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Falls in frontotemporal dementia and related syndromes
Handbook of Clinical Neurology, Vol. 159 (3rd series) Balance, Gait, and Falls B.L. Day and S.R. Lord, Editors https://doi.org/10.1016/B978-0-444-63916-5.00012-4 Copyright © 2018 Elsevier B.V. All rights reserved
Chapter 12
Falls in frontotemporal dementia and related syndromes JAMES R. BURRELL1,2* AND JOHN R. HODGES2 Concord Clinical School, Sydney Medical School, University of Sydney, Sydney, Australia
1
2
Brain and Mind Centre, University of Sydney Medical School, Sydney, NSW, Australia
Abstract Frontotemporal dementia (FTD) and related diseases are important causes of younger-onset dementia. Falls may be a source of morbidity and mortality in FTD, but remain underreported, and very few high-quality studies have been performed. In this chapter, we briefly review the clinical features of FTD and related syndromes such as motor neuron disease (MND) and atypical parkinsonian syndromes, such as progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). Falls are frequently encountered in patients who present with FTD syndromes. Although cognitive impairment is associated with falls generally, motor symptoms and signs, as seen in FTD cases that overlap with atypical parkinsonian disorders such as PSP or CBS, or MND, appear to pose the greatest risk. At present, very few systematic studies have been performed to determine the precise frequency, timing, diagnostic implications, and complications of falls in FTD. Further studies are required to understand the scope of this problem, and to develop effective treatments and management strategies.
INTRODUCTION First described more than 100 years ago by Arnold Pick, frontotemporal dementia (FTD) is now recognized as one of the commonest causes of younger-onset dementia (i.e., dementia affecting people before the age of 65 years). Prevalence estimates in this age group vary between 10 and 15 affected individuals per 100,000, making FTD and related syndromes important, albeit underrecognized, neurodegenerative diseases (Coyle-Gilchrist et al., 2016). Disturbed gait, impaired balance, and falls are important manifestations of these progressive and incurable diseases, although formal studies of these aspects are sparse. Typically, FTD affects behavior or language, so why would patients have impaired gait or be prone to falls? FTD remains clinically and pathologically heterogeneous, despite efforts to refine clinical phenotypes and improve clinicopathologic correlation (Cairns et al., 2007; Gorno-Tempini et al., 2011; Rascovsky et al., 2011), and a number of different pathologic entities cause
overlapping clinical signs and symptoms. Motor deficits are particularly common in cases of FTD that overlap with other neurodegenerative disorders, notably motor neuron disease (MND) or atypical parkinsonian syndromes, such as progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) (Burrell et al., 2014, 2016). Such motor overlaps can evolve over time, even in patients with pure cognitive / behavioral syndromes at diagnosis, resulting in impaired gait, increased risk of falls (Talerico and Evans, 2001), and even a revision of the diagnosis (Snowden et al., 2011). Falls may be a source of morbidity and mortality in FTD and related diseases, but remain relatively underreported, and very few high-quality studies have been performed. In this chapter, we briefly review the clinical features of FTD and related syndromes. We review the evidence for disturbed gait, impaired balance, and falls in FTD syndromes, and highlight areas that require further study and more specific management.
*Correspondence to: Dr. James R. Burrell, Neurosciences 5 West, Concord General Hospital, Sydney NSW 2139, Australia. Tel: +61-2-9767-5000, Fax: +61-2-8244-1950, E-mail: [email protected]
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CLINICAL SYNDROMES What is frontotemporal dementia? The earliest descriptions of FTD are more than 100 years old, but the disease remained shrouded in mystery until the last 30 or 40 years. Gradually, a picture emerged of focal neurodegenerative syndromes predominantly affecting behavior and language, executive function, and other cognitive abilities. Three FTD phenotypes are described: (1) the behavioral variant of FTD (bvFTD), where marked changes in behavior and personality predominate; (2) progressive nonfluent aphasia (PNFA), which is characterized by progressive nonfluent speech and language disturbances; and (3) semantic dementia (SD), which is characterized by breakdown in word and object knowledge, despite fluent speech. Approximately half of cases present as bvFTD, with the other half presenting as either PNFA or SD. Between a quarter and a third of patients with FTD have a family history of early-onset dementia or a closely related disorder such as MND and in the majority of these familial cases a gene mutation can now be identified (Rohrer et al., 2009; Po et al., 2014). While textbook descriptions of FTD present these three clinical phenotypes as distinct from each other and other neurodegenerative diseases, considerable overlap exists. In particular, marked disturbances of language, behavior, and other cognitive deficits – similar to those encountered in FTD – may occur in PSP, CBS, and even atypical Alzheimer disease, leading to diagnostic uncertainty in a significant proportion of patients. Clinical, pathologic, and genetic overlaps between FTD and MND have been a focus of research over the last decade. Such overlaps may explain gait disturbances and falls in FTD.
Behavioral variant frontotemporal dementia Changes in personality and social behavior are the earliest and most significant clinical symptoms in bvFTD. Marked apathy, impaired social conduct, reduction in empathy and affection, and striking disinhibition may be present to a variable extent, and often coexist (Rascovsky et al., 2011). Patients may be difficult to motivate, and often spend their time sitting on the couch watching television, wearing soiled clothing for several days, or refusing to shower for several weeks at a time. Despite such marked inertia, disinhibition may also be present, characterized by changes in libido, preference for sweet food and overeating, a tendency to collect unneeded objects, disturbed sleep, and increases in spending, gambling, and drug and alcohol use. Other changes include increased stereotyped behaviors (e.g., pacing, counting, or checking) or rigidity in daily
routine. Although language, and other cognitive abilities, may be relatively preserved in the earliest stages, more widespread deficits usually emerge over time. Importantly, patients often display a striking lack of insight into their symptoms and deficits. Impulsive behavior can lead to significant risk-taking, with potential for increasing the risk of falls. In addition to characteristic behavioral symptoms, a specific pattern of cognitive deficits on neuropsychologic testing may suggest a diagnosis of bvFTD. In particular, detailed testing usually demonstrates evidence of executive dysfunction and disinhibition (Hornberger et al., 2008), although it can be hard to demonstrate without the use of specific neuropsychologic tests of inhibition. The diagnosis of bvFTD is made on clinical grounds, through recognition of characteristic symptoms and signs, analysis of performance on neuropsychologic testing, and documentation of frontotemporal atrophy on magnetic resonance imaging (MRI) (Fig. 12.1B), or frontotemporal hypometabolism on fluorodeoxyglucose positron emission tomography (Rascovsky et al., 2011). Over recent years, genetic testing has emerged as an important diagnostic tool, particularly for familial cases (Burrell et al., 2016).
Progressive nonfluent aphasia Reflecting prominent involvement of the left temporal lobe, progressive language disturbance may not be surprising in FTD. More surprising, perhaps, is the striking differences in the pattern of language disturbances. For instance, PNFA is characterized by nonfluent speech with word-finding difficulties, motor speech errors (i.e., apraxia of speech), as well as errors in syntactic production or interpretation, or even a complete absence of grammar in verbal or written output. A range of cognitive deficits may be seen in PNFA on formal neuropsychologic testing, but impaired single-word and sentence repetition, along with impaired production and interpretation of grammar, are the most consistent findings. Imaging typically shows focal atrophy of the peri-insular cortex on the left-hand side (Fig. 12.1C), with less dramatic involvement of other temporal and frontal brain regions.
Semantic dementia Of all FTD syndromes, SD is the most consistent in terms of clinical presentation, performance on neuropsychologic testing, changes on brain imaging, and findings on pathologic examination (Burrell and Hodges, 2010). The phenotype is characterized by completely fluent speech, with preserved single-word and sentence repetition (Hodges et al., 1992) despite surface dyslexia (i.e., difficulty reading irregular words) and what may be severe deficits in word and object knowledge (Hodges
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Fig. 12.1. Magnetic resonance imaging in frontotemporal dementia and related diseases. (A) Normal brain volumes. (B) Behavioral variant frontotemporal dementia; severe frontal atrophy affecting the dorsolateral, interhemispheric, and orbitofrontal cortices. (C) Progressive nonfluent aphasia; left-sided atrophy, most notable in the peri-insular cortex. (D) Semantic dementia; severe anterior temporal atrophy, predominantly affecting the left-hand side, with less significant involvement on the right-hand side. (E) Progressive supranuclear palsy; severe midbrain atrophy, with the so-called hummingbird sign.
et al., 1992; Gorno-Tempini et al., 2004, 2011). Neuropsychologic assessment may reveal relatively intact performance across nonlanguage cognitive domains. Severe anterior temporal atrophy on MRI is almost invariably present (Fig. 12.1D). In classic SD, the left anterior temporal lobe is most severely affected, and this accounts for about two-thirds of focal anterior temporal neurodegeneration cases. In the other one-third of cases, the right anterior temporal lobe is most severely affected; this presentation may be referred to as right temporal variant of FTD and disturbances of behavior are the most common manifestation, though progressive deficits in language akin to those seen in classic SD occur as significant left anterior temporal involvement develops (Kamminga et al., 2015). Motor deficits (Burrell et al., 2011) and falls (Coyle-Gilchrist et al., 2016) are infrequent in SD, perhaps reflecting the consistency of the syndrome and the focality of pathology.
Atypical parkinsonian syndromes PROGRESSIVE SUPRANUCLEAR PALSY PSP was originally described by Richardson et al. (1963) as a parkinsonian disorder characterized by axial rigidity, symmetric bradykinesia, postural instability with early and prominent falls, and conjugate gaze paralysis on voluntary eye movement (Richardson et al., 1963; Steele et al., 1964). Over time, cognitive deficits were gradually recognized, and it is now known that approximately 70% of PSP patients will develop a form of dementia throughout the disease course (Burrell et al., 2014). Behavioral disturbance, executive impairment, and cognitive slowing appear to be most characteristic of the syndrome, but memory, language, and visuospatial function may also be affected (Burrell et al., 2014).
Behavioral changes may be significant in PSP. All pervasive apathy, often combined with impulsivity, is frequent in PSP, as is impaired social conduct. Such observations reinforce the clinical overlap with bvFTD (Kobylecki et al., 2015). In terms of language, adynamic aphasia, characterized by a reduction in verbal output and selective impairment of action verbs, accompanied by reduced cognitive processing speed (Esmonde et al., 1996; Albert, 2005; Bak et al., 2005; Cordato et al., 2006; Robinson et al., 2006, 2015; Brown et al., 2010; Burrell et al., 2014), has been the most frequently reported abnormality. Other aspects of language, such as single-word / sentence repetition and syntactic comprehension (Esmonde et al., 1996; Bak et al., 2005; Cotelli et al., 2006; Daniele et al., 2013; Kim and McCann, 2015), are thought to be relatively preserved. Patients with PSP often develop disproportionate midbrain atrophy, most obvious on sagittal T1 MRI, leading to the development of the so-called hummingbird sign (Fig. 12.1E). Measures of midbrain atrophy demonstrate potential in the distinction of PSP from other FTD syndromes (Silsby et al., 2017).
CORTICOBASAL SYNDROME CBS was described with the report of 3 cases by Rebeiz et al. in the late 1960s (Rebeiz et al., 1968). From the outset, a wide range of motor deficits was recognized, including limb apraxia, alien-limb phenomenon, tremor, impaired gait, abnormalities of eye movements, dystonia, hyperreflexia, and rigidity, occurring in any combination. Cognitive deficits were reported, but initially considered a late-stage phenomenon. It is now clear that most, if not all, patients with CBS have cognitive and/or behavioral features from early in the course of their illness (Huang et al., 2014).
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The most distinctive motor feature of CBS is marked asymmetric limb apraxia, which often interferes with limb function dramatically. Limb apraxia may be defined as the inability to perform a motor task, despite intact power, sensation, coordination, comprehension, and cooperation (Gross and Grossman, 2008). Like parkinsonism, limb apraxia is present in almost all patients with CBS. Indeed, the documentation of limb apraxia is important for making a diagnosis of CBS and has been included in many diagnostic criteria (Boeve et al., 2003; Bak and Hodges, 2008; Mathew et al., 2012; Armstrong et al., 2013). Although apraxia may be seen in other neurodegenerative diseases (Zadikoff and Lang, 2005; Holl et al., 2011), it is generally accepted as an important component of CBS.
MOTOR NEURON DISEASE MND is a progressive neurodegenerative disorder that affects both the upper and lower motor neurons of the bulbar and limb regions (Kiernan et al., 2011; Burrell et al., 2016). The pattern and severity of motor involvement may vary significantly; some patients present with symptoms and signs reflecting bulbar involvement with dysarthria, dysphagia, and respiratory symptoms (i.e., bulbar MND), while others present with symptoms and signs of limb upper and lower motor neuron involvement
with fasciculations, wasting, weakness, hyperreflexia, and spasticity (i.e., limb MND). Even in so-called bulbar MND, limb involvement, with potential for gait impairment and falls, may develop over time.
CLINICAL EVOLUTION AND OVERLAPS Frontotemporal dementia, progressive supranuclear palsy, and corticobasal syndrome FTD overlaps with several other neurodegenerative diseases at both a clinical and pathologic level (Fig. 12.2). For example, patients who present with PNFA can develop a typical PSP motor syndrome through the course of their illness (Deramecourt et al., 2010; Rohrer et al., 2010). Separately, the typical tauopathy of PSP pathology has been reported in patients with PNFA, even in the context of minimal or absent parkinsonism (Mochizuki et al., 2003; Kertesz et al., 2005; Deramecourt et al., 2010). Finally, several studies report the presence of a nonfluent aphasia in patients who present with the typical PSP motor syndrome (Bak et al., 2006; Cotelli et al., 2006; Daniele et al., 2013; Josephs et al., 2014; Spaccavento et al., 2014), making PSP difficult to distinguish from PNFA in the clinic in the earliest stages. The overlap between FTD and PSP is not confined to the PNFA phenotype. For instance, almost
Fig. 12.2. Clinical overlaps in frontotemporal dementia and related disorders. Behavioral variant frontotemporal dementia overlaps clinically with motor neuron disease, corticobasal syndrome, and progressive supranuclear palsy. Progressive nonfluent aphasia overlaps clinically with motor neuron disease, progressive supranuclear palsy, and corticobasal syndrome. Finally, progressive supranuclear palsy overlaps clinically with corticobasal syndrome.
FALLS IN FRONTOTEMPORAL DEMENTIA AND RELATED SYNDROMES a third (32%) of clinically defined PSP patients in one study met criteria for possible or probable bvFTD (Kobylecki et al., 2015). The same study found that 2 of 7 pathologically confirmed PSP cases met criteria for the diagnosis of bvFTD. Similarly, FTD also overlaps with CBS. Otherwise typical pathologic changes of corticobasal degeneration have been associated with non-CBS clinical presentations, such as bvFTD or PNFA (Kertesz et al., 2000, 2005; Knibb et al., 2006). One published series found that, of 35 patients, 13 presented with PNFA and 7 presented with bvFTD (Kertesz et al., 2000), before developing a motor syndrome that was sufficient to meet clinical criteria for CBS. Of these cases, 7 had underlying corticobasal degeneration pathology, although 3 had the characteristic 4-repeat tauopathy of Pick disease and 1 had “atypical” PSP pathology.
The frontotemporal dementia–motor neuron disease (FTD–MND) continuum Cognitive and behavioral symptoms were recognized in some of the earliest descriptions of MND phenotypes (Duchenne et al., 1883), but it was the recognition of TDP-43 inclusions (Neumann et al., 2006), and the identification of the C9orf72 repeat expansion (DeJesusHernandez et al., 2011; Renton et al., 2011), in FTD and MND that cemented the relationship between the two diseases. Surprisingly few studies have examined the natural history of FTD–MND, although one retrospective study suggested that FTD precedes that of MND in most cases (Coon et al., 2011); a larger and more recent study found that FTD and MND were present at the time of referral in the vast majority of FTD–MND cases (Saxon et al., 2017). The prevalence of cognitive dysfunction and behavioral change in MND cohorts has been extensively studied. Approximately 10–15% of MND patients meet criteria for the diagnosis of FTD (Lomen-Hoerth et al., 2003; Ringholz et al., 2005; Strong et al., 2009; Phukan et al., 2012), although some degree of cognitive impairment (e.g., executive, language, or memory deficits) or behavioral disturbance may be detectable in up to 50–75% of patients. Likewise around 15% of FTD patients develop MND (Lomen-Hoerth et al., 2002; Burrell et al., 2011), sometimes years after the onset of dementia (Coon et al., 2011). A further 30–40% of patients demonstrate subtle clinical (e.g., fasciculations, weakness, or wasting), neurophysiologic, or pathologic (i.e., FTD-MND pathology) motor system abnormalities (Lomen-Hoerth et al., 2002; Josephs et al., 2006; Burrell et al., 2011). When FTD and MND occur synchronously, the prognosis is worse than if the diseases occur sequentially (Lillo et al., 2010).
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FALLS IN FRONTOTEMPORAL DEMENTIA AND RELATED SYNDROMES: Several lines of evidence have linked gait disturbance and increased risk of falls in older individuals with the development of cognitive impairment. Conversely, the presence of gait disturbance in cognitively intact elderly individuals may predict the development of dementia subsequently, especially dementias due to diseases other than Alzheimer disease (Verghese et al., 2002; Beauchet et al., 2016). A relationship between falls and cognitive dysfunction may not be surprising, when the nature of walking is considered. Specifically, safe walking requires attention, adequate visuospatial awareness, set shifting to adjust for unexpected obstacles, and reasonable cognitive processing speed in order to safely negotiate a physical environment (Dorfman et al., 2014). Dementias that are associated with motor deficits appear to pose the greatest risk of falls. For example, among older age groups, the frequency of falls appears to be higher in dementia with Lewy bodies, Parkinson disease dementia, or vascular dementia, than amnestic Alzheimer disease (Verghese et al., 2002; Allan et al., 2005; Rochester et al., 2014; Beauchet et al., 2016). To date, most studies of gait disturbance and falls in dementia have concentrated on older-aged cohorts, and the results reflect this bias. Less is known about the risk of falls in younger-onset dementia, where FTD is more prevalent.
Falls in frontotemporal dementia Extrapyramidal gait disturbances appear to be common in FTD, although prevalence estimates vary significantly. For example, in one study 71% of 31 bvFTD patents were reported to have a “parkinsonian” gait or posture, as detected by the United Parkinson’s Disease Rating Scale (Diehl-Schmid et al., 2007). In contrast, only 22.7% of 75 bvFTD patients in another study had any feature of parkinsonism, with bradykinesia and rigidity being most common (Padovani et al., 2007), and the prevalence of gait disturbance or falls was not specifically reported. A third study of a clinical cohort reported parkinsonism in 22% of FTD patients (Kertesz et al., 2011), but again the precise rate of falls was not reported. Gait analysis studies in bvFTD are uncommon; however, one study demonstrated an increased prevalence of gait disturbances in bvFTD compared to Alzheimer’s disease patients and controls (Allali et al., 2010). The presence of parkinsonism is not confined to bvFTD. One study specifically examined the presence of parkinsonian signs in patients with PNFA, SD, and the logopenic progressive aphasia phenotype of Alzheimer’s disease. As might have been expected,
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patients with SD had very few parkinsonian signs. In contrast, up to 40% of PNFA patients had at least one parkinsonian sign on examination, most commonly rigidity or bradykinesia. Gait disturbance was reported in almost 20% of PNFA patients (Kremen et al., 2011). One recent study of clinical characteristics and survival in FTD and related syndromes provides important insights into the prevalence of falls in these diseases (Coyle-Gilchrist et al., 2016). The study employed a population-based approach, utilizing multiple patient sources, to include cases of bvFTD, PNFA, SD, PSP, and CBS. In all, 200 patients were included and a range of clinical features were assessed. Parkinsonian signs such as akinesia and rigidity were common, especially in PSP and CBS, but also in bvFTD, in which 64.3% of patients were reported to have akinesia and 21.4% were reported to have rigidity. In contrast, akinesia was less common in PNFA (17.9% of cases) and SD (13% of cases). The rates of gait disturbance and falls mirrored the prevalence of parkinsonian signs, affecting 16.7% of bvFTD patients, but only 7.1% of PNFA patients. No SD patients were found to have gait disturbance or a history of falls. In contrast, 66.7% of CBS patients and 97.9% of PSP patients were reported to have gait disturbance or falls. In light of these results, it is possible that the prevalence of gait disturbance and falls reflects the clinical and pathologic overlaps between bvFTD, PNFA, PSP, and CBS.
Falls in progressive supranuclear palsy and corticobasal syndrome Along with supranuclear gaze palsy, gait disturbance and falls are considered cardinal symptoms of PSP. As clinical criteria for the diagnosis of PSP emphasize the presence of early falls, almost all patients have falls soon after the onset of symptoms, even in patients who might present initially to a behavioral neurology, rather than a movement disorders, clinic. For example, one recent study examined the prevalence and time to onset of gait disturbance and falls, among other motor and nonmotor symptoms, in a cohort of 35 patients with PSP diagnosed clinically. Almost all patients had falls at the initial assessment, with the prevalence reaching almost 100% by 2 years after the initial assessment (Arena et al., 2016). Another clinically defined cohort study reported falls in 88% of patients, and established that onset of falls within the first 12 months was associated with a worse prognosis (Nath et al., 2003). Specifically, patients who had the onset of falls within 12 months of symptom onset had a median survival of 7.2 years compared to a median survival of 14.6 years for patients who developed falls more than 12 months after the onset of symptoms (Nath et al., 2003).
Similar findings have been reported in pathologically confirmed cohorts of PSP. For example, in one pathologic series, 93% of patients who were diagnosed with pathologic PSP had early falls, which were associated with cerebellar atrophy (Song et al., 2011). In contrast, another pathologically confirmed series found falls at symptom onset in only 39% of PSP patients, increasing thereafter in most patients with a mean latency to falls of 6 months (Wenning et al., 1999). Ultimately, recurrent falls at any time point of the disease course occurred in all patients with pathologically confirmed PSP, although a very high rate of recurrent falls was also seen in other pathologically confirmed extrapyramidal diseases such as Parkinson’s disease, multiple system atrophy, dementia with Lewy bodies, and corticobasal degeneration, albeit later in the disease course than in PSP (Wenning et al., 1999). Unfortunately, less is known about the frequency and prevalence of falls in CBS than in other extrapyramidal disorders. Several challenges hamper efforts to understand the risk of falls in CBS. Firstly, the disorder is clinically and pathologically heterogeneous, which makes case definition difficult; should studies use clinically defined cohorts, which may have variable underlying pathologies, or examine pathologically confirmed cases of corticobasal degeneration, potentially risking excluding a significant proportion of clinical cases? Another challenge is the marked variability in motor and cognitive symptoms in CBS; such variability hampers efforts to develop consensus for diagnostic criteria. The absence of a pathologic gold standard compounds these difficulties. Notwithstanding these difficulties, falls do appear to be common in CBS. One study of clinically defined CBS reported falls or postural instability in 66.7% of cases, a frequency that was second only to PSP across the range of FTD and related diseases (Coyle-Gilchrist et al., 2016). In our own experience, gait disturbance and falls are commonly encountered in patients with clinically defined CBS. In 35 CBS cases seen in our clinic, 15 (42.9%) had falls at the time of their initial assessment, with balance problems in 20 (57.1%) and gait disturbance in 23 (65.7%) (unpublished data). Pathologic confirmed studies of corticobasal degeneration portray a similar picture. For example, one study reported falls in 29% of cases at symptom onset, with falls at some stage during the illness in 92% of cases (Wenning et al., 1999).
CONCLUSION The disorders grouped under the FTD umbrella comprise a range of clinical syndromes with overlapping and evolving cognitive, behavioral, and motor symptoms.
FALLS IN FRONTOTEMPORAL DEMENTIA AND RELATED SYNDROMES The underlying pathologies are varied, and clinicopathologic correlation is often challenging. Falls are frequently encountered in patients who present with FTD, and related syndromes. Motor symptoms and signs, as seen in FTD cases that overlap with atypical parkinsonian disorders such as PSP or CBS, or MND, appear to pose the greatest risk. At present, very few systematic studies have been performed to determine the precise frequency, timing, diagnostic implications, and complications of falls in FTD. Further studies are required to understand the scope of this problem, and to develop effective treatments and management strategies.
ACKNOWLEDGMENTS This work was supported by funding to ForeFront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neuron disease, from the National Health and Medical Research Council of Australia (NHMRC) program grant (#1037746) and the Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Node (#CE110001021). We are grateful to the research participants involved with the ForeFront research studies. In addition, JRB is supported by an NHMRC early career fellowship (#1072451).
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FALLS IN FRONTOTEMPORAL DEMENTIA AND RELATED SYNDROMES Ringholz GM, Appel SH, Bradshaw M et al. (2005). Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology 65: 586–590. Robinson G, Shallice T, Cipolotti L (2006). Dynamic aphasia in progressive supranuclear palsy: a deficit in generating a fluent sequence of novel thought. Neuropsychologia 44: 1344–1360. Robinson GA, Spooner D, Harrison WJ (2015). Frontal dynamic aphasia in progressive supranuclear palsy: distinguishing between generation and fluent sequencing of novel thoughts. Neuropsychologia 77: 62–75. Rochester L, Lord S, Yarnall AJ et al. (2014). Falls in patients with dementia. In: M Merello (Ed.), Movement disorders in dementias. Springer-Verlag, London, pp. 45–60. Rohrer JD, Guerreiro R, Vandrovcova J et al. (2009). The heritability and genetics of frontotemporal lobar degeneration. Neurology 73: 1451–1456. Rohrer JD, Paviour D, Bronstein AM et al. (2010). Progressive supranuclear palsy syndrome presenting as progressive nonfluent aphasia: a neuropsychological and neuroimaging analysis. Mov Disord Off J Mov Disord Soc 25: 179–188. Saxon JA, Harris JM, Thompson JC et al. (2017). Semantic dementia, progressive non-fluent aphasia and their association with amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 88: 711–712. Silsby M, Tweedie-Cullen RY, Murray CR et al. (2017). The midbrain-to-pons ratio distinguishes progressive supranuclear palsy from non-fluent primary progressive aphasias. Eur J Neurol 24: 956–965.
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Chapter 12
Falls in frontotemporal dementia and related syndromes JAMES R. BURRELL1,2* AND JOHN R. HODGES2 Concord Clinical School, Sydney Medical School, University of Sydney, Sydney, Australia
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Brain and Mind Centre, University of Sydney Medical School, Sydney, NSW, Australia
Abstract Frontotemporal dementia (FTD) and related diseases are important causes of younger-onset dementia. Falls may be a source of morbidity and mortality in FTD, but remain underreported, and very few high-quality studies have been performed. In this chapter, we briefly review the clinical features of FTD and related syndromes such as motor neuron disease (MND) and atypical parkinsonian syndromes, such as progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). Falls are frequently encountered in patients who present with FTD syndromes. Although cognitive impairment is associated with falls generally, motor symptoms and signs, as seen in FTD cases that overlap with atypical parkinsonian disorders such as PSP or CBS, or MND, appear to pose the greatest risk. At present, very few systematic studies have been performed to determine the precise frequency, timing, diagnostic implications, and complications of falls in FTD. Further studies are required to understand the scope of this problem, and to develop effective treatments and management strategies.
INTRODUCTION First described more than 100 years ago by Arnold Pick, frontotemporal dementia (FTD) is now recognized as one of the commonest causes of younger-onset dementia (i.e., dementia affecting people before the age of 65 years). Prevalence estimates in this age group vary between 10 and 15 affected individuals per 100,000, making FTD and related syndromes important, albeit underrecognized, neurodegenerative diseases (Coyle-Gilchrist et al., 2016). Disturbed gait, impaired balance, and falls are important manifestations of these progressive and incurable diseases, although formal studies of these aspects are sparse. Typically, FTD affects behavior or language, so why would patients have impaired gait or be prone to falls? FTD remains clinically and pathologically heterogeneous, despite efforts to refine clinical phenotypes and improve clinicopathologic correlation (Cairns et al., 2007; Gorno-Tempini et al., 2011; Rascovsky et al., 2011), and a number of different pathologic entities cause
overlapping clinical signs and symptoms. Motor deficits are particularly common in cases of FTD that overlap with other neurodegenerative disorders, notably motor neuron disease (MND) or atypical parkinsonian syndromes, such as progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) (Burrell et al., 2014, 2016). Such motor overlaps can evolve over time, even in patients with pure cognitive / behavioral syndromes at diagnosis, resulting in impaired gait, increased risk of falls (Talerico and Evans, 2001), and even a revision of the diagnosis (Snowden et al., 2011). Falls may be a source of morbidity and mortality in FTD and related diseases, but remain relatively underreported, and very few high-quality studies have been performed. In this chapter, we briefly review the clinical features of FTD and related syndromes. We review the evidence for disturbed gait, impaired balance, and falls in FTD syndromes, and highlight areas that require further study and more specific management.
*Correspondence to: Dr. James R. Burrell, Neurosciences 5 West, Concord General Hospital, Sydney NSW 2139, Australia. Tel: +61-2-9767-5000, Fax: +61-2-8244-1950, E-mail: [email protected]
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CLINICAL SYNDROMES What is frontotemporal dementia? The earliest descriptions of FTD are more than 100 years old, but the disease remained shrouded in mystery until the last 30 or 40 years. Gradually, a picture emerged of focal neurodegenerative syndromes predominantly affecting behavior and language, executive function, and other cognitive abilities. Three FTD phenotypes are described: (1) the behavioral variant of FTD (bvFTD), where marked changes in behavior and personality predominate; (2) progressive nonfluent aphasia (PNFA), which is characterized by progressive nonfluent speech and language disturbances; and (3) semantic dementia (SD), which is characterized by breakdown in word and object knowledge, despite fluent speech. Approximately half of cases present as bvFTD, with the other half presenting as either PNFA or SD. Between a quarter and a third of patients with FTD have a family history of early-onset dementia or a closely related disorder such as MND and in the majority of these familial cases a gene mutation can now be identified (Rohrer et al., 2009; Po et al., 2014). While textbook descriptions of FTD present these three clinical phenotypes as distinct from each other and other neurodegenerative diseases, considerable overlap exists. In particular, marked disturbances of language, behavior, and other cognitive deficits – similar to those encountered in FTD – may occur in PSP, CBS, and even atypical Alzheimer disease, leading to diagnostic uncertainty in a significant proportion of patients. Clinical, pathologic, and genetic overlaps between FTD and MND have been a focus of research over the last decade. Such overlaps may explain gait disturbances and falls in FTD.
Behavioral variant frontotemporal dementia Changes in personality and social behavior are the earliest and most significant clinical symptoms in bvFTD. Marked apathy, impaired social conduct, reduction in empathy and affection, and striking disinhibition may be present to a variable extent, and often coexist (Rascovsky et al., 2011). Patients may be difficult to motivate, and often spend their time sitting on the couch watching television, wearing soiled clothing for several days, or refusing to shower for several weeks at a time. Despite such marked inertia, disinhibition may also be present, characterized by changes in libido, preference for sweet food and overeating, a tendency to collect unneeded objects, disturbed sleep, and increases in spending, gambling, and drug and alcohol use. Other changes include increased stereotyped behaviors (e.g., pacing, counting, or checking) or rigidity in daily
routine. Although language, and other cognitive abilities, may be relatively preserved in the earliest stages, more widespread deficits usually emerge over time. Importantly, patients often display a striking lack of insight into their symptoms and deficits. Impulsive behavior can lead to significant risk-taking, with potential for increasing the risk of falls. In addition to characteristic behavioral symptoms, a specific pattern of cognitive deficits on neuropsychologic testing may suggest a diagnosis of bvFTD. In particular, detailed testing usually demonstrates evidence of executive dysfunction and disinhibition (Hornberger et al., 2008), although it can be hard to demonstrate without the use of specific neuropsychologic tests of inhibition. The diagnosis of bvFTD is made on clinical grounds, through recognition of characteristic symptoms and signs, analysis of performance on neuropsychologic testing, and documentation of frontotemporal atrophy on magnetic resonance imaging (MRI) (Fig. 12.1B), or frontotemporal hypometabolism on fluorodeoxyglucose positron emission tomography (Rascovsky et al., 2011). Over recent years, genetic testing has emerged as an important diagnostic tool, particularly for familial cases (Burrell et al., 2016).
Progressive nonfluent aphasia Reflecting prominent involvement of the left temporal lobe, progressive language disturbance may not be surprising in FTD. More surprising, perhaps, is the striking differences in the pattern of language disturbances. For instance, PNFA is characterized by nonfluent speech with word-finding difficulties, motor speech errors (i.e., apraxia of speech), as well as errors in syntactic production or interpretation, or even a complete absence of grammar in verbal or written output. A range of cognitive deficits may be seen in PNFA on formal neuropsychologic testing, but impaired single-word and sentence repetition, along with impaired production and interpretation of grammar, are the most consistent findings. Imaging typically shows focal atrophy of the peri-insular cortex on the left-hand side (Fig. 12.1C), with less dramatic involvement of other temporal and frontal brain regions.
Semantic dementia Of all FTD syndromes, SD is the most consistent in terms of clinical presentation, performance on neuropsychologic testing, changes on brain imaging, and findings on pathologic examination (Burrell and Hodges, 2010). The phenotype is characterized by completely fluent speech, with preserved single-word and sentence repetition (Hodges et al., 1992) despite surface dyslexia (i.e., difficulty reading irregular words) and what may be severe deficits in word and object knowledge (Hodges
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Fig. 12.1. Magnetic resonance imaging in frontotemporal dementia and related diseases. (A) Normal brain volumes. (B) Behavioral variant frontotemporal dementia; severe frontal atrophy affecting the dorsolateral, interhemispheric, and orbitofrontal cortices. (C) Progressive nonfluent aphasia; left-sided atrophy, most notable in the peri-insular cortex. (D) Semantic dementia; severe anterior temporal atrophy, predominantly affecting the left-hand side, with less significant involvement on the right-hand side. (E) Progressive supranuclear palsy; severe midbrain atrophy, with the so-called hummingbird sign.
et al., 1992; Gorno-Tempini et al., 2004, 2011). Neuropsychologic assessment may reveal relatively intact performance across nonlanguage cognitive domains. Severe anterior temporal atrophy on MRI is almost invariably present (Fig. 12.1D). In classic SD, the left anterior temporal lobe is most severely affected, and this accounts for about two-thirds of focal anterior temporal neurodegeneration cases. In the other one-third of cases, the right anterior temporal lobe is most severely affected; this presentation may be referred to as right temporal variant of FTD and disturbances of behavior are the most common manifestation, though progressive deficits in language akin to those seen in classic SD occur as significant left anterior temporal involvement develops (Kamminga et al., 2015). Motor deficits (Burrell et al., 2011) and falls (Coyle-Gilchrist et al., 2016) are infrequent in SD, perhaps reflecting the consistency of the syndrome and the focality of pathology.
Atypical parkinsonian syndromes PROGRESSIVE SUPRANUCLEAR PALSY PSP was originally described by Richardson et al. (1963) as a parkinsonian disorder characterized by axial rigidity, symmetric bradykinesia, postural instability with early and prominent falls, and conjugate gaze paralysis on voluntary eye movement (Richardson et al., 1963; Steele et al., 1964). Over time, cognitive deficits were gradually recognized, and it is now known that approximately 70% of PSP patients will develop a form of dementia throughout the disease course (Burrell et al., 2014). Behavioral disturbance, executive impairment, and cognitive slowing appear to be most characteristic of the syndrome, but memory, language, and visuospatial function may also be affected (Burrell et al., 2014).
Behavioral changes may be significant in PSP. All pervasive apathy, often combined with impulsivity, is frequent in PSP, as is impaired social conduct. Such observations reinforce the clinical overlap with bvFTD (Kobylecki et al., 2015). In terms of language, adynamic aphasia, characterized by a reduction in verbal output and selective impairment of action verbs, accompanied by reduced cognitive processing speed (Esmonde et al., 1996; Albert, 2005; Bak et al., 2005; Cordato et al., 2006; Robinson et al., 2006, 2015; Brown et al., 2010; Burrell et al., 2014), has been the most frequently reported abnormality. Other aspects of language, such as single-word / sentence repetition and syntactic comprehension (Esmonde et al., 1996; Bak et al., 2005; Cotelli et al., 2006; Daniele et al., 2013; Kim and McCann, 2015), are thought to be relatively preserved. Patients with PSP often develop disproportionate midbrain atrophy, most obvious on sagittal T1 MRI, leading to the development of the so-called hummingbird sign (Fig. 12.1E). Measures of midbrain atrophy demonstrate potential in the distinction of PSP from other FTD syndromes (Silsby et al., 2017).
CORTICOBASAL SYNDROME CBS was described with the report of 3 cases by Rebeiz et al. in the late 1960s (Rebeiz et al., 1968). From the outset, a wide range of motor deficits was recognized, including limb apraxia, alien-limb phenomenon, tremor, impaired gait, abnormalities of eye movements, dystonia, hyperreflexia, and rigidity, occurring in any combination. Cognitive deficits were reported, but initially considered a late-stage phenomenon. It is now clear that most, if not all, patients with CBS have cognitive and/or behavioral features from early in the course of their illness (Huang et al., 2014).
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The most distinctive motor feature of CBS is marked asymmetric limb apraxia, which often interferes with limb function dramatically. Limb apraxia may be defined as the inability to perform a motor task, despite intact power, sensation, coordination, comprehension, and cooperation (Gross and Grossman, 2008). Like parkinsonism, limb apraxia is present in almost all patients with CBS. Indeed, the documentation of limb apraxia is important for making a diagnosis of CBS and has been included in many diagnostic criteria (Boeve et al., 2003; Bak and Hodges, 2008; Mathew et al., 2012; Armstrong et al., 2013). Although apraxia may be seen in other neurodegenerative diseases (Zadikoff and Lang, 2005; Holl et al., 2011), it is generally accepted as an important component of CBS.
MOTOR NEURON DISEASE MND is a progressive neurodegenerative disorder that affects both the upper and lower motor neurons of the bulbar and limb regions (Kiernan et al., 2011; Burrell et al., 2016). The pattern and severity of motor involvement may vary significantly; some patients present with symptoms and signs reflecting bulbar involvement with dysarthria, dysphagia, and respiratory symptoms (i.e., bulbar MND), while others present with symptoms and signs of limb upper and lower motor neuron involvement
with fasciculations, wasting, weakness, hyperreflexia, and spasticity (i.e., limb MND). Even in so-called bulbar MND, limb involvement, with potential for gait impairment and falls, may develop over time.
CLINICAL EVOLUTION AND OVERLAPS Frontotemporal dementia, progressive supranuclear palsy, and corticobasal syndrome FTD overlaps with several other neurodegenerative diseases at both a clinical and pathologic level (Fig. 12.2). For example, patients who present with PNFA can develop a typical PSP motor syndrome through the course of their illness (Deramecourt et al., 2010; Rohrer et al., 2010). Separately, the typical tauopathy of PSP pathology has been reported in patients with PNFA, even in the context of minimal or absent parkinsonism (Mochizuki et al., 2003; Kertesz et al., 2005; Deramecourt et al., 2010). Finally, several studies report the presence of a nonfluent aphasia in patients who present with the typical PSP motor syndrome (Bak et al., 2006; Cotelli et al., 2006; Daniele et al., 2013; Josephs et al., 2014; Spaccavento et al., 2014), making PSP difficult to distinguish from PNFA in the clinic in the earliest stages. The overlap between FTD and PSP is not confined to the PNFA phenotype. For instance, almost
Fig. 12.2. Clinical overlaps in frontotemporal dementia and related disorders. Behavioral variant frontotemporal dementia overlaps clinically with motor neuron disease, corticobasal syndrome, and progressive supranuclear palsy. Progressive nonfluent aphasia overlaps clinically with motor neuron disease, progressive supranuclear palsy, and corticobasal syndrome. Finally, progressive supranuclear palsy overlaps clinically with corticobasal syndrome.
FALLS IN FRONTOTEMPORAL DEMENTIA AND RELATED SYNDROMES a third (32%) of clinically defined PSP patients in one study met criteria for possible or probable bvFTD (Kobylecki et al., 2015). The same study found that 2 of 7 pathologically confirmed PSP cases met criteria for the diagnosis of bvFTD. Similarly, FTD also overlaps with CBS. Otherwise typical pathologic changes of corticobasal degeneration have been associated with non-CBS clinical presentations, such as bvFTD or PNFA (Kertesz et al., 2000, 2005; Knibb et al., 2006). One published series found that, of 35 patients, 13 presented with PNFA and 7 presented with bvFTD (Kertesz et al., 2000), before developing a motor syndrome that was sufficient to meet clinical criteria for CBS. Of these cases, 7 had underlying corticobasal degeneration pathology, although 3 had the characteristic 4-repeat tauopathy of Pick disease and 1 had “atypical” PSP pathology.
The frontotemporal dementia–motor neuron disease (FTD–MND) continuum Cognitive and behavioral symptoms were recognized in some of the earliest descriptions of MND phenotypes (Duchenne et al., 1883), but it was the recognition of TDP-43 inclusions (Neumann et al., 2006), and the identification of the C9orf72 repeat expansion (DeJesusHernandez et al., 2011; Renton et al., 2011), in FTD and MND that cemented the relationship between the two diseases. Surprisingly few studies have examined the natural history of FTD–MND, although one retrospective study suggested that FTD precedes that of MND in most cases (Coon et al., 2011); a larger and more recent study found that FTD and MND were present at the time of referral in the vast majority of FTD–MND cases (Saxon et al., 2017). The prevalence of cognitive dysfunction and behavioral change in MND cohorts has been extensively studied. Approximately 10–15% of MND patients meet criteria for the diagnosis of FTD (Lomen-Hoerth et al., 2003; Ringholz et al., 2005; Strong et al., 2009; Phukan et al., 2012), although some degree of cognitive impairment (e.g., executive, language, or memory deficits) or behavioral disturbance may be detectable in up to 50–75% of patients. Likewise around 15% of FTD patients develop MND (Lomen-Hoerth et al., 2002; Burrell et al., 2011), sometimes years after the onset of dementia (Coon et al., 2011). A further 30–40% of patients demonstrate subtle clinical (e.g., fasciculations, weakness, or wasting), neurophysiologic, or pathologic (i.e., FTD-MND pathology) motor system abnormalities (Lomen-Hoerth et al., 2002; Josephs et al., 2006; Burrell et al., 2011). When FTD and MND occur synchronously, the prognosis is worse than if the diseases occur sequentially (Lillo et al., 2010).
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FALLS IN FRONTOTEMPORAL DEMENTIA AND RELATED SYNDROMES: Several lines of evidence have linked gait disturbance and increased risk of falls in older individuals with the development of cognitive impairment. Conversely, the presence of gait disturbance in cognitively intact elderly individuals may predict the development of dementia subsequently, especially dementias due to diseases other than Alzheimer disease (Verghese et al., 2002; Beauchet et al., 2016). A relationship between falls and cognitive dysfunction may not be surprising, when the nature of walking is considered. Specifically, safe walking requires attention, adequate visuospatial awareness, set shifting to adjust for unexpected obstacles, and reasonable cognitive processing speed in order to safely negotiate a physical environment (Dorfman et al., 2014). Dementias that are associated with motor deficits appear to pose the greatest risk of falls. For example, among older age groups, the frequency of falls appears to be higher in dementia with Lewy bodies, Parkinson disease dementia, or vascular dementia, than amnestic Alzheimer disease (Verghese et al., 2002; Allan et al., 2005; Rochester et al., 2014; Beauchet et al., 2016). To date, most studies of gait disturbance and falls in dementia have concentrated on older-aged cohorts, and the results reflect this bias. Less is known about the risk of falls in younger-onset dementia, where FTD is more prevalent.
Falls in frontotemporal dementia Extrapyramidal gait disturbances appear to be common in FTD, although prevalence estimates vary significantly. For example, in one study 71% of 31 bvFTD patents were reported to have a “parkinsonian” gait or posture, as detected by the United Parkinson’s Disease Rating Scale (Diehl-Schmid et al., 2007). In contrast, only 22.7% of 75 bvFTD patients in another study had any feature of parkinsonism, with bradykinesia and rigidity being most common (Padovani et al., 2007), and the prevalence of gait disturbance or falls was not specifically reported. A third study of a clinical cohort reported parkinsonism in 22% of FTD patients (Kertesz et al., 2011), but again the precise rate of falls was not reported. Gait analysis studies in bvFTD are uncommon; however, one study demonstrated an increased prevalence of gait disturbances in bvFTD compared to Alzheimer’s disease patients and controls (Allali et al., 2010). The presence of parkinsonism is not confined to bvFTD. One study specifically examined the presence of parkinsonian signs in patients with PNFA, SD, and the logopenic progressive aphasia phenotype of Alzheimer’s disease. As might have been expected,
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patients with SD had very few parkinsonian signs. In contrast, up to 40% of PNFA patients had at least one parkinsonian sign on examination, most commonly rigidity or bradykinesia. Gait disturbance was reported in almost 20% of PNFA patients (Kremen et al., 2011). One recent study of clinical characteristics and survival in FTD and related syndromes provides important insights into the prevalence of falls in these diseases (Coyle-Gilchrist et al., 2016). The study employed a population-based approach, utilizing multiple patient sources, to include cases of bvFTD, PNFA, SD, PSP, and CBS. In all, 200 patients were included and a range of clinical features were assessed. Parkinsonian signs such as akinesia and rigidity were common, especially in PSP and CBS, but also in bvFTD, in which 64.3% of patients were reported to have akinesia and 21.4% were reported to have rigidity. In contrast, akinesia was less common in PNFA (17.9% of cases) and SD (13% of cases). The rates of gait disturbance and falls mirrored the prevalence of parkinsonian signs, affecting 16.7% of bvFTD patients, but only 7.1% of PNFA patients. No SD patients were found to have gait disturbance or a history of falls. In contrast, 66.7% of CBS patients and 97.9% of PSP patients were reported to have gait disturbance or falls. In light of these results, it is possible that the prevalence of gait disturbance and falls reflects the clinical and pathologic overlaps between bvFTD, PNFA, PSP, and CBS.
Falls in progressive supranuclear palsy and corticobasal syndrome Along with supranuclear gaze palsy, gait disturbance and falls are considered cardinal symptoms of PSP. As clinical criteria for the diagnosis of PSP emphasize the presence of early falls, almost all patients have falls soon after the onset of symptoms, even in patients who might present initially to a behavioral neurology, rather than a movement disorders, clinic. For example, one recent study examined the prevalence and time to onset of gait disturbance and falls, among other motor and nonmotor symptoms, in a cohort of 35 patients with PSP diagnosed clinically. Almost all patients had falls at the initial assessment, with the prevalence reaching almost 100% by 2 years after the initial assessment (Arena et al., 2016). Another clinically defined cohort study reported falls in 88% of patients, and established that onset of falls within the first 12 months was associated with a worse prognosis (Nath et al., 2003). Specifically, patients who had the onset of falls within 12 months of symptom onset had a median survival of 7.2 years compared to a median survival of 14.6 years for patients who developed falls more than 12 months after the onset of symptoms (Nath et al., 2003).
Similar findings have been reported in pathologically confirmed cohorts of PSP. For example, in one pathologic series, 93% of patients who were diagnosed with pathologic PSP had early falls, which were associated with cerebellar atrophy (Song et al., 2011). In contrast, another pathologically confirmed series found falls at symptom onset in only 39% of PSP patients, increasing thereafter in most patients with a mean latency to falls of 6 months (Wenning et al., 1999). Ultimately, recurrent falls at any time point of the disease course occurred in all patients with pathologically confirmed PSP, although a very high rate of recurrent falls was also seen in other pathologically confirmed extrapyramidal diseases such as Parkinson’s disease, multiple system atrophy, dementia with Lewy bodies, and corticobasal degeneration, albeit later in the disease course than in PSP (Wenning et al., 1999). Unfortunately, less is known about the frequency and prevalence of falls in CBS than in other extrapyramidal disorders. Several challenges hamper efforts to understand the risk of falls in CBS. Firstly, the disorder is clinically and pathologically heterogeneous, which makes case definition difficult; should studies use clinically defined cohorts, which may have variable underlying pathologies, or examine pathologically confirmed cases of corticobasal degeneration, potentially risking excluding a significant proportion of clinical cases? Another challenge is the marked variability in motor and cognitive symptoms in CBS; such variability hampers efforts to develop consensus for diagnostic criteria. The absence of a pathologic gold standard compounds these difficulties. Notwithstanding these difficulties, falls do appear to be common in CBS. One study of clinically defined CBS reported falls or postural instability in 66.7% of cases, a frequency that was second only to PSP across the range of FTD and related diseases (Coyle-Gilchrist et al., 2016). In our own experience, gait disturbance and falls are commonly encountered in patients with clinically defined CBS. In 35 CBS cases seen in our clinic, 15 (42.9%) had falls at the time of their initial assessment, with balance problems in 20 (57.1%) and gait disturbance in 23 (65.7%) (unpublished data). Pathologic confirmed studies of corticobasal degeneration portray a similar picture. For example, one study reported falls in 29% of cases at symptom onset, with falls at some stage during the illness in 92% of cases (Wenning et al., 1999).
CONCLUSION The disorders grouped under the FTD umbrella comprise a range of clinical syndromes with overlapping and evolving cognitive, behavioral, and motor symptoms.
FALLS IN FRONTOTEMPORAL DEMENTIA AND RELATED SYNDROMES The underlying pathologies are varied, and clinicopathologic correlation is often challenging. Falls are frequently encountered in patients who present with FTD, and related syndromes. Motor symptoms and signs, as seen in FTD cases that overlap with atypical parkinsonian disorders such as PSP or CBS, or MND, appear to pose the greatest risk. At present, very few systematic studies have been performed to determine the precise frequency, timing, diagnostic implications, and complications of falls in FTD. Further studies are required to understand the scope of this problem, and to develop effective treatments and management strategies.
ACKNOWLEDGMENTS This work was supported by funding to ForeFront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neuron disease, from the National Health and Medical Research Council of Australia (NHMRC) program grant (#1037746) and the Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Node (#CE110001021). We are grateful to the research participants involved with the ForeFront research studies. In addition, JRB is supported by an NHMRC early career fellowship (#1072451).
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