are psp ftd cbd the different entities

REVIEWwww.nature.com/clinicalpractice/neuro

Are frontotemporal lobar degeneration, progressive supranuclear palsy and corticobasal degeneration distinct diseases?Sharon Sha, Craig Hou, Indre V Viskontas and Bruce L Miller*

INTRODUCTIONKnowledge about the clinical, pathological and genetic bases for neurodegenerative disorders is rapidly expanding. As modern molecular and genetic techniques are exploited, distinctions between disorders once considered separate diseases are beginning to blur. Recent genetic and pathological findings suggest that there are common molecular mechanisms for cortico basal degeneration (CBD) and progressive supranuclear palsy (PSP), two atypical parkinsonian syndromes that were initially considered un related. Also, it is now apparent that some patients who meet the clinical criteria for frontotemporal lobar degen-eration (FTLD) show CBD or PSP at autopsy. Growing awareness of the similarities between CBD, FTLD and PSP has led their classifica-tion as distinct disorders to be challenged.1,2 In particular, some authors argue that FTLD with tau mutations, CBD and PSP should all be consider ed as subtypes of Pick’s disease.1,3 Fundamental differences between these three syndromes still exist, however, and these differences justify their continued separation.

Early descriptions of CBD, PSP and FTLD are reviewed here to provide insights into how these diseases became classified as separate entities. This review is followed by a discussion regarding the similarities and differences between CBD, PSP and FTLD (Tables 1 and 2). Implications for clinical diagnosis and treatment are consider ed with regard to combining or splitting these disorders. Finally, an argument for continued separation of CBD, PSP and FTLD is made.

CORTICOBASAL DEGENERATIONThe clinical features of CBD were first described in case reports by Rebeiz, Kolodny and Richardson.4 In 1967, the term ‘cortico-dentatonigral degeneration with neuronal achromasia’ was introduced to describe three individuals who presented with progressive awkwardness and slowness of voluntary limb movement. This motor abnormality began in an asymmetric fashion before it became generalized.

New findings relating to the clinical, genetic and molecular bases of neurodegenerative disorders have led to a shift away from traditional nomenclatures of clinical syndromes. Historically, frontotemporal lobar degeneration (FTLD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) were classified on the basis of distinct clinical and pathological features. In recent years, however, advances in molecular and genetic research have led clinicians to suggest that the similar etiologies of the three disorders warrant their amalgamation into a single disorder with three subtypes. In this Review, we consider the utility and validity of combining FTLD, CBD and PSP. The earliest reports of these disorders demonstrate their distinctiveness, whereas recent findings challenge traditional nomenclatures by showing etiological overlap. For example, tau inclusions have been confirmed in patients with CBD and those with PSP, and in some patients with FTLD, implying that all three disorders are ‘tauopathies’. Furthermore, most patients with progressive nonfluent aphasia, a subtype of FTLD, show PSP or CBD post-mortem. Even tau-related cases of FTLD, CBD and PSP are distinguishable on the basis of other criteria, however, and many FTLD cases do not show tau pathology. We argue, therefore, that FTLD, CBD and PSP should be considered as pathologically similar but distinct syndromes. New research criteria for CBD and PSP should note that progressive nonfluent aphasia is often a precursor of these conditions.

KEYWORDS dementia, genetic, movement disorders, neuronal inclusions, tau protein

S Sha is an intern in internal medicine at California Pacific Medical Center, C Hou is a neurology physician at Kaiser Permanente Hospital, IV Viskontas is a postdoctoral fellow at the Memory and Aging Center at the University of California, San Francisco (UCSF), and BL Miller is Professor of Neurology, holds the AW & Mary Margaret Clausen Distinguished Chair, and is clinical director of the Memory and Aging Center at UCSF, San Francisco, CA, USA.

Correspondence *UCSF Memory and Aging Center, 350 Parnassus Avenue, Suite 706, San Francisco, CA 94143–1207, [email protected]

Received 29 August 2006 Accepted 6 October 2006

www.nature.com/clinicalpracticedoi:10.1038/ncpneuro0357

REVIEW CRITERIAPubMed was searched using Entrez for articles published up to 1 August 2006. Search terms used were “corticobasal degeneration”, “corticobasal syndrome”, “frontotemporal dementia”, “frontotemporal lobar degeneration”, “progressive non-fluent aphasia”, “semantic dementia”, “speech apraxia”, “progressive supranuclear palsy”, “tau” and “ubiquitin”. The abstracts of retrieved citations were reviewed and prioritized by relevant content. Full articles were obtained and references were checked for additional material when appropriate.

SUMMARY

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Involuntary motor activity was prominent and, in one case, the affected left arm resisted purposeful action of the right arm. Despite the severity of motor deficits, it was reported that “mental faculties were relatively spared until the end”. Post-mortem examination showed asymmetric frontal and parietal lobe atrophy, cortical neuron loss, swelling of the remaining cell bodies, and absence of the Nissl substance (achromasia). The substantia nigra showed severe cell loss.4

In the early studies, movement abnormalities were noted, whereas more recently the frontal executive, speech or behavioral disorders often seen in CBD have been emphasized. In 1989, Gibb, Luthert and Marsden5 shortened the disease name to ‘corticobasal degeneration’ and described three main clinical features: abnormality of motor function, construc-tional difficulty, and impaired eye movement. Motor symptoms included akinesia–rigidity, myo clonus, dystonia, and alien limb. In the cognitive domain, the authors described prob-lems with the copying of simple designs and shapes, which suggested parietal dysfunction. Horizontal and vertical saccades were absent in two cases. ‘Ideomotor apraxia’, which is character ized by impairments in demonstrating an object’s use in the absence of the object itself,

was common. Patients showed the conventional improvement in gesturing when the object itself was made available to them, or when they imitated the examiner, indicating that the apraxia is not caused simply by motor difficul-ties.6–8 Neuropathology showed frontoparietal atrophy and swollen ‘ballooned achromatic neurons’ that resembled Pick cells.5

Changes in movement can be the presenting feature of CBD, but cognitive changes are remarkably common. In 10 of 13 autopsy-proven CBD cases, memory loss, word finding difficulty and global cognitive dysfunction were presenting symptoms.9 Early reports of CBD noted parietal deficits, but impairments in frontal function are probably more typical,10 with impaired set shifting, verbal fluency and memory retrieval, apathy, depression, and repeti-tive behaviors being commonly observed.10–12 If frontal lobe degeneration begins in the domi-nant hemisphere, CBD can present as progres-sive nonfluent aphasia (PNFA).12,13 Finally, in a recent study of patients with PNFA, 70% showed CBD or PSP at autopsy, suggesting particularly close links between PNFA, CBD and PSP.3

The tau protein is central to the neuro-pathology of CBD; the neuronal inclusions, intracellular coiled bodies and astrocytic plaques associated with this condition all stain

Table 1 Overview of the features of corticobasal degeneration, progressive supranuclear palsy, and the three subtypes of frontotemporal lobar degeneration (frontotemporal dementia, progressive nonfluent aphasia and semantic dementia).

Disease Cognitive and behavioral features

Movement Anatomy Pathology Genetics

Corticobasal degeneration

Nonfluent aphasia, frontal executive deficits, oral and limb apraxia, apathy, depression

Asymmetric parkinsonism, ocular apraxia, myoclonus, alien limb, dystonia

Mesial frontal, frontal opercular, sometimes parietal, basal ganglia

Tau 4R, astrocytic plaques,achromatic neurons

H1 tau haplotype, tau mutations (rare)

Progressive supranuclear palsy

Nonfluent aphasia, frontal executive deficits, apathy

Axial rigidity, falls, impaired vertical gaze, dysphagia in the early stages

Dorsal midbrain and widespread brainstem, sometimes frontal insular

Tau 4R, neurofibril tangles, globose neurons

H1 tau haplotype, tau mutations (rare)

Frontotemporal dementia

Disinhibition, apathy, emotional blunting, overeating, frontal executive deficits

Amytrophic lateral sclerosis develops in 15% of cases, CBD or PSP features can be observed

Frontal insular, anterior temporal, sometimes parietal

Tau or ubiquitin inclusions

Tau (rare) or progranulin mutations

Progressive nonfluent aphasia

Speech deficits, nonfluent aphasia, oral apraxia, agrammatic, frontal executive deficits

Evolves into CBD or PSP (commonly)

Frontal insular, basal ganglia

Tau, CBD or PSP Unknown

Semantic dementia

Lack of knowledge for words, faces, emotion

Spared until late in the disease course

Anterior temporal, orbital frontal

Usually ubiquitin Uncommon

Abbreviations: 4R, four-microtubule repeat; CBD, corticobasal degeneration; PSP, progressive supranuclear palsy.



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for tau.14 Similarly, mutations in the gene on chromosome 17 that codes for the tau protein can cause CBD. Blurring the distinction between CBD and frontotemporal dementia (FTD) is the discovery that identical tau muta-tions within a family resulted clinically in CBD in the son and FTD in the father.15 With sporadic and genetic forms of CBD, the four-microtubule repeat (4R) isoform of tau is the main pathological inclusion. Also, the A0 tau allele is over-represented in patients with CBD compared with controls, further linking CBD to tau at the molecular level.16 Over time, CBD has, therefore, evolved from an idiopathic asymmetric basal ganglia disorder with parietal involvement to a frontal–parietal–basal ganglia disorder in which frontal executive, behavioral or speech deficits are often the first symptoms to emerge. Tau provides the link between the pathology and genetics of CBD.

PROGRESSIVE SUPRANUCLEAR PALSYThe clinical features of the nine cases of PSP first described by Steele et al. in 196417 included axial rigidity, supranuclear palsy, pseudobulbar palsy and dysarthria. The axial rigidity mani-fested as dystonic rigidity of the neck and upper body. Impaired vertical gaze—particularly with regard to looking downward on command—was an early sign, whereas horizontal eye movements were affected only later in the course

of the disease. Dementia was mild, but changes in personality and behavior were presenting symptoms in three patients. Neuropathological findings included neurofibrillary tangles, granulo vacuolar degenera tion, neuronal loss, and gliosis.17

Since these first cases, descriptions of the abnormalities in eye movements associated with PSP have been refined.18,19 Square-wave jerks during fixation are common, and in addition to impaired vertical eye movements saccades are now known to be hypometric with decreased velocity in the horizontal direction.18,19 Prominent motor symptoms present early in the disease and include bradykinesia, axial rigidity, falls and myoclonus.20–23

As with CBD, despite early emphasis on the parkinsonian features of the condition, PSP often begins as a cognitive disorder affecting executive function or language, or as a neuro-psychiatric disorder with apathy or other behav-ioral symptoms.24–26 Albert et al.27 originally described the dementia of PSP as a “subcortical dementia”, hypothesizing that degeneration of the midbrain led to dysfunction of circuits projecting to the cortex. Cognitive slowing is common, but deficits extend beyond slowed processing speed.28,29 Patients with PSP perform poorly on tasks of verbal fluency, sequencing, set shifting and abstract thought.21 As with CBD, PNFA can be a prodrome of PSP.

Table 2 Myths and facts about corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, progressive nonfluent aphasia and semantic dementia.

Disease Potential myths The facts

Corticobasal degeneration

1. Primarily presents as a movement disorder and cognition is relatively spared until later in the illness 2. Always asymmetric3. Parietal lobes are affected more than the frontal lobes

1. Usually begins with executive, language or speech deficits2. Often symmetrical3. When parietal involvement is greater than frontal involvement, suspect Alzheimer’s disease

Progressive supranuclear palsy

1. Primarily presents as a movement disorder, the dementia is mild, and the cortex is largely spared 2. Not asymmetric, if so suspect CBD3. Easily separated from CBD

1. Often begins as a frontal or PNFA syndrome and frontal lobes can be involved2. Often asymmetric3. CBD and PSP are difficult to predict at autopsy

Frontotemporal dementia

1. Only affects movement later in the disease course, and is cortically predominant2. FTD is a tauopathy

1. Many cases begin as a basal ganglia or motor neuron syndrome2. Half of cases are ubiquitin-positive but tau-negative

Progressive nonfluent aphasia

A cortical disorder that is clinically and pathologically unrelated to CBD or PSP

Most PNFA cases develop PSP or CBD features and neuropathology

Semantic dementia Temporally predominant degeneration is associated with Pick bodies

Most semantic dementia cases are ubiquitin-positive but tau-negative

Abbreviations: 4R, four-microtubule repeat; CBD, corticobasal degeneration; PSP, progressive supranuclear palsy.



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In common with CBD, the key patho logical feature of PSP is the presence of abnormally phosphorylated tau in neurons and glia. Diagnosis is determined by neurofibrillary tangles or neuropil threads in the basal ganglia and brainstem.30 Mutations in the intron region near exon 10 on the tau gene can lead to a familial PSP-like syndrome.31 Similarly, as in CBD, genetic studies show that the A0 tau allele is over-represented in cases with PSP compared with normal controls.16,32 The nearly identical percentage of PSP and CBD patients with the H1 tau haplotype further links the two disorders.33

The amyloid deposits or neuritic plaques that characterize Alzheimer’s disease (AD) are not present in pure PSP, but AD and PSP can be seen together.32,34 The majority of PSP and CBD cases, however, can be pathologically differenti-ated from AD. In AD, tau accumulation has been shown to result from amyloid-β (Aβ)-induced neuronal damage.35 Tau mutations do not cause AD; rather, inherited forms of AD result from mutations in the amyloid precursor protein (APP) or presenilin 1 and 2, which lead to an increase in Aβ42-amyloid deposition. The form of tau found in PSP is morphologically, ultrastructurally and biochemically distinct from that found in AD: in PSP, tau exists as mainly straight tubules, which are slightly thinner than the paired helical fragments found in AD.36 Also, in PSP tau deposits are found in both glial cells and neurons, whereas they are found only in neurons in AD. The PSP and CBD forms of tau are more similar to each other than to the tau in AD; in both PSP and CBD 4R tau is the predomi-nant isoform, there is glial pathology, and the tau filaments are mainly straight. CBD and PSP are differentiable in that in CBD there are ballooned neurons that are weakly immunoreactive to tau, and tau-positive astrocytic plaques.

FRONTOTEMPORAL LOBAR DEGENERATIONFTLD was first described by Arnold Pick in 1892,37 and language and behavioral changes were emphasized in the disorder’s early history. Pick’s first patients had focal left anterior temporal atrophy, although he also described a frontally predominant patient. Later, Alzheimer showed that these focal atrophy patients had argyrophilic inclusions that he called ‘Pick bodies’.37,38 Onari and Spatz coined the term ‘Pick’s disease’ for patients with a frontal or temporal degenerative disorder, ballooned

neurons, and Pick bodies.39 It was not until 1994, however, that the Lund and Manchester groups published formal research criteria and introduced the term ‘frontotemporal dementia’ (FTD).40 These groups noted that Pick bodies were absent in most cases of FTD. In 1998, a consensus conference proposed the term FTLD, dividing the syndrome into FTD, PNFA and semantic dementia (SD) subtypes, implying that the pathology was similar in all three.37

The core features of FTD were defined as insidious onset, slow progression, a decline in social conduct, impaired regulation of personal conduct, emotional blunting, and loss of insight.41 Impulsivity, inflexibility, disinhibi tion, repetitive behaviors, apathy, hyperorality, carbo-hydrate craving and poor hygiene are common symptoms. The core features of FTD are behav-ioral, but the cognitive profile is notable for executive deficits with relatively spared memory, language and visuospatial functions. Like CBD and PSP, verbal fluency, set shifting (as measured by the Trails B task), attention, abstraction, in hibition of an over-learned response (as measured by the Stroop test), and planning are impaired. Although FTD was initially character-ized as cortically based, many patients with FTD show movement syndromes similar to those asso ciated with CBD or PSP, along with behav-ioral deficits. Furthermore, there is a strong link with motor neuron disease; 15% of patients with FTD develop amyotrophic lateral sclerosis (ALS). Conversely, many patients with ALS develop frontal executive disorders.

Unlike CBD and PSP, FTD pathology is molec-ularly heterogeneous. Atrophy of the frontal or anterior temporal lobes is universal, and cortical and basal ganglia neuron loss and gliosis are evident microscopically.42,43 Approximately half of FTD cases are associated with insoluble tau aggregates within neurons and glia; these aggre-gates usually consist predominantly of 4R or three-microtubule repeat (3R) isoforms. 4R tau is over-represented in CBD, PSP and some FTD cases, whereas 3R tau is associated with classical Pick’s disease. In FTD, this tau pathology has been seen both with tau mutations44,45 and in sporadic cases. Patients in whom FTD has been diagnosed sometimes show CBD or PSP pathology.

Many FTD cases show tau-negative but ubiq-uitin-positive inclusions. Patients with these inclusions are classified as having FTD with motor neuron disease (FTD–MND). Some, but not all, patients with FTD–MND pathology develop ALS.



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More recently, mutations in the progranulin gene on chromosome 17 have been associated with this FTD-ubiquitin pathology.46 There are other families in whom FTD and ALS co-occur and show linkage to chromosome 9,47 and the H1 haplotype of the tau gene on chromo some 17q21 is also associated with FTLD.48 Unlike PSP and CBD, however, many FTD patients with the H1 haplotype do not show tau-positive inclusions via immuno histochemistry. It seems likely, therefore, that the mechanism for degeneration is distinct between the disorders. Furthermore, the A0 tau allele that asso ciates with CBD and PSP does not associate with FTD.16,49

Language impairment is the primary mani-festation of the two other subtypes of FTLD—PNFA and SD. With PNFA, the syndrome begins with speech apraxia, decreased fluency and agrammatism.50 Anatomically, PNFA is asso-ciated with asymmetric, left-greater-than-right, frontal, opercular, insular degeneration. Like CBD and PSP, cognitive deficits often involve frontal executive function, while memory is rela-tively spared. Typically, behavior is spared until later in the illness. The most likely pathological outcome in PNFA is CBD or PSP.3

SD is a temporally predominant subtype of FTLD. Patients with SD most commonly show asymmetric neural degeneration, with left temporal lobe atrophy more severe than right, and the disorder begins with deficits in knowl-edge about facts, objects, words and names. Prosody and syntax of speech are intact, allowing fluent verbal language, but patients will often have empty speech. This pattern is also apparent in written language. Neuropathologically, most SD cases show ubiquitin-positive inclusions, and only rarely does the temporal variant overlap pathologically with PSP or CBD.

OVERLAP AND DISTINCTIVE FEATURES The similarities and differences between CBD, PSP and FTLD are summarized in Figure 1. As described above, CBD, PSP and the three FTLD subtypes FTD, PNFA and SD, all represent clinically defined syndromes that are linked to specific neuropathological patterns. CBD and PSP were originally defined as atypical parkin-sonian syndromes and were associated with relative sparing of cortical functions, whereas FTD, PNFA and SD were considered to be corti-cally based syndromes in which movement was relatively spared. Since the generation of these original definitions, the characterization of the

clinical syndromes for CBD, PSP, FTD, PNFA and SD has expanded and become more precise.

There is little overlap between the tempo-rally predominant SD syndrome and CBD or PSP. Specifically, CBD and PSP tend to spare the temporal lobes, whereas SD involves basal ganglia only late in the disease, and SD is usually associated with ubiquitin, not tau, inclusions. The remainder of this discussion, therefore, focuses on the similarities and differences between CBD, PSP, FTD and PNFA.

PSP, CBD, PNFA and some cases of FTD are strongly linked from both clinical and patho logical perspectives. The rigid definition of CBD and PSP as movement disorders has dis appeared and there is increasing evidence for early involvement of frontal regions in both. Also, it is now evident that CBD and PSP are not purely movement disorders, but are clinical syndromes that encompass motor, cognitive, behavioral and language deficits that might overlap clinically with FTD and PNFA.7 Conversely, although PNFA—and sometimes FTD—begin as cortical syndromes, they can rapidly evolve into CBD-like or PSP-like move-ment disorders. This overlap is apparent anatomi-cally, as PSP, CBD, PNFA and FTD all affect basal ganglia and frontal structures.50

Tau pathology and genetics also link these syndromes. Nearly all PSP, CBD and PNFA and some FTD cases show overexpression of the 4R tau isoform in neurons and glia. Over 90% of PSP and CBD patients, but only 57% of controls, are homozygous for the H1 tau haplotype.32,51–53 Although PSP, CBD and FTD are usually sporadic, in familial cases tau mutations might lead to CBD in one generation, FTD in another, or a syndrome similar to PSP.15,54,55 On the basis of clinical and pathological data, it now seems that PNFA usually represents an asymmetric, dominant-hemisphere, cortically predominant manifestation of CBD or PSP.3,56,57

Significant differences still remain, however, between CBD, PSP and FTD. First, the three disorders have distinct anatomical patterns of degeneration: PSP is associated with extensive pathological changes in the cerebellum and pons, whereas CBD, PNFA and FTD generally spare this region. CBD is much more likely than FTD to affect the basal ganglia and parietal regions. In FTD the most prominent atrophy is generally frontal, temporal or both. Second, the inclusions found in each of the disorders are reliably differentiable on pathology: whereas the insoluble tau form in CBD and PSP is 4R



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tau, FTD tau inclusions are commonly 3R tau. Furthermore, although tau links some FTD cases to CBD and PSP, most patients with FTD do not in fact show tau inclusions. Third, genetic factors provide additional distinctions: even though there are occasional families with tau mutations in whom FTD, CBD and PSP overlap, there are many more in which the FTD or PSP phenotype remains constant across many generations. Last, there are still substan-tial clinical differences between the disorders: by definition FTD does not begin with aphasia, whereas it is now evident that many PSP and CBD patients start with PNFA. Cognitive impairment is also more common in CBD than

in PSP; eye-movement abnormalities are more prominent in PSP than in CBD; and manifesta-tions of parietal damage such as graphesthesia and astereognosis are much more frequent in CBD than in PSP. FTD is differenti able from CBD and PSP when behavioral impairments are dominant and the patient shows rela-tively spared language and memory function. Although the overlap between CBD, PSP and FTD is extensive, careful attention to clinical findings and advances in neuro imaging tech-niques have enhanced the differential diag-nosis. Taken together, these differences are sufficient to support continued separation of the disorders.

CBD PSP

FTLD

Nonfluent aphasiaTau inclusionsTau mutationsBasal ganglia

Frontal executivedeficitsApathy

4R tau

H1 tauhaplotype

A0 tau allele

Parietal atrophy

Pathology:■ Ballooned neurons■ Astrocytic plaques■ Achromatic neurons

Pathology:■ Neurofibrillary tangles■ Globose neurons

Genetics: Pathology:■ Progranulin mutations ■ Ubiquitin inclusions

Frontotemporal dementiaBehavioral symptoms: Anatomy:■ Emotional blunting ■ More orbital frontal■ Spared memory■ Overeating■ Disinhibition

Behavioral symptoms: Anatomy:■ Loss of knowledge for ■ Anterior words, faces, objects temporal

Semantic dementia

Movement:■ Axial rigidity■ Falls■ Vertical gaze■ Early dysphagia

Anatomy:■ More dorsal midbrain■ More widespread brainstem

Anatomy:■ Mesial frontal■ Frontal opercular■ More parietal

Movement:■ Asymmetric parkinsonism■ Ocular apraxia■ Myoclonus■ Alien limb■ Dystonia

Figure 1 Venn diagram summarizing the similarities and differences between corticobasal degeneration, progressive supranuclear palsy and frontotemporal lobar degeneration. Abbreviations: 4R, four-microtubule repeat; CBD, corticobasal degeneration; FTLD, frontotemporal lobar degeneration; PSP, progressive supranuclear palsy.



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CONCLUSIONCurrently, PSP, CBD and FTLD can be distin-guished on the basis of clinical and pathological observations. The overlapping characteristics of these disorders, however, will continue to create controversy with respect to their classifica-tion2,58,59 until the etiologies are better under-stood. Little is known about the epidemiological and genetic factors that cause these disorders. Recent data support strong links between CBD, PSP, PNFA and some cases of FTD via their common tau pathology. Most cases of SD and many cases of FTD are, however, associated with ubiquitin rather than tau pathology, and appear to be etiologically distinct from CBD and PSP.

As biochemical, pathological and genetic discoveries are made, new and better nomen-clature systems might become possible. Beyond pathology and genetics, the effectiveness of treatments that focus on the underlying pathological mechanisms will be important in refining taxonomies.60 For example, if an anti-tau therapy was available that benefited patients with CBD, PSP, PNFA and FTD equally, consideration of these disorders as a single entity would be more compelling. At present, however, no such therapy exists, and many questions remain with regard to the anatomical, genetic and pathological vari-ability of these disorders. The rapid evolution of knowledge regarding CBD, PSP, PNFA and FTD offers hope not only for understanding these disorders, but also for finding effective therapies with which to treat them.

KEY POINTS ■ Traditionally, frontotemporal lobar

degeneration (FTLD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) have been distinguishable on the basis of presenting clinical symptoms

■ Recently, molecular and genetic findings have suggested a link between the three disorders

■ PSP and CBD cases show tau inclusions post-mortem, as do some FTLD cases

■ Progressive nonfluent aphasia, a subtype of FTLD, often leads to PSP and CBD

■ Not all FTLD cases are tauopathies

■ As there are currently no treatments available that target the molecular and genetic etiologies of these three disorders, they should continue to be considered distinct

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AcknowledgmentsThis work was supported by the Larry L Hillblom Foundation, National Institute on Aging grant P01-AG1972403, and an Alzheimer’s Disease Research Center grant P50-AG023501.

Competing interestsThe authors declared they have no competing interests.



are psp ftd cbd the different entities

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