Characterizing a neurodegenerative syndrome: primary progressive apraxia of speech

Introduction

Apraxia of speech (AOS) is a disorder of speech motor planning or programming that affects the production of speech (Duffy, 2005; McNeil et al., 2009). Probable synonyms include phonetic disintegration (Alajouanine et al., 1939), cortical dysarthria (Bay, 1962) and aphemia (Cohen et al., 1993). Among the most common clinical characteristics of AOS are slow rate, articulatory distortions, distorted sound substitutions and segmentation of syllables in multisyllabic words or across words. Articulatory groping and trial and error articulatory movements are frequently evident. Its original description and designation as AOS dates back to the 1960s where the term was coined by Darley to specify a disorder of speech that was distinguishable from dysarthria and aphasia (Darley, 1967). AOS is most commonly associated with left hemisphere stroke, and when stroke induced, there is little if any progression of its severity and there is often some improvement over time.

In recent years, we and others have documented the occurrence of AOS in the context of degenerative diseases (Duffy, 2006; Josephs et al., 2006a; Josephs and Duffy, 2008; Deramecourt et al., 2010). Unlike in vascular events, AOS in degenerative diseases is characterized by insidious onset that worsens with time, often culminating in mutism. In degenerative diseases, AOS and aphasia commonly co-occur. In such circumstances, subjects are traditionally diagnosed as having primary progressive aphasia (PPA), in spite of the fact that PPA refers to a disorder of isolated language impairment (Mesulam, 1982, 2001). In addition, AOS can be a component of a more widespread degenerative syndrome, for example, corticobasal syndrome (Bergeron et al., 1996; Boeve et al., 2003; Josephs and Duffy, 2008). In both of these scenarios, AOS is typically relegated to ‘accompanying’ symptom status and its presence and importance is minimized or even ignored. Yet AOS as the initial presentation of neurodegenerative disease, in the absence of aphasia or other motor dysfunction, has been reported in retrospective case reports and case series (Cohen et al., 1993; Broussolle et al., 1996; Josephs et al., 2005, 2006a; Duffy, 2006; Ricci et al., 2008; Deramecourt et al., 2010). Unfortunately, the retrospective nature of these reports has not resulted in general acceptance that AOS can be the dominant or isolated feature of neurodegenerative disease.

The limited recognition of AOS in degenerative disease may be driven by two factors. First, it can be difficult to differentiate AOS from aphasia. Second, even when recognized, it is usually subsumed under a diagnosis of aphasia, or even dysarthria. Unlike dysarthria, which is due to disturbance of the neuromuscular control of speech (Darley et al., 1975), or aphasia which reflects language processing deficits that typically cross language domains (e.g. semantics, syntax, phonology) and modalities (e.g. spoken and written language comprehension and expression) and cannot be attributed to primary motor or sensory deficits (Duffy and McNeil, 2008), AOS is attributable to impaired planning or programming of the movements for speech (Wertz et al., 1984), which results in phonetically and prosodically abnormal speech.

Although AOS and some dysarthria types share some common features (Box 1), they are distinguishable on the basis of several characteristics. For example, dysarthrias are not associated with the distorted sound substitutions or additions, trial and error articulatory groping, or increased difficulty with increased length, complexity or rate that are common in AOS, and AOS is not associated with the strained or hypophonic voice quality, reduced loudness, hypernasality, or rapid/accelerated rate that occur in some dysarthria types, including those that are relevant to this study (spastic and hypokinetic).

AOS is sometimes mistaken as aphasia, especially when phonetic (motor) errors secondary to abnormal motor planning are misconstrued as phonological (linguistic or phonemic) errors. Phonological errors, however, typically do not result in distorted sound production and often occur within utterances that are normal in rate and prosody. It is therefore possible to separate AOS from aphasia, and plausible to predict the existence of a neurodegenerative syndrome in which AOS is the sole or dominant feature.

The aim of this study was to document that AOS, in the absence of aphasia or obvious signs of a prominent motor disorder such as corticobasal syndrome, can be the presenting manifestation of neurodegenerative disease, a clinical presentation we will refer to as primary progressive AOS, or primary progressive apraxia of speech (PPAOS) (Duffy and McNeil, 2008). In addition, we aimed to assess commonalities and variability in the neurological, neurobehavioural, neuropsychological and neuroimaging characteristics of individuals with this syndrome.

Patients and methods

Results

Discussion

In this study, we describe the clinical and imaging features of 12 subjects with a progressive neurological disorder dominated by AOS in the absence of aphasia or other prominent neurological signs. We refer to these subjects as having PPAOS.

Mesulam (1982) first described a series of patients with a progressive loss of language function which he later referred to as PPA (Mesulam, 1987). The diagnosis of PPA requires that for at least the first 2 years the most prominent clinical feature must be difficulty with language (Mesulam, 2003). Importantly, PPA should not include syndromes characterized by ‘pure progressive dysarthria or disruption of the formation of words rather than their use’ (Mesulam, 2003), i.e. AOS. Recently, a consensus panel of experts published a manuscript further dividing PPA into different variants based on the pattern of impaired language (Gorno-Tempini et al., 2011). Three subtypes were recognized: a non-fluent/agrammatic variant that can include AOS; a semantic variant; and a logopenic variant. In order to receive a diagnosis of one of these three variants, however, the subject must first meet criteria for PPA. The 12 subjects reported in this manuscript all had preserved language function and, therefore, did not meet criteria for a diagnosis of PPA. The below average performance on action and letter fluency measures alone are insufficient to diagnose aphasia.

Some researchers have suggested that subjects with AOS should be considered no different from subjects with the non-fluent/agrammatic variant of PPA (Knibb et al., 2009). However, subjects with the non-fluent agrammatic variant of PPA must be aphasic and specifically exhibit agrammatism in verbal and/or written form. Subjects with this PPA variant typically perform poorly on the Western Aphasia Battery fluency measure (Gorno-Tempini et al., 2004). This was not the case for our subjects with PPAOS. We acknowledge that we did not perform specific testing of complex sentence production, for example with the Northwestern Anagram Test (Weintraub et al., 2009), however there was no evidence of agrammatism in their spoken language or in their narrative writing performance, which is a core feature for the diagnosis. In addition, the neuroanatomical pattern of grey and white matter loss found in the current study is different from that reported in the non-fluent/agrammatic variant of PPA as discussed below.

We have suggested that subjects with isolated AOS may represent a pathophysiologically distinct group (Josephs et al., 2006a). Indeed, in comparison with the PPA literature, our subjects with PPAOS were approximately a decade older at average age of onset than subjects with non-fluent/agrammatic aphasia. This age difference was also observed in a recent study that classified subjects on the presence or absence of aphasia and AOS (Rohrer et al., 2010). In fact, only three of our subjects had onset before 65 years. This is important since the pathology of frontotemporal lobar degeneration is as likely as Alzheimer’s disease with onset below age 65 (Ratnavalli et al., 2002), whereas Alzheimer’s disease pathology is much more commonly associated with degenerative syndromes above age 65. We did not, however, find evidence for Alzheimer’s disease on PiB-PET scanning in our subjects with PPAOS, suggesting that PPAOS is a distinct syndrome, pathologically, as well as clinically.

Differentiating PPAOS from the semantic and logopenic variants of PPA is not particularly difficult because no subject’s profile across all of the measures, defined by previous or recent consensus criteria (Neary et al., 1998; Gorno-Tempini et al., 2004, 2011), would meet criteria for the logopenic or semantic dementia subtypes of PPA. The issue of whether our subjects with PPAOS will eventually develop non-fluent/agrammatic aphasia cannot be answered at this time. However, even if some do eventually develop aphasia, which is likely given that PPAOS is a progressive degenerative disease, AOS would still have been the presenting and dominant syndrome during the early-mid course of the disease. In addition, we cannot rule out the possibility that in at least some subjects, aphasia will not emerge at any time during the disease course. In fact, Subject 3 has had illness disease duration of 6 years without emergence of any aphasia. Previous studies have also reported cases where AOS remained isolated, without the development of aphasia, for up to 8–10 years (Tebartz van Elst et al., 2002; Gerstner et al., 2007).

We previously reported an association of AOS with underlying tau pathologies, particularly with 4 repeat (4 R) tau. (Josephs et al., 2005, 2006a). In that study it appeared that subjects with what we now call PPAOS were more likely to have the underlying pathology of progressive supranuclear palsy (Hauw et al., 1994). This association with tau has subsequently been identified by other groups (Deramecourt et al., 2010). It is interesting; however, that neurological examination did not identify more features commonly associated with progressive supranuclear palsy in our subjects with PPAOS, with the exception of Subject 3. This subject had a pure motor speech disorder for 5.5 years before developing eye movement abnormalities suggestive of underlying progressive supranuclear palsy. The fact that this was the only subject with disease duration >5 years, and the fact that four subjects with disease duration of between 4 and 5 years did not show typical clinical features of progressive supranuclear palsy, suggests that progressive supranuclear palsy features may be more likely to emerge at least 5 years into the illness. It remains unclear, however, whether subjects with PPAOS will develop the full blown characteristics of progressive supranuclear palsy, since falls in the first year, a symptom typical of progressive supranuclear palsy, was not reported in any of our 12 subjects with PPAOS and none met criteria for probable progressive supranuclear palsy (Litvan et al., 1996). Interestingly though, Subject 3 had executive dysfunction on neurological testing, with a score of 14 on the Frontal Assessment Battery. Four other subjects had mild executive dysfunction as measured by the Frontal Assessment Battery, although no other subject with PPAOS scored <15. Executive dysfunction, in particular a Frontal Assessment Battery score of <15, has been associated with progressive supranuclear palsy (Paviour et al., 2005).

Three of our subjects (Subjects 6, 7 and 10) had limb apraxia which is a feature of the corticobasal syndrome. However, given that the chief complaint in these subjects was difficulty speaking, the AOS was moderate, Parkinsonism was absent-mild, and dystonia and myoclonus typical of corticobasal syndrome were absent at the time of evaluation, these subjects’ most appropriate diagnosis was PPAOS. Additional abnormalities were noted in these three subjects too, including spastic dysarthria, poorer performance on the Trail Making Test A, a measure of processing speed, and Frontal Assessment Battery a measure of executive dysfunction suggesting the evolution of corticobasal syndrome features in these three subjects. It should be noted though that the underlying pathology in these subjects could be progressive supranuclear palsy, since limb apraxia was previously reported in subjects with AOS and progressive supranuclear palsy pathology (Josephs et al., 2006a). This would be in keeping with the fact that while only about half of subjects with corticobasal syndrome have corticobasal degeneration pathology (Josephs et al., 2006b; Ling et al., 2010; Lee et al., 2011), many also have progressive supranuclear palsy pathology (Josephs et al., 2006b; Ling et al., 2010; Lee et al., 2011). Regardless, the evidence indirectly suggests that the underlying pathology associated with PPAOS is likely to be tau, either progressive supranuclear palsy or corticobasal degeneration (Josephs et al., 2006a; Josephs and Duffy, 2008; Deramecourt et al., 2010). The absence of family history in all our subjects argues against progranulin gene mutation as a cause of PPAOS and the impending corticobasal syndrome; not surprising since progranulin gene mutations appear to be associated with aphasia (Mesulam et al., 2007), and are not associated with tau pathology (Mackenzie, 2007).

Findings from the neuropsychological tests suggest that PPAOS is a relatively focal neurodegenerative syndrome. Similar to neuropsychological findings in the three variants of PPA (Gorno-Tempini et al., 2004), we also did not find consistent evidence of visuospatial or visuoperceptual deficits in PPAOS. We did find some evidence for executive dysfunction consistent with the neurological examination. Executive dysfunction appeared to be more common in the subjects with PPAOS with longer disease duration. However, executive dysfunction is not only observed in PPAOS but has also been identified in subjects with the non-fluent/agrammatic variant of PPA (Gorno-Tempini et al., 2004). Other cognitive deficits were absent in PPAOS that differs from the other PPA variants. For example, there was no evidence for memory loss or poor calculation skills, which occur in the logopenic aphasia variant of PPA. The preservation of facial recognition in PPAOS also differentiates it from the semantic variant of PPA (Warrington, 1975; Neary et al., 1998; Snowden et al., 2004; Josephs et al., 2008).

Mild functional decline as measured by the Clinical Dementia Rating scale was observed in only one subject at the time of evaluation. This is not to say that there is no functional impairment in subjects with PPAOS. The Clinical Dementia Rating scale is a metric that was designed to assess functional decline in subjects with episodic memory loss and Alzheimer’s disease (Hughes et al., 1982). There is no assessment of function related to speech on the Clinical Dementia Rating scale and even the modified Clinical Dementia Rating scale (Knopman et al., 2008) is inadequate to assess function related to motor speech impairment. Mild neurobehavioural abnormalities were noted in three subjects suggesting that neurobehavioural changes were not a typical feature of PPAOS and did not affect functional status.

We previously reported that subjects with prominent AOS showed a pattern of grey matter loss affecting the posterior superior frontal and supplementary motor areas while those with non-fluent aphasia had more involvement of the posterior inferior frontal or Broca’s area (Josephs et al., 2006a). In keeping with that retrospective study, the subjects with PPAOS in this prospective study had a very focal pattern of grey matter atrophy affecting the lateral premotor and supplementary motor area. An almost identical pattern was observed with fluorodeoxyglucose-PET, with hypometabolism in premotor and supplementary motor areas. Both analyses therefore point towards the premotor cortex as the neuroanatomical correlate of PPAOS. There was no evidence for unilateral involvement in these regions at the group-level, although we did observe asymmetry in some subjects with PPAOS. However, while cases with right-dominant atrophy and hypometabolism were observed, the majority did show greater involvement of the left hemisphere. Involvement of the premotor region of the frontal lobe would account for the findings of executive dysfunction in some of the subjects with PPAOS, as well as the poor performance on the action and letter fluency tests. In fact, these measures have been shown to be associated with frontal lobe pathology, including premotor cortex (Weiss et al., 2004).

We did not find any involvement of the insula cortex, a region that has been associated with AOS in vascular insults (Dronkers, 1996). The insular cortex, as well as the inferior frontal (superior opercular) area has been associated with non-fluent/agrammatic aphasia (Abe et al., 1997; Gorno-Tempini et al., 2004; Grossman et al., 2004). However, none of these regions were affected in our group analysis, nor did we see involvement of these areas on the cortex ID analysis of the fluorodeoxyglucose-PET scan for each individual subject.

The voxel-based morphometry analysis of white matter volume showed a more widespread pattern of loss than observed with grey matter volume. Similar to the grey matter analysis, the lateral premotor and supplementary motor area white matter was affected. However, white matter volume loss was also observed extending down into inferior premotor cortex and mid corpus callosum. These regions were also found to be abnormal with our diffusion tensor imaging analysis, a more sensitive and specific technique for assessing white matter tract pathology. The diffusion tensor imaging analysis showed degeneration of the body of the corpus callosum and the superior longitudinal fasciculus, particularly in regions of the premotor cortex with degeneration observed in fibres extending into the inferior, middle and superior frontal gyri. While no previous diffusion tensor imaging studies have assessed PPAOS, degeneration of the body of the corpus callosum and superior longitudinal fasciculus have been observed in progressive supranuclear palsy (Whitwell et al., 2011a). This association between PPAOS and premotor cortex is biologically plausible as the premotor area is believed to be involved with motor programming. This is remarkable given that AOS was postulated to be a disorder of programming by Darley when first described in the 1960s (Darley, 1967).

The fact that white matter volume loss was more extensive than grey matter volume loss raises the possibility that white matter loss may actually precede grey matter loss, as opposed to white matter loss occurring via Wallerian degeneration. White matter degeneration could be directly related to the deposition of tau. The finding of only white matter loss in the inferior frontal lobe, in the absence of aphasia, suggests that grey matter loss in this region may be necessary for the development of aphasia. Non-fluent/agrammatic aphasia has indeed been linked to grey matter loss of the inferior premotor area (Abe et al., 1997; Gorno-Tempini et al., 2004; Grossman et al., 2004; Whitwell et al., 2010). The presence of white matter volume loss in this region would support the suggestion that some of these subjects will later develop aphasia, presumably as a result of subsequent grey matter involvement. Longitudinal studies will be needed to test this hypothesis.

We do not have autopsy diagnosis in any of these 12 subjects with PPAOS. However, the PiB-PET results in our subjects is evidence that amyloid deposition is unlikely to be the aetiology underlying PPAOS similar to the non-fluent/agrammatic and semantic variants of PPA (Rabinovici et al., 2008). Only one of our 12 subjects was considered PiB-positive and even in this subject it is unclear whether amyloid is playing any direct role in PPAOS. This subject was relatively old (age 76) at the time of the scan and her fluorodeoxyglucose-PET scan was not entirely typical of Alzheimer’s disease, with minimally less frontal than parietal/temporal hypometabolism that was more prominent on the right but with sparing of the posterior cingulate gyrus (Foster et al., 2008). It is therefore possible that this subject has diffuse amyloid that is characteristic of ageing and unrelated to her PPAOS. Previous reports have shown that the PiB amyloid ligand does indeed bind to diffuse plaques (Burack et al., 2010; Whitwell et al., 2010). The currently accepted criteria for a positive PiB-PET scan is also based on information gained from typical Alzheimer’s dementia subjects and, therefore, may not generalize to PPAOS.

A syndrome of motor speech impairment in the absence of aphasia exists that we refer to as PPAOS. It is a relatively homogeneous syndrome, and should be diagnosed when AOS is the sole or predominant presenting sign, especially when the subject’s chief complaint is one of progressive speech impairment. Additional neurological, neuropsychological and neurobehavioural deficits are typically absent, especially early in the disease course. In some instances, however, especially later in the disease course, other cognitive, behavioural and motor signs may become evident, as would be expected, given that PPAOS is a neurodegenerative disorder. The primary neuroanatomical correlate of PPAOS appears to be the superior and mid premotor cortex. The underlying histopathology is unlikely to be amyloid related; the evidence points more towards tau.

Funding

NIH grant R01 DC010367 from the National Institute of Deafness and Other Communication Disorders.

Supplementary material

Supplementary material is available at Brain online.