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In the past decade there have been enormous advances in our understanding of frontotemporal dementia and related syndromes. The impetus for these advances has come from a number of directions, including genetic discoveries, new approaches to neuroimaging and improved neuropsychological understanding of the cognitive aspects of the condition. This book provides a much needed review of the current status of our knowledge of these syndromes.
The book starts with chapters reviewing the history of the condition and describes the presenting clinical, neuropsychiatric and neuropsychological features, before reviewing, in detail, the areas of greatest recent research progress: brain imaging, histopathology and molecular genetics. The book concludes with a chapter proposing a multidisciplinary approach to patient management, with illustrative case studies.
Frontotemporal Dementia Syndromes will be essential reading for neurologists, psychologists, psychiatrists and other clinicians interested in cognitive and behavioural disorders, as well as for basic scientists working in the area of neurodegeneration.
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Cambridge University Press
9780521854771 - Frontotemporal Dementia Syndromes - Edited by John R. Hodges
Overview of frontotemporal dementia
Over the past decade there have been considerable advances in our understanding of the neurodegenerative diseases producing focal cognitive deficits, most commonly referred to collectively as either Pick’s disease or, more recently, frontotemporal dementia (FTD). These advances have come from the fields of neuropsychology, neuropsychiatry, neuroimaging and molecular genetics. Unfortunately most non-experts’ ability to follow these developments has been hindered by the confusing plethora of terms which have been used. Central to the problem is a lack of clarity concerning the level of description (clinical syndrome vs clinico-pathological entity vs specific histological diagnosis) and the poor concordance between these levels. In other words, while some labels denote a clinical syndrome without specific histological implications (e.g. progressive aphasia, semantic dementia or dementia of frontal type), others denote specific neuropathological entities (e.g. Pick’s disease, familial tauopathy, ubiquitin-inclusion disease), hybrid clinico-pathological entities (frontotemporal dementia), or even specific genetic disorders (e.g. Chromosome 17 linked frontotemporal dementia with parkinsonism). The resurgence of interest in these disorders and the differences in opinion over terminology are well illustrated by the titles of the previous books published onthe topic: Pick’s Disease and Pick’s complex (Kertesz and Munoz, 1998), Frontotemporal Dementia (Pasquier et al., 1996) and Frontotemporal Lobar Degeneration: Frontotemporal Dementia, Progressive Aphasia, Semantic Dementia (Snowden et al., 1996b).
The aims of this introductory chapter are to review the evolution of the terms used to describe this spectrum of disorders, to highlight recent advances and areas of continuing controversy, and to set the scene for the rest of the book. While my own preference has always been to use the term Pick’s disease for this group of disorders – partly because this term is more readily understood by carers and parallels our use of the label Alzheimer’s disease – the tide of medical opinion turned in favour of FTD in the late 1990s. We have, therefore, adopted this general label within which we distinguish three main clinical variants: frontal or behavioural variant FTD (bv-FTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA). The sections that follow describe the meandering route that led to the adoption of these terms. The chapter draws heavily upon our own experience of more than 300 patients assessed in Cambridge over the past 15 years.
2 What did Arnold Pick actually describe?
In 1892 Arnold Pick (Girling and Berrios, 1994), working in Prague, reported a 71-year-old man with progressive mental deterioration and unusually severe aphasia who at post-mortem had marked atrophy of the left temporal lobe. Twelve years later in 1904 he published his landmark paper (“On the symptomatology of left-sided temporal lobe atrophy”) in which he described three further cases (Girling and Berrios, 1997). The first, a 58-year-old woman (Josephina) had a 2-year history characterised by a striking loss of memory for names (amnesic aphasia) culminating in almost complete loss of speech and accompanied by changes in personality. She deteriorated rapidly and at post-mortem, 2 years after presentation, Pick observed asymmetric temporal lobe atrophy involving particularly the inferior and middle gyri (i.e. not Wernicke’s area). Methods of staining brain sections were not available at that time and Pick was able to make observations on the macroscopic pathology only. The other two cases were clinically similar, except that case three had the complication of cerebral syphilis, preventing firm conclusions about the cause of the focal brain atrophy. Pick wanted to draw attention to the fact that progressive brain atrophy may lead to symptoms of focal disturbance (in this instance aphasia) through local accentuation of the disease process. He also made specific and, as we will see below, highly perceptive, predictions regarding the role of the mid temporal region of the left hemisphere in the representation of word meaning. It was only in his later publication that Pick turned his attention to bilateral frontal atrophy with resultant behavioural disturbance.
Pick made major contributions which have sadly been rather overlooked in recent reviews. Current classifications have also relegated him to a minor role but several points should be emphasised: (1) Pick’s primary interest was the language and behavioural disorder, particularly the clinico-anatomical correlates of aphasia; (2) he did not claim to have discovered a new disease, merely novel phenomena arising from asymmetric degeneration; (3) two of the major syndromes now included under the rubric of frontotemporal dementia (bv-FTD and semantic dementia) were clearly described by Pick; (4) he did not describe distinct histopathological changes in his patients with focal atrophy.
The histological abnormalities associated with Pick’s disease were, in fact, described a few years later by Alzheimer (1911) who recognised changes distinct from those found in the form of cerebral degeneration later associated with his name. Alzheimer recognised both argyrophilic intracytoplasmic inclusions (Pick bodies), and diffusely staining ballooned neurons (Pick cells) in association with focal lobar atrophy. It is interesting to note that a comprehensive review of 20 patients from the literature with aphasia due to focal lobar atrophy written soon after Alzheimer’s description (Mingazzini, 1913) did not use the label Pick’s disease.
Onari and Spatz (1926) were among the first to use the eponym Pick’s disease but Carl Schneider (1927, 1929) is probably most responsible for its introduction. Unfortunately, however, he concentrated on the frontal lobe component of the syndrome and began the neglect of the temporal lobe syndromes associated with focal atrophy that continued for at least half a century. He distinguished three clinical phases – the first characterised by impaired judgement and behaviour, the second by focal symptoms, and the third by generalised dementia. Many papers describing similar cases appeared in the 1930s and 1940s (e.g. Ferrano and Jervis, 1936; Lowenberg and Arbor, 1936; Lowenberg et al., 1939; Neuman, 1949; Nichols and Weigner, 1938) which mainly focused on the frontal lobe aspects of the disorder. Given the more recent genetic discoveries related to tau, special mention should be made of the large Dutch family first reported by Sanders in 1939 and then again by Schenk (1951). These families were central to developments in the 1990s when linkage to the tau gene region on Chromosome 17 was established by workers in the USA (Wilhelmsen et al., 1994) and Europe (Heutink et al., 1997): see below and Chapter 9.
With the general waning of interest in the cognitive aspects of neurology in the English-speaking world, interest in focal dementia syndromes faded, as reflected by the dearth of clinical papers in the neurological literature after the Second World War. Indeed, many authors went as far as to claim that Alzheimer’s and Pick’s disease were clinically indistinguishable in life (Kamo et al., 1987; Katzman, 1986). The focus of interest in English language publications became the neuropathology, and latterly the genetics, of these conditions. This resulted in a gradual change in the criteria for Pick’s disease, which evolved to include the necessity for specific pathological changes (i.e., focal atrophy with Pick cells and/or Pick bodies). In continental Europe, however, there remained a strong interest in the clinical phenomena of the dementias; Pick’s remained an in vivo diagnosis based on a combination of clinical features suggestive of frontal and/or temporal lobe dysfunction and focal lobar atrophy (e.g. Mansvelt, 1954; Tissot et al., 1975, 1985). This controversy continues and has contributed to the adoption of the many labels to describe patients with the clinical syndrome of progressive frontal or temporal lobe degeneration.
3 Rediscovering Pick’s disease: from dementia of the frontal type and progressive aphasia to frontotemporal dementia
A renaissance of interest in the focal dementias began in the 1980s. Workers from Lund, Sweden (Brun, 1987; Gustafson, 1987) reported on a large series of patients with dementia and found that of 158 patients studied prospectively who came to post-mortem, 26 had evidence of frontal lobe degeneration. Since only a small proportion had Pick cells and Pick bodies – the remainder had very similar findings but without specific inclusions (i.e. focal lobar atrophy with severe neuronal loss and spongiosis) – the Lund group preferred to adopt the term “frontal degeneration of non-Alzheimer type”. At approximately the same time, Neary and co-workers in Manchester (Neary et al., 1986), began a series of important clinico-pathological studies of patients with pre-senile dementia. They, likewise, found a high proportion of cases with a progressive frontal lobe syndrome who had neither specific changes of Alzheimer’s disease (plaques and tangles) nor specific inclusion pathology. They introduced the term “dementia of frontal type”. Over the next few years other groups described very similar cases under the labels “frontal lobe degeneration” (Miller et al., 1991) and “dementia lacking distinct histological features” (Knopman et al., 1990). These papers were important in defining the key clinical features associated with progressive frontal lobe degeneration notably alterations in social conduct, inhibitory control, sexual behaviour, appetite, ritualised and stereotypic behaviours, reduced empathy and apathy.
In more recent classifications (see below) these patients have either been given the general label of FTD (as distinct from progressive aphasia and semantic dementia) or alternatively frontal/behaviour variant FTD (bv-FTD), a term which we prefer in Cambridge. Key advances have been the development of carer-based interview schedules or questionnaires such as the Neuropsychiatric Inventory (NPI; Cummings et al., 1994), the Frontal Behavioural Inventory (FBI; Kertesz et al., 2000) and the Cambridge Behavioural Inventory (CBI; Bozeat et al., 2000). It has become apparent that conventional frontal lobe tests based largely on executive abilities (planning, set-shifting, problem solving) are not very sensitive to the beginnings of this behavioural form of FTD. A range of exciting recent research has focused on ways of measuring the alterations in social conduct, emotion processing and complex decision making (Gregory et al., 2002; Keane et al., 2002; Lough et al., 2006; Rahman et al., 1999; Rankin et al., 2003; Torralva et al., 2006) (see Chapter 5). A challenge for the next few years is to develop clinically applicable tests of social cognition. Controversy continues concerning the precise location of pathology within the frontal lobes. It had been long assumed that the orbital cortex bears the brunt, particularly in the early stages of the disease, but recent imaging work has emphasised rather the role of the mesial surface (see Chapter 6). Moreover, some of the symptoms typically regarded as “frontal” in nature may, in fact, be secondary to amygdala or insula damage. Studies attempting to relate individual clinical features to site(s) of brain dysfunction using structural or functional imaging are in their infancy (Rankin et al., 2003; Rosen et al., 2002a, 2005; Williams et al., 2005) and it is certain that there will be considerable advances over the next few years.
3.1 Progressive aphasia and semantic dementia
The other strand of the story concerns the rediscovery of the syndrome of progressive aphasia in association with focal left temporal lobe or peri-Sylvian atrophy. In 1982 Mesulam (1982) reported six patients with a history of insidiously worsening aphasia in the absence of signs of more generalised cognitive failure. One of these patients underwent a brain biopsy, which revealed non-specific histology without specific markers of either Alzheimer’s or Pick’s disease. Following Mesulam’s seminal paper, approximately 100 patients with so-called primary progressive aphasia (PPA) were reported over the next decade (for reviews, see Hodges and Patterson, 1996; Mesulam and Weintraub, 1992; Snowden et al., 1996a). It became gradually clear that, although the term PPA was being applied to a range of very different cases, within this spectrum there were two identifiable and distinct aphasic syndromes: progressive non-fluent aphasia and semantic dementia, sometimes referred to as progressive fluent aphasia. In the former syndrome, speech is halting and distorted with frank phonological and syntactic errors. Comprehension mirrors output in that single-word (semantic) comprehension is relatively intact but patients have difficulty understanding syntactically complex sentences. Oro-buccal apraxia commonly accompanies the language disorder (see Chapter 3). In the latter syndrome, speech remains fluent and well articulated but becomes progressively devoid of content words. The language and other non-verbal cognitive deficits observed in these fluent-aphasic patients reflect a breakdown in semantic memory, which has led many authors to apply the label of “semantic dementia” first coined by Snowden et al. in 1989 (Hodges and Patterson, 1996; Hodges et al., 1992, 1994; Snowden et al., 1989).
Although the term “semantic dementia” (SD) is recent, the syndrome has been recognised under different labels for many years. As emphasised above, Pick (1892, 1904) and a number of other early authors (Mingazzini, 1913; Rosenfeld, 1909; Schneider, 1927; Stertz, 1926) recognised the outstanding clinical manifestation of temporal lobe atrophy as “amnesic aphasia” or “transcortical sensory aphasia”, together with a type of dementia variously described as a reduction in categorical or abstract thinking, psychic blindness or associative agnosia (Malamud and Boyd, 1940; Mingazzini, 1913; Robertson et al., 1958). These features – amnesic aphasia and associative agnosia – were united under the rubric of degraded semantic memory by Warrington (1975) who reported three patients. Drawing on the work of Tulving (1972, 1983), Warrington recognised that the progressive anomia in her patients was not simply a linguistic deficit, but reflected a fundamental loss of semantic memory (or knowledge) about objects and concepts which thereby affected naming, word comprehension and object recognition. Semantic memory is the term applied to the component of long-term memory that represents our knowledge about things in the world and their inter-relationships, facts and concepts as well as words and their meaning (Garrard et al., 1997; Hodges et al., 1992, 1998; Hodges and Patterson, 1997). Cases of SD have also been recognised for many years in Japan as cases of “Gogi (word meaning) aphasia” (Imura et al., 1971; Morita et al., 1987; Sasanuma and Mondi, 1975; Tanabe, 1992; Tanabe et al., 1992). The syndrome of SD has been particularly important from a theoretical perspective because, in contrast to Alzheimer’s disease, patients have relatively good day-to-day (episodic) memory and autobiographical memory, intact immediate or working memory (at least as assessed by digit span), and good visually based problem solving and visuo-perceptual abilities (Graham and Hodges, 1997; Hodges and Graham, 1998; Hodges et al., 1995, 1999; Patterson and Hodges, 2000). This relative selectivity of the semantic memory impairment in SD makes these patients ideal subjects for the study of the effects of semantic dissolution, uncontaminated by other cognitive deficits. As will be discussed more fully in Chapter 5, however, the situation is somewhat more complex that it first appeared both in terms of the purity of the syndrome and the insights afforded into the interaction between semantic memory and other putative “cognitive modules”.
The above description is, of course, an oversimplification and gives the impression that cases can be neatly divided into PNFA and SD. In practice things are much less straightforward. First of all, some authors have claimed that there is a coherent third progressive aphasic syndrome (sometimes called logopenic PA), characterised by word-finding difficulty and anomia but without significant comprehension impairment, and associated with peri-sylvian or angular gyrus pathology (Gorno Tempini et al., 2004; Sonty et al., 2003). In our experience, at post-mortem such cases most typically turn out to have Alzheimer’s pathology; furthermore they usually have other “tell-tale” cognitive features even at presentation, and also lack the subtle alterations in personality often seen from an early stage in SD. Moreover, in a recent study we examined the clustering of individual specific language deficits (anomia, reduced output, agrammatism, semantic errors, etc.) in 38 patients followed longitudinally to post-mortem (Knibb et al., 2006). This analysis confirmed the presence of two separable and coherent language clusters corresponding to SD and PNFA; although there were certainly a few overlap cases between these two clusters, no third pattern emerged.
Secondly, although this does not affect the issue of the two main language presentations of FTD (SD and PNFA), many patients with features of SD also have prominent behavioural changes, and semantic deficits can be seen in patients with bv-FTD. Indeed in our clinic we often see patients with a mixture of these two syndromes. Finally, there is the problem of how to categorise cases who have all of the classic features of PNFA or SD but have additional “exclusion” features, such as subtle, but definite, visuo-spatial defects or poor episodic memory. These issues will be discussed in greater detail in Chapter 3.
Our paper in 1992 defined the core cognitive aspects of SD and drew attention to the association between this cognitive profile and the relatively circumscribed and asymmetric L > R temporal lobe atrophy that has subsequently been confirmed and refined in a number of publications (Davies et al., 2004; Galton et al., 2001; Mummery et al., 1999). This typical L > R pattern raises the issue of the cognitive and/or behavioural signatures of the less common pattern of relatively isolated right, or R > L, temporal atrophy. Although we almost certainly encountered earlier patients with the syndrome now associated with prominent right temporal atrophy, the first clearly documented patient (VH) was reported as a case of gradually progressive prosopagnosia (Evans et al., 1995): VH was unable to identify from face or name even very famous people (e.g. Margaret Thatcher) yet had relatively intact general semantic and autobiographical memory (Kitchener and Hodges, 1999). Over the past few years a number of authors have reported such cases, confirming the role of the right temporal lobe in the representation of knowledge about people (Gainotti et al., 2003; Gentileschi et al., 1999, 2001; Thompson et al., 2003). In parallel with this literature, the group led by Bruce Miller drew attention to the bizarre behaviours (including irritability, impulsiveness, alterations in dress, limited and fixed ideas and decreased facial expression) exhibited by patients with predominantly right temporal lobe atrophy (Edwards Lee et al., 1997; Miller et al., 1997).
A study in 2003, drawing on our experience of 80 cases of whom a quarter had right-predominant atrophy, pulled together these observations by demonstrating that the right > left group tended to present with changes in person recognition and alterations in personality, while the more common left > right group had the typical deterioration of semantic memory for words and objects (Thompson et al., 2003).
3.2 Frontotemporal dementia and frontotemporal lobar degeneration
The final terms to be considered are frontotemporal dementia (FTD) and frontotemporal lobar degeneration (FTLD). In 1994 the Lund and Manchester groups introduced the term FTD (Brun et al., 1994) to describe patients with progressive changes in behaviour/personality and suggested tentative criteria for the diagnosis. Then 4 years later a broad group of experts met and unified FTD with the progressive aphasias (Neary et al., 1998). They proposed the general label frontotemporal lobar degeneration (FTLD) with three subforms: frontotemporal dementia (FTD) by which was meant the predominantly behavioural variant without prominent language deficits, and the two aphasic variants, SD and PNFA. Criteria for each syndrome were proposed (see Table 1.1) with major and minor inclusion features and exclusion features. This clearly represented a major advance, but did have the consequence of mixing levels of description in that FTD implies a distinct anatomical locus, whereas SD and PNFA are descriptive clinical syndromes. The use of the label FTD for those without prominent aphasia is confusing and implies that temporal lobe involvement is an invariable accompaniment of the behavioural syndrome. The “criteria” are also more akin to clinical guidelines since it is not clear how many features need to be present and whether the exclusion features are absolute. For instance, severe amnesia is said to be an exclusion feature, but it is now clear that a fairly high proportion of patients with pathologically proven FTD have significant memory impairment and in some this is of the severity seen in Alzheimer’s disease (Graham et al., 2005). A number of retrospective clinico-pathological studies have examined the utility of the FTLD criteria (Hodges et al., 2004; Josephs et al., 2006; Rosen et al., 2002b) but prospective studies are required to validate and refine these criteria.
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Figure 1.1 A hybrid classification of frontotemporal dementia (FTD), with a subdivision into the variants bv-FTD (behavioural variant), semantic dementia (SD) and PNFA (progressive non-fluent aphasia).
In Cambridge we have adopted a hybrid classification. The term FTD is preferred as the superordinate label applied to the whole group with a subdivision into three main variants (bv-FTD, SD, PNFA: see Figure 1.1). A very similar classification was proposed by Grossman (2002) who used the terms behaviour disorder and dysexecutive syndrome instead of bv-FTD. An all-American group led by Guy McKhann (2001), the originator of the famous NINCDS–ADRDA criteria for AD (McKhann et al., 1984), have also proposed clinical criteria for FTD with a dichotomy between a behavioural presentation and a language presentation. This has the benefit of simplicity but conflates PNFA and SD.
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© Cambridge University Press
Table of Contents
List of contributors vii
Overview of frontotemporal dementia John R. Hodges 1
Epidemiology of frontotemporal dementia Andrew Graham 25
Clinical presentations of frontotemporal dementia Christopher M. Kipps Jonathan A. Knibb John R. Hodges 38
Overlap syndromes Thomas H. Bak 80
The neuropsychology of frontotemporal dementia John R. Hodges Karalyn Patterson 102
Neuroimaging and other investigative findings Peter J. Nestor 134
The histopathology of frontotemporal dementia R. Rhys Davies John H. Xuereb 161
Molecular neuropathology in familial and sporadic frontotemporal dementia Laura Gasparini Maria Grazia Spillantini 208
The genetics of frontotemporal dementia Jeremy Brown 257
Psychological interventions in frontotemporal dementia Sinclair Lough Vanessa Garfoot 277