Frontotemporal lobar degeneration: clinical and pathologic overview

Handbook of Clinical Neurology, Vol. 89 (3rd series) Dementias C. Duyckaerts, I. Litvan, Editors # 2008 Elsevier B.V. All rights reserved

Frontotemporal dementias Chapter 33

Frontotemporal lobar degeneration: clinical and pathologic overview GIL D. RABINOVICI *, KATYA RASCOVSKY AND BRUCE L. MILLER UCSF Memory and Aging Center, San Francisco, CA, USA

33.1. Historical perspective “Circumscribed atrophies” were first described by the Czech-German neurologist and psychiatrist Arnold Pick, who in 1892 reported the case of a 71-year-oldman with behavioral symptoms and a progressive aphasia associated with focal left temporal lobe atrophy (Pick, 1892). Pick reported several other cases of circumscribed atrophies presenting with combined behavioral and language disturbances (Pick, 1904). In one (initially unpublished) case with a frontal syndrome, Alois Alzheimer (Alzheimer, 1911) observed swollen neurons and the argyrophilic “kugel”, later known as Pick’s body. Onari and Spatz performed extensive pathological studies on Pick’s case examined by Alzheimer and on similar cases (Onari and Spatz, 1926). Significantly, Onari and Spatz noted that in many cases characteristic “Pick bodies” (Fig. 33.3C), were entirely absent, without altering the remainder of the clinical or pathologic picture. Another salient observation was that cases could be divided into those with primarily frontal or primarily temporal atrophy. Tissot and Constantinidis confirmed these data and recognized three types of so-called “Pick disease” (clinically defined): (A) with swollen neurons and Pick bodies, (B) with only swollen neurons and (C) without swollen neurons or Pick bodies (Constantinidis et al., 1974). In 1982, Marsel Mesulam coined the term “primary progressive aphasia” to describe patients with focal left hemisphere degeneration who presented with either non-fluent or fluent aphasia, initially without additional cognitive deficits (Mesulam, 1982). In the late 1970s, Arne Brun and Lars Gustafson in Sweden,

and later David Neary and Julie Snowden in the UK, described the clinical, neuroimaging and pathologic features of a dementia syndrome characterized by focal frontal lobe degeneration, coined “frontal lobe dementia of the non-Alzheimer’s type” by the Swedish group (Brun, 1987), and “dementia of the frontal type” by the British group (Neary et al., 1988). Snowden and John Hodges described the language disturbance in patients with focal left anterior temporal atrophy, a syndrome they called “semantic dementia” (Snowden et al., 1989). Pathologically, these syndromes were all characterized by a typical gross and microscopic appearance, the absence of Alzheimer’s pathology, and the variable presence of Pick bodies. In 1994 the Swedish and British groups published the first consensus clinical and neuropathological criteria for “frontotemporal dementia” (Clinical and neuropathological criteria for frontotemporal dementia; The Lund and Manchester Groups, 1994). The clinical criteria were refined in 1998, using the term “frontotemporal lobar degeneration” (FTLD) to encompass three distinct clinical syndromes: frontotemporal dementia (FTD), a primary disturbance of behavior and comportment; progressive non-fluent aphasia (PNFA), a disturbance of expressive language; and semantic dementia (semantic dementia), a syndrome characterized by loss of meaning of verbal and non-verbal concepts (Neary et al., 1998). Further insight into the biology of the disease was provided by Kirk Wilhelmsen and colleagues, who discovered the link between familial frontotemporal dementia and a locus on chromosome 17 containing the gene for the microtubule-associated protein tau (Wilhelmsen et al., 1994b; Wilhelmsen, 1997).

*Correspondence to: Gil Rabinovici, MD, UCSF Memory & Aging Center, 350 Parnassus Ave., Suite 706, San Francisco, CA 94143, USA. E-mail: [email protected], Tel: þ1-(415) 514-9320, Fax: þ1-415-476-4800.

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The subsequent unveiling of multiple tau mutations associated with various FTLD phenotypes (Foster et al., 1997; Clark et al., 1998; Hutton et al., 1998; Poorkaj et al., 1998; Spillantini et al., 1998, 2000a, b) has strengthened the link between FTLD and other “tauopathies”, such as corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) (Kertesz et al., 1999). While a link between motor-neuron disease and FTLD had long been suspected (Hudson et al., 1993), this association was found to be much more common than previously thought (Lomen-Hoerth et al., 2002), and to be associated with a distinctive pathologic (Cooper et al., 1995; Jackson et al., 1996) and genetic (Hosler et al., 2000) profile. Most recently, the discovery of causative mutations in the secreted growth factor progranulin and the identification of the DNA-binding protein TDP-43 as a key component in the inclusions found in tau-negative FTLD cases have provided new and important clues towards understanding the pathophysiology of this clinically and pathologically heterogeneous disorder (Baker et al., 2006; Cruts et al., 2006; Gass et al., 2006, Neumann et al., 2006).

33.2. Epidemiology Frontotemporal lobar degeneration comprises 5–6% of all dementias, but 8–17% of early-onset (under 70) dementias in autopsy series (Barnett and Zucker, 1977; Knopman et al., 1990; Barker et al., 2002). The disease most commonly presents in the sixth decade, though presentation may occur as early as the third and as late as the ninth decade of life (Knopman et al., 1990; John and Srivastava, 1999; Barker et al., 2002; Ratnavalli et al., 2002; Hodges et al., 2003; Johnson et al., 2005). FTLD is generally considered an early-onset dementia, but up to one-quarter of cases can present after age 65 (Rosso et al., 2003a; Johnson et al., 2005). Progressive non-fluent aphasia presents later than other clinical syndromes in some series (Hodges et al., 2003; Johnson et al., 2005). FTLD approaches Alzheimer’s disease (AD) as the leading cause of dementia among patients under 65 (Ratnavalli et al., 2002). Population-based studies have estimated prevalence rates of 4.0–15/100,000 person years in the 45–64-year-old population in the Netherlands and Cambridge, UK, respectively. A number of large studies have detected a male preponderance in FTD, while some studies have suggested a male predominance for semantic dementia and a female preponderance in PNFA (Ratnavalli et al., 2002; Hodges et al., 2003; Johnson et al., 2005; Roberson et al., 2005). Median survival from symptom onset and diagnosis are 6 and 3 years respectively, with the clinical syndrome of FTD-MND associated with a more

rapidly progressive course (2 and 1 years respectively) (Hodges et al., 2003; Johnson et al., 2005; Roberson et al., 2005). Significantly, mean time from diagnosis to institutionalization can be as short as 1 year, probably due to the high prevalence of behavioral symptoms. Survival is shorter and cognitive and functional decline are much more rapid than in AD (Rascovsky et al., 2005; Roberson et al., 2005).

33.3. Genetics Up to 40% of FTLD cases are genetic, with most following an autosomal dominant pattern of inheritance (Stevens et al., 1998; Chow et al., 1999). FTD and FTD with motor neuron disease are more strongly familial than the other clinical syndromes (Goldman et al., 2005). The first association between autosomaldominant FTLD and chromosome 17 was described in 1994 (Lynch et al., 1994; Wilhelmsen et al., 1994a), giving rise to the clinical syndrome frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). In 1998 it was found that many cases of FTDP-17 were caused by mutations in the microtubule-associated protein tau (MAPT) (Wilhelmsen, 1997; Hutton et al., 1998; Spillantini et al., 1998). The causative gene in FTDP-17 with tau-negative, ubiquitin-positive pathology (see section 33.6: Pathology) was unknown until 2006, when mutations in the progranulin gene (PGRN) were found to account for most cases (Baker et al., 2006; Cruts et al., 2006; Gass et al., 2006). Over 30 mutations in MAPT and over 20 mutations in PGRN have been described to date (Goldman et al., 2004; Gass et al., 2006). Mutations in MAPT or PGRN can lead to a broad range of phenotypes, including all three variants of FTLD, CBD and PSP (the latter has only been described with MAPT mutations thus far). Clinical presentation can vary broadly even within single pedigrees (Benussi et al., 2006). Conversely, other families maintain a similar phenotype across generations (Masellis et al., 2006; Mesulam et al., 2007). Neuropathologic findings may also vary considerably between patients with MAPT mutations, while the pathologic findings associated with PGRN mutations are now being defined (Bird et al., 1999; Nasreddine et al., 1999; Mackenzie et al., 2006b; Spina et al., 2007). MAPT mutations can lead to disease by various mechanisms. Mutant protein may have an increased propensity to self-aggregate into Pick bodies or other neurofibrillary inclusions composed of various species of insoluble tau (Hasegawa et al., 1998; Rizzini et al., 2000; Neumann et al., 2001; Hayashi et al., 2002; Hogg et al., 2003; Pickering-Brown et al., 2004). Alternatively, mutations may lead to impaired microtubule

FRONTOTEMPORAL LOBAR DEGENERATION: CLINICAL AND PATHOLOGIC OVERVIEW 345 binding, assembly or axonal transport (Hasegawa et al., 1998; Hong et al., 1998; Murrell et al., 1999; Rizzu et al., 1999; Rizzini et al., 2000; Hayashi et al., 2002; Hogg et al., 2003). Many mutations have been shown to cause disease via both mechanisms. For example, mutations in the alternatively spliced exon 10 or in the intron that follows it can lead to over-representation of 4R isoforms (see section 33.6: Pathology), leading to poor microtubule binding and function, and aggregation of 4R insoluble tau (Hutton et al., 1998; Spillantini et al., 1998; D’Souza et al., 1999). The extended tau haplotypes H1 and H2 (Baker et al., 1999) may also affect tau processing, as the H1/H1 genotype is over-represented in PSP and CBD (Baker et al., 1999; Houlden et al., 2001), both 4R tauopathies. Finally, pre-symptomatic gene carriers have frontal/executive deficits on neuropsychologic tests decades before the predicted onset of dementia (Geschwind et al., 2001), raising the possibility of a neurodevelopmental component to what had hitherto been considered a purely degenerative disorder. Progranulin is a widely expressed secreted growth factor that plays a role in development, tumorigenesis, wound repair and inflammation (He and Bateman, 2003; He et al., 2003). Interestingly, most pathogenic mutations identified thus far are nonsense, splice-site or frameshift mutations that lead to premature coding termination and null alleles. Since most inheritance patterns are autosomal dominant, the hypothesized pathogenic mechanism involves loss of function, with inadequate growth factor support leading to neurodegeneration (Baker et al., 2006). The mechanisms by which this occurs have not yet been elucidated. Furthermore, though progranulin mutations lead to intra-neuronal and cytoplasmic inclusions composed of the DNA-binding protein TDP-43 (see section 33.6: Pathology), a direct relationship between TDP-43 and progranulin has not yet been established (Baker et al., 2006; Neumann et al., 2006). Familial FTLD has also been associated with other, rarer mutations. In one Dutch family an FTD-like phenotype is associated with a mutation in the endosomal ESCRTIII-complex subunit on chromosome 3 (Gydesen et al., 2002; Skibinski et al., 2005). Mutations in the valosin protein are linked to an autosomal dominant FTD syndrome associated with Paget’s disease and inclusion body myositis (Schroder et al., 2005). Families with FTD-ALS have been linked to chromosome 9 (Hosler et al., 2000). Of note, the apolipoprotein E4 allele, an established risk factor for AD, does not appear to be a risk factor for FTLD (Geschwind et al., 1998; Pickering-Brown et al., 2000; Riemenschneider et al., 2002).

33.4. Clinical syndromes Considerable confusion exists in the literature regarding the nomenclature of frontotemporal dementia, with similar clinical syndromes referred to by a variety of different names (Gustafson, 1987; Neary et al., 1988; Snowden et al., 1989; Mesulam, 2001). For the purposes of this chapter we have adopted the nomenclature used in the Neary diagnostic criteria (Neary et al., 1998). Under this nomenclature, the term frontotemporal lobar degeneration (FTLD) encompasses three distinct clinical syndromes: FTD, semantic dementia and PNFA. Each syndrome has a unique anatomy: FTD is characterized by bifrontal atrophy, semantic dementia by anterior temporal atrophy, and PNFA by left peri-sylvian atrophy (Fig. 33.1). While one clinical syndrome tends to predominate early on, with time atrophy tends to spread to previously unaffected brain regions, and the clinical syndromes may overlap (Neary et al., 1998). In addition to common pathologic features and genetics, the three syndromes share several clinical features. Onset of the disorder is insidious and gradually progressive, with first symptoms occurring most commonly (though not exclusively) before age 65. Notably absent from all syndromes are early, severe amnesia, spatial disorientation, and the physical signs of myoclonus, pyramidal weakness, cerebellar ataxia and choreoathetosis. Evidence of motor-neuron disease in a patient with a behavioral or language disorder is highly suggestive of FTLD (Neary et al., 1998). 33.4.1. Frontotemporal dementia (frontal-variant FTLD) Frontotemporal dementia (FTD) is a behavioral syndrome characterized by changes in personal and interpersonal conduct (Gustafson, 1987, 1993; Neary et al., 1988, 1998; Miller et al., 1991; The Lund and Manchester Groups, 1994). When FTD affects dorsomedial prefrontal structures, patients are apathetic and passive. They become withdrawn, losing interest in personal affairs and neglecting hygiene and personal responsibilities. Affect is blunted, and there is a decrease in spontaneous speech. Conversely, when the disease affects orbitofrontal and ventromedial frontal cortex, patients become disinhibited and childlike, with an inappropriately jovial, euphoric affect (Gustafson, 1987, 1993; Neary et al., 1988, 1998; Miller et al., 1991; The Lund and Manchester Groups, 1994; Levy et al., 1996; Liu et al., 2004). There is a decline in manners and social decorum, with a tendency to make rude or tactless comments to others.

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Fig. 33.1. MRI findings in FTLD syndromes. (A)–(C) are coronal T1-weighted images, (D) is a coronal fluid-attenuated inversion recovery (FLAIR) image. All images are in radiologic orientation. (A) FTD: severe bilateral atrophy of dorsolateral prefrontal cortex, insula, anterior cingulate, orbitofrontal cortex and caudate nuclei. (B) PNFA: asymmetric atrophy of left peri-sylvian cortex, including insula and frontal operculum. (C) semantic dementia: left greater than right anterior temporal atrophy involving amygdala, anterior hippocampus, inferior and middle greater than superior temporal gyri. (D) FLAIR image reveals white matter gliosis in left temporal lobe of a patient with semantic dementia.

Patients violate interpersonal space and show a new tendency to approach strangers. Disinhibition can lead to confrontation-seeking, and at times to frankly sociopathic behaviors such as unsolicited sexual approaches, traffic violations, shoplifting and physical assault (Gustafson, 1993; Miller et al., 1997; Mendez et al., 2005a). Patients may be aware that their behavior is wrong, but either lack emotional concern for its consequences, or fail to inhibit it (Mendez et al., 2005a). Patients may exhibit psychomotor hyperactivity, with a tendency to pace and wander. Speech output is increased and pressured, and patients often display “verbal dysdecorum”, speaking in an inappropriately high volume, and tending to interrupt others and manipulate conversation (Neary et al., 1998). Often, features of apathy and disinhibition are inter-mixed (Swartz et al., 1997a). Given the dramatic changes in behavior and personality, patients may first present to a psychiatric clinic (Gregory and Hodges, 1996). Apathetic behavior is confused with depression, while disinhibited behavior is mistaken for mania or hypomania (Gustafson,

1987). The presentation is one of an atypical mood disorder, with irritability, increased appetite and weight gain (as opposed to the anorexia and weight loss typical of AD). Suicidal ideations and guilt, which are common in late-life depression, are absent in FTD (Perry and Miller, 2001). In contrast to AD, where apathy and depression coexist, FTD patients have high apathy scores, often without depression (Levy et al., 1996). Delusions can be a presenting feature (in contrast to AD, where they appear late in disease). When present, delusions are often bizarre, and, in contrast to AD, rarely persecutory (Gustafson et al., 1987; Miller et al., 1991). Hallucinations and delusions of reference are rare (Swartz et al., 1997a). Patients universally show an emotional shallowness, with loss of warmth and empathy towards others (Gregory and Hodges, 1996; Neary et al., 1998; Rankin et al., 2005). They appear self-centered, with an inability to take others’ perspectives and a lack of concern for the implications of their behavior on others. There is a dramatic loss of insight, with either frank denial or a very shallow recognition of the illness

FRONTOTEMPORAL LOBAR DEGENERATION: CLINICAL AND PATHOLOGIC OVERVIEW 347 (often described as mild memory or word-finding difficulties) and no concern for its impact on social, occupational or financial matters. In extreme cases patients change religious beliefs, political conviction, dress and social style. These dramatic personality changes, likened to a “change in self”, are associated with right-predominant lesions (Miller et al., 2001). The combination of loss of empathy, apparent coldheartedness, loss of humor and abnormal non-verbal communication (e.g., loss of facial expression and prosody) leads to an “alien” affect that makes other people uneasy. This is in stark contrast to AD, where social graces are preserved late into the course. Stereotyped behaviors range from aberrant motor behaviors to complex compulsions (Ames et al., 1994; Miller et al., 1995; Mendez et al., 1997). Repetitive motor behaviors have similarities to those encountered in autism and schizophrenia (rubbing, picking, clapping, rocking) (Mendez et al., 2005b), and are more complex and idiosyncratic than the simple, stimulus-bound motor behaviors seen in AD (Nyatsanza et al., 2003). Compulsions are complex, and include repetitive checking of clocks, locks or windows, hygiene rituals, repetitive urination, throatclearing, counting, collecting and hoarding (Perry and Miller, 2001). Changes in eating behavior are highly characteristic, and include overeating (despite endorsing satiety), weight gain, overstuffing the mouth, and idiosyncratic food fads. Craving for sweet, carbohydrate- or lipid-rich foods is common, but less specific for FTD (Miller et al., 1995; Swartz et al., 1997a; Ikeda et al., 2002). Hyperorality may also manifest as excessive drinking, alcohol intake, cigarette smoking and gum- or tobacco-chewing (Gustafson, 1987). Oral exploration of inedible objects, as described in the Kluver-Bucy syndrome, may occur (Kluver and Bucy, 1937). Early in the disease patients may display increased somatic concern or even hypochondriasis (Gustafson, 1987). Later, the valence of disturbing signals from the internal milieu is lost, and patients show loss of disgust or pain (Bathgate et al., 2001; Snowden et al., 2001; Scherder et al., 2003). Patients willingly pick objects off the ground and place them in their mouth. A patient recently walked into our clinic completely unconcerned about the purulent burns on her arm. Indifference to bladder or bowel incontinence is also common. Patients may have an uncontrollable urge to explore the environment (utilization behavior), manifested by grasping at items in view, repeatedly switching lights on and off or opening and closing doors (Gustafson, 1993). Patients are often perseverative and discussions focus on recurrent themes. They develop characteristic “catch phrases”, and, in later

disease stages, manifest echolalia and mutism (Neary et al., 1998). Cognitive complaints are typically less dramatic than behavioral changes, and patients may require custodial care despite normal scores on screening cognitive tests such as the Mini-Mental State Exam (Folstein et al., 1975; Gregory et al., 1999). Families may note that patients are disorganized, have difficulty with planning, multi-tasking and problem-solving, or are inattentive and distractible. Poor judgment is common. On neuropsychologic testing patients have deficits on frontal/executive tasks including tests of working memory, attention, set-shifting, mental flexibility, verbal fluency, response inhibition and abstract reasoning (Neary et al., 1988, 2005; Kramer et al., 2003; Rosen et al., 2004). However, performance on these tasks does not reliably differentiate FTD from AD (Frisoni et al., 1995b; Pachana et al., 1996; Gregory et al., 1997; Thomas-Anterion et al., 2000; Pasquier et al., 2001; Kertesz et al., 2003; Kramer et al., 2003; Rosen et al., 2004). There are at least three possible explanations for this: (1) impairments in executive skills, while present in FTD, are not specific to this condition (Kumar et al., 1990); (2) the complexity of these tasks causes poor performance by both patient groups; or (3) these tests measure impairment in dorsolateral prefrontal functioning, while it is the orbitofrontal and ventromedial frontal injury that occurs early and is more specific to FTD (Sarazin et al., 1998; Rahman et al., 1999a, b) (see Fig. 33.2B). Supporting this third hypothesis, FTD patients are more impaired than AD patients in theory-of-mind tasks (Gregory et al., 2002) that require making inferences about the mental status of others, and are mediated at least in part by ventromedial frontal cortex (Stuss et al., 2001). Memory complaints are variable, and often have a “frontal” flavor (paramnesias mistaking timing and context, confabulation) (Neary et al., 1988, 1998). Several studies have found that declarative verbal (Elfgren et al., 1994; Lindau et al., 1998; ThomasAnterion et al., 2000; Kramer et al., 2003; Rosen et al., 2004) and visual (Frisoni et al., 1995a; Pachana et al., 1996; Kertesz et al., 2003; Kramer et al., 2003; Lee et al., 2003) memory are preserved in FTD compared with AD. Temporal and spatial orientation and praxis are also spared (Elfgren et al., 1994; Mendez et al., 1996; Rascovsky et al., 2002). Driving difficulties are due to impulsivity and non-compliance with traffic regulations rather than topographical disorientation (Gustafson, 1987). Thus, a “cognitive profile” showing impairment on frontal/executive tasks with relative preservation of memory and visuospatial function discriminates FTD from AD in most cases

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Fig. 33.2. Voxel-based morphometry (VBM) demonstrates regional atrophy patterns in autopsy-proven cases of FTLD (n ¼ 13) and AD (n ¼ 7) (Rabinovici et al., unpublished results). (A) Compared to controls, both FTLD and AD show dorsolateral prefrontal volume loss. FTLD also demonstrates atrophy of medial frontal structures and the temporal poles, while in AD atrophy extends more posteriorly in the temporal and parietal lobes. (B) Direct comparison of FTLD with AD reveals selective atrophy of bilateral anterior cingulate, insula, ventromedial prefrontal cortex and striatum in FTLD. There was no significant difference in dorsolateral prefrontal regions. All images are displayed at P < 0.001 uncorrected.

(Elfgren et al., 1994; Pachana et al., 1996; Perry and Hodges, 2000; Rascovsky et al., 2002; Kramer et al., 2003; Diehl et al., 2005). Importantly, quantitative scores on visuospatial and memory tasks may be confounded by poor attention, organization or strategy and should be interpreted with caution (Varma et al., 1999). Qualitative observations of performance on cognitive testing, and especially the presence of rule violations, perseverative errors and confabulations, may be more helpful than quantitative scores in differentiating FTD from AD (Kramer et al., 2003; Nedjam et al., 2004). 33.4.2. Semantic dementia (temporal-variant FTLD) Semantic dementia is a disorder characterized by progressive loss of knowledge about words and concepts (Neary et al., 1998; Hodges, 2001). The syndrome was first characterized by Snowden et al. (1989), though in retrospect Pick’s initial case may have had semantic dementia (Hodges et al., 1992). Anatomically, semantic dementia is defined by progressive anterior temporal atrophy (Fig. 33.1C), with the presenting clinical syndrome strongly influenced by the

side of the brain with the greatest atrophy (Thompson et al., 2003). Left-predominant cases present as a fluent, anomic aphasia. Patients complain of wordfinding difficulties and trouble naming people, places and things (Seeley et al., 2005). Often this is perceived as a memory problem, but when the history is probed, episodic day-to-day memory is preserved. Rather, it is “semantic memory”, the knowledge of words, facts and concepts that is impaired. This form of memory depends less on context, is culturally shared, not temporally specific and acquired to a large extent early in life (Hodges et al., 1992). Speech remains fluent and effortless, with intact syntax and prosody, but impoverished content and semantic paraphasic errors. The meaning of words is lost despite preserved ability to read, write and spell them (Edwards-Lee et al., 1997). Loss of meaning follows a hierarchical pattern: first, patients lose the ability to differentiate between members of a subordinate category (e.g., types of apples), then within a category (e.g., apple versus orange) and finally within a supraordinate category (e.g., fruits versus vegetables). Initially a “poodle” is called a “dog”, then all dogs are called “animals”, and finally all animals are

FRONTOTEMPORAL LOBAR DEGENERATION: CLINICAL AND PATHOLOGIC OVERVIEW 349 referred to as “things” (Hodges et al., 1992). Eventually, broad generic terms entirely replace precise nominal terms. Word usage may be idiosyncratic— for example the word “container” may be used to describe all small objects, regardless of their facility to contain (Neary et al., 1998). Loss of knowledge extends beyond language, and patients lose the ability to put objects in their appropriate context, as demonstrated by the non-verbal Pyramids and Palm Tree task (Hodges et al., 1992; Howard and Patterson, 1992). This differentiates the anomia of semantic dementia from AD. When an AD patient cannot name a pencil, he may respond with a circumlocution (“that’s the thing you write with”). In turn, a semantic dementia patient might respond with “what is a pencil?” Eventually, patients are impaired in recognizing objects and non-verbal sounds and in demonstrating correct object use (Hodges and Graham, 1998; Lambon Ralph et al., 1998; Bozeat et al., 2000; Hodges et al., 2000). Surface dyslexia (reading “PINT” to rhyme with “MINT”) and surface dysgraphia with regularization errors (e.g., “CAUGHT” written as “CORT”) are common and easy to demonstrate at the bedside (Neary et al., 1998). These phenomena probably represent the loss of semantic knowledge of the correct pronunciation and spelling of irregular words (Patterson et al., 1994). On cognitive testing, patients fail at confrontation naming, word-to-picture matching, and category fluency tasks, with preservation of spatial abilities and executive functions (Hodges et al., 1992, 1999; Perry and Hodges, 2000; Thompson et al., 2003). Episodic memory is preserved early in the disease, as evidenced by patients’ ability to remember prospective appointments and keep track of the preceding days and weeks (Edwards-Lee et al., 1997). Interestingly, patients may show a reversal of the typical pattern of retrograde amnesia, with preserved recollection of recent personal events, coupled with significantly impaired recollection of remote autobiographical events from childhood and early adulthood (Graham and Hodges, 1997). Behavioral disturbances are usually not apparent early in the disease, and insight is typically preserved (Snowden et al., 2001). Depression is the most common affective disorder (Edwards-Lee et al., 1997). In contrast, patients who have predominantly right anterior temporal atrophy present with a behavioral syndrome characterized by a flat and sometimes bizarre affect, emotional blunting, and alterations in social conduct with rude, tactless, or awkward behavior in social situations (Mychack et al., 2001; Thompson et al., 2003). Initially, this is difficult to differentiate from a psychiatric illness. The first symptom may be somatic (e.g., weight changes (gain or loss), sleep

disturbance, decreased libido) or affective (e.g., irritability, apathy) (Seeley et al., 2005). Insight is typically absent (Edwards-Lee et al., 1997). Patients may exhibit elements of the “Geschwind syndrome” described in temporal-lobe epilepsy patients, including excessive verbal output, hypergraphia, intensification of philosophical or religious feelings and hyposexuality (Waxman and Geschwind, 1975; Benson, 1991). Early reports of right temporal variants emphasized the importance of prosopagnosia or associative agnosia (visual and tactile) (Evans et al., 1995), and these remain part of the diagnostic criteria (Neary et al., 1998). However, a behavioral syndrome usually precedes the agnosia by years (Seeley et al., 2005). The behavioral changes are caused, at least in part, by a breakdown in the recognition of emotions in others (Rosen et al., 2002b). Loss of fear is also characteristic—two patients followed in our clinic picked up rattlesnakes without any concern for injury to themselves or others. Patients who present with a semantic syndrome typically develop behavioral symptoms after a mean of 3 years, while the patients who begin with behavioral symptoms develop semantic deficits within a similar time frame. The progression of symptoms probably represents spread of atrophy to the contralateral temporal pole (Seeley et al., 2005). After a mean of 5–7 years, patients develop additional behavioral symptoms reminiscent of FTD, perhaps coincident with spread of disease to ventromedial and orbitofrontal cortex (Liu et al., 2004). These include changes in eating, such as restrictive dieting or food fads, that are distinct from the over-eating and hyperorality seen in FTD. Compulsions are also characteristic, with left temporal patients developing visually oriented compulsions (e.g., collecting bright objects or coins), while right temporal patients develop compulsions involving verbal or symbolic stimuli (e.g., playing word jumbles, quoting the bible, or playing solitaire) (Seeley et al., 2005). New artistic interests or talent may emerge in left temporal patients (Miller et al., 1998). The ratio of left to right temporal variants is around 3:1 in most series (Thompson et al., 2003; Seeley et al., 2005). This may represent a referral bias, since many right temporal patients are initially diagnosed with a psychiatric illness (Thompson et al., 2003). 33.4.3. Progressive nonfluent aphasia Progressive nonfluent aphasia (PNFA) is as a disorder of expressive language and speech production, characterized anatomically by left peri-sylvian atrophy (Fig. 33.1) (Hodges and Patterson, 1996; Turner et al., 1996; Neary et al., 1998; Hodges, 2001). Speech

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is slow, effortful and telegraphic, with a relative increase in content (nouns and verbs) compared to function (articles, verb auxiliaries, prepositions) words. Patients make errors in word order, tense and conjugation. For example, “boy falled chair” may be used to express “the boy fell off the chair”. Collectively, these errors are known as “agrammatism”. Phonemic paraphasic errors are common—these may involve incorrect phoneme use (“kair” for “chair”) or phoneme transposition (“aminal” for “animal”). As in semantic dementia, word-retrieval deficits and anomia are common. Repetition is impaired, but comprehension of single word meaning and all but the most complex syntactic structures is preserved (Gorno-Tempini et al., 2004b). Speech may be more fluent when a referrant is used (e.g., when describing a picture) than when attempting spontaneous speech (Mesulam et al., 2005). Reading is non-fluent and effortful, and writing is agrammatic with phonemic errors. Speech apraxia, defined as a failure of correct motor production of speech in the absence of primary motor weakness, is a common feature. This may present as difficulty in initiating speech, a slow rate of speech, or incorrect sequencing or omission of syllables (Duffy, 1995). The absence of motor weakness is confirmed by cranial nerve examination and by intact production of elemental sounds. Subtle speech apraxia can be demonstrated at the bedside by rapid repetition of multi-syllabic, consonant-rich words that require moving quickly from the back to the front of the mouth (e.g., “artillery” or “Methodist Episcopal”). Thus, impaired speech production in PNFA represents the merging of a language disorder with the failure of sensorimotor integration of speech, i.e., speech apraxia. Anatomically, the aphasia relates to atrophy of the left frontal operculum (Broca areas 44, 45 and 47), while the apraxia may relate to atrophy of the left anterior insula (Fig. 33.1B) (Gorno-Tempini et al., 2004b). Interestingly, an identical clinical syndrome has been reported in left-handers with focal atrophy or hypometabolism of the corresponding structures in the right hemisphere (Drzezga et al., 2002; Mesulam et al., 2005). PNFA can be readily differentiated from the aphasia of semantic dementia, which is fluent, with intact grammar, semantic rather than phonemic paraphasic errors, and frequent use of nonspecific or supraordinate nouns. PNFA is more difficult to distinguish from “logopenic aphasia”, in which speech is slow, with frequent word-finding pauses. Logopenic aphasia is characterized by more severely impaired comprehension and the absence of agrammatism or speech apraxia. Anatomically, atrophy in logopenic aphasia occurs more posteriorly, in parietotemporal regions.

This anatomy, along with the high prevalence of ApoE4 carriers in one series, raises suspicion that logopenic aphasia may be associated with AD pathology (Gorno-Tempini et al., 2004b). In contrast to FTD, personal and interpersonal conduct, behavior and insight are preserved early in PNFA. Spatial skills and short-term memory are also preserved until late in the course (Gorno-Tempini et al., 2004b). However, neuropsychologic test performance in these domains may be compromised by the aphasia. Non-verbal testing should be performed to the extent possible. There may be a large discrepancy between apparently poor cognitive test results (including on the verbally oriented Mini-Mental State Exam) and normal function in daily life. To the extent they can compensate for the aphasia, PNFA patients continue to work, drive, and remain independent in many domains (Mesulam, 2003). Typically, the elemental neurologic examination is either normal, or may show subtle signs of hemiparesis or reflex asymmetry. However, the presence of rigidity, supranuclear gaze palsies or gait disturbance, in addition to more obvious signs such as limb apraxia, alien hand or myoclonus, should raise suspicion of underlying CBD or PSP pathology (Kertesz et al., 2000; Gorno-Tempini et al., 2004c). As in all FTLD syndromes, a careful neuromuscular examination to exclude motor-neuron disease is paramount (Caselli et al., 1993). 33.4.4. Frontotemporal lobar degeneration with amyotrophic lateral sclerosis The relationship between dementia and amyotrophic lateral sclerosis (ALS) was first noted soon after the initial description of ALS in the late 1800s, but was underappreciated for many years. The emergence of geographic (Plato et al., 2002) and familial clustering (McGeer et al., 1997; Plato et al., 2002), as well as numerous reports of co-occurrence with the newly described frontal lobe dementias (Caselli et al., 1993; Cavalleri and De Renzi, 1994; Niizato et al., 1997; Portet et al., 2001), refocused attention on this possible link. Finally, the discovery of overlapping genetics (Foster et al., 1997) and neuropathology (Cooper et al., 1995; Jackson et al., 1996) strongly suggested a pathophysiologic connection between the two syndromes. In prospective studies, up to 50% of FTD patients had possible or probable ALS (Lomen-Hoerth et al., 2002), while conversely 50% of ALS patients who underwent behavioral and neuropsychologic evaluation had measurable (mainly frontal/executive and behavioral) cognitive deficits, and many met criteria for an FTLD syndrome (Lomen-Hoerth et al., 2003).

FRONTOTEMPORAL LOBAR DEGENERATION: CLINICAL AND PATHOLOGIC OVERVIEW 351 Patients who develop frontotemporal lobar degeneration with amyotrophic lateral sclerosis (FTLD-ALS) may present with either cognitive or motor symptoms (Lomen-Hoerth, 2004). ALS can co-exist with any of the clinical FTLD syndromes, though FTD is most common (Lomen-Hoerth et al., 2003). Patients with bulbar-onset ALS may be at increased risk of developing dementia compared to limb-onset patients (Neary et al., 2000; Lomen-Hoerth et al., 2003). FTLD can occur in association with a variety of upper-motor neuron (UMN) or lower-motor neuron (LMN) syndromes (Strong et al., 2003). While early data suggested that LMN presentations are more common in FTLD (Neary et al., 2000), recent data suggest that UMN signs are at least as frequent (Lomen-Hoerth and Miller, unpublished data). Fasciculations, generally considered benign in isolation, may herald the emergence of ALS in an FTLD patient (Lomen-Hoerth et al., 2002). The presence of motor-neuron disease significantly worsens the prognosis of FTLD (Hodges et al., 2003; Roberson et al., 2005) and requires preventive interventions, including early evaluations of swallowing, nutrition and respiratory status. Every FTLD patient should undergo a thorough neuromuscular exam, with electrodiagnostic studies pursued in patients with even subtle physical signs. Similarly, the evaluation of all ALS patients should include a thorough behavioral history and screening cognitive testing. The MMSE alone is insufficient, as scores are often normal in early FTD. Word-generation tasks (which can be completed in the office in 2 minutes) are a more sensitive marker of cognitive dysfunction (Lomen-Hoerth et al., 2003).

33.5. Diagnostic tests 33.5.1. Neuroimaging Structural neuroimaging, preferably with MRI, is an essential part of the evaluation of suspected FTLD (Fig. 33.1). Early in the course of disease, MRI may be essentially normal (Miller et al., 1991). As the disease progresses, focal atrophy of frontal and anterior temporal structures is nearly universally present (Miller and Gearhart, 1999). The ventricles enlarge, and the head of the caudate becomes atrophic. With advanced disease, atrophy becomes severe, and may produce a “knife blade” appearance of affected gyri (Fig. 33.1A). These findings are usually also apparent on CT (McGeachie et al., 1979; Kobayashi et al., 1984; Tobo et al., 1984). On MRI, T2 signal hyperintensity may be seen in the subcortical white matter of affected gyri, and may extend into the deep white matter (Fig. 33.1D) (Kitagaki et al., 1997). The corpus

callosum can appear atrophic either anteriorly or diffusely, differentiating FTD from AD, in which the posterior callosum is more prominently affected (Kaufer et al., 1997; Yamauchi et al., 2000). Quantitative volume comparisons between FTLD and controls, utilizing both region of interest analysis (Frisoni et al., 1996; Fukui and Kertesz, 2000; Chan et al., 2001; Galton et al., 2001) and voxel-based morphometry (VBM) (Mummery et al., 2000; Rosen et al., 2002a; Boxer et al., 2003; Gorno-Tempini et al., 2004a; Boccardi et al., 2005), have detected distinct focal atrophy patterns for each of the FTLD syndromes. Both FTD and semantic dementia patients have volume loss in ventromedial frontal and insular cortices, anterior insula and anterior cingulate (Rosen et al., 2002a; Boccardi et al., 2005). FTD patients also show widespread atrophy throughout dorsolateral prefrontal cortex and medial premotor regions (Rosen et al., 2002a). Semantic dementia patients demonstrate anterior temporal atrophy involving the amygdala and anterior hippocampus, and anterior portions of the middle and inferior temporal gyri (Mummery et al., 2000; Chan et al., 2001; Galton et al., 2001; Rosen et al., 2002a). Atrophy in semantic dementia is often asymmetric, with left-sided predominance in most cases (Fig. 33.1C). In FTD atrophy is either symmetric, or with a right-hemisphere bias. Patients with PNFA show selective atrophy in the left peri-sylvian region, including the insula, middle and inferior frontal gyri and precentral gyrus (Fig. 33.1B) (Gorno-Tempini et al., 2004b). FTD/ALS patients demonstrate atrophy in motor and premotor cortex, anterior temporal lobes, and middle and inferior frontal gyri (Chang et al., 2005). While most of these studies were based on clinical diagnosis, results have been confirmed in autopsy-proven cases (Fig. 33.2A) (Whitwell et al., 2005; Rabinovici et al., in press). Several studies have correlated regional atrophy with specific symptoms. Patients with right hemisphere degeneration tend to have a greater degree of behavioral disturbance (Miller et al., 1993, 2001; Miller and Gearhart, 1999; Liu et al., 2004; Seeley et al., 2005). Atrophy of ventromedial frontal cortex is correlated with disinhibition, ventral anterior cingulate with apathy, dorsal anterior cingulate and premotor cortex with aberrant motor behavior, left anterior temporal lobe with loss of semantic memory, and right amygdala with inability to recognize facial emotions (Mummery et al., 2000; Rosen et al., 2002b, 2005; Liu et al., 2004). Selective atrophy of medial and ventral frontal structures, including ventromedial and orbitofrontal cortex, anterior cingulate and anterior insula (but not dorsolateral prefrontal cortex) discriminates between FTLD and AD (Fig. 33.2B) (Rabinovici et al., in press).

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These structures, in association with the amygdala and ventral striatum (which are also affected in FTLD), constitute the rostral limbic system. This network is involved in evaluating internal and external stimuli for motivational and emotional valence, and ultimately in regulating context-dependent, adaptive behavior (Devinsky et al., 1995; Boccardi et al., 2005). Dysfunction of this network may cause the FTLD behavioral syndrome. Functional imaging using xenon 133 (Stigsby et al., 1981; Gustafson, 1987), 99mTC-HMPAO SPECT (Neary et al., 1987; Talbot et al., 1995; Talbot and Morgan, 1998; Talbot et al., 1998) and 18FDG (Kamo et al., 1987) has been instrumental in elucidating the anatomical signatures of FTD (Neary et al., 1987; Miller et al., 1991; Salmon et al., 2003), semantic dementia (Edwards-Lee et al., 1997), PNFA (Chawluk et al., 1986) and FTLD-ALS (Caselli et al., 1993; Talbot et al., 1995; Garraux et al., 1999a). Functional imaging results essentially mirror the structural imaging findings for each clinical subtype. Some studies report extension of functional deficits to sub-cortical structures, including the striatum, globus pallidus and thalamus (Ishii et al., 1998; Jervis and Manson, 2002; Jeong et al., 2005). Functional imaging may be more sensitive than MRI in early disease (Miller et al., 1991; Miller and Gearhart, 1999) and is also helpful in differentiating FTLD from other dementias (Talbot et al., 1995, 1998; Ishii et al., 1998; Garraux et al., 1999a; Silverman et al., 2001). While characteristic of FTD, bifrontal hypoperfusion or hypometabolism has also been reported in AD (though usually accompanied by more posterior deficits) (Silverman et al., 2001), vascular dementia (Kim et al., 1996; Talbot et al., 1998), HIV dementia (Kim et al., 1996), PSP (Garraux et al., 1999b), Jakob-Creutzfeldt disease, psychiatric disorders and toxic-metabolic encephalopathies (Risberg et al., 1993), among others. As in structural imaging, focal functional deficits correlate with behavior and are helpful in elucidating brain– behavior relationships (Elfgren et al., 1996; Pasquier et al., 2003; Franceschi et al., 2005; Mendez et al., 2005a). Novel functional and molecular imaging techniques will improve diagnostic accuracy and provide further insight into FTLD pathophysiology. White matter changes in FTLD are more apparent using diffusion tensor imaging (DTI) than on conventional MRI, correlating pathologically with frontal white matter gliosis and demyelination (Larsson et al., 2004). PET imaging of the nigrostiatal pathway using 11CCIT PET correlated extrapyramidal signs with a decrease in pre-synaptic dopaminergic neurons (Rinne et al., 2002). PET imaging with 11CMDL found a decrease in frontal 5HT2A receptors in FTD compared to con-

trols (Franceschi et al., 2005), as has been described in pathologic series. Molecular imaging of amyloid and tau (Shoghi-Jadid et al., 2002; Klunk et al., 2004; Nordberg, 2004), currently under active investigation in AD, may prove helpful in diagnosing taupositive forms of FTLD and differentiating between FTLD and AD (Rabinovici et al., 2007). 33.5.2. EEG The EEG in FTD is often normal (Johannesson et al., 1977, 1979; Neary et al., 1988), though diminution or slowing of normal background rhythm can be seen, especially in temporal variants and advanced disease (Chan et al., 2004). Quantitative spectral comparisons have shown significant differences between EEGs in FTD and AD, but these differences may not be apparent on qualitative assessment (Yener et al., 1996; Neary et al., 1998; Lindau et al., 2003; Chan et al., 2004). 33.5.3. CSF Lumbar puncture should be pursued only to exclude infectious or inflammatory conditions, as the basic cerebrospinal fluid (CSF) profile in FTLD is normal. CSF levels of unphosphorylated and phosphorylated tau have generated interest as potential biomarkers for FTLD. Results have varied, with CSF tau levels found to be lower (Grossman et al., 2005), equal (Sjogren et al., 2000; Clark et al., 2003; Grossman et al., 2005), or higher (Green et al., 1999; Fabre et al., 2001) in FTD than in controls. The majority of studies were based on clinical diagnosis, and thus represent a pathologically heterogeneous group. Of interest, CSF tau levels were found to be normal in patients with tau mutations (Rosso et al., 2003b), and low in a small number of patients with non-tau pathology (Grossman et al., 2005). These equivocal results do not justify the use of CSF tau for diagnosis in routine clinical practice.

33.6. Pathology 33.6.1. Common gross and microscopic changes FTLD is pathologically heterogeneous, but all subtypes share common gross and microscopic features. At autopsy, there is grossly apparent, circumscribed atrophy of the frontal or anterior temporal lobes (Fig. 33.3A) (McKhann et al., 2001). The pattern of atrophy in early disease determines which clinical syndrome predominates, with bifrontal atrophy leading to

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Fig. 33.3. Pathology in FTLD. (A) Gross specimen shows selective frontal lobe atrophy. (B) Low-power H & E stain revealing neuronal loss, spongiosis and gliosis in frontal cortex. (C) Tau immunohistochemistry stains classic Pick bodies. (D) Ballooned tau-positive neuron (Pick cell), seen in Pick’s disease and other tauopathies. (E)–(F) Low- (E) and high-powered (F) views of tau-negative, ubiquitin-positive inclusions in dentate fascia in a patient with FTLD-U. Slides provided courtesy of Drs Stephen J. DeArmond, Mark S. Forman and John Q. Trojanowski.

FTD, anterior temporal presenting as semantic dementia, and dominant hemisphere peri-sylvian atrophy presenting as PNFA. Posterior cortical structures are spared until the advanced stages of the disease. Atrophy can be severe, with brain weights reported as low as 750 g (Dickson, 2001). Other grossly apparent changes include thinning of the cortical ribbon, blurring of the gray–white junction, discoloration and softening of white matter, and variable atrophy of the basal ganglia and thalamus (Dickson, 2001; Munoz et al., 2003).

A gross pathologic staging system has been proposed based primarily on findings in patients diagnosed with frontal-variant FTLD (FTD) during life (Broe et al., 2003). The earliest atrophy was found in orbital and superior medial frontal cortex and hippocampus (Stage 1). Atrophy then spread to adjacent anterior frontal structures, the temporal poles, inferior temporal cortex and the basal ganglia (caudate > putamen > globus pallidus; Stage 2). Further progression led to grossly apparent white matter atrophy, ventricular dilatation and thinning of the corpus callosum

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(Stage 3). In advanced disease there was global cortical atrophy (though more severe anteriorly), further atrophy of the basal ganglia, involvement of the thalamus, and near dissolution of medial inferior temporal cortex (Stage 4). Hemispheric asymmetry was not apparent at the end-stage of disease. Progression of atrophy was independent of specific histopathologic subtype, and correlated with clinical severity (Broe et al., 2003; Kril and Halliday, 2004). Microscopically, routine stains reveal microvacuolar degeneration and pyramidal cell loss in superficial frontal and temporal cortex, creating a spongiform appearance (Fig. 33.3B). There is a variable degree of gliosis within cortex. Subcortical white matter, especially subjacent to the areas of greatest cortical atrophy, shows loss of myelinated fibers, gliosis, and axonal loss (Constantinidis et al., 1974; Brun, 1987, 1993; Brun and Passant, 1996; Dickson, 2001; McKhann et al., 2001; Munoz et al., 2003; Kertesz et al., 2005).

33.7. FTLD histologic subtypes After excluding Alzheimer’s and a-synuclein pathology, cases can be further classified pathologically into three subtypes based on the patterns of intracellular inclusions and immunohistochemical staining: (1) tau-positive pathology with or without inclusions (Pick’s disease and related disorders); (2) tau-negative, ubiquitinpositive inclusions (FTLD with motor-neuron disease inclusions); and (3) tau-negative, ubiquitin-negative pathology (dementia lacking distinctive histology) (McKhann et al., 2001). 33.7.1. Pick’s disease and other tauopathies (FTLD-T) Pick’s disease is characterized by the presence of classic Pick bodies—round or oval, intensely argyrophilic, cytoplasmic neuronal inclusions (Fig. 33.3C). Pick bodies are stained by Bielschowsky but not Gallyas stains, and are most readily detected by tau immunohistochemical stains. They are usually found in hippocampus (including dentate fascia), amygdala, and in superficial frontal and temporal neocortex (Dickson, 2001; McKhann et al., 2001; Munoz et al., 2003; Kertesz et al., 2005). They are uncommon in parietal and occipital cortex, and are variably found in the basal ganglia, monoaminergic nuclei, hypothalamus and brainstem. They stain variably for ubiquitin (Dickson, 2001). Pick bodies are only one of many tau-immunoreactive pathologic features. Others include ballooned achromatic neurons (Pick cells, Fig. 33.3D), and

intracytoplasmic neuronal and glial inclusions of various morphologies, including gray and white matter coils, threads and neurofibrillary tangles (Dickson, 2001). These inclusions are variably present in Pick’s disease, but are also found in the absence of Pick bodies in the family of diseases known as “tauopathies”. Given considerable overlap in morphology, further discrimination between syndromes can be achieved by tau biochemical analysis (Munoz et al., 2003). In humans, tau exists as six isoforms, each expressing either three or four repeated amino-acid sequences that serve as microtubulebinding sites. Exon 10 encodes the fourth repeated sequence, and alternative splicing includes or excludes exon 10, leading to 4-repeat (4R) or 3-repeat (3R) isoforms respectively. Pathologic tau may be predominantly composed of 3R, 4R or a mix of the two (Munoz et al., 2003). Pick’s disease is usually (but not always) a 3R tauopathy, argyrophilic grain disease is a 4R tauopathy (Braak and Braak, 1998; Jellinger and Bancher, 1998), and tangle-predominant dementia has a mix of 3R and 4R isoforms (Jellinger and Bancher, 1998). Frontotemporal dementia with Parkinsonism associated with chromosome 17 (FTDP-17) may include 3R, 4R, or mixed isoforms (McKhann et al., 2001). Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are 4R tauopathies that have considerable clinical and pathologic overlap with FTLD (Kertesz, 1997). These diseases are covered elsewhere in this volume. 33.7.2. FTLD with ubiquitin- and TDP-43-positive inclusions (FTLD-U) Okamoto and colleagues first described ubiquitinpositive inclusions outside motor cortex in patients with ALS (Okamoto et al., 1991). Jackson et al. found similar inclusions associated with dementia, with or without clinically apparent motor-neuron disease (Cooper et al., 1995; Jackson et al., 1996). Inclusions are small, rounded or crescent-shaped, tau- and synuclein-negative, and ubiquitin-positive. They are most abundant in dentate gyrus granule cells in hippocampus (Fig. 33.3E,F), and in layer II neurons in frontotemporal cortex (McKhann et al., 2001). Inclusions may be cytoplasmic or nuclear, and may be accompanied by coiled or curvilinear ubiquitin-staining bodies within dystrophic neurites. Skein-like ubiquitin inclusions are variably present in anterior horn cells and cranial nerve nuclei (Shi et al., 2005). There is a wide range in the morphology and distribution of ubiquitin inclusions, with significant overlap between the clinical syndromes of ALS, FTD and FTD-ALS, suggesting that these syndromes are strongly related

FRONTOTEMPORAL LOBAR DEGENERATION: CLINICAL AND PATHOLOGIC OVERVIEW 355 (Mackenzie and Feldman, 2005). Three distinct patterns of ubiquitin inclusion pathology have recently been demonstrated: (i) long neuritic inclusions in superficial cortex; (ii) cytoplasmic inclusions in both superficial and deep cortex; and (iii) predominantly ring-shaped cytoplasmic inclusions in superficial cortex (Mackenzie et al., 2006a; Sampathu et al., 2006). The relationship between these heterogeneous pathologic patterns, clinical presentation and pathogenesis is not yet understood. For years the ubiquitin-positive inclusions found in FTLD were hypothesized to represent a proteolytic tag for another, unknown pathogenic protein. Recent work by Neumann and colleagues suggests this mysterious protein may be the TAR DNA-binding protein TDP43 (Neumann et al., 2006). TDP-43 is a ubiquitously expressed nuclear protein that plays a role in DNA transcription and splicing. TDP-43 is found in all forms of ubiquitin-inclusions in sporadic and familial FTLD-U, FTLD-U with motor-neuron disease, and in sporadic ALS, whereas it is not commonly found in inclusions in FTLD-tau or other neurodegenerative disorders (Arai et al., 2006; Neumann et al., 2006; Davidson et al., 2007). Interestingly, under pathologic conditions TDP-43 is displaced from the cell nucleus to the cytoplasm (Neumann et al., 2006). The sensitive and specific association between TDP-43 and FTLD-U supports the hypothesis that TDP-43 is the pathogenic protein in FTLD-U, but it is important to emphasize that a direct causal relationship between TDP-43 and FTLD has not yet been established. Nevertheless, the discovery of this protein represents a potential major breakthrough towards understanding FTLD pathophysiology. 33.7.3. Dementia lacking distinctive histology and other histopathologic forms The term dementia lacking distinctive histology (DLDH) describes cases in which gross and microscopic atrophic changes are clearly evident, yet tau and ubiquitin immunohistochemistry is negative (McKhann et al., 2001). The term was originally coined by Knopman to describe the bland pathology found in non-Pick’s cases, which initially appeared to represent the majority of FTLD cases (Knopman et al., 1990; Knopman, 1993). A significant number of cases initially diagnosed as DLDH have been restained for ubiquitin and found to be positive (Josephs et al., 2004; Lipton et al., 2004), and DLDH is now found only in a minority of cases (see below). While FTLD-T, FLTD-U and DLDH encompass the vast majority of pathology in FTLD, rare cases of other pathologic subtypes have been reported. An early-onset,

rapidly progressive behavioral syndrome characterized by various degrees of extrapyramidal and motor-neuron signs is associated with inclusions containing neurofilament and alpha-internexin (Josephs et al., 2003; Cairns et al., 2004). A familial syndrome of inclusion body myositis, Paget’s disease and FTD is associated with a mutation in the valosin-containing protein, with valosin and TDP-43 inclusions found in muscle and neuronal nuclei (Schroder et al., 2005; Neumann et al., 2007). Finally, some patients who present with the FTLD clinical syndrome will have non-FTLD neuropathology. AD, vascular dementia, Lewy body dementia, multiple systems atrophy, prion disease and normal brains have all been found on autopsy in patients clinically diagnosed with an FTLD syndrome (Galton et al., 2000; Davies et al., 2005; Kertesz et al., 2005; Forman et al., 2006). 33.7.4. Clinicopathologic correlations A number of large series of autopsy-proven FTLD have recently been published (Hodges et al., 2003, 2004; Lipton et al., 2004; Davies et al., 2005; Kertesz et al., 2005; Shi et al., 2005; Forman et al., 2006). Direct comparison of data from these series is limited by their different methodologies: some studies prospectively studied the pathological diagnosis in all patients clinically diagnosed as an FTLD syndrome, while others retrospectively examined clinical data in autopsy-proven FTLD. Some studies included CBD and PSP while others did not. Nevertheless, a number of common themes have emerged. First, all forms of FTLD pathology can present as any of the FTLD clinical syndromes. Gender distributions are equal amongst all pathologies. A number of studies have found an older age of onset and longer survival in FTLD-T (Hodges et al., 2003, 2004; Roberson et al., 2005), though this has been an inconsistent finding (Kertesz et al., 2005; Shi et al., 2005). Survival is shortened in FTLD-U (Hodges et al., 2003, 2004), an effect that is most prominent in cases of clinically apparent ALS, and does not hold true for semantic dementia (Davies et al., 2005). FTLD-U is the most prevalent pathology, ranging from 26% to 62% in the various series, and accounting for 140/305 (46%) of autopsy-proven FTLD cases reported in the literature (Shi et al., 2005). Prevalence of classic Pick’s disease (not including other tauopathies) is 11–33%, while DLDH is present 13–23% of the time. FTLD-U accounts for a large proportion of semantic dementia presentations (13/18 cases in one series) (Davies et al., 2005; Shi et al., 2005; Forman et al., 2006). Of the FTLD clinical syndromes, PNFA is more likely to be associated with non-FTLD

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pathology, such as CBD or AD (Hodges et al., 2004; Kertesz et al., 2005; Knibb et al., 2006). When FTLD pathology is implicated in PNFA, one study found a high (6/8) proportion of Pick’s disease (Hodges et al., 2004). Early onset of a movement disorder makes tau pathology more likely (Kertesz et al., 2005; Forman et al., 2006), and the clinical syndromes of CBD and PSP often correlate with either CBD or PSP pathology (Hodges et al., 2004; Kertesz et al., 2005). Clinically apparent motor-neuron disease virtually ensures tau-negative pathology, and very strongly predicts FTLD-U (Hodges et al., 2004; Kertesz et al., 2005). The behavioral FTD syndrome does not appear to have a predilection for a specific pathology.

33.8. Treatment 33.8.1. Pharmacotherapy The absence of animal models and the heterogeneous pathology of FTLD have hampered efforts to identify effective therapies. Symptomatic treatment has focused on treating behavioral symptoms, including disinhibition, impulsiveness, altered appetite, and compulsive and stereotypical behaviors. Drugs that modify serotonin have the strongest theoretical rationale, given the serotonergic deficits identified by neurochemical studies (Sparks and Markesbery, 1991; Procter et al., 1999) and functional imaging (Franceschi et al., 2005). Moreover, these drugs are effective in treating similar behaviors in non-demented individuals. Selective serotonin reuptake inhibitors (SSRIs) were effective at controlling behavior in small studies without placebo controls (Swartz et al., 1997b; Moretti et al., 2003), though a recent placebo-controlled study has challenged these findings (Deakin et al., 2004). Trazodone, another serotonergic drug, was effective in a placebo-controlled crossover study (Lebert et al., 2004). Rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase used in Alzheimer’s disease (Farlow et al., 2000), was found to be effective in one open-label study (Moretti et al., 2004). However, as opposed to AD, there is no cortical cholinergic deficit in FTLD (Yates et al., 1980; Meier-Ruge et al., 1984; Hansen et al., 1988), and in our experience cholinesterase inhibitors may exacerbate agitation in FTLD patients (Perry and Miller, 2001). In our clinical practice, SSRIs are the first-line treatment for behavioral symptoms. SSRIs can also be helpful in curbing stereotypical movements (Mendez et al., 2005b). Low-dose atypical neuroleptics (e.g., quetiapine) are sometimes necessary to control aggressive behaviors, but these should be used sparingly as they may exacerbate parkinsonism, and slightly increase

mortality in elderly dementia patients (http://www.fda. gov/cder/drug/infopage/antipsychotics/default.htm). Anticonvulsants such as carbamazepine and valproic acid can also be helpful in modulating agitation and aggression, while benzodiazepines should be avoided (Perry and Miller, 2001). Memantine, an NMDA antagonist used in AD (Reisberg et al., 2003) has sparked recent interest, especially given the effectiveness of anti-glutamatergic therapy in ALS (Bensimon et al., 1994), and is under active investigation. 33.8.2. Non-pharmacologic therapy As always, the treating physician can alleviate stress by educating families and caregivers about the disease. Understanding the biological basis of difficult behaviors helps put these behaviors in a different perspective. Anticipating the progression of illness can help families reach difficult decisions (e.g., transition to an assisted-living or long-term care facility) in a more gradual, controlled manner. Participation in support groups, ideally with family members of other FTD patients, can be extremely helpful. Semantic dementia and PNFA patients may benefit from speech therapy or the use of augmentative or alternative communication devices. Caregiver and family education about aphasia helps facilitate effective communication. Early in FTD, the physician should stress the importance of avoiding situations in which a patient’s poor judgment or impulsivity can have dire consequences (e.g., driving, financial decision-making) (Perry and Miller, 2001). Later in the disease, environmental modification can be helpful by removing cues that trigger undesired behaviors, and utilizing stimuli that trigger adaptive behaviors (e.g., setting out clothes in the order they are to be worn) (Talerico and Evans, 2001). Caregivers of dementia patients are at risk for depression and medical illness (Schulz et al., 1995), and the physician must ensure that caregivers are obtaining sufficient help and respite and addressing their own health needs. Physical activity in the form of a structured exercise program is a universal recommendation for both patients and caregivers, and it has been our anecdotal experience that it helps delay or slow motor symptoms. In the end-stages of disease, the physician should guide families towards setting goals that maximize function and quality of life, rather than “safety at all costs” (Talerico and Evans, 2001).

Acknowledgements The authors would like to thank Dr. William W. Seeley for helpful contributions to this manuscript.

FRONTOTEMPORAL LOBAR DEGENERATION: CLINICAL AND PATHOLOGIC OVERVIEW 357 GDR is a fellow of the John Douglas French Alzheimer’s Foundation. Supported by NIA grant P01AG1972403, ADRC grant P50-AG023501 and the Hillblom Foundation.

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