Motor speech disorders associated with primary progressive aphasia

Background: Primary progressive aphasia (PPA) and conditions that overlap with it can be accompanied by motor speech disorders. Recognition and understanding of motor speech disorders can contribute to a fuller clinical understanding of PPA and its management as well as its localisation and underlying pathology.

Aims: To review the types of motor speech disorders that may occur with PPA, its primary variants, and its overlap syndromes (progressive supranuclear palsy syndrome, corticobasal syndrome, motor neuron disease), as well as with primary progressive apraxia of speech.

Main Contribution: The review should assist clinicians’ and researchers’ understanding of the relationship between motor speech disorders and PPA and its major variants. It also highlights the importance of recognising neurodegenerative apraxia of speech as a condition that can occur with little or no evidence of aphasia.

Conclusion: Motor speech disorders can occur with PPA. Their recognition can contribute to clinical diagnosis and management of PPA and to understanding and predicting the localisation and pathology associated with PPA variants and conditions that can overlap with them.     

Afasia progresiva primaria: del síndrome a la enfermedad

Introduction

Primary progressive aphasia (PPA) is a clinical syndrome characterised by a progressive decline in language and speech of neurodegenerative origin. Major breakthroughs made in recent years have lent us a better understanding of this syndrome, which may be the first manifestation of any of a number of neurodegenerative diseases.

Development

We reviewed the main aspects of PPA epidemiology, clinical manifestations, diagnosis, aetiology and treatment. Most cases manifest sporadically and the typical age of onset is between 50 and 70 years. Three clinically distinct variants have been described: nonfluent or agrammatic PPA, semantic PPA and logopenic PPA. Each of these variants tends to be associated with specific histopathological findings, but clinical diagnostic methods are imperfect predictors of underlying pathology. Anatomical and functional neuroimaging can provide useful biomarkers. Several treatments have been proposed, and while no clear benefits have been demonstrated, acetylcholinesterase inhibitors may be useful, especially in the logopenic variant.

Conclusions

PPA is an emerging syndrome which may be more prevalent than we might expect. It was previously listed as part of the frontotemporal dementia spectrum, and it is also related to Alzheimer disease. Clinical diagnosis, complemented by a biomarker evaluation, may predict the underlying pathology, which in turn will improve treatment possibilities.     

Primary progressive aphasia: defining genetic and pathological subtypes

The primary progressive aphasias (PPA) are a group of clinically, genetically and pathologically heterogeneous neurodegenerative disorders caused by FTLD-tau, FTLD-TDP or Alzheimer's disease pathology. Clinically, three subtypes are recognized, the semantic, logopenic and nonfluent variants but there remains ongoing discussions over how the clinical subtypes should be dissected. This review looks at the genetic and pathological basis of PPA and argues that with the advent of clinical trials in PPA, establishing the underlying pathology accurately during life will become increasingly important. Current and future biomarkers that may help make a pathological diagnosis in life, i.e. PPA-tau, PPA-TDP and PPA-AD, are reviewed including clinical and neuropsychological data, neuroimaging, blood and CSF markers.     

The patterns of progression in primary progressive aphasia—Implications for assessment and management

Background: Primary progressive aphasia (PPA) is a progressive language disorder with preserved cognitive function for at least 2 years from onset. The main variants currently distinguished are: non-fluent/agrammatic (nfvPPA), semantic (svPPA), and logopenic (lvPPA). Patients with initial language presentation may subsequently develop other symptoms, such as behavioural dysfunction or apraxia. The clinical pattern of PPA depends on the location of atrophy, the underlying pathology, and the stage of the disease.

Aims: This review aims at characterising longitudinal changes in clinical presentations of different PPA variants and at presenting implications of these changes for the assessment, diagnosis, and management.

Main contribution: The three PPA variants differ not only in terms of language impairment, but also with regard to cognitive and behavioural profile. Apraxia and rigidity frequently occur in the course of nfvPPA. Patients with lvPPA seem to follow the pattern of aphasic Alzheimer’s disease, where language impairment is accompanied by episodic memory deficit. Individuals diagnosed with svPPA often develop behavioural dysfunction similar to that observed in behavioural variant of frontotemporal dementia.

Conclusions: Implications for patient care are dependent on PPA variant and on the stage of the disease. In svPPA, emphasis should be on the management of semantic and behavioural problems in daily life. Caregivers of nfvPPA patients should be informed about the possible emergence of apraxia and other movement disorders. In contrast, families of individuals with lvPPA should be made aware of and trained to cope with an episodic memory decline and possible progression to other varieties of PPA.     

Understanding and living with primary progressive aphasia: Current progress and challenges for the future

Background: Primary progressive aphasia (PPA) is a progressive language disorder in which aphasia is the first and most prominent symptom of degenerative brain disease. PPA has received increasing attention in the scientific literature over the past 30 years, but there remains a relative lack of awareness and understanding of it in the wider clinical community. As editors of the volume, Clinical Perspectives on Primary Progressive Aphasia, we invited the contributing authors to provide an up-to-date survey of research on a range of topics that are relevant to clinical practice in PPA.

Aims: The aim of this article is to address some key questions that may arise when an individual receives a diagnosis of PPA and to direct readers to additional sources of information in this volume and elsewhere that will allow them to gain further knowledge about topics of interest.

Main Contribution: We address the following questions: (1) What is PPA? (2) How is PPA diagnosed? (3) What happens to a person’s language when they have PPA? (4) How will the disease progress over time? (5) How does PPA impact a person’s life and the life of their family and friends? (6) What treatments and support are available? (7) What other services should we be providing?

Conclusions: Considerable progress has been made in our understanding of PPA and the relationship between the symptomatology, progression, pathology, and genetics of PPA. However, there are many challenges remaining, particularly in terms of ensuring that people with PPA and their families and friends receive optimal information and support at diagnosis and appropriate interventions and/or management strategies throughout their journey with PPA.     

Therapy for naming deficits in two variants of primary progressive aphasia

Background: Primary progressive aphasia (PPA) refers to a progressive and selective decline in language due to neurodegenerative disease. There are three variants of PPA, progressive nonfluent aphasia (PNFA), semantic dementia (SD), and logopaenic progressive aphasia (LPA). All variants include impaired object naming, but distinct underlying deficits might interfere with naming. Therefore, individuals with different types of PPA may respond differently to naming therapy.

Aims: To identify differences in patterns of success and generalisation in response to the same treatment in patient with LPA and a patient with SD. Furthermore, we wished to identify whether the treatment effect was item specific (trained words) or generalised to untrained words in trained or untrained categories.

Methods & Procedures: Participants included an individual with LPA and one with SD. An assessment of lexical processing was administered before and after a naming treatment to assess underlying deficits and generalisation effects. Therapy consisted of a cueing hierarchy treatment. Treatment items consisted of pictured objects in the categories of fruits/vegetables and clothing.

Outcomes & Results: Two different patterns of performance were observed. The LPA participant improved in naming of treated items and untreated items in both treated and untreated categories. The participant with SD improved in naming treated items only, but showed less deterioration in untreated items in treated than untreated categories.

Conclusions: Individuals with PPA can show improved naming (at least temporarily) with therapy, but generalisation to untrained items may depend on the underlying cause of the naming deficit, which may differ across subtypes.     

Longitudinal study of single‐word comprehension in semantic dementia: A comparison with primary progressive aphasia and Alzheimer's disease

Background: Although semantic dementia (SD) is characterised by a multimodal loss of semantic knowledge, it has been demonstrated that lexical‐semantic representations are not equally disrupted in SD and that some categories may be recognised better than others. Little is known, however, about the pattern of the category‐specific comprehension deficits in SD and whether it differs from that of other forms of progressive aphasias.

Aims: This exploratory study aimed to investigate the evolution of category‐specific deficits of single‐word comprehension in progressive aphasias.

Methods & Procedures: A total of 19 patients with a clinical diagnosis of SD, 25 patients with primary progressive aphasia with agrammatic and relatively nonfluent speech (PPA), and 25 patients with Alzheimer's disease (AD) with aphasia were studied longitudinally with the Western Aphasia Battery (WAB). The Auditory Word Recognition subtest of the WAB was utilised to assess comprehension of words derived from different semantic categories.

Outcomes & Results: The analysis revealed that, over time, category‐specific deficits of single‐word comprehension were seen in all three groups of patients. Participants with SD as well as those with PPA and AD were impaired on both pointing to fingers and the right–left orientation task. However, patients with SD were the only group that showed defective recognition of their own body parts. Interestingly, individuals with SD had no difficulties identifying colours, letters, and numbers, even during the follow‐up testing. In addition, in all three groups the extent of category‐specific deficits was associated with the severity of aphasia.

Conclusions: These results indicate that category‐specific deficits of single‐word comprehension are frequently seen not only in patients with SD but also in individuals with PPA or AD, and that the extent of these deficits is associated with the severity of aphasia. However, the pattern of these deficits is often different in these three forms of neurodegenerative conditions and more dissociations between semantic categories are observed as each of these diseases progresses.     

Differential diagnosis of primary progressive aphasia variants using the international criteria

Background: Based upon the profile linguistic and speech deficits, the current International Criteria for diagnosis and classification of primary progressive aphasia (PPA) suggest the distinction of semantic, nonfluent/agrammatic and logopenic variants, each of which is commonly associated with specific pathology and distribution of brain atrophy. Although the vast majority of cases fit in this tripartite schema, some cases remain unclassifiable because of the presence of overlapping deficits, or conversely, because of the presence of isolated deficits.

Aims: In this review, we describe relevant clinical features that characterise each variant and discuss emerging issues derived from the application of the International Criteria.

Main Contribution: Based on a hierarchical approach that comprises the evaluation of single-word comprehension, motor speech disorder, agrammatism and sentence repetition, we propose a heuristic solution aimed to reduce the number of cases with ambiguous identification and thereby optimise the application of the current International Criteria.

Conclusions: Despite the clinical heterogeneity of cases with PPA, the current International Criteria, together with the proposed heuristic solution, provide a valid framework into which the vast majority of cases can be classified. The development of robust clinical markers aimed to distinguish cases with motor speech disorders from those with logopenic variant remains clinically challenging.     

Review: Fluid biomarkers for frontotemporal dementias

Frontotemporal dementias (FTDs) are clinically, genetically and pathologically heterogeneous neurodegenerative disorders that affect the frontal and anterior temporal lobes of the brain. They are relatively common causes of young‐onset dementia and usually present with behavioural disturbance (behavioural variant FTD) or language impairment (primary progressive aphasia), but there is also overlap with motor neurone disease and the atypical parkinsonian disorders, corticobasal syndrome and progressive supranuclear palsy. At post mortem, neuronal inclusions containing tau, TDP‐43 or infrequently FUS protein are seen in most cases. However, a poor correlation between clinical syndrome and underlying pathology means that it is difficult to diagnose the underlying molecular basis using clinical criteria. At this point, biomarkers for the underlying pathology come into play. This paper provides a brief update on fluid biomarkers for FTDs that may be useful to dissect the underlying molecular changes in patients presenting with signs of frontal and/or temporal lobe dysfunction. The hope is that such biomarkers, together with genetics and imaging, would be useful in clinical trials of novel drug candidates directed against specific pathologies and, in the long run, helpful in clinical practice to select the most appropriate treatment at the right dose for individual patients.     

Primary progressive aphasia: a review of neuropsychological tests for the assessment of speech and language disorders

Background: Speech and language impairments are the key clinical feature in several neurodegenerative disorders and primary progressive aphasia (PPA) is the syndrome where they are the prominent features. Their accurate and early identification may increase the diagnosis in the clinical setting. This approach may allow a better discrimination between the different neurodegenerative disorders and the PPA variants, i.e., nonfluent, semantic, logopenic.

Aims: The aim of this work is twofold: (1) to provide an overview of the available neuropsychological tests for the diagnosis of PPA and/or for the differentiation among the PPA variants and (2) to evaluate the methodological quality and the psychometric characteristics of these tests.

Methods & Procedures: This review was conducted following PRISMA guidelines. Search terms were chosen based on the research questions and used in a search in two databases. Then, inclusion criteria were formulated and papers meeting the criteria were reviewed. The methodological quality of the studies was evaluated examining the following items: (1) blindness of personnel, (2) consecutive inclusion of patients, and (3) representativeness of the sample.

Outcomes & Results: A total of 907 papers have been selected from the databases, and 9 of them were included in this review. Among these, three tests aimed to differentiate between PPA variants, two tests were designed for the assessment of language disorders in PPA patients, and four tests were developed to stage the severity of speech/language disorders in PPA patients. All the included studies provided psychometric data about the clinical validity of the tests; however, they present several limitations, both psychometric and methodological.

Conclusion: The number of validation studies is still limited. This brief review reveals the need of linguistically sophisticated tests, characterized by better quality of methods and psychometric characteristics, to be used to systematically evaluate the linguistic abilities of individuals with PPA.     

Clinical phenotypes and genetic biomarkers of FTLD

Frontotemporal lobar degeneration (FTLD) is the most frequent neurodegenerative disorder with a presenile onset. It presents with a spectrum of clinical manifestations, ranging from behavioural and executive impairment to language disorders and motor dysfunction. New diagnostic criteria identified two main cognitive syndromes: behavioural variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA). Regarding bvFTD, new criteria that include the use of biomarkers have been proposed. According to them, bvFTD can be classified in "possible" (clinical features only), "probable" (inclusion of imaging biomarkers) and "definite" (in the presence o f a known causal mutation or at autopsy). Concerning autosomal dominant mutations, microtubule associated protein tau gene mutations have been the first ones identified and are generally associated with early onset bvFTD phenotype. More recently, progranulin gene mutations were recognized in association with familial form of FTLD. In addition, other genes are linked to rare cases of familial FTLD, primarily the newly discovered C9ORF72 hexanucleotide expansion repeats. As regards PPA, new consensus criteria identify three syndromes: primary non-fluent aphasia, semantic variant of PPA and logopenic aphasia, which seems to be associated, in the majority of cases, with underlying Alzheimer's disease pathology. In this review, new criteria, including MRI, cerebrospinal fluid and genetic biomarkers, will be presented and discussed.     

Word retrieval therapies in primary progressive aphasia

Background: Primary progressive aphasia (PPA) with its three variants is a progressive neurodegenerative dementia in which language impairment is the first and most dominant symptom. Traditionally, speech-language pathologists who deliver therapy to adults with acquired neurogenic language disorders shy away from treatment of progressive aphasia as there is no promise of lasting effects and only limited data regarding treatment efficacy.

Aims: This paper comprises the most current review of the literature focused on treatment of naming impairments in PPA, and aims to encourage and assist clinicians in selecting intervention approaches for individuals with PPA. It highlights current trends and challenges in delivering successful therapy for naming deficits in PPA.

Main Contribution: We reviewed papers that reported different forms of naming therapy for patients with PPA, which included interventions that, although not always aimed directly at anomic deficits, brought about improvement in naming. Immediate gains, maintenance, and generalisation effects are summarised, along with a variety of approaches and methodologies that can be applied to the PPA population. We also provide a list of factors that were found to contribute to the success of therapy and to the maintenance and/or generalisation of treatment gains.

Conclusions: Current literature delivers encouraging evidence for clinicians wanting to provide naming therapy to patients with PPA. Although PPA is a progressive disorder, both the immediate treatment effects and, in many cases, maintenance results show that improvements are possible. The issues of generalisation of naming gains beyond the clinician’s office still require more studies to determine the best conditions, designs, and patient suitability.     

Language,executive function and social cognition in the diagnosis of frontotemporal dementia syndromes

Abstract

Frontotemporal dementia (FTD) represents a spectrum of non-Alzheimer's degenerative conditions associated with focal atrophy of the frontal and/or temporal lobes. Frontal and temporal regions of the brain have been shown to be strongly involved in executive function, social cognition and language processing and, thus, deficits in these domains are frequently seen in patients with FTD or may even be hallmarks of a specific FTD subtype (i.e. relatively selective and progressive language impairment in primary progressive aphasia). In this review we have attempted to delineate how language, executive function, and social cognition may contribute to the diagnosis of FTD syndromes, namely the behavioural variant FTD as well as the language variants of FTD including the three subtypes of primary progressive aphasia (PPA): non-fluent/agrammatic, semantic and logopenic. This review also addresses the extent to which deficits in these cognitive areas contribute to the differential diagnosis of FTD versus Alzheimer’s disease (AD). Finally, early clinical determinants of pathology are briefly discussed and contemporary challenges to the diagnosis of FTD are presented.     

Our journey with primary progressive aphasia

Background: My husband Boyd and I had a 6-year journey with primary progressive aphasia (PPA) that held many challenges for us along the way. This article describes that journey.

Aims & Main Contribution: I hope that hearing about our experience may be helpful to other people with a family member who has PPA, and provide clinicians and researchers insight into the PPA journey.

Conclusions: I hope that through more research, there can be more understanding about PPA and consequently more support for families with members suffering this cruel disease.     

Electroencephalography in primary progressive aphasia and apraxia of speech

ABSTRACT

Background: Past research has demonstrated that electroencephalography (EEG) is sensitive to what we now know as Primary Progressive Aphasia (PPA); however, the EEG profiles of patients with Primary Progressive Apraxia of Speech (PPAOS) and PPA, in the context of current consensus criteria, have not been studied.

Aims: The primary goal of this study was to explore the EEG profiles of patients of the nonfluent/agrammatic variant of PPA (agPPA) and PPAOS.

Methods and Procedures: Three patients with agPPA and five patients with PPAOS (two with aphasia) completed a head MRI scan and clinical EEG recording. Clinical radiologists and electrophysiologists reviewed respective imaging, blinded to clinical diagnosis.

Outcomes and Results: Patients with PPAOS who did not have aphasia had normal EEGs, while those with aphasia demonstrated theta slowing. Patients with agPPA also showed theta slowing, with one exception. MRI scans showed non-specific, age-related changes across clinical presentations.

Conclusions: This preliminary study suggests theta slowing is consistent with neurodegenerative aphasia, but not isolated apraxia of speech. EEG is a low-cost mechanism to identify possible biomarkers for use when clinical severity limits behavioral examinations or expert examiners are unavailable.     

Long-term follow-up in primary progressive aphasia: Clinical course and health care utilisation

Background: Primary progressive aphasia (PPA) is a rare disorder. Data on health care utilisation and care-relevant symptoms are scarce.

Aims: The study aimed at finding out how patients with PPA are cared for, the extent of professional support utilised by family caregivers, and which care-relevant clinical symptoms and signs occur with advanced disease.

Method & Procedures: Forty-three family caregivers of patients with PPA were interviewed with a standardised questionnaire.

Outcomes & Results: A majority of caregivers cared for the patients at home without any support. More than 40% of the patients were treated with cholinesterase inhibitors or memantine. Only 9% of the patients received speech therapy. In advanced PPA, the majority of patients were unable to communicate and almost all needed 24-hr care. Other neurological symptoms appeared, and a considerable number of patients suffered from moderate or severe somatic illnesses.

Conclusion: Future studies are necessary to investigate the reasons why the PPA caregivers hardly utilise informal and formal support, what their specific needs are, and which kind of support and interventions prove to be useful.     

Grammatical impairments in PPA

Background: Grammatical impairments are commonly observed in the agrammatic subtype of primary progressive aphasia (PPA-G), whereas grammatical processing is relatively preserved in logopenic (PPA-L) and semantic (PPA-S) subtypes.

Aims: We review research on grammatical deficits in PPA and associated neural mechanisms, with discussion focused on production and comprehension of four aspects of morphosyntactic structure: grammatical morphology, functional categories, verbs and verb argument structure, and complex syntactic structures. We also address assessment of grammatical deficits in PPA, with emphasis on behavioural tests of grammatical processing. Finally, we address research examining the effects of treatment for progressive grammatical impairments.

Main Contribution: PPA-G is associated with grammatical deficits that are evident across linguistic domains in both production and comprehension. PPA-G is associated with damage to regions including the left inferior frontal gyrus and dorsal white matter tracts, which have been linked to impaired comprehension and production of complex sentences. Detailing grammatical deficits in PPA is important for estimating the trajectory of language decline and associated neuropathology. We, therefore, highlight several new assessment tools for examining different aspects of morphosyntactic processing in PPA.

Conclusions: Individuals with PPA-G present with agrammatic deficit patterns distinct from those associated with PPA-L and PPA-S, but similar to those seen in agrammatism resulting from stroke, and patterns of cortical atrophy and white matter changes associated with PPA-G have been identified. Methods for clinical evaluation of agrammatism, focusing on comprehension and production of grammatical morphology, functional categories, verbs and verb argument structure, and complex syntactic structures are recommended and tools for this are emerging in the literature. Further research is needed to investigate the real-time processes underlying grammatical impairments in PPA, as well as the structural and functional neural correlates of grammatical impairments across linguistic domains. Few studies have examined the effects of treatment for grammatical impairments in PPA; research in this area is needed to better understand how (or if) grammatical processing ability can be improved, the potential for spared neural tissue to be recruited to support this and whether the neural connections within areas of dysfunctional tissue required for grammatical processing can be enhanced using cortical stimulation.     

Longitudinal imaging and deterioration in word comprehension in primary progressive aphasia: Potential clinical significance

Background: Three variants of primary progressive aphasia (PPA), distinguished by language performance and supportive patterns of atrophy on imaging, have different clinical courses and the prognoses for specific functions. For example, semantic variant PPA alone is distinguished by impaired word comprehension. However, sometimes individuals with high education show normal performance on word-comprehension tests early on, making classification difficult. Furthermore, as the condition progresses, individuals with other variants develop word-comprehension deficits and other behavioural symptoms, making distinctions between variants less clear. Longitudinal brain imaging allows identification of specific areas of atrophy in individual patients, which identifies the location of disease in each patient.

Aims: We hypothesised that the areas of atrophy in individual PPA participants would be closely correlated with the decline in word comprehension over time. We propose that areas where tissue volume is correlated with word comprehension are areas that: (1) are essential for word comprehension, (2) compensate for word comprehension in some individuals with semantic variant PPA early in the course, and (3) show atrophy in individuals with logopenic and nonfluent variant PPA only late in the course.

Methods and Procedures: Fifteen participants with PPA (five logopenic variant PPA; eight semantic variant PPA; two nonfluent/agrammatic variant PPA; mean age 67.8), underwent high resolution magnetic resonance imaging and cognitive tests at least 9 months apart. The correlations between change in regional volumes and change in auditory word-comprehension scores were investigated using Spearman test.

Outcomes & Results: While scores on auditory word comprehension at Time 1 were correlated with volume loss in right and left temporal pole and left inferior temporal cortex (areas of atrophy associated with semantic variant PPA), deterioration in auditory word comprehension from Time 1 to Time 2 was associated with individual atrophy in left middle temporal cortex, left angular gyrus, and right inferior and middle temporal cortex.

Conclusions: Progressive atrophy in focal areas surrounding left temporal pole and left inferior temporal cortex, and right homologous area is closely related to progressive decline in auditory word comprehension. These correlations likely reflect areas that compensate for subtle deficits early in the course of semantic variant PPA, as well as areas that are critical for auditory word comprehension that eventually atrophy in individuals with other variants of PPA. Individual patterns of atrophy also help us understand and predict the clinical course of individuals, such as associated behavioural or motor deficits.