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.     

Familial primary progressive aphasia

Primary progressive aphasia (PPA) is a neurodegenerative disease presenting with isolated, progressive, language dysfunction. After at least 2 years, dementia may develop, but the aphasia predominates. Few families with hereditary PPA have been reported; some have autosomal dominance. A chromosome 17 mutation in tau exon 13 has been found in one family, and a few have linkage to chromosome 17. However, early appearance of prominent memory, behavior, and motor impairments differentiates these patients from typical PPA. The objective was to report clinical features, pathology, and genetic analysis of a family with typical PPA. We report three siblings with the typical clinical syndrome of PPA. Each presented with word-finding difficulties and early anomia. Ages at onset were 60, 61, and 65 years. Aphasia was the only symptom for at least 2 years. A nonaffected brother is 75 years of age. Family history review found no other affected relatives. Neuropathology in one patient demonstrated "dementia lacking distinctive histopathology" with ubiquitin-positive cortical neurons. DNA analysis of the proband did not detect any known mutation in tau exons 1-5, 7, or 9-13. To our knowledge, this is the first family presenting with hereditary aphasia in which typical PPA occurs in all affected members.     

Vasectomy in men with primary progressive aphasia.

OBJECTIVE: To study the frequency of vasectomy in men with primary progressive aphasia (PPA). BACKGROUND: PPA is a dementia syndrome in which aphasia emerges in relative isolation during the initial stages of illness. On the basis of a clinical observation in a patient who dated the onset of symptoms to the period after a vasectomy, and because of the curious sharing of the tau protein exclusively by brain and sperm, vasectomy rates were examined in men with PPA. METHOD: This study used a case control design. Forty-seven men with PPA and 57 men with no cognitive impairment (NC) between 55 and 80 years of age were surveyed about a history of vasectomy. RESULTS: The age-adjusted rate of vasectomy in PPA patients (40%) was higher than in NC (16%, P=0.02). There was a younger age at onset for the patients with vasectomy (58.8 vs. 62.9 y, P=0.03). CONCLUSIONS: Vasectomy may constitute one risk factor for PPA in men. Potential mechanisms mediating risk include vasectomy-induced immune responses to sperm, which shares antigenic epitopes with brain. Antisperm antibodies can also develop in women and become risk factors for PPA.     

Genetic screen in a large series of patients with primary progressive aphasia

Introduction

Primary progressive aphasia (PPA) is a neurological syndrome, associated with both frontotemporal dementia and Alzheimer's disease, in which progressive language impairment emerges as the most salient clinical feature during the initial stages of disease.

Agrammatic primary progressive aphasia in two dextral patients with right hemispheric involvement

Agrammatic primary progressive aphasia (PPA-G) has been known to be associated with focal brain atrophy involving the left posterior frontal and anterior insular regions. However, aphasia can also rarely result from right hemispheric lesions in right-handed patients, so-called crossed aphasia in dextrals (CAD). We report two right-handed patients with PPA-G whose 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) showed hypometabolism predominantly in the right hemisphere, implicating “crossed PPA-G.”     

Functional disability in primary progressive aphasia

Background: In primary progressive aphasia (PPA), assessment of language predominates over assessment of functional impairment in activities of daily living (ADLs) in clinical and research environments. Most of the knowledge on functional disability in PPA relies largely on anecdotal experience and limited numbers of studies published to date.

Aims: (1) To describe the different patterns of ADL functional disability in the main PPA variants: semantic variant, nonfluent aphasia, and the more recently defined logopenic variant; (2) to draw relations between functional disability, cognitive, and behavioural symptoms in the PPAs; (3) to examine the impact of functional disability on carer burden, and (4) to provide specific strategies to address the described problems.

Main Contribution: Profiles of disease progression are described from a functional perspective, as well as the relationship (or lack thereof) between functional disability and cognitive and behavioural symptoms. Dementia-management strategies for carers and professionals in overcoming day-to-day difficulties are provided, and the impact of functional deficits on those around the patient, including their spouses and children, are discussed.

Conclusions: Patterns of ADL functional disability and their progression vary between PPA subtypes. Understanding these different profiles of impairment is critical to the development of tailored interventions. There is a range of therapeutic strategies which can be trialled to promote improved ADL functioning, which in turn may also help in reducing levels of carer burden in PPA.     

Molecular neuroimaging in primary progressive aphasia with predominant agraphia

A 62-year-old male presented with progressive isolated writing and spelling difficulties. Neurological, neuropsychological, speech, and language evaluations identified only minimal additional abnormalities. The presenting characteristics did not meet criteria for any particular variant of primary progressive aphasia; his clinical presentation is best described as primary progressive aphasia, with a predominant, almost pure agraphia. Brain MRI showed asymmetric, bilateral parenchymal volume loss, with left hippocampal atrophy. Fluorodeoxyglucose-F18 positron emission tomography showed hypometabolism in the lateral left frontal lobe, including Exner’s area. Beta-amyloid and tau-positron emission tomography scans were negative, indicating the etiology was not Alzheimer’s disease. The underlying neurodegenerative process is most likely related to TDP-43, although a 4-repeat tauopathy cannot be excluded. Following his clinical evolution, and ultimately identifying the underlying pathology from autopsy, will elucidate the etiology of this interesting clinical presentation.     

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.     

Telerehabilitation of anomia in primary progressive aphasia

Background: The efficacy of telerehabilitation-based treatment for anomia has been demonstrated in post-stroke aphasia, but the efficacy of this method of anomia treatment delivery has not been established within the context of degenerative illness.

Aims: The current study evaluated the feasibility and efficacy of a telerehabilitation-based approach to anomia treatment within the three subtypes of primary progressive aphasia (PPA).

Methods & Procedures: Each of the three telerehabilitation participants represented a distinct subtype of PPA. Following a baseline evaluation of language and cognition, a phonological treatment and an orthographic treatment were administered to all participants over the course of 6 months. One month after the end of treatment, a post-treatment evaluation began. All treatment sessions and the majority of the evaluation sessions were administered via telerehabilitation. Treatment effects were examined within each subject, and treatment effects were also compared between each telerehabilitation participant and a group of in-person participants who had the same subtype of PPA.

Outcomes & Results: All three telerehabilitation participants exhibited positive treatment effects. CGR (nonfluent/agrammatic variant PPA) and WCH (logopenic variant PPA) showed maintenance of naming for prophylaxis items under both treatment conditions, while ACR (semantic variant PPA) demonstrated increased naming of remediation items under the phonological treatment condition. Compared to in-person participants with the same subtype of PPA, each of the telerehabilitation participants typically showed effects that were either within the expected range or larger than expected.

Conclusions: Telerehabilitation-based anomia treatment is feasible and effective in all three subtypes of PPA.     

Writing disorders in primary progressive aphasia]

We investigated longitudinally three patients with primary progressive aphasia (PPA) who exhibited fluent aphasia at the early stage, in terms of writing disorders. The writing disorders were the most striking during the aphasia quotient (AQ) was 50-60 for all these patients. The characteristic features were as follows: (i) several types of perseverative errors, especially on spontaneous writing rather than on dictation (ii) confusion between letters and pictures (iii) preserved copying ability and (iv) total loss of writing ability at the final stage. Additionally, through the progression, linguistic level of the perseverative errors changed from sentence to word and finally to phoneme. The results suggest that the fluent type PPA patients have difficulty to recall proper letters and to arrange them in correct order following the writing plan, in addition to disinhibition and lexical stereotyping which were commonly observed in perseverative patients. The results also suggest that their writing disorders seem to be based on difficulty of letter manipulation as symbols.     

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.     

The genetics of primary progressive aphasia

Background: Primary progressive aphasia (PPA) is a disorder in which language impairment is the initial and predominant symptom. Three main phenotypes are described, the nonfluent variant (nfvPPA), the semantic variant (svPPA) and the logopenic variant (lvPPA). Although PPA is most commonly a sporadic disorder, recent studies have shown an association of PPA with mutations in a number of genes.

Aims: To understand the extent to which PPA may be inherited, which genetic mutations may cause it, and whether the phenotypes of genetic PPA differ from sporadic PPA.

Main Contribution: In around 20–30% of patients with PPA, a family history is present although nfvPPA is more heritable than svPPA and lvPPA which are both usually sporadic disorders. Mutations in the progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72), genes are the major causes of genetic PPA.

Conclusions: Key pointers that may suggest testing for a GRN mutation in PPA are a family history of one of the disorders within the frontotemporal dementia spectrum, a nfvPPA phenotype, particularly if presenting with a prominent anomia and asymmetrical fronto-temporo-parietal atrophy. In someone with nfvPPA and a family history, GRN should be tested initially but a search for hexanucleotide repeat expansions in the C9orf72 gene should be performed if negative, particularly if there are features of motor neurone disease, or a family history of someone with motor neurone disease. Mutations in other genes are only very rare causes of PPA but if GRN and C9orf72 are both negative, testing for mutations in the microtubule-associated protein tau (MAPT), valosin-containing protein (VCP) and presenilin 1 (PSEN1) should be considered.     

An update on primary progressive aphasia

Primary progressive aphasia is a neurodegenerative syndrome characterized by a relentless dissolution of language but relative sparing of other cognitive domains during the initial stages of the disease. Substantial progress has been made in understanding the clinical characteristics, imaging, genetics, and neuropathology of this syndrome. This article reviews the clinical criteria for diagnosing primary progressive aphasia and some of the more recent research advances in this field.     

Progranulin-associated PiB-negative logopenic primary progressive aphasia

The logopenic variant of primary progressive aphasia (lvPPA) strongly associates with Alzheimer’s disease, but can also associate with frontotemporal lobar degeneration. We aimed to assess the frequency of lvPPA in patients with speech and language disorders without β-amyloid deposition, and to perform detailed neuroimaging and genetic testing in such lvPPA patients. Seventy-six patients with a neurodegenerative speech and language disorder and Pittsburgh compound B (PiB) PET imaging demonstrating no β-amyloid deposition were analyzed. Six lvPPA patients (8 %) were identified. All six underwent progranulin (GRN) gene testing. Structural abnormality index maps and Cortex ID analysis were utilized to assess individual patterns of grey matter atrophy on MRI and hypometabolism on 18-F fluorodeoxyglucose (FDG) PET. Statistical parametric mapping was used to perform MRI and FDG-PET group comparisons between those with (GRN-positive) and without (GRN-negative) progranulin mutations. All six lvPPA patients showed left temporoparietal atrophy and hypometabolism. Three patients (50 %) were GRN-positive. Speech, language, and neurological and neuropsychological profiles did not differ between GRN-positive and negative patients, although GRN-positive patients had family histories, were on average 8 years younger, and had lower PiB-PET ratios. All six patients showed similar patterns of atrophy and hypometabolism, although, as a group, GRN-positive patients had more severe abnormalities, particularly in anteromedial temporal lobes. Logopenic PPA accounts for a small minority of neurodegenerative speech and language disorders not associated with β-amyloid deposition. Identification of such patients, however, should prompt testing for GRN mutations, since GRN-positive patients do not have distinctive features, yet account for 50 % of this patient population.     

A review on primary progressive aphasia

Primary progressive aphasia (PPA) is a neurodegenerative disease of insidious onset presenting with progressive isolated loss of language function, without significant impairment in other cognitive domains. Current diagnostic criteria require the language dysfunction to remain isolated for at least two years, and to remain the salient feature as the disease progresses, usually to involve other domains such as behavior, executive functions, and judgment. Although PPA in its early stages can usually be differentiated from probable Alzheimer’s disease (PRAD) and the behavioral variant of frontotemporal lobar degeneration by the absence of significant changes in memory and behavior, and the preservation of activities daily living, progression of the disease often leads to deficits more consistent with the latter. Underlying etiologies remain heterogeneous: the neuropathological characteristics associated with frontotemporal lobar degeneration, cortocobasal degeneration, and motor neuron disease are usually found. There is a strong genetic susceptibility with affliction of first-degree relatives with similar disease in up to 40 to 50% in some series. Pathogenic mutations in genes coding for the proteins tau and progranulin have been isolated. These are leading to a better understanding of the neuropathological mechanisms and hopefully targeted disease-modifying therapy. Current therapy is limited to improving mood symptoms and targeting behavior changes as they develop. Referral to specialized centers where speech therapy, counseling, and education for both patient and caregiver are available may be helpful.     

Neuropsychiatric aspects of primary progressive aphasia

Few studies have reported neuropsychiatric symptoms (NPS) in primary progressive aphasia (PPA), a neurodegenerative disorder that primarily affects the left hemisphere. Depression is associated with left-sided stroke, but it remains unclear whether depression and other NPS are also associated with PPA. The authors compared the frequency of neuropsychiatric symptoms in 55 cases of PPA with 110 cognitively normal persons matched for age, sex, and education. Depression, apathy, agitation, anxiety, appetite change, and irritability are associated with PPA. Hallucinations, delusions, and night-time behavior were not associated with PPA.