of the course development the main idea was to share, jointly develop and organise knowledge in the field of information technology in construction. They identified current education practice as an important reason why IT is not effectively used in construction.

Consequently a consortium of nine universities started the project and developed European Master in construction IT in order to improve and speed up the transfer of latest findings in the field of IT into construction practice.

While it would be almost impossible for every university to have experts in all fields of ITC, partner institutions were among the leading ones in the ITC field [START_REF] Rebolj | Another step towards a virtual university in construction IT[END_REF], so the idea was for each of them to offer the best knowledge and experience it possesses. Instead of sharing that knowledge in small classes at multiple places, lectures are given in virtual classroom using appropriate technology solutions (Figure 1). Virtual classroom is used to give lectures and share knowledge on topics from various fields of ITC.

The curriculum is focused on graduate students with university degree in civil, building or structural engineering [START_REF] Rebolj | Another step towards a virtual university in construction IT[END_REF]) and span the whole range of ITC: (1) technological aspects, (2) theoretical aspects, (3) models (including their functionality) and ( 4) processes (including their simulation) [START_REF] Dado | Towards establishing a distant learning environment for a European Master in Construction IT[END_REF].

Comparison was made using two approaches: close observation of both courses discussed, using the results of the questionnaire which was sent to the students in order to compare their view on the programme they participated and technology that was involved.

Considering the fact that in both cases learning is more or less student-oriented, it was concluded that evaluation should also be student-oriented and questionnaire was chosen as an appropriate option.

Observations

Even though both courses are using similar approach, they are quite different at the same time. While AEC global teamwork is project-oriented, ITC Euromaster is a postgraduate programme, covering more than one topic. The strongest link between both programmes is the use of modern IT tools in learning and working process. Some of them were introduced by course personnel while others were used on the initiative of the participating students.

As shown in Table 1 and Figure 1, although similar technologies were identified as important in both courses, different solutions were introduced. In AEC Global Teamwork, modular approach using easy accessible software was chosen. Some of the software (MSN NetMeeting, MSN Messenger, Skype) can be obtained for free from the internet, while other (Recall TM , Think Tank TM ) has been developed at University of Stanford. In that way, each module (for chat, audio, video etc.) can be quickly replaced if there is a problem with the tool currently used or if a better solution becomes available. There are also some drawbacks:

AEC Global Teamwork

• it is necessary to obtain, maintain and master many tools,

• with many different software solutions there is higher probability that something will go wrong,

• more opened ports in corporate firewalls,

• usage of 'unusual', patented (although excellent) non-free tools (Recall TM , Think Tank TM ),

• confusion (MSN NetMeeting is used only for application sharing although it is capable of providing audio as well as video channel).

5(14)

Figure 1: AEC Global Teamwork -decentralised approach to lectures On the other hand, ITC Euromaster is using centralised solution (Figure 2) named ClickToMeet (CTM). CTM is a client/server solution for on-line meetings. It runs on a server and enables students and lecturers to use everything they need from their web browser (audio, video, chat, presentations, whiteboard, application sharing) so that there is no need to download, install and maintain other software tools. The only thing needed is a single ActiveX control for user's browser. The advantage of the solution is that it is very easy to use and that there is less effort needed to get things moving despite firewalls. The main advantages are at the same time major disadvantages of this system:

• CTM is not free (license fee per user),

• student is limited to Internet Explorer (and to Windows operating system),

• ActiveX controls are considered to be potentially dangerous and therefore prevented on some corporate systems, • it is harder to identify and deal with possible problems. The only major thing that ITC Euromaster lacks is a system module for recording lectures and sessions in order to listen to them asynchronously. This feature can be useful if student misses a lecture, mentor session or something similar and would like to see and listen to it anyway. For that reason in AEC Global Teamwork software package Recall TM is used.

In both cases there is a central portal with all information needed for the course together with the learning material. While with the AEC Global Teamwork Think Tank TM is used as the central system (in-house solution of the University of Stanford), ITC Euromaster uses a well known open-source system Moodle. In either case the public asynchronous communication between the persons involved (students, lecturers, mentors) is possible.

Survey

In the development of ICT assisted learning is the main aim to foster student-oriented learning and to support teachers' facilitative/transformative function. Communication is very important in a process of forming knowledge of concepts and theories. It helps individuals to better understand others knowledge and at the same time strengthen their own knowledge. As a consequence the use of ICT in teaching and learning has shifted from individual use to collaborative learning. The individual use can be limited in some ways when, for example, limitations in ICT assisted learning design originate from difficulties in (1) identification of individual's learning styles, motivation, needs, and (2) acknowledging their differences. Individual teaching limits the resources to the individual; the support of the groups of learners in developing shared mental models is lost [START_REF] Johnson | Cooperation and the use of technology[END_REF].

Primarily the survey was intended for getting some feedback on the courses from the students who participated in the course. It was intended to evaluate and compare both courses in two crucial respects: the communication technologies used, the experiences and impressions of the course.

The survey was conducted by Webswey, a tool for creating surveys on the Web (http://www.scix.net/). The survey population was selected among the students who participated in one of the courses in the year 2006. Due to a small number of students participating in ITC Euromaster, similar number of students participating in AEC Global Teamwork was randomly selected. The total number of survey respondents was 15 (8 from AEC Global Teamwork and 7 from ITC Euromaster).

Students were asked several questions of different types. First, some questions were asked in order to determine whether educational background had affected course experience and then questions regarding course experience and technologies used followed. Last, some questions regarding the whole experience were asked.

As mentioned before, 15 (83% of invited) students responded to the survey. The average age of respondents from the AEC Global Teamwork was 25 (Figure3) with 75% males and 25% females (Figure 4), while the average age of respondents from ITC Euromaster was 33 (Figure 3), with 63% percent of male students and 27% of female students (Figure 4). When students were asked to evaluate their knowledge of communication technologies (from 1 to 5), the average answer in both groups was the same (Figure 5).

8

AEC Global Teamwork ITC Euromaster It can be concluded that both groups were fairly comparable.

As seen in Figure 6, least known technologies prior to taking the course were application sharing and video communication. When asked for most useful tool during the course, 50% of students from AEC Global Teamwork answered that most useful was instant messaging, while on the other hand 43% of students of the ITC Euromaster thought that most useful was application sharing (Figure 7). To sum up, as far as technology is concerned, the least important technologies for use during the two courses are wiki, game engine and forums (Figure 9). In order to be precise, it has to be mentioned that wiki and game engine were not introduced as a part of the courses but were used on recommendation of some students in the AEC Global Teamwork.

11(14) What is interesting is that the forum (discussion boards) was not highly rated although the advantages are clear. AEC Global Teamwork student #4 noted:

"It is most similar to email and instant messaging, but has the benefit of being recorded for everyone to see. Email does not necessarily let everyone see the conversation. Instant messaging may not keep a good record of conversations. Forums have both of these."

Students were also asked if they had any problems with technology and the related tools. Results show (Figure 10) that almost all participants had some problems. Regarding question on specific problems that emerged during the lectures, similar answers were given. Among the AEC Global Teamwork students most answers were related to FTP and forum inaccessibility, usage of diverse software solutions and the lack of a central solution.

"FTP servers and the forum servers went down every once in a while, which caused problems for our team. Then we had to rely on other methods of communication and distribution." AEC Global Teamwork student #4

On the other hand it seems that ITC Euromaster students had a lot of problems with ClickToMeet system. ITC Euromaster student #1 wrote:

"Sometimes it just didn't work."

Despite the problems, 93% of all students think that IT knowledge gained during the course is invaluable in their further work and 87% of students are convinced that IT can be one of the major factors in competitiveness of the BC industry.

Conclusions

In order to educate the next generation of professionals to be able to work in multi-discipline collaborative environments it is necessary to present the advantages of information technologies. This study showed two examples of such transfer of ICT related knowledge into practice and comparison of two approaches taken. Survey confirms that participants gained valuable experiences using technologies that were available and presented. It was also presented that despite the clear benefits of the use of some tools available, students use technology they know best if it is more convenient to them.

The paper once again shows the lack of modular integrated systems required to support distributed learning environments. Results show that students prefer ITC Euromasters' centralised virtual classroom to more than decentralised solution and usage of diverse software tools in AEC Global Teamwork. To illustrate why, AEC Global Teamwork student #5 reported: "Computers were not capable of handling multiple softwares."

On the other hand, ITC Euromaster students reported bandwidth and firewall problems using centralised system.

What is interesting is that when participants were asked about their reflection on the course and what they have gained from that experience, the majority of AEC Global Teamwork participants wrote about social aspects of the whole experience while IT Euromaster students focused more on IT issues although they arguably had fewer problems.

Despite some technological drawbacks both courses seems to be delivering what they have promised. AEC Global Teamwork student #6 wrote: "I gained the ability to compete in a worldwide market and obtain skills that I will use to pursue a career that is challenging and insightful. I also gained many valuable resources in many specialties and in many places."

And that is why it is worth developing them further.

Figure 2 :

 2 Figure 2: ITC Euromaster -centralised solution

Figure 3 :Figure 4 :

 34 Figure 3: The average age of the participants answering the questionnaire.

Figure 5 :

 5 Figure 5: Answers to the question: "Please, evaluate from 1 (poor) to 5 (excellent) your knowledge of communication technologies prior to taking this course?"

Figure 6 :

 6 Figure 6: "Which tool was least known to you prior to taking the course?"

Figure 8 :

 8 Figure 8: "Which tool did you mostly use during the course?"

Figure 9 :

 9 Figure 9: "In your opinion, how important is each of the following technologies for the course? (1 = not important at all, 5 = very)"

Figure 10 :

 10 Figure 10: "Did you experience any problems during the course?"

Table 1 :

 1 Technologies used in AEC Global Teamwork and ITC Euromaster

	ITC Euromaster

  This is mostly related to the tools used during the lectures. While ITC Euromaster uses ClickToMeet which has audio\video capabilities and application sharing included and works out of the box, it is more convenient for AEC Global Teamwork students to use what they know best.

	60% 60%
	50% 50%
	40%
	40%
	30%
	30%
	20%
	20%
	10%
	10%
	instant messaging 14% 50% instant messaging application sharing application sharing 29% 0% 0% AEC Global Teamwork ITC Euromaster 0%	audio communication 29% 25% audio communication communication 14% video 0% video communication forum	0% 13% forum	e-mail	audio) lectures (video, 14% archive of the 13% archive of the other 0% 0% audio) e-mail lectures (video,	0% 0% other
	AEC Global Teamwork	50%	25%	13%	0%	13%		0%	0%	0%
	ITC Euromaster	0%	43%	29%	14%	0%		0%	14%	0%
	Figure 7: "Which tool was most useful to you during the course?"
	Considering the answers, most used technology in AEC Global Teamwork was instant messaging,
	while students of ITC Euromaster most often used audio and video communication and application
	sharing (Figure 8).
	Respondents wrote:
	"Because it was the most convenient method to communicate with others." (audio commucation)
	ITC Euromaster student #6
	"Helps in making quick decisions. Avoids lag time of e-mail." (instant messaging)
	AEC Global Teamwork student #6
	"It was the easiest and fastest way to convey a message. It also took the least amount of time to set
	up." (instant messaging)
	AEC Gobal Teamwork student #7
										9(14) 10(14)

Acknowledgments

The authors of this paper would like to thank prof. Renate Fruchter for invitation to the AEC Global Teamwork course 2006 and prof. Žiga Turk who made the whole experience possible. The authors would also like to thank all the students participating in the survey, mentors, team and course mates from PBL 2006, lecturers and classmates from ITC Euromaster. It was worthwhile experience. Thank you all.

Authors: