Elsevier

Cortex

Volume 69, August 2015, Pages 220-236
Cortex

Research report
Classification and clinicoradiologic features of primary progressive aphasia (PPA) and apraxia of speech

https://doi.org/10.1016/j.cortex.2015.05.013Get rights and content

Abstract

The consensus criteria for the diagnosis and classification of primary progressive aphasia (PPA) have served as an important tool in studying this group of disorders. However, a large proportion of patients remain unclassifiable whilst others simultaneously meet criteria for multiple subtypes. We prospectively evaluated a large cohort of patients with degenerative aphasia and/or apraxia of speech using multidisciplinary clinical assessments and multimodal imaging. Blinded diagnoses were made using operational definitions with important differences compared to the consensus criteria. Of the 130 included patients, 40 were diagnosed with progressive apraxia of speech (PAOS), 12 with progressive agrammatic aphasia, 9 with semantic dementia, 52 with logopenic progressive aphasia, and 4 with progressive fluent aphasia, while 13 were unclassified. The PAOS and progressive fluent aphasia groups were least impaired. Performance on repetition and sentence comprehension was especially poor in the logopenic group. The semantic and progressive fluent aphasia groups had prominent anomia, but only semantic subjects had loss of word meaning and object knowledge. Distinct patterns of grey matter loss and white matter changes were found in all groups compared to controls. PAOS subjects had bilateral frontal grey matter loss, including the premotor and supplementary motor areas, and bilateral frontal white matter involvement. The agrammatic group had more widespread, predominantly left sided grey matter loss and white matter abnormalities. Semantic subjects had bitemporal grey matter loss and white matter changes, including the uncinate and inferior occipitofrontal fasciculi, whereas progressive fluent subjects only had left sided temporal involvement. Logopenic subjects had diffuse and bilateral grey matter loss and diffusion tensor abnormalities, maximal in the posterior temporal region. A diagnosis of logopenic aphasia was strongly associated with being amyloid positive (46/52 positive). Our findings support consideration of an alternative way of identifying and categorizing subtypes of degenerative speech and language disorders.

Introduction

Over the last three decades, the diagnostic criteria for, and classification of, neurodegenerative speech and language disorders have been evolving. That the impairment of language may be the only or predominant feature of a degenerative neurologic disease was recognized more than a century ago by Pick and Dejerine and Serieux (Déjerine and Sérieux, 1897, Pick, 1892, Serieux, 1893). A few case reports followed, but only in the latter half of the century did our understanding of degenerative speech and language disorders begin to deepen. In the 1970s, Warrington and colleagues described a series of patients with anomia, loss of word meaning and ‘visual associative agnosia’ (Warrington, 1975). In 1977 Wechsler described a case of presenile dementia with aphasia as the most prominent feature for the first few years of illness (Wechsler, 1977). In 1982, Mesulam reported a series of patients who had a selective and insidiously progressive disruption of spoken language (Mesulam, 1982). A series of similar case reports followed and, in 1987 the term ‘primary progressive aphasia’ (PPA) was coined (Mesulam, 1987).

Around this time, frontotemporal dementia was becoming increasingly recognized as a degenerative dementia distinct from Alzheimer's disease (Neary, Snowden, Northen, & Goulding, 1988), as were other forms of ‘lobar atrophy’ (Neary, 1990). Early classifications of ‘asymmetric cortical degenerations’ included ‘progressive aphasia’, which was divided into ‘nonfluent’ and ‘fluent’ variants (Caselli and Jack, 1992, Neary et al., 1993). Early criteria for frontotemporal dementia did not include a language variant (Englund et al., 1994, Kumar and Gottlieb, 1993), but did include speech and language dysfunction as co-existing or supportive findings. In 1989, the term ‘semantic dementia’ was applied to three patients who presented with profound language impairment characterized by marked anomia and loss of word meaning, loss of person and object knowledge, and fluent and syntactically correct speech, a disorder likened to that described by Warrington and colleagues (Baxter and Warrington, 1987, McCarthy and Warrington, 1986, Snowden et al., 1989). This syndrome was further refined by Hodges et al. in 1992, as was the underlying pathology, with asymmetric, bilateral temporal pole atrophy noted in most cases (Hodges, Patterson, Oxbury, & Funnell, 1992).

It was against this backdrop that the first set of codified criteria for PPA emerged, first in the form of consensus criteria for frontotemporal dementia proposed in 1998 (Neary et al., 1998), which included ‘progressive nonfluent aphasia’ and ‘semantic aphasia and associative agnosia’ as subtypes, followed by Mesulam's criteria for PPA in 2001 (Mesulam, 2001), which included ‘PPA with agrammatism’ and ‘PPA with comprehension (verbal semantics) deficits’. Shortly thereafter, the spectrum was expanded to the three main syndromes, with the addition of logopenic aphasia (Gorno-Tempini et al., 2004).

While these criteria served the important purpose of providing diagnostic guidelines and facilitated comparisons among studies by different investigators, several areas of diagnostic uncertainty emerged. First, no clear consensus regarding the basis for the fluency-nonfluency distinction exists, with some emphasizing reduced output and telegraphic speech, and others stressing the presence of ‘hesitant, effortful production’ as markers for nonfluency (Gorno-Tempini et al., 2004, Kertesz et al., 2003, Mesulam, 2001, Neary et al., 1998). Some patients with motor speech disorders, such as apraxia of speech, met the nonfluency criterion when the latter was emphasized, despite the fact that they did not meet the ‘core’ PPA criterion for aphasia (Didic et al., 1998, Mesulam, 2001, Nestor et al., 2003). In addition, some patients were designated as nonfluent by some investigators on the basis of word finding pauses and hesitancy that resulted in a reduced speaking rate (Mesulam, Wieneke, et al., 2009).

Another matter of disagreement or uncertainty was the degree of overlap between ‘semantic dementia’ and ‘PPA with comprehension (verbal semantics) deficits’ (Adlam et al., 2006, Kertesz et al., 2003, Mesulam et al., 2003, Neary et al., 1998). The 1998 consensus criteria required the presence of an ‘associative agnosia’ as evidence for involvement beyond the language system. This seemed to contradict the requirement by Mesulam's criteria that aphasia must be the dominant and most debilitating feature of the disease, and that it was the verbal ‘access’ to semantic knowledge that was impaired rather than semantic memory itself (Mesulam, 2001). As such, two opposing views emerged (Adlam et al., 2006). One regarded semantic dementia and the semantic variant of PPA as one disease, possibly at different stages (Kertesz et al., 2003), caused by disruption of the amodal semantic memory system secondary to bilateral temporal pathology (Hodges et al., 1992, Patterson and Hodges, 2000, Rogers et al., 2004). The other hypothesized that there were two systems involved in semantic dementia – the left sided language network and the bilateral temporal network for face/object knowledge – and that semantic variant PPA represented a selective disruption of the former (Gorno-Tempini et al., 2004, Mesulam, 2001, Mesulam et al., 2003, Sonty et al., 2003). The validity of the logopenic subtype was also questioned, as it was unclear whether or not it was simply a label for patients who did not meet criteria for either of the other two subtypes (Knibb, Xuereb, Patterson, & Hodges, 2006).

Despite advances following publication of these early sets of criteria, no classification scheme was universally accepted. Several groups subsequently proposed classifications that sought to address shortcomings of the early frontotemporal dementia and PPA criteria (Josephs et al., 2010, Josephs, Duffy, et al., 2006, Kertesz et al., 2003, Knibb et al., 2006, Mesulam, Wieneke, et al., 2009, Rabinovici et al., 2008), but none were widely adopted.

In 2011, the first consensus set of criteria for the diagnosis and classification of PPA was published. It formally recognized the logopenic variant, clarified the relationship between the semantic variant of PPA and semantic dementia, and made no assumptions regarding the underlying pathology (Gorno-Tempini et al., 2011). Furthermore, strict inclusion and exclusion criteria for PPA were proposed, in order to exclude other conditions that may result in prominent language impairment without it being the first or dominant feature (Gorno-Tempini et al., 2011, Mesulam, 2001, Mesulam, 2003).

The consensus criteria served to guide the diagnosis of PPA and its subtypes, and represented a marked improvement over the plethora of diagnostic schemes that existed prior to its publication. Nonetheless, several issues persist. For example, a large proportion of patients remain unclassifiable, and some patients simultaneously meet criteria for more than one subtype (Harris et al., 2013, Mesulam et al., 2012, Sajjadi et al., 2012, Wicklund et al., 2014). Variable interpretations of ‘nonfluency’ also persist, as does the uncertainty regarding the relationship between progressive motor speech disorders and PPA. Recently, some groups have used modified versions of the consensus criteria, and have suggested changes to make the criteria more inclusive (Mesulam, 2013, Mesulam and Weintraub, 2014, Sajjadi et al., 2014).

Over the past 4 years, we have prospectively evaluated patients with degenerative speech and language disorders with detailed, multidisciplinary clinical assessments and multimodal imaging with one goal of better characterizing and classifying the spectrum of disorders. In this paper, we present our operational definitions for the diagnosis of PPA and progressive apraxia of speech (PAOS), which have been modified somewhat from our previously published definitions (Josephs et al., 2010, Josephs, Duffy, et al., 2006). Although there is a large degree of overlap with the existing consensus criteria (Gorno-Tempini et al., 2011), there are important differences. We present several lines of evidence as justification for this classification, including speech and language data, volumetric and diffusion tensor imaging findings and data regarding the proportion of cases with probable underlying Alzheimer's pathology through amyloid imaging. As well as advancing our understanding of PPA and PAOS, our findings support consideration of an alternative classification, and highlight modifications that may be needed to resolve some of the issues that have emerged with the consensus criteria.

Section snippets

Subjects

Between July 2010 and October 2013 we prospectively evaluated a large cohort of patients with aphasia and/or apraxia of speech presumed to be due to a degenerative etiology. Patients were eligible for inclusion if they were over the age of 18, had English as their primary language and had an informant. Patients were excluded if they had a coexisting or alternative degenerative diagnosis, such as Alzheimer's disease (Albert et al., 2011, Dubois et al., 2014, McKhann et al., 1984, McKhann et al.,

Demographics

A total of 130 patients were included. Forty were diagnosed with PAOS, twelve with progressive agrammatic aphasia, nine with semantic dementia, fifty-two with logopenic progressive aphasia and four with progressive fluent aphasia. Thirteen patients did not meet criteria for any specific subtype (PPA-Unclassified). Subject demographics are shown in Table 2.

The majority of patients were right handed, but there were eleven left-handed patients and two ambidextrous patients. The distribution of

Discussion

Based on a large cohort of prospectively recruited patients, our data show that the syndromes as we have classified for this study show specific patterns of grey and white matter loss. Using amyloid imaging, the data also show the proportion of cases in each syndrome with probable underlying Alzheimer's pathology. The operational definitions presented here evolved from our prior definitions, used over the course of several years of studying a large, prospectively recruited group of patients

Conclusions

We have presented an alternative way of identifying and categorizing subtypes of degenerative speech and language disorders, and showed that this classification results in distinct clinical and radiologic syndromes. Our findings may help guide modifications to existing criteria. The strengths of the study include the large group of prospectively recruited patients, standardized evaluation by a multidisciplinary team, multimodal imaging and the blinded consensus categorization of patients. The

Funding

This study was funded by R01 DC010367 (PI KAJ) from the National Institute on Deafness and Communication Disorders.

Acknowledgments

The authors would like to thank Drs. Ahlskog, Boeve, Bower, Drubach, Knopman and Petersen for subject referral and Mrs. Sarah Boland, Mayo Clinic Rochester, MN, for performing the neuropsychometric testing and organizing all subjects test schedules.

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