Differential diagnosis of primary progressive aphasia ...

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Aphasiology Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/paph20

Differential diagnosis of primary progressive aphasia variants using the international criteria ab

Cristian E. Leyton a

ab

& John R. Hodges

Neuroscience Research Australia, Randwick, NSW, Australia

b

ARC Centre of Excellence in Cognition and Its Disorders, North Ryde, NSW, Australia Published online: 03 Jan 2014.

To cite this article: Cristian E. Leyton & John R. Hodges (2014): Differential diagnosis of primary progressive aphasia variants using the international criteria, Aphasiology, DOI: 10.1080/02687038.2013.869306 To link to this article: http://dx.doi.org/10.1080/02687038.2013.869306

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Aphasiology, 2014 http://dx.doi.org/10.1080/02687038.2013.869306

REVIEW

Differential diagnosis of primary progressive aphasia variants using the international criteria Cristian E. Leyton1,2 and John R. Hodges1,2 1

Neuroscience Research Australia, Randwick, NSW, Australia ARC Centre of Excellence in Cognition and Its Disorders, North Ryde, NSW, Australia

Downloaded by [UNSW Library] at 16:31 20 July 2014

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Background: Based upon the profile linguistic and speech deficits, the current International Criteria for diagnosis and classification of primary progressive aphasia (PPA) suggest the distinction of semantic, nonfluent/agrammatic and logopenic variants, each of which is commonly associated with specific pathology and distribution of brain atrophy. Although the vast majority of cases fit in this tripartite schema, some cases remain unclassifiable because of the presence of overlapping deficits, or conversely, because of the presence of isolated deficits. Aims: In this review, we describe relevant clinical features that characterise each variant and discuss emerging issues derived from the application of the International Criteria. Main Contribution: Based on a hierarchical approach that comprises the evaluation of single-word comprehension, motor speech disorder, agrammatism and sentence repetition, we propose a heuristic solution aimed to reduce the number of cases with ambiguous identification and thereby optimise the application of the current International Criteria. Conclusions: Despite the clinical heterogeneity of cases with PPA, the current International Criteria, together with the proposed heuristic solution, provide a valid framework into which the vast majority of cases can be classified. The development of robust clinical markers aimed to distinguish cases with motor speech disorders from those with logopenic variant remains clinically challenging. Keywords: Primary progressive aphasia; Semantic variant; Logopenic variant; Nonfluent/agrammatic variant.

EVOLUTION OF THE CONCEPT OF PPA Patients with what we now term primary progressive aphasia (PPA) were first described over a century ago when Arnold Pick reported cases with predominant language impairment due to unspecific brain atrophy (Pick, 1892, 1904). In his landmark paper, “On the symptomatology of left-sided temporal lobe atrophy”, Pick described three cases, with what corresponds to what was later termed semantic Address correspondence to: Cristian E. Leyton, Neuroscience Research Australia, Barker Street, Randwick, NSW 2031, Australia. E-mail: [email protected] © 2014 Taylor & Francis


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dementia, characterised by striking memory loss for names (amnesic aphasia) that culminated in almost complete loss of speech accompanied by changes in personality. After a number of reports in the first two decades of twentieth century, interest faded until the 1980s when Mesulam reported six cases with slowly progressive aphasia without generalised dementia (Mesulam, 1982). In his first formulation, Mesulam proposed that PPA patients should present with aphasia as the predominant cognitive deficit with no other behavioural symptom or cognitive deficits for at least 2 years, and no pathological condition other than neurodegeneration should explain the deficits (Mesulam, 2001, 2003). Mesulam conceptualised this condition, as a language-based disorder, is clinically and pathologically different from Alzheimer’s disease. As the number of reports increased over the next two decades, it became evident that the term PPA was being applied to a wide spectrum of cases with deficits that mirrored the classic dichotomy of “fluent” versus “nonfluent” aphasia (Hodges & Patterson, 1996; Kertesz, Davidson, McCabe, Takagi, & Munoz, 2003; Kertesz, Hudson, Mackenzie, & Munoz, 1994; Knibb, Xuereb, Patterson, & Hodges, 2006; Snowden, Neary, Mann, Goulding, & Testa, 1992; Tyrrell, Warrington, Frackowiak, & Rossor, 1990). Some patients with “fluent” aphasia had, in fact, been described in the parallel cognitive neuropsychology literature as patients with “amnesic aphasia” and associative agnosia. Warrington (1975) suggested that these deficits were a reflection of breakdown of a common cognitive system, namely disintegration of semantic memory. The label semantic dementia was introduced by Snowden, Goulding, and Neary (1989) to reflect both the semantic deficit and the progressive nature of the disorder. The syndrome was more fully characterised by Hodges and colleagues, who defined its core features and drew attention to the consistent anterior temporal lobe atrophy (Hodges & Patterson, 1996; Hodges, Patterson, Oxbury, & Funnell, 1992; Hodges, Patterson, & Tyler, 1994) The remaining PPA cases displayed a wide range of disturbances, including effortful and halting speech, distorted articulation, prosodic changes, phonological errors, oversimplification of linguistic structures or frank agrammatism, which were altogether lumped within the spectrum of “nonfluent presentation” (Ash et al., 2009; Knibb et al., 2006; Ogar, Dronkers, Brambati, Miller, & Gorno-Tempini, 2007; Rohrer, Rossor, & Warren, 2010b; Turner, Kenyon, Trojanowski, Gonatas, & Grossman, 1996; Wilson et al., 2010b). Given the range of these disturbances, it proved impossible to conceptualise the myriad of manifestations seen in non-semantic cases as a result of the impairment of a single core cognitive system. Instead, different aspects were emphasised; while some authorities focused on the impaired capacity of planning or programming movements for speech, which results in apraxia of speech (Duffy, 2006; Ogar et al., 2007; Rohrer, Rossor, & Warren, 2010a), others drew their attention to the breakdown of syntactic (grammatical) components of speech as key language symptoms (Grossman, 2012; Grossman et al., 1996; Gunawardena et al., 2010; Mesulam et al., 2009). The discrepancy among experts reflects not only the heterogeneity of non-semantic patients, but also the relative ignorance about the key mechanisms responsible for nonfluency. As such, it was clear that pooling non-semantic cases under the rubric of nonfluency represented an oversimplification of the reality. Efforts to divide the non-semantic cases into robust sub-syndromes were unsuccessful until Gorno-Tempini, Dronkers, et al. (2004) published an

DIFFERENTIAL DIAGNOSIS OF PPA

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important paper that defined a third variant of PPA comprised of patients who had been previously forced largely into the “nonfluent” category. Patients with this logopenic variant have frequent word-finding pauses with hesitations that interrupt the flow of conversation and give their speech a nonfluent quality, coupled with, less consistently, the production of phonological errors. But, unlike other non-semantic patients, those with logopenic aphasia have neither apraxia of speech nor agrammatism. Like patients with semantic dementia; however, they are anomic but do not have the impaired word comprehension that typifies semantic cases.


THE INTERNATIONAL CRITERIA Progress in the clinical characterisation and the development of sophisticated structural brain imaging technologies, together with improved neuropathological characterisation of the protein inclusions underlying dementia syndromes, demanded a common framework which was achieved by the formulation of the international criteria for diagnosis and classification of PPA (hereafter, for the sake of brevity called International Consensus Criteria, ICC) (Gorno-Tempini et al., 2011). In brief, the ICC proposes a two-step diagnostic process. Based on Mesulam’s definition, the diagnosis of PPA should be first established. Then, based on the presence or absence of core speech and language deficits shown in Table 1, each case is classified into any of three proposed variants: semantic (sv-PPA), nonfluent/agrammatic (nfv-PPA) and logopenic variant (lv-PPA).

TABLE 1 Summary of international recommendations for the diagnosis and classification of PPA Primary progressive aphasia (PPA) Most prominent clinical feature is a difficulty with language (word-finding deficits, paraphasias, effortful speech, grammatical and/or comprehension deficits). Aphasia should be the most prominent deficit at symptom onset and for the initial phases of the disease (other prominent symptoms, such as behavioural, memory, or visuospatial impairments should not be present at the onset). No other conditions that may be better account for the language deficits are present (i.e., non-degenerative or psychiatric conditions). Semantic variant Poor confrontation naming and impaired single-word comprehension, explained by dissolution of semantic knowledge. No motor speech disorders or agrammatism. Nonfluent/agrammatic variant Either agrammatism or motor speech disorders with effortful, halting speech, inconsistent sound errors and distortions. Spared single-word comprehension and object knowledge. Logopenic variant Impaired single-word retrieval in spontaneous speech (speech fluency interrupted by word finding pauses) and confrontational naming; and impaired repetition of sentences and phrases. Spared single-word comprehension and absence of motor speech disorders. Taken from Gorno-Tempini et al. (2011).

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CLINICAL AND LINGUISTIC FEATURES


Semantic variant The semantic variant, also known as semantic dementia, is the most thoroughly defined and consistent PPA syndrome. According to ICC, anomia and impaired single-word comprehension are the core deficits, both essential for diagnosis. Although naming problems are present in other variants of PPA and in other neurodegenerative conditions causing aphasia, this disturbance in the semantic variant is severe, particularly when it is compared to the relative sparing of other language domains. Errors are typically semantic in nature (“dog” for “kangaroo”) and modulated by familiarity and prototypicality. In the same way, single-word comprehension is substantially impaired, especially for low-frequency items (e.g., production and comprehension of “zebra” versus the more familiar/frequent “cat”) (Hodges et al., 1992, 1994). Poor comprehension of single words is usually the earliest and most obvious manifestation of a widespread semantic memory deficit that causes impairments in object, people and music recognition when knowledge is tested by presenting stimuli in other modalities of input such as visual (pictorial representations and real objects), tactile, olfactory, auditory (sounds and music) and gustatory (Adlam et al., 2006; Bozeat, Lambon Ralph, Patterson, Garrard, & Hodges, 2000; Hsieh, Hornberger, Piguet, & Hodges, 2011). Semantic deficits are usually global, involving virtually all categories (i.e., tools, animals, people), although some patients show greater impairment of person knowledge (Evans, Heggs, Antoun, & Hodges, 1995; Gainotti, 2007). These cases are usually associated with greater right temporal atrophy and early behavioural changes, such as loss of empathy and compulsions (Chan et al., 2009; Gorno-Tempini, Rankin, et al., 2004). Surface dyslexia and dysgraphia are features of the semantic variant and refer to impairment in reading and writing words with “irregular” or atypical relationship between spelling and pronunciation (Wilson et al., 2009). Patients typically “regularise” such words, so that “sew” is read as /su:/ and “pint” to rhyme with “hint”. Sparing of single-word repetition and motor speech, even when semantic deficits are prominent, are the other two core features. Although language production is usually grammatically accurate, it can, at times, contain some “paragrammatic” errors such as substituting less appropriate closed-class words or inflections, for instance, “I know what they’re doing but I can’t think the words what they’re doing” (Meteyard & Patterson, 2009). Patients with the semantic variant of PPA demonstrate consistent bilateral, but often markedly left-sided, atrophy involving the anterior temporal lobes, notably the polar and perirhinal cortices (Davies, Halliday, Xuereb, Kril, & Hodges, 2009; Rohrer et al., 2009). The majority show inclusions of TAR-DNA binding protein (TDP-43) (Hodges et al., 2010).

Nonfluent/agrammatic variant Agrammatism in language production and effortful speech attributed to motor speech disorders are the core criteria, and at least one should be present. The most common disturbance, and often the initial sign of the disease, is an articulationplanning deficit, i.e., apraxia of speech (Gorno-Tempini, Dronkers, et al., 2004; Josephs et al., 2006). Patients with apraxia of speech typically make articulatory



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errors consisting of distortions of speech sounds, of which they are often aware. Prosody is disrupted, leading to segmentation of words or sentences and markedly reduced rate of speech (Gorno-Tempini, Murray, Rankin, Weiner, & Miller, 2004; Ogar et al., 2007). Agrammatism typically consists of errors in word arrangement (syntax), inflection (morphology) or omission of grammatical structures, such as prepositions, determiners and auxiliary verbs, which leads to oversimplification of language. Effortful speech and production errors can be the first symptoms of nfvPPA, even before clear apraxia of speech or agrammatic errors occur. In these cases, a written language production test (such as a written description of a picture) or syntax comprehension tasks can often reveal early grammatical errors. At least two of three other features shown in Table 1 should also be present. Deficits in syntax comprehension are evidenced by impairment in sentence comprehension, initially only for most difficult syntactic constructions, such as negative passives and object relative clauses (e.g., “The car that the truck hit was green”) (Gorno-Tempini, Dronkers, et al., 2004; Grossman et al., 1996; Hodges & Patterson, 1996; Peelle, Cooke, Moore, Vesely, & Grossman, 2007). Single-word comprehension and object knowledge should be spared in nfv-PPA, while performance on sentence comprehension, which can also be impaired in lv-PPA, is clearly influenced by the grammatical complexity of the sentence rather than limited phonological short-term memory. It is important to distinguish patients with nfv-PPA onset from those with corticobasal degeneration or progressive supranuclear palsy onset. Even though these syndromes may eventually merge in an individual (Kertesz, McMonagle, Blair, Davidson, & Munoz, 2005), the clinical diagnosis of nfv-PPA should be limited to patients who do not present with a prominent motor syndrome, such as generalised rigidity or tremor. Imaging changes in nfv-PPA cases are much less consistent than in sv-PPA cases and involve atrophy in the left inferior frontal region (Broca’s area), anterior insula and the temporo-parietal junction (Gorno-Tempini, Dronkers, et al., 2004; Mesulam et al., 2009; Nestor et al., 2003; Rohrer et al., 2009; Schroeter, Raczka, Neumann, & Yves von Cramon, 2007). Neuropathological studies reveal that while many nfv-PPA individuals have frontotemporal lobar degeneration with tau-positive inclusions (FTLD-tau), a significant minority show changes characteristic of Alzheimer’s disease (Grossman, 2010; Knibb et al., 2006). Nevertheless, those with apraxia of speech show a strong association with FTLD-tau pathology (Josephs et al., 2006).

Logopenic variant Impairments in word retrieval (in spontaneous speech and confrontation naming) and sentence repetition are the core deficits of the logopenic variant. Spontaneous speech is characterised by slow rate, with frequent pauses and false starts due to significant word-finding problems, but there is no frank agrammatism. Speech production is, therefore, distinct from that seen in patients with nfv-PPA, who also speak in a slow and halting manner, but with output that is dysprosodic and marked by motor speech errors and/or agrammatism (Ash et al., 2009; Gorno-Tempini et al., 2008; Grossman et al., 1996). The confrontation naming impairment in lv-PPA may be as severe as that in the semantic variant, but errors are usually phonological, don’t knows, or circumlocutions rather than semantic, coordinate and superordinate errors seen in sv-PPA (Gorno-Tempini, Dronkers, et al., 2004; Leyton et al., 2011). Another


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key differentiating feature between these two variants is the sparing of single-word comprehension in logopenic patients (Leyton et al., 2011; Mesulam, Wieneke, Thompson, Rogalski, & Weintraub, 2012). In contrast to single-word repetition, which is largely spared, sentence and phrase repetition is severely impaired in almost all patients (Leyton et al., 2011), suggesting that a reduction of phonological shortterm memory plays a role in some of the language symptoms of lv-PPA (GornoTempini et al., 2008; Leyton, Piguet, Savage, Burrell, & Hodges, 2012). As such, sentence repetition is often impaired because some words are omitted or replaced with a similar one. For instance, instead of repeating, “The Chinese fan contained the rare emerald”, the patient may say, “The Chinese fan contained…” or “The Chinese fan had an emerald”. The same mechanism can cause impairment in sentence comprehension, which is influenced more by the length and familiarity than by the grammatical complexity of the given sentence. Hence, performance on tests of syntactic comprehension, such as the test for reception of grammar (TROG) (Bishop, 1989) does not differentiate lv-PPA from nfv-PPA (Leyton, personal communication, 2013). Other diagnostic features include phonological paraphasias that can be present during spontaneous speech, naming and sentence repetition. These errors are characterised by substitution, addition or deletion of well-articulated phonemic segments that reflect a disorder of the selection and ordering of the target word form. There have been descriptions of cases with extremely frequent phonological substitutions which lead to the production of inappropriate words or neologisms, resembling cases with phonological jargon aphasia (Caffarra et al., 2013; Rohrer, Rossor, & Warren, 2009). Although the distinction between lv-PPA and nfv-PPA is not always easy, the lack of frank agrammatic errors and preservation of articulation and prosody help distinguish the logopenic from the nonfluent variants (Wilson et al., 2010b). Although not mentioned in the ICC, we have observed a few lv-PPA cases with a type of dyslexia, where the reading problems are characterised by the relative facility of reading short over long words and the use of letter-by-letter reading rather than reading the whole word as a single entity. This deficit has been described in cases with posterior cortical atrophy and could account for a nosological continuum of both atypical Alzheimer’s disease presentations (Crutch, Lehmann, Warren, & Rohrer, 2013; Magnin et al., 2013). Imaging of cases with logopenic aphasia reveals a pattern of brain atrophy focused on the left temporo-parietal junction (Gorno-Tempini, Dronkers, et al., 2004), but the extensive involvement of the left parietal and temporal cortices, including precuneus, is a often encountered (Leyton et al., 2012; Rohrer et al., 2009). Gorno-Tempini, Dronkers, et al. (2004) hypothesised that lv-PPA cases might have Alzheimer’s disease as the underlying pathology. This hypothesis has been supported by imaging studies using the amyloid-binding ligand PiB (Leyton et al., 2011; Rabinovici et al., 2008) and by a limited number of post-mortem studies (Mesulam et al., 2008; Rohrer, Rossor, & Warren, 2012). Despite having the same pathological changes, cases with the logopenic variants have higher pathological burden (Gefen et al., 2012) and more rapid decline (Hsieh, Hodges, Leyton, & Mioshi, 2012) than cases with the typical presentation.

APPLICATION OF THE ICC As Table 2 shows, the systematic application of ICC has demonstrated that each variant displays a characteristic speech and language profile that allows the


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TABLE 2 Pattern of linguistic alterations in PPA variants Clinical variant Feature Phonetic errors Phonological errors Agrammatism Anomia Single-word comprehension Single-word repetition Sentence comprehension Sentence repetition Surface dyslexia

Semantic

Nonfluent/agrammatic

Logopenic

– – – +++ +++ – −/+ −/+ +++

++ + ++ + – +++ ++ ++ –

– ++ −/+ ++ −/+ + +++ +++ –


Present in >80% of cases (+++); 80–50% (++); 50–20 (+);