INÊS RIBEIRO
CADÓRIO
EFICÁCIA DE UMA ABORDAGEM INTEGRADA DE
INTERVENÇÃO NEUROLINGUÍSTICA NA AFASIA
PROGRESSIVA PRIMÁRIA
THE EFFECTS OF A COMBINED NEUROLINGUISTIC
INTERVENTION FOR PRIMARY PROGRESSIVE
INÊS RIBEIRO
CADÓRIO
EFICÁCIA DE UMA ABORDAGEM INTEGRADA DE
INTERVENÇÃO NEUROLINGUÍSTICA NA AFASIA
PROGRESSIVA PRIMÁRIA
THE EFFECTS OF A COMBINED NEUROLINGUISTIC
INTERVENTION FOR PRIMARY PROGRESSIVE
APHASIA
Tese apresentada à Universidade de Aveiro para cumprimento dos requisitos necessários à obtenção do grau de Doutor em Psicologia, realizada sob a orientação científica da Doutora Marisa Lobo Lousada, Professora Adjunta da Universidade de Aveiro e coorientação da Doutora Daniela Maria Pias de Figueiredo, Professora Adjunta da Universidade de Aveiro e Doutora Paula Vaz Martins, Professora Adjunta da Escola Superior de Saúde da Universidade de Aveiro.
o júri
presidente Professor Doutor Fernando Manuel Bico Marques
professor catedrático da Universidade de Aveiro
Prof. Doutor António Freire Gonçalves
professor associado com Agregação Jubilado da Faculdade de Medicina da Universidade de Coimbra
Prof. Doutora Ana Paula de Carvalho Soares
professora auxiliar da Universidade do Minho
Prof. Doutor Óscar Manuel Soares Ribeiro
professor auxiliar em Regime Laboral da Universidade de Aveiro
Prof. Doutora Inês Tello Rato Milheiras Rodrigues
professora adjunta Convidada da Escola Superior de Saúde do Alcoitão
Prof. Doutora Marisa Lobo Lousada
agradecimentos Agradeço aos participantes, profissionais de saúde e instituições envolvidas neste projeto de investigação, o valioso contributo e disponibilidade.
Agradeço à minha orientadora, Prof. Doutora Marisa Lousada, e co- orientadoras, Prof. Doutora Daniela Figueiredo e Prof. Doutora Paula Martins, por terem reconhecido em mim potencial para chegar sempre mais longe. Obrigada pelo empenho, dedicação, prontidão na resposta e motivação dada nos momentos mais críticos.
Salvaguardo e destaco a importância da colaboração dos Médicos Neurologistas no processo de recrutamento e encaminhamento de utentes, o que foi fundamental para a realização deste projeto.
Um especial agradecimento às Terapeutas Rita Cardoso e Joana Santos, pelo tempo e rigor que dedicaram à avaliação dos participantes deste estudo. Ao Professor Carlos Ferreira, pela generosidade em dedicar um pouco do seu precioso tempo à realização de um estudo piloto parcialmente relacionado com este projeto.
palavras-chave Afasia progressiva primária, anomia, intervenção neurolinguística, novas tecnologias, qualidade de vida.
resumo A afasia progressiva primária tem sido reconhecida como uma área de intervenção emergente nos últimos anos. Considerando-se uma síndrome de origem neurodegenerativa, a afasia progressiva primária requer uma resposta diferenciada que vá ao encontro das características inerentes a esta condição. Várias abordagens de intervenção têm sido exploradas, de entre as quais se destacam as intervenções comportamentais, pelos resultados promissores que têm oferecido. Embora se defenda cada vez mais que a intervenção se deva focar na manutenção de competências linguísticas residuais e na maximização das competências comunicativas, no sentido de aumentar os níveis de funcionalidade da pessoa, grande parte das intervenções têm valorizado a reaprendizagem de competências perdidas. Neste sentido, o presente trabalho teve como principal objetivo desenhar, implementar e avaliar os efeitos de uma intervenção que promove a manutenção de um vocabulário funcional e o treino de estratégias comunicativas a par da utilização de meios de comunicação aumentativa e alternativa. Especificamente, este estudo de caso visou analisar o efeito de uma intervenção neurolinguística na capacidade de nomeação de palavras treinadas e não treinadas, e qualidade de vida.
Dois pacientes diagnosticados com afasia progressiva primária participaram no estudo que teve uma duração total de cinco meses. Foram recolhidos dados antes da intervenção, durante a intervenção a cada duas semanas, imediatamente após a intervenção e um mês após o fim do tratamento. Para tal foram utilizados instrumentos de medida formais e estandardizados, adaptados e aferidos à população portuguesa.
A abordagem de intervenção implementada teve um impacto limitado, mas promissor, nos participantes. Registou-se uma melhoria das competências de nomeação num dos casos, e manutenção de competências adquiridas em ambos os casos. Vários fatores metodológicos limitaram a representatividade dos resultados obtidos e aplicabilidade das conclusões à prática clínica, nomeadamente o reduzido número de participantes, a heterogeneidade no diagnóstico e o desenho do estudo.
Os resultados deste estudo providenciam dados preliminares acerca do efeito de abordagens integradas de intervenção e impacto na qualidade de vida das pessoas com afasia progressiva primária. Destaca-se a importância do envolvimento de familiares diretos nas sessões terapêuticas, como fator facilitador.
keywords Primary progressive aphasia, technologies, quality of life.
anomia, neurolinguistic intervention, new
abstract In the past few years, primary progressive aphasia has been acknowledged as
an emerging field of practice. Considered a neurodegenerative-based syndrome, primary progressive aphasia requires a singular pathway that addresses the associated characteristics of the syndrome. Among the several treatment approaches that have been investigated, behavioural interventions seem to offer some promise. Despite evidence suggests that intervention should capitalize on spared language abilities and improve communication performance to increase functioning levels, a large number of interventions has focused on remediating impaired skills. Accordingly, the present work aimed to design, implement and evaluate the effects of an intervention that targets the maintenance of a core vocabulary and the training of communication strategies along with the use of augmentative and alternative communication devices. Particularly, this case report aimed to analyse the effect of a neurolinguistic intervention on naming performance for trained and untrained words, and quality of life.
Two patients diagnosed with primary progressive aphasia participated in this study that took place over the period of five months. Data collection occurred before intervention, during intervention every two-week interval, immediately after the intervention and one month after treatment was complete. Outcome measures consisted of formal and standardized instruments, adapted and validated to Portuguese population.
The intervention approach used in this study produced a limited but promising impact on participants. One participant improved naming accuracy and both participants retained therapy gains. Several methodological aspects limited the outcomes representativeness and generalization of conclusions to clinical practice, namely the reduced number of participants, the presence of different diagnosis and the design.
This study provides preliminary data on the effects of combined intervention approaches and their impact on patients’ quality of life. The involvement of close family members on therapy sessions is highlighted as beneficial.
List of Figures ... xxi
List of Tables ... xxi
List of Abbreviations ... xxii
General
introduction Introduction ... 21. Frontotemporal dementia: significance, definition and epidemiology ... 3
1.1. Behavioural type ... 4
1.2. Language type ... 5
2. Primary progressive aphasia ... 5
2.1. Brief history5 2.2. Semantic variant of PPA ... 6
2.2.1. Clinical presentation ... 6
2.2.2. Neuroanatomic and neuropathologic correlates ... 7
2.3. Non-fluent variant of PPA ... 7
2.3.1. Clinical presentation ... 7
2.3.2. Neuroanatomic and neuropathologic correlates ... 8
2.4. Logopenic variant of PPA ... 8
2.4.1. Clinical presentation ... 8
2.4.2. Neuroanatomic and neuropathologic correlates ... 9
2.5. Other variants of PPA ... 10
2.6. An outline of treatment approaches ... 11
2.6.1. Pharmacological treatments ... 11
2.6.2. Neuromodulatory treatments ... 12
2.6.3. Behavioural treatments ... 12
2.7. Caregivers role in primary progressive aphasia ... 14
2.8. Quality of life in primary progressive aphasia ... 15
3. Neuroimaging in the diagnosis and treatment of PPA ... 16
4. Aims and structure of the thesis ... 17
4.1. Aims ... 17
4.2. Structure of the thesis ... 17
1. Introduction ... 33 2. Methods ... 34 2.1. Eligibility criteria ... 34 2.1.1. Types of studies ... 34 2.1.2. Types of participants ... 34 2.1.3. Types of interventions ... 34
2.1.4. Types of outcome measures ... 35
2.2. Search strategy ... 35
2.3. Selection of studies... 35
2.4. Data extraction and quality assessment ... 36
2.5. Data synthesis ... 36 3. Results ... 39 3.1. Study selection ... 39 3.2. Quality appraisal ... 39 3.3. Participants’ characteristics ... 39 3.4. Treatment characteristics ... 40 3.5. Effects of intervention ... 40 3.6. Generalization ... 40
3.6.1. Semantic variant PPA... 40
3.6.2. Non-fluent variant PPA ... 41
3.6.3. Logopenic variant PPA ... 42
3.7. Maintenance ... 42
3.7.1. Semantic variant PPA... 43
3.7.2. Non-fluent variant PPA ... 43
3.7.3. Logopenic variant PPA ... 43
4. Discussion ... 51
4.1. Semantic variant PPA ... 51
4.2. Non-fluent variant PPA ... 53
4.3. Logopenic variant PPA ... 53
5. Conclusions ... 54
1. Introduction ... 63
2. Methods ... 64
3. Results... 68
3.1. Outcome measures of linguistic skills ... 68
3.2. Psychometric characteristics of the outcome measures ... 68
3.3. Outcome measures divided by variant ... 71
4. Discussion ... 75
5. References ... 78
Chapter 3. Combined restorative and compensatory treatment for primary progressive aphasia: A case report 1. Introduction ... 85
1.1. PPA treatment ... 86
1.1.1. Pharmacological treatments ... 86
1.1.2. Behavioural interventions ... 86
1.1.3. Generalisation and maintenance of therapy gains ... 87
2. Methods ... 88 2.1. Participants ... 88 2.1.1. Case 1 (C1) ... 88 2.1.2. Case 2 (C2) ... 89 2.2. Stimuli selection ... 89 2.3. Procedures ... 91 2.4. Outcomes measures ... 96 2.5. Statistical analyses... 96 3. Results... 96 3.1. Restorative intervention ... 96
3.1.1. General therapy gains ... 96
3.1.2. Generalisation of therapy gains ... 98
3.1.3. Maintenance of therapy gains ... 98
3.2. Compensatory intervention ... 99
4. Discussion ... 100
4.1. Interventions effects ... 100
4.1.4. Maintenance effects ... 102
4.1.5. Family involvement... 103
4.2. Limitations and future research ... 103
5. References ... 104
Chapter 4. Which strategies facilitate word retrieval in non-fluent progressive aphasia? A single case study 1. Introduction ... 115
1.1. Learning mechanisms applied to anomia treatment in PPA ... 115
1.2. Clinicopathological characteristics of nfvPPA ... 118
2. Methods ... 119
2.1. Case report ... 119
2.2. Baseline assessment ... 119
2.3. Procedures ... 122
2.4. Statistical analysis of behavioural data ... 122
3. Results... 122
4. Discussion ... 123
5. References ... 125
General conclusion Introduction ... 132
1. Summary of main findings ... 132
2. Theoretical and methodological considerations ... 134
2.1. Theoretical considerations ... 134
2.2. Methodological considerations ... 134
2.2.1. Type of study and study design ... 135
2.2.2. Number of participants ... 136
2.2.3. Outcome measures ... 136
2.2.4. Treatment protocol ... 137
3. Relevance of the research ... 137
4. Guidelines for clinical practice ... 138
4.1. Assessment ... 138
Figure 2. Selection of studies... 38
Figure 3. Selection of studies... 66
Figure 4. Naming accuracy levels obtained pre- and post-treatment by Case 1 in each list of words ... 97
Figure 5. Naming accuracy levels obtained pre- and post-treatment by Case 2 in each list of words ... 97
Figure 6. FP naming performance with and without cueing ... 123
List of Tables Table 1. Behavioural characteristics associated with semantic, non-fluent, and logopenic variants of PPA ... 9
Table 2. Brief description of the chapters comprised in the body of the thesis ... 19
Table 3. Methodological quality of the included studies ... 37
Table 4. Characteristics of intervention studies on semantic variant of PPA ... 44
Table 5. Characteristics of intervention studies on non-fluent variant of PPA ... 48
Table 6. Characteristics of intervention studies on logopenic variant of PPA ... 49
Table 7. Characteristics of intervention studies on different variants of PPA ... 50
Table 8. Psychometric properties and scale quality criteria ... 67
Table 9. Psychometric properties of scales used to assess linguistic skills in anomia treatment targeting PPA population ... 73
Table 10. Instruments used in the studies selected divided by PPA subtype ... 75
Table 11. Words distribution by number of syllables for therapy and control sets ... 90
Table 12. Total number of therapy items C1 and C2 could (↑N) and could not (↓N) name at pre-test and post-test across semantic categories ... 91
Table 13. Summary of baseline neurolinguistic testing ... 93
Table 14. Naming performance of Case 1 and Case 2 at pre-test, post-test and one month after treatment completion ... 99
FTD – Frontotemporal Dementia AD – Alzheimer’s Disease
PPA – Primary Progressive Aphasia SD – Semantic Dementia
svPPA – Semantic variant of Primary Progressive Aphasia nfvPPA – non-fluent variant of Primary Progressive
Aphasia lvPPA – Logopenic variant of Primary Progressive Aphasia FDA – Food and Drug Administration WHO – World Health Organization
NHS – National Health System GRN – Progranulin gene
TDP-43 – TAR DNA-binding Protein 43 TBK 1 – TANK Binding Kinase 1 PSP – Supranuclear Palsy
CBD – Corticobasal Degeneration MRI – Magnetic Resonance Imaging fMRI – functional Magnetic Resonance
Imaging PET – Positron Emission Tomography rTMS – repetitive Transcranial Magnetic Stimulation tDCS – transcranial Direct Current Stimulation
PRISMA – Preferred Reporting Items for Systematic Reviews and Meta-Analyses BNT – Boston Naming Test
PNT – Philadelphia Naming Test PPTT – Pyramids and Palm Trees Test PPVT – Peabody Picture Vocabulary Test MMSE – Mini Mental State Examination
BAAL – Battery of Aphasia Assessment of Lisbon
PALPA – Psycholinguistic Assessments of Language Processing in Aphasia SAQOL-39 – Stroke and Aphasia Quality of Life Scale – 39 CIU – Correct Information Unit
WAB – Western Aphasia Battery AAT – Aachen Aphasia Test
CSB – Cambridge Semantic Memory Test Battery K&D – Kissing and Dancing
BDAE – Boston Diagnostic Aphasia Examination TROG – Test for the Reception of Grammar SPT – Sentence Production Test
BORB – Birmingham Object Recognition Battery SPSS – Statistical Package for the Social Sciences MCID – Minimal Clinically Important Difference
Introduction
According to the World Health Organization (2012), approximately 35.6 million people were identified with dementia by 2010, and this number is expected to double every twenty years.
Frontotemporal dementia (FTD) represents the second most frequent form of early-onset dementia (Kurz, Kurz, Ellis, & Lautenschlager, 2014). FTD might be underdiagnosed all over the world, as for decades this neurocognitive disorder was considered rare and difficult to distinguish from Alzheimer’s Disease (AD) (Guimarães, Fonseca, & Garrett, 2006), due to the lack of clear diagnosis criteria. FTD and AD represent the main cause of Primary Progressive Aphasia (PPA) (Mesulam, et al., 2014), a neurodegenerative syndrome characterized by an increasing decline in communicative function, reflecting selective degradation of brain regions important for speech and/or language (Gorno-Tempini et al., 2011; Mesulam, 2001). With an insidious onset and gradual progression, PPA highly affects everyday activities and participation (American Psychiatric Association [APA], 2013), as semantic knowledge, grammar, and speech become compromised. Currently, there are no approved treatments to reverse or halt the course of the condition and consequent symptoms (Rogalski & Khayum, 2018), neither by the World Health Organization (WHO), the United States Food and Drug Administration (FDA), or the United Kingdom National Health System (NHS). Guidelines towards PPA management remain scarce, perhaps because in the past few years the priority was to establish international classification of PPA and clinical diagnostic criteria.
This thesis aims to develop, implement and analyse the effects of a neurolinguistic intervention for individuals diagnosed with PPA that combines a restorative and compensatory approach. Most experimental studies employ treatments directed to the prominent deficits experienced by the patients, seeking for the relearning of some skills and disregard the importance of compensate those deficits. In a neurodegenerative condition, it only makes sense to prepare the patients to handle the increasing deterioration of specific body functions. The success is achieved when the intervention involves person-centred care with dyadic instruction for disease education, counselling, and tailored forms of impairment- and compensatory-based communication strategy training (Rogalski & Khayum, 2018).
By implementing a combined approach to treat PPA, it is expected that the benefits are not only immediate but remain over time. Thus, this study attempts to contribute with valuable findings to future research and clinical practice.
The introduction provides a comprehensive background of the research that was carried out over the different stages of this study. Initially, it presents an overview of frontotemporal dementia, looking at the cluster of syndromes included, the clinical manifestations, the incidence and prevalence. Then, it describes the origin of primary progressive aphasia and discusses the available treatments to date. This is followed by a detailed characterization of the PPA subtypes that addresses the clinical profile, neuroanatomic correlates, pathological bases, and treatment. The need to understand that when planning the treatment, regaining or maintaining target skills is as important as compensating the deficits in a long run is crucial. The main findings and limitations of the existing treatments to individuals diagnosed with PPA are summarized and the significance of cognitive-linguistic interventions in this context is highlighted. It ends by stating the goals and organizational structure of the thesis.
1. Frontotemporal dementia: significance, definition and epidemiology
What once before was called Pick’s disease, on behalf of the person who described the first clinical cases, is currently known as FTD. FTD refers to a neurocognitive disorder caused by a progressive nerve cell loss in the frontal and anterior temporal lobes (Kurz et al., 2014). It comprises a group of syndromes that could either manifest as a personality change and/or language dysfunction (American Psychiatric Association [APA], 2013). The diagnosis of FTD is challenging due to its insidious onset. It requires patient’s clinical background, family history, as well as psychiatric, neuropsychological and neurological evaluation complemented by laboratory testing for genetic mutations and neuroimaging. Worldwide, prevalence studies of FTD are limited. The prevalence of FTD was estimated in 18 per 100,000 in Italian population aged >50 years (Bernardi et al., 2012). The estimated point prevalence in the United Kingdom is approximately 15 per 100,000 (Harvey, Skelton-Robinson, & Rossor, 2003; Ratnavalli, Brayne, Dawson, & Hodges, 2002). A much lower rate was identified in Japanese population at the same age, with a prevalence of 2.0 in 100,000 (Ikejima et al., 2009). In the Netherlands, the prevalence of FTD varied across age groups, assuming values ranging from 0.2 to 9.4 per 100,000 inhabitants (Rosso et al., 2003). So far, the prevalence of FTD in the Portuguese population remains unknown (Organização para a Cooperação e Desenvolvimento Económico [OECD], 2017). In comparison to the prevalence data, the estimates of FTD incidence have documented little variability: 2.7–4.1/100,000 in individuals <70 years (Onyike & Diehl-Schmid, 2013).
Frontotemporal neurocognitive disorders affect more males than females (American Psychiatric Association [APA], 2013). A genetic etiology is suggested in the face of a considerable percentage of patients presenting familial incidence of tau and progranulin mutations on chromosome 17 – between 40-50% (Kertesz, 2011; Neary, Snowden & Mann, 2005). Amongst the wide range of presentations that belong to FTD family, the majority assume the form of ubiquinopathy and less than half of the cases appear to assume the form of tauopathies (Kertesz, 2011).
In depth, the neuropathology of FTD follows three main patterns as shown below (Hodges & Patterson, 2007).
i) Tau-positive disorders: Pick’s disease with tau-positive and ubiquitin-positive spherical
inclusions; familial FTD with parkinsonism and associated mutations in the microtubule associated protein tau gene (MAPT) on chromosome 17; corticobasal degenerations with tau-positive inclusions; and argyrophilic grain disease.
ii) Ubiquitin-positive, tau-negative disorders: motor-neuron disease; familial FTD with
mutations in the progranulin gene (GRN); familial and sporadic FTD with mutations in the TAR DNA-binding protein 43 (TDP-43) associated with ubiquitin-positive inclusions.
iii) Microvascular degeneration and gliosis lacking distinctive inclusions.
Despite the recent findings, the research community has a long way to thrive towards the full understanding of FTD neurobiological substrate and clinical management.
FTD is divided in two major types, according to the localization of the underlying proteinopathy (Kurz et al., 2014). A Portuguese study highlighted the fact that very often patients with the behavioural type are referred to the Psychiatric service and the ones with the language type are referred to Neurology (Guimarães et al., 2006).
1.1. Behavioural type
The most prominent features reported in individuals diagnosed with the behavioural type are asocial behaviour, disinhibition, loss of self-judgement and insight, apathy, disinterest in people, lack of basic emotions (e.g., sadness, empathy), and impaired executive function. Other signs and symptoms might arise through the course of the disease, such as neglecting personal hygiene, rigid thinking, rudeness, change of food habits, perseverative routines, stereotypies. The patients may show some impulsiveness (e.g., careless driving) and inattention, along with inappropriate joking and compulsive exploration of the environment (Kertesz, 2011). An additional characteristic that discriminates FTD from AD and other conditions is an abnormal response to sensory stimuli. A typical example would be the reduced pain response, associated with
hypersensitivity to neutral stimuli (Bathgate, Snowden, Varma, Blackshaw, & Neary, 2001; Snowden et al., 2001).
Regardless the large phenotypic variations, the profound changes in personality and social conduct usually prompt the families to seek the opinion of a physician.
1.2. Language type
The language type of FTD has been recognized as primary progressive aphasia since 1987, in accordance with the classification proposed by Mesulam for differential diagnosis (see Mesulam, 1987). Age of onset in PPA ranges from 55-65 years and there is a preponderance of male patients over female (Mesulam, 2001). Advances in genetics show that a large number of patients inherit mutations in the progranulin gene, in an autosomal dominant way (Mesulam et al., 2007; Snowden et al., 2006; van Swieten & Spillantini, 2007).
Broadly, PPA can be conceptualized as a gradual and progressive degradation of language network for the first two years (Gorno-Tempini et al., 2011), while memory, nonverbal cognition, visual processing, and personality remain relatively preserved (Mesulam, 2003). At first, patients experience word-finding difficulties, followed by deficits in grammatical structure and comprehension of language (Mesulam, 2001). The speech might be fluent or non-fluent. At the advanced stages, some patients experience mutism or near-mutism with relative preservation of comprehension (Mesulam, 2001) and become dependent on the use of augmentative and alternative communication devices (Fried-Oken, 2008).
The course of the disease is variable across individuals (Kertesz, 2011). Sometimes it may be considerably prolonged and other times it might present a fast development onto swallowing difficulties and eventually aspiration. This topic is further explored in the following section.
2. Primary progressive aphasia
2.1. Brief history
For more than a century, progressive aphasias have come to the attention of some researchers who reported the first patients (Franceschi, 1908; Rosenfeld, 1909; Sérieux, 1893). However, aphasia with circumscribed frontotemporal atrophy was described by Arnold Pick (Pick, 1892; 1904). A particular interest in progressive aphasias resurged with a study that enrolled six patients and served as the foundation of a new syndrome (Mesulam, 1982). Primary progressive aphasia was the term subsequently introduced by
Mesulam, as an attempt to establish a more accurate nomenclature of a separate entity from Alzheimer’s disease (Mesulam, 1987; Mesulam & Weintraub, 1992). As described at that time, many patients would fail to meet the current diagnostic criteria for PPA. Since 1987, many studies have emerged on this topic and criteria have evolved over the years. Alternatives to PPA diagnoses in the literature have been semantic dementia, progressive aphasia, progressive nonfluent aphasia, progressive aphemia, dysphasic dementia, left temporal variant of frontotemporal dementia, and frontotemporal lobar atrophy with aphasia. In the face of such variations of the terminology, international consensus was imperative and in 2011, the team led by Gorno-Tempini proposed a classification of PPA and its variants to improve the uniformity of case reporting and reliability of research outcomes (Gorno-Tempini et al., 2011). PPA was divided into three different variants: semantic variant (svPPA); nonfluent/agrammatic variant (nfvPPA); and logopenic variant (lvPPA). The correct classification of the three variants requires the analysis of speech and language profile and the pattern of brain atrophy on neuroimaging (Butts et al., 2015). Over the past decades, the literature has confirmed that frontotemporal lobar degeneration is most commonly the underlying pathology of the non-fluent and semantic variants, while AD pathology has been associated with the logopenic variant (Mesulam et al., 2014).
2.2. Semantic variant of PPA
2.2.1. Clinical presentation
The semantic variant is the most studied clinical syndrome and perhaps the most consistently defined. Prominent early features and presenting complaints include reduction of expressive vocabulary and single-word comprehension deficits (Gorno-Tempini et al., 2011; Pijnenburg, Gillissen, Jonker, & Scheltens, 2004; Thompson, Patterson, & Hodges, 2003). The deterioration of receptive vocabulary is greater for low-frequency words (Hodges & Patterson, 2007).
Earlier in the course of the illness, conversations reflect spared phonology, grammar structure, motor speech and fluency (Adlam et al., 2006; Asch et al., 2006; Rohrer, Rossor, & Warren, 2010). However, in depth, spontaneous speech is marked by word-finding and word recognition pauses in parallel with the increasing use of generic cyphers (e.g., thing, place, animal), to compensate the difficulty to retrieve specific terms. Object knowledge becomes severely impaired as patients gradually loose the meaning of the words (Garrard et al., 2001; Lambon Ralph & Patterson, 2008). For example, patients
start misusing objects and no longer recognize persons who are part of their social circle. These behaviours are the result of a widespread semantic memory disruption.
When reading aloud or writing irregular words, individuals typically apply the regular phonological rules as if grapheme/phoneme correspondence was transparent, exhibiting surface dyslexia and dysgraphia (Wilson et al., 2009). Finally, repetition of words, sentences and numbers remains preserved over time (Gorno-Tempini et al., 2011).
2.2.2. Neuroanatomic and neuropathologic correlates
Anatomically, the semantic variant has been linked to an asymmetric atrophy involving, at a larger scale, the left anteroinferior and mesial temporal lobe (amygdala and anterior hippocampus) (Chan et al., 2001; Gorno-Tempini et al. 2011). In more advanced stages, atrophy encompasses more posterior temporal regions and homologous gyri in the contralateral temporal lobe as well as orbitofrontal cortex (Kumfor et al., 2016; Rohrer et al., 2008b) – the core of semantic memory network (Lambon Ralph, Jefferies, Patterson, & Rogers, 2017). In most cases, TDP-43 pathologic changes are found at post-mortem (Chare et al., 2014; Rohrer et al., 2011; Spinelli et al., 2017). Both tauopathies and AD account for a minority of svPPA cases (Rohrer et al., 2011; Spinelli et al., 2017). At last, occasional pathogenic TBK1 mutations related to motor neuron are also a possibility (Caroppo et al., 2015).
2.3. Non-fluent variant of PPA
2.3.1. Clinical presentation
The clinical spectrum of nfvPPA is the most heterogeneous of the canonical PPA syndromes. The hallmark of nfvPPA is the frank agrammatism, or altered production of grammatically correct sentences, due to compromised syntactic and morphological skills (Mesulam, 2013; Weintraub et al., 2009). The verbal output is considered slow, hesitant, and effortful (Jokel, Cupit, Rochon, & Leonard, 2009), with inconsistent speech sound production errors conforming to co-occurring orofacial apraxia (Gorno-Tempini et al., 2011). An evident difficulty producing polysyllabic words and sequences of syllables to command (diadochokinesia) is usually observed, as a consequence of reduced motor programming of speech and articulatory agility.
The symptom cluster also includes impaired comprehension of syntactically complex sentences (Machado, Campanha, Caramelli, & Carthery-Goulart, 2014), anomia, and auditory/phonological processing deficits (Louis et al., 2001). In contrast, the
comprehension of concepts and simple sentences is intact. At the outset, oral verbal communication is usually more affected than written communication. However, between moderate to advanced stages, spelling errors arise in writing tasks. As verbal communication becomes increasingly hard, patients rely on nonverbal means of expression (Marshall et al., 2018).
2.3.2. Neuroanatomic and neuropathologic correlates
On neuroimaging, nfvPPA has been associated with predominant left posterior fronto-insular atrophy and hypoperfusion or hypometabolism (Gorno-Tempini et al., 2011), with variable extension around the superior temporal gyrus. The referred brain regions subserve language output, motor speech programming and sentence processing (Rohrer et al., 2008a). To a lesser extent, homologous right-sided peri-sylvian atrophy has been identified (Ghacibeh & Heilman, 2003; Vitali et al., 2004), possibly correlated with central nonverbal auditory deficits or dysprosody (Hailstone, Crutch, Vestergaard, Patterson, & Warren, 2010). According to the literature, most patients with non-fluent progressive aphasia show a tauopathy, such as progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD), while a fewer percentage show TDP-43 or AD at the autopsy (Josephs et al., 2006; Knibb, Xuereb, Patterson & Hodges, 2006; Nestor et al., 2007; Rittman et al., 2013; Rogalski et al., 2016). Genetic abnormalities affect GRN, MAPT, C9 genes, causing distinct phenotypes within the same variant (Rohrer et al., 2010).
2.4. Logopenic variant of PPA
2.4.1. Clinical presentation
Anomia and impaired repetition of sentences and phrases are the typical presenting symptoms (Henry & Gorno-Tempini, 2010; Mesulam et al., 2008). In lvPPA, conceptual knowledge is preserved and available, but phonological representations are insufficiently accessed or assembled (Lambon Ralph, Moriarty, & Sage, 2002; Schwartz, Dell, Martin, Gahl, & Sobel, 2006). Once semantic processing and motor control for speech are largely spared, anomia possibly occurs as a result of a degraded phonological network (Gorno-Tempini et al., 2008; Wilson et al., 2010). Accordingly, individuals with lvPPA present with phonological deficits. For example, they may produce phonological paraphasias, jargon and neologisms in confrontation naming tasks and conversation (Caffarra et al., 2013; Rohrer, Rossor, & Warren, 2009). Despite spontaneous speech present a slow rate and
frequent pauses due to word-finding problems, there is no evidence of frank agrammatism or altered prosody (Gorno-Tempini et al., 2011).
2.4.2. Neuroanatomic and neuropathologic correlates
The pattern of cerebral atrophy varies widely between individuals diagnosed with lvPPA. Typically, a posterior perisylvian or parietal atrophy is observed in the left hemisphere (Gorno-Tempini et al., 2004). The temporo-parietal junction area of the
language-dominant hemisphere is intimately involved in phonological processing (Gorno-Tempini et al., 2008; Henry & Gorno-Tempini, 2010), specifically in decoding speech sounds and activating phonological sequences to link verbal semantic stores to language output (Giannini et al., 2017; Rohrer et al., 2008a; Spitsyna, Warren, Scott, Turkheimer, & Wise, 2006). The pattern of atrophy often extends to more anterior regions, comprising other structures, such as hippocampi. Recent studies show that AD might be the most frequent underlying pathology associated with lvPPA (Mesulam et al., 2008; Rabinovici et al., 2008).
Table 1 shows the clinical profile of the three main subtypes of PPA: svPPA, nfvPPA, and lvPPA.
Table 1. Behavioural characteristics associated with semantic, non-fluent, and logopenic variants of PPA (adapted from Gorno-Tempini et al., 2011; Henry et al., 2013).
svPPA nfvPPA lvPPA
Word retrieval in confrontation Χ Χ Χ Χ
naming
Word retrieval in spontaneous Χ Χ Χ Χ
speech
Single word comprehension Χ Χ ✓ ✓
Object knowledge Χ Χ ✓ ✓
Grammatical competence ✓ Χ Χ ✓
Comprehension of lengthy sentences ✓ ✓ Χ
Comprehension of syntactically ✓ Χ ✓
complex constructions
Reproduction of single words ✓ ✓ ✓
Repetition of sentences and phrases ✓ ✓ Χ Χ
Speech sound production ✓ Χ Χ Χ
Reading and writing skills Χ X ✓
Motor speech control ✓ Χ Χ ✓
Speech fluency Χ Χ Χ Χ
Prosody ✓ Χ ✓
2.5. Other variants of PPA
The variability of phenotypes and associated pathology within the same PPA subtype is highly recognized in the literature. However, when a subject does not fall into the boundaries of the currently accepted classification guidelines, a new designation arises. Perez and colleagues (2013) described an individual with insidious onset, progressively diminished verbal output, and minimal associated language, cognitive, behavioural or motor deficits. T1-weighted Magnetic Resonance Imaging (MRI) acquisitions identified gyral atrophy in the left frontal region and Positron Emission Tomography (PET) scan showed focal hypometabolism in the left superior and middle frontal gyri. A careful analysis led to the conclusion that the asymmetric atrophy of the superior frontal region and the cerebrospinal fluid profile were not consistent with AD pathology. Perez’s team suggested that this new profile represented an isolated case of progressive dynamic aphasia, a distinct variant of PPA.
Another form of PPA intended to encompass cases experiencing agrammatism in language production, word comprehension deficits, poor fluency and frequent paraphasias. Mesulam and colleagues (2009) designated this new subtype as mixed PPA.
Ultimately, there are patients whose clinical presentation does not fit any of the previous subtypes at the initial stages of the disease. These cases were designated as unclassifiable (Gorno-Tempini et al., 2011; Senaha et al., 2013). As the pathological process evolves, the clinical syndrome becomes clearer and appropriate classification is possible.
Figure 1. presents international diagnostic criteria for the classification of the three main variants of PPA.
Marshall et al., 2018).
2.6. An outline of treatment approaches
In the past, the limited awareness on PPA and its implications by the referring and treating clinicians (Henry et al., 2013) might have been responsible for the underdiagnosis of this disorder and late referral for treatment. Speech-language therapists gradually perceived that they should play an active role in the management of people with progressive language dysfunction (Taylor, Kingma, Croot, & Nickels, 2009). In fact, there is a growing body of evidence suggesting that individuals with mild PPA may largely benefit from language rehabilitation (Jokel, Graham, Rochon, & Leonard, 2014). Yet, a gold question remains unanswered: which intervention pathway offers more promise in PPA population? So far, evidence-based practice guidelines towards PPA intervention have not been published. As such, speech and language therapists face the challenge of applying and adapting the knowledge established for stroke-related aphasia to neurodegenerative-related aphasia, an emerging area of practice (Croot, Nickels, Laurence, & Manning, 2009).
2.6.1. Pharmacological treatments
The small number of studies testing the effects of drugs on language functioning in PPA include mainly pilot studies and one randomised placebo-controlled trial. A group of 17 participants diagnosed with behavioural type of FTD and svPPA completed 26 weeks of memantine treatment and revealed worse cognitive performance on naming and processing speed tests, compared to the placebo group (Boxer et al., 2013). In another study, 36 patients diagnosed with behavioural and PPA variants of FTD underwent 18 weeks of galantamine treatment. No main differences in behaviour or language ability were observed immediately after the treatment period (Kertesz et al., 2008). In contrast, a nfvPPA patient responded well to a steroid treatment (prednisone), as he showed great improvement on measures of speech fluency, naming and working memory (Decker & Heilman, 2008). In a different preliminary study, rivastigmine, a cholinesterase inhibitor, was administered to 5 patients with nfvPPA and 1 with svPPA (Kowa, Seki, Yamamoto, Kanda, & Toda, 2012). All patients except from one demonstrated improved naming and repetition. Close relatives also noted some benefit in terms of spontaneous speech.
Overall, the small amount of studies which have evaluated the effect of pharmacological therapy in PPA do not provide strong enough evidence to derive firm conclusions.
Additional studies using randomised controlled trials are needed to support the efficacy of pharmacological approaches in PPA.
2.6.2. Neuromodulatory treatments
In recent years, there have been some studies showing that non-invasive brain stimulation techniques might minimize some symptoms in individuals with PPA. Worldwide, the two most used methods of neuromodulation are Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS). The first induces cortical excitability when applied with high frequency (5-20Hz) or cortical inhibition when applied with low frequency (≤1 Hz) (Diana et al., 2017). The second influences brain function through the administration of small direct currents (Nitsche & Paulus, 2000). While TMS generates action potentials, tDCS alter neuronal resting membrane potentials in order to increase or decrease the brain activity in larger regions (Stagg & Nitsche, 2011).
An experimental study tested two groups of patients with non-fluent variant of PPA. One group received tDCS treatment combined with language training, while the other group received language training alone. A better naming accuracy was found for the group allocated to the combined condition (Cotelli et al., 2014). Two weeks of daily tDCS treatment applied to patients with the same form of PPA resulted in improved speech production and grammatical comprehension, in six people with the non-fluent PPA (Gervits et al., 2016). In the same line, tDCS combined with written production intervention seemed to augment generalization and maintenance of positive outcomes in the short-term (Tippett, Hillis, & Tsapkini, 2015).
A significant improvement in the linguistic skills was found following the application of high frequency rTMS, specifically on verb production (Finocchiaro et al., 2006), verbal phonetic fluency and written production (Trebbastoni, Raccah, de Lena, Zangen, & Inghilleri, 2013). In summary, brain stimulation techniques seem to offer some promise as a means of maximizing language therapy in PPA. Nevertheless, compensatory recruitment of brain regions that subserve language function warrants further investigation.
2.6.3. Behavioural treatments
In the absence of clearly effective intervention options, an increasing interest in behavioural treatments has been observed among the research community (Carthery-Goulart et al., 2013). Behavioural approach to treatment comprises impairment and activity/participation-directed interventions (Croot et al., 2009). Impairment-directed
interventions aim to retain or improve baseline speech and language skills (e.g., picture naming, reading/writing, speech fluency), while activity/participation-directed interventions aim to increase everyday life functioning, by training functional communication (e.g., environmental modifications, compensatory strategies, levels of participation in communication interactions) (Carthery-Goulart et al., 2013). In both approaches, realistic goals and expectations should be set since the beginning. PPA individuals have often been subjected to impairment-based therapeutic programs, as comprehensive activity/participation or functional interventions are still emerging and being developed (Croot et al., 2009; Taylor et al., 2009).
The interventions that target remediation of language impairments seem to produce immediate gains in all subtypes of PPA (Jokel et al., 2014). Overall results point to an advantage of treated items over untreated items after treatment. In some cases, the gains reach statistical significance and last between one and six months after therapy completion. Frequently, effective therapies employ a phonological approach when targeting nfvPPA patients (e.g., Jokel et al., 2009), and a semantic approach in patients with svPPA (e.g., Jokel & Anderson, 2012), in response to each variant related core deficits. No specific approach has been recommended regarding lvPPA subtype. Generalization and maintenance effects are further explored in Chapter 1.
Activity/participation-directed interventions also seem to yield positive outcomes. Over the last decade, the increasing number of published studies that formally evaluate the effectiveness of interventions are contributing to inform therapy planning for patients with progressive language impairments and maximize their communication ability.
The literature suggest that successful functional communication may be dependent on the use of:
i) written and pictorial information – communication booklets, boards and cards;
ii) gestures and signs – pantomime and communicative gestures, or Sign
Language;
iii) other Augmentative and Alternative Communication (AAC) technologies – text-
to-speech machines, smartphone applications, and emergency wrist devices. In this type of interventions, speech and language therapy sessions provide family training and/or counselling. Additionally, there are group sessions that encourage the use of communication techniques, social interaction with others with aphasia, and receptiveness to feedback and peer support (Croot et al., 2009).
Rogers, King & Alarcon (2000) have published extensive work on this topic and highlight the importance of three main considerations when planning the treatment protocol:
implement goals in anticipation of decline; implement dyad-focused therapy; and use AAC techniques that rely on preserved abilities to increase participation levels. Of equal importance is the need of tailoring interventions to the individual client and context, as different patients might experience different difficulties and present different needs.
Some beneficial effects of activity/participation-directed interventions have been reported in the literature: improved quality of life and decreased sense of isolation (Thompson & Johnson, 2006), increased feeling of personal control (McNeil & Duffy, 2001; Robinson, 2001; Thompson & Johnson, 2006), enhanced sense of life purpose (McNeil & Duffy, 2001), and neuroprotective effects of cognitive stimulation (see Cartwright & Elliot, 2009). New technologies have considerable potential to support people with PPA in their everyday lives, but evidence is still sparse. Recently, technological advances have prompted the implementation of some computer-assisted treatments aiming to address word retrieval deficits. Impairment-directed approaches have used specific software programmes to display therapy items during training sessions, such as Microsoft Power Point (Croot et al., 2015), or software programmes that consist of modules for practice, such as MossTalk Words® (see Jokel, Rochon & Anderson, 2010). On the other hand, functional approaches have focused on the use of new technologies to compensate for language deficits. A small number of studies have used smartphone functions and applications as a compensatory strategy to facilitate communication (see Bier, Paquette, & Macoir, 2018; Routhier et al., 2012). Empirical evidence show that computer-assisted treatments for language impairments can be beneficial as an adjunct to one-on-one speech-language therapy, and are an effective way to intensify and continue the rehabilitation process (Fink, Brecher, Sobel & Schwartz, 2005).
2.7. Caregivers role in primary progressive aphasia
The support of family members can facilitate the way patients cope with a neurological condition and its limitations in everyday life functioning and participation (Senanarong et al., 2004). Moreover, spouses and/or carers seem to play a key role in transferring communication strategies from the clinical setting to everyday life (Croot et al, 2009). The importance of providing training on communication strategies, preventing caregiver depression, and alleviating caregiver burden in aphasia is noteworthy.
Published studies reporting behavioural treatments in PPA have referred the active participation of caregivers in the selection of stimuli assigned to training, considering personal relevance and use. Only recently, a ground-breaking study fully engaged the patients’ spouses in the therapeutic program, by offering a group intervention. According
to Jokel and colleagues (2017), group intervention provides knowledge acquisition, coping abilities, problem-solving experiences, and professional as well as peer support. In this study, while PPA worked on their communication skills, the spouses networked with each other and received informative sessions that addressed their needs. In each meeting day, caregivers discussed previous education sessions and existent topics of concern. They shared experiences and participated in problem solving regarding daily communication interactions in the first part. In the second part, the spouses joined the patient group for communication strategy sessions and counselling conducted by experts in different fields (e.g., Social Worker, Neuropsychologist, Speech-Language Pathologist, Neuropsychiatrist, etc.). The active participation of caregivers in educational and counselling sessions mainly improved their level of preparedness, knowledge of PPA, awareness of progression, managing psychosocial issues and communication challenges, daily problem solving and comfort level of talking about the spouse’s PPA. In summary, the authors highlighted the importance to address the needs of both patients and caregivers in health services.
2.8. Quality of life in primary progressive aphasia
Language impairments negatively impact the individual’s ability to communicate with others, since psycho-social well-being and therefore quality of life become affected (Jokel et al., 2014). Previous research has shown that PPA induces considerable changes on mood, everyday participation and relationships – all aspects that influence quality of life (Nickels & Croot, 2014).
Despite healthcare models highly encourage a quality of life approach to managing communication handicap within the context of neurodegenerative conditions, only few studies have investigated the quality of life in PPA (Ruggero, Nickels, & Croot, 2019). An empirical study conducted by Cartwright (2015) demonstrated that PPA was associated with main self-reported socio-emotional consequences, such as embarrassment, self-consciousness, worry, frustration and anxiety. These adverse emotional reactions to the diagnosis of PPA sometimes result in maladaptive coping strategies that may be avoided by a variety of internal and external parameters (e.g., individual’s personality, clinical history of depression, awareness, and family support). Some insights can also be withdrawn from the reduced number of studies that have used quality of life outcome measures to analyse the impact of speech-language interventions in PPA population. Four studies documented therapy-induced gains in quality of communication, coping skills, self-perspective and participation through the application of
different quality of life rating scales (Jokel et al., 2010; 2017; Whitworth et al., 2018) and semistructured interview (Rogalski et al., 2016).
In brief, despite speech-language interventions enable positive changes in quality of life, not always those changes reach significance. More importantly, the positive changes assume different pathways in different individuals (e.g., communication confidence, participation in everyday activities, feeling in control of life, feeling respected and accepted, looking forward more positively, perceived ability to join in complex conversations). Quality of life in PPA warrants further investigation, since available literature points to a heterogeneous impact across patients and to the involvement of many factors.
3. Neuroimaging in the diagnosis and treatment of PPA
Neuroimaging has been considered an important tool in the differential diagnosis of PPA. The imaging-supported diagnosis requires the identification of specific pattern of either atrophy on MRI or hypoperfusion/hypometabolism on single photon emission computed tomography (SPECT) or PET. A study that investigated a small group of PPA individuals (n=6) concluded that hypoperfusion abnormalities were more variant-specific than patterns of atrophy, suggesting that differential diagnosis is more feasible when supported by quantitative analysis of SPECT images, as opposed to qualitative visual analysis of MRI (Sitek et al., 2014).
A limited number of studies have used neuroimaging to measure treatment outcomes in PPA. After receiving a model-oriented treatment, one individual with svPPA improved naming accuracy and revealed changes in cortical activity (fMRI), predominantly located in right superior and inferior temporal gyrus (Dressel et al., 2010). A lvPPA patient also responded positively to an intensive behavioural treatment, revealing improved lexical retrieval of items for trained and untrained semantic categories associated with increased activation of left dorsolateral prefrontal regions in post-treatment fMRI (Beeson et al., 2011). In a case of nfvPPA, semantic feature analysis therapy led to the activation of semantic processing areas and network expansion, observed in fMRI (Marcotte & Ansaldo, 2010). Recent advances in neuroimaging have facilitated the study of therapy-induced brain plasticity in the recovery from anomia. Besides the mentioned practical applications, neuroimaging also seems to offer some promise in the understanding of the neurobiological processes behind PPA syndromes. Very often, the difficulty of access, variability of protocols and the associated costs limit the use of neuroimaging in clinical practice. Appendix 3 presents a pilot study that evaluates the differences between inner
and overt speech mechanisms in a fMRI language task and attempt to map activation of related areas. The feasibility of fMRI to analyse confrontation naming related areas is tested in European Portuguese healthy adults.
4. Aims and structure of the thesis 4.1. Aims
The general aim of this thesis was to design, implement, and evaluate the effects of a combined anomia treatment for patients diagnosed with PPA. The treatment intended to address not only baseline deficits but also everyday life functioning, to positively impact individuals’ quality of life.
PPA population is an underserved population, as to what clinical service delivery is concerned. The need of evidence-based knowledge regarding the assessment and rehabilitation of progressive aphasia required a comprehensive literature review. A case study, informed by the literature review, included two patients diagnosed with PPA. Specifically, this interventional study aimed to assess the outcomes of a neurolinguistic treatment that combined the restorative and compensatory approaches, measuring its generalisation effects and maintenance of gains with continued home practice. Additionally, the study aimed to determine whether semantic and phonological learning strategies facilitate word retrieval in nfvPPA. The participants engaged in language-training tasks for nine weeks and subsequently received language-training on augmentative and alternative communication strategies for three weeks. Before participants enrolled the experimental study, ethical approval was obtained from the Ethics committee of the Nursing School of Coimbra – Health Sciences Research Unit: Nursing (UICISA:E), Portugal (reference P351-06/2016).
Neuroimaging has been increasingly used as an outcome measure in PPA intervention studies. Therefore, this study tested a fMRI paradigm on healthy adults with the ultimate goal of encouraging future studies to test the feasibility of this paradigm in detecting change pre- to post-treatment, in PPA patients.
4.2. Structure of the thesis
The main body of this thesis contains four chapters, reporting the studies that were conducted throughout the project, to achieve the goals stated in the previous section (see Table 2).
Chapter 1 reports a systematic literature review on the effects of semantic therapy on generalization and maintenance of treatment outcomes in patients with PPA, considering
its different variants. Most of the experimental studies available in the literature are case reports and case series, considering that PPA is a rare condition. For the same reason, the samples usually include participants diagnosed with different subtypes of PPA, which makes it difficult to derive conclusions representative of this specific population.
Chapter 2 presents a narrative review on the psychometric properties of the instruments used to assess the effects of anomia treatment in the PPA population. A total of twelve standardized language tests were assessed regarding the acceptability, reliability, validity, and responsiveness. The fact that most tests were not considered psychometrically robust, neither validated for use with the PPA population poses important concerns. Additionally, it emphasizes the need of future development of objective, reliable, valid and responsive outcome measures that ensure the accuracy of results after treatment.
Chapter 3 reports on the effects of an innovative anomia treatment in two participants with different variants of PPA, immediately after treatment and one month after treatment completion.
Chapter 4 reviews the learning mechanisms used to address anomia deficits in the three subtypes of PPA. This study also describes an experiment in which two different learning strategies are compared in the context of a confrontation naming task.
The thesis ends with a general conclusion where theoretical and methodological aspects, as well as clinical practice implications are discussed in detail. Suggestions for future research are directed to increase the level of evidence about PPA interventions.
Table 2. Brief description of the chapters comprised in the body of the thesis.
Type of study Sample Data collection Outcome
variables
Chapter 1 Systematic 25 studies Experimental studies Generalization
literature review published in scientific journals and
indexed in Central, PubMed, maintenance of
Medline, Web of Knowledge treatment gains
and Scopus
Chapter 2 Narrative review 14 studies Clinical trials published in Psychometric
scientific journals indexed in properties of
Central, PubMed, Web of language tests
Knowledge, Medline and used in PPA
Scopus
Chapter 3 Case report: 2 subjects Mini Mental State Examination Picture naming
multiple baseline (MMSE), Battery of Aphasia and quality of
design Assessment of Lisbon (BAAL), life
Snodgrass & Vanderwart
Naming Test, Stroke and
Aphasia Quality of Life Scale –
39 (SAQOL-39)
Chapter 4 Case report 1 subject MMSE, BAAL, Snodgrass & Semantic and
Vanderwart Naming Test phonological
learning
strategies
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