East Asian Arch Psychiatry 2013;23:120-125

THEME PAPER

Ms Naoko Ichimi, MS, Clinical Psychologist, Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Japan.
Dr Mamoru Hashimoto, MD, PhD, Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Japan.
Mr Masateru Matsushita, PhD, Clinical Psychologist, Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Japan.
Mr Hiroyuki Yano, MS, Clinical Psychologist, Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Japan.
Dr Yusuke Yatabe, MD, PhD, Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Japan.
Prof. Manabu Ikeda, MD, PhD, Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Japan.

Address for correspondence: Prof. Manabu Ikeda, Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
Tel: (81-96) 373 5184; Fax: (81-96) 373 5184;
email: mikeda@kumamoto-u.ac.jp

Submitted: 19 April 2013; Accepted: 10 June 2013

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Introduction

Progressive aphasia, which results from a neurodegenerative disease, is characterised by a progressive loss of specific language functions with relative sparing of other cognitive domains. The understanding of this syndrome generally depends on either of the following 2 schools of thought (Fig 1).^1-9

The first school of thought views progressive aphasia as a subtype of neurodegenerative dementia associated with anterior brain atrophy. This archetype was first described by Pick¹ in the 1890s as a progressive disorder of language with atrophy of the frontal and temporal regions of the left hemisphere and became known as Pick’s disease. In 1975, Warrington² reported 3 cases with associative agnosia and a fluent-type aphasia characterised by anomia and impaired word comprehension attributed to circumscribed asymmetric atrophy in the anterior temporal lobe, which was considered a selective impairment of semantic memory. Later, this condition was also described by Snowden et al³ as semantic dementia (SD). In the 1990s, a comprehensive characterisation of SD was provided by Hodges et al.⁴ Subsequently, Grossman et al^5,10 reported a different form of progressive language disorder, which was marked by dysfluent and effortful speech, hesitations and errors in the production of speech sounds and termed progressive non-fluent aphasia (PNFA). In 1998, Neary et al⁶ developed diagnostic criteria for SD and PNFA in relation to frontotemporal lobar degeneration (FTLD). For several years, cases of progressive aphasia were broadly classified into SD or PNFA.

The second school of thought regarding progressive aphasia was described in 1982 by Mesulam,⁷ who discussed a series of cases he referred to with “slowly progressive aphasia without generalised dementia”. He used the term ‘progressive’ to differentiate these patients from those with stroke-caused aphasia, and the word ‘slowly’ to differentiate them from those with a progressive but a relatively faster course (e.g. due to a neoplasm). The term ‘without generalised dementia’ was used to highlight differences from typical forms of Alzheimer’s disease (AD). After some modifications, he proposed the concept of primary progressive aphasia (PPA).^8,11,12 Primary progressive aphasia could be diagnosed in any patient who had a fluent or non- fluent language disorder (aphasia) due to a neurodegenerative (progressive) disease and in whom aphasia was initially the most salient (primary) clinical feature. Mesulam^7,8,11,12 intended PPA to be a symptomatologically distinct clinical entity that selectively involved the language network. However, a number of studies have revealed that PPA is a clinical syndrome with heterogeneous neuropathological causes.^12-14

Based on these 2 viewpoints, 3 subtypes of PPA are currently recognised: semantic variant PPA (svPPA), non- fluent / agrammatic variant PPA (navPPA), and logopenic variant PPA (lvPPA). The third clinical variant, termed logopenic progressive aphasia (LPA) by Gorno-Tempini et al,^9,13 is characterised by slow spontaneous speech output with frequent word-finding pauses and phonemic paraphasias. Several investigations have demonstrated that lvPPA is associated with atrophy of the posterior perisylvian and inferior parietal regions in the brain and is closely related to AD pathology.¹⁴

Despite advances in the concept of PPA, it is still unclear whether it is an independent disease entity or an atypical phenotype of neurodegenerative dementia such as FTLD or AD. This controversy could be addressed to a certain degree by examining the relationship between svPPA and SD. Both syndromes have similar language impairments. Nevertheless, a critical difference is the presence of a visual recognition deficit for faces and objects (prosopagnosia and associative agnosia) in SD that is not prominent in svPPA. In addition, some patients with SD, particularly those in whom the right temporal lobe is dominantly involved, exhibit remarkable behavioural changes even in the early stages of the disease. However, it has been pointed out that svPPA patients invariably progress to clear presentations of SD, and both syndromes share a common pathology. These findings suggest that svPPA may be an early phase of SD and it may not be important to differentiate it from SD. A more accurate clinical diagnosis of neurodegenerative dementia based on the background pathology may be required when aetiology-specific treatments become available in the future. In the present study, we reconsidered the relationship between PPA and neurodegenerative dementia by investigating consecutive patients with progressive aphasia in a dementia clinic.

Methods

All procedures in this study strictly followed the Clinical Study Guidelines of the Ethics Committee of Kumamoto University Hospital and were approved by the Internal Review Board. After a complete description of all procedures of the study was provided, written informed consent was obtained from patients or their caregivers.

Subjects were recruited from a consecutive series of 1723 patients who had undergone a medical examination at the Dementia Clinic of the Department of Neuropsychiatry, Kumamoto University Hospital, from April 2007 to October 2012. All patients were examined by senior neuropsychiatrists experienced in assessing dementia and aphasia, and underwent routine laboratory tests and standard neuropsychological examinations, including the Mini-Mental State Examination (MMSE)¹⁵ and Clinical Dementia Rating (CDR) scale.¹⁶ Behavioural and psychiatric symptoms were assessed by structured caregiver interviews using the Neuropsychiatric Inventory (NPI).¹⁷ In addition, stereotypic behaviours were assessed using the Stereotypy Rating Inventory (SRI).¹⁸ Brain magnetic resonance imaging or computed tomographic scans were performed in all patients and single-photon emission computed tomography of the brain was performed in most. The clinical, neuropsychological, and neuroimaging data collected prospectively in a standardised fashion were entered into the Kumamoto University Dementia Follow- up Registry. Selection was then based on inclusion and exclusion criteria as described below.

Clinical Diagnosis of Semantic Dementia and Progressive Non-fluent Aphasia

The diagnoses of SD and PNFA were based on a consensus regarding clinical diagnostic criteria developed by the international workshop on FTLD.⁶ The diagnosis of SD required a gradually progressive language disorder characterised by fluent, empty spontaneous speech, loss of word meaning manifested by impaired naming and comprehension, preserved single-word repetition, and preserved ability to read aloud and write down orthographically regular words that were dictated. However, instead of the language disorder, patients with prosopagnosia (impaired recognition of identity of familiar faces) and / or associative agnosia (impaired recognition of object identity) could also be diagnosed as having SD. Other aspects of cognition, including autobiographic memory, could be intact or relatively well preserved. Behavioural and personality changes characterised by loss of sympathy and empathy, narrowed preoccupations, and parsimony were included in the supportive diagnostic features, as these changes were considered characteristic of SD and often associated with high diagnostic specificity. In all, 27 patients met the SD criteria. The clinical characteristics of the SD patients are shown in Table 1. Fifteen patients had left-predominant involvement and 12 had right-predominant involvement.

The diagnosis of PNFA required gradually progressive non-fluent spontaneous speech with at least one of the following symptoms: agrammatism, phonemic paraphasias, or anomia. Other aspects of cognition could be intact or relatively well preserved. Late behavioural changes similar to behavioural variant frontotemporal dementia (bvFTD) were included as supportive diagnostic features. Four patients met the PNFA criteria (Table 1).

Clinical Diagnosis of Primary Progressive Aphasia

The diagnosis and classification of PPA were made with a 2-step process on the basis of the recent international consensus criteria.⁹ First, patients were diagnosed with PPA and then divided into clinical variants based on specific speech and language features. A PPA clinical diagnosis required the following 3 conditions: (1) the most prominent clinical feature was difficulty with language; (2) this deficit was the principal cause of impaired daily living activities; and (3) aphasia was the most prominent deficit at symptom onset and during the initial phases of the disease. Based on these criteria, behavioural disturbances could be early features in PPA, but should not be the main complaint or cause of functional impairment. Therefore, we excluded patients who had 3 or more of the following behavioural symptoms: (1) disinhibition, (2) apathy or inertia, (3) loss of sympathy or empathy, (4) perseverative or stereotyped behaviour, and (5) dietary changes at the initial assessment. Three of these 5 behavioural symptoms had to be present to meet the recent international consensus criteria for bvFTD.¹⁹ Similarly, patients with a clear parkinsonian syndrome at the time of diagnosis were excluded from the PPA group. In the present study, 15 patients fulfilled these PPA criteria.

After a PPA diagnosis was established, these 15 subjects were classified into 3 semantic variants according to specific diagnostic criteria⁹: svPPA (n = 12), navPPA (n = 2), and lvPPA (n = 1). The clinical features of each diagnostic category are shown in Table 1.^6,9,13

Neuropsychological Assessments

Language function of subjects who met the SD, PNFA, or PPA criteria was evaluated using the Japanese Standard Language Test of Aphasia consisting of 26 subtests (listening, speaking, reading, writing, and calculating).²⁰ In addition, the naming and word-comprehension ability of subjects who fulfilled the SD or svPPA criteria were assessed by object naming from 80 line drawings of common everyday objects and 10 colours, as well as word-picture matching with spoken word targets and 10 line drawing choices; the target plus 9 within-category distracters used the same 90 items as in the naming test.²¹

Statistical Analysis

To examine differences between patients with SD and svPPA, we divided the SD patients into 2 groups. One group included patients who met the SD criteria but did not meet the svPPA criteria (SD+PPA-), and the other group met both the SD and svPPA criteria (SD+PPA+). Gender, age, duration of language disturbance, education, MMSE score, CDR score, dominant side of atrophy, and performance on the picture naming and matching tests in the SD patients who did and did not meet the svPPA criteria were compared. Student’s t test and the χ² test were used as appropriate.

Results

The overlap between the SD and the svPPA groups is shown in Figure 2a. Among the 27 SD patients, 12 fall into the category of SD+PPA+ group, whereas the remaining 15 patients were under SD+PPA- group due to prominent behavioural disturbances. No SD patients had disturbed object identification if they had intact language function. The overlap between the PNFA and navPPA groups is shown in Figure 2b. Among these 4 PNFA patients, 2 met both the PNFA and navPPA criteria whereas the other 2 met only the former criteria due to clear parkinsonian syndrome. The neurological findings in the latter were thought to be better accounted for by corticobasal degeneration (CBD).

The demographic and clinical profiles in the SD+PPA- and the SD+PPA+ groups are shown in Table 2. There were trends for the SD+PPA- group to have higher NPI scores than the SD+PPA+ group (p = 0.07). There were no significant differences with respect to age, gender, duration of language disturbance, MMSE score, CDR score, dominant side of atrophy, performance on the naming and matching tests, and the SRI score between the groups.

Discussion

In this study, patients who presented with severe behavioural disturbances were not labelled as having PPA according to recent diagnostic criteria.⁹ However, these criteria do not define the severity and features of the prominent behavioural disturbance. Therefore, we defined behavioural disturbance as prominent when patients had 3 or more of the following behavioural symptoms: (1) disinhibition, (2) apathy or inertia, (3) loss of sympathy or empathy, (4) perseverative or stereotyped behaviour, and (5) dietary changes. According to the recent criteria for bvFTD, we can diagnose patients with this disorder whenever they manifest 3 of the 5 behavioural symptoms.¹⁹ For this reason, the present procedure was considered valid. Results of the present study also show the validity of the PPA criteria that classified those 15 patients into these 3 subgroups: svPPA group, navPPA group, or lvPPA group.

In this study, 15 of 27 patients with SD did not fulfil the svPPA criteria due to prominent behavioural disturbances. It is noteworthy that we found no significant differences in picture naming and matching performances between the SD+PPA- group and SD+PPA+ group. In addition, there were no significant differences between these 2 groups in terms of other clinical characteristics including dominant atrophy side. These results suggest that SD and svPPA may be identical conditions, regardless of their associations with different behavioural disturbance severities.

Two of the 4 PNFA patients fulfilled the navPPA criteria. The other 2 had parkinsonian syndrome and were diagnosed as having CBD. Recently, there have even been reports of non-fluent aphasia due to CBD or progressive supranuclear palsy (PSP).²² Because it is important to arrive at an early diagnosis and disease-specific care for Parkinson’s disease and related disorders such as CBD or PSP, the recent PPA criteria that exclude patients with parkinsonism⁹ might well be suitable in clinical practice.

One limitation of this study was that data were based on patients from a dementia clinic, rather than from a population-based cohort. Thus, it is possible that our results were affected by selection bias. In addition, there were only a small number of patients with PNFA and lvPPA, and behavioural disturbances in these patients were less evident than in patients with SD. However, we believe that the present results provide a good reflection of PPA patients that currently attend dementia clinics.

In this study, more than half of the SD patients were not considered to have PPA, despite presenting with a comparable language disorder. As it is reported that the background pathology of SD and svPPA is common,⁹ there is crucial problem in the 2-step diagnostic process for PPA variants when considering disease-modified treatment in any future study. In addition, it is reported that there are many LPA cases with AD pathology. Therefore, it is possible to estimate background pathology by classifying subtypes of language disorder. The results of this study show that it is important to classify which type of language disorder prevails in neurodegenerative dementia, whether or not there is cognitive dysfunction and / or behavioural disorder.

It is impractical to regard PPA as an independent clinical entity because of the symptomathological and neuropathological variations that prevail in patients with this disorder. On the other hand, 3 subtypes of PPA seem to reflect the background pathology at least to some degree. Thus, it is more important to directly identify the subtype of language disorder than to emphasise presentations of isolated language deficits, whenever language disorder of neurodegenerative dementia is being considered.

Acknowledgements

This research was performed as a part of the scientific research conducted by the Ministry of Education, Culture, Sports, Science and Technology of Japan for M.I. (Grant No. 23591718). The authors gratefully acknowledge the assistance of the staff of Department of Neuropsychiatry, Kumamoto University Hospital.

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