Continuing Education Activity

Aphasia is the inability to vocalize or understand spoken or written language. Primary progressive aphasia refers to the group of neurodegenerative diseases showing gradual speech and language impairment as the primary presenting symptom without significant cognitive, physical, or behavioral components. Although aphasia is usually the sudden onset of deficits in expressing or understanding language, such as in stroke, primary progressive aphasia involves the gradual impairment of these functions. This activity reviews the evaluation and management of progressive nonfluent aphasia and highlights the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Identify the etiology and epidemiology of progressive nonfluent aphasia.
• Review the appropriate history, physical, and evaluation to diagnose progressive nonfluent aphasia.
• Outline the treatment and management options available for progressive nonfluent aphasia.
• Summarize the interprofessional team strategies for improving care coordination and communication to advance recovery and rehabilitation from progressive nonfluent aphasia and improve outcomes.

Introduction

Aphasia is a language disorder caused by damage in a specific brain area that controls language expression and comprehension. Primary progressive aphasia (PPA) refers to the group of neurodegenerative diseases showing gradual speech and language impairment as the primary presenting symptom without significant cognitive, physical, or behavioral components.[1] Although aphasia has a sudden onset of deficits, such as in stroke, PPA involves gradual impairment of these functions.

Regarding clinical advances, recent studies have enabled better characterization and differentiation based on linguistic and nonlinguistic profiles of PPA patients. Regarding neuroimaging, techniques such as diffusion imaging and resting-state fMRI allow us to go beyond distinct patterns of focal gray matter atrophy to a deeper understanding of the effects of his PPA on changes in structural and functional connectivity. Finally, despite significant advances in PPA, clinicopathological consensus on pathology is still far from conclusive. Nevertheless, improved characterization of PPA may positively impact patient management.

Fluent aphasia refers to deficits related to comprehension and is usually associated with Wernicke's brain area pathologies. In contrast, nonfluent aphasias produce a failure in language expression, written or verbal, and are often associated with pathologies in Broca's brain area. Although the general concept of a primary progressive language impairment disease process without cognitive effects was first described in the 1890s by Pick and Serieux, it wasn't until the 1980s that PPA was coined and was further explored by Mesulam.[2][3] It was initially called slowly progressive aphasia but was later replaced by the Primary progressive aphasia (PPA) name.[4]

Because of its close relation to Alzheimer's disease and Pick disease, the classification and diagnosis of PPA can sometimes be controversial.[5] PPA is primarily divided into three main variants: nonfluent/agrammatic, semantic, and logopenic.[6] There also exists the disorder of primary progressive apraxia, which is a similarly gradual, degenerative disorder affecting the planning, programming, and sensorimotor commands required for the actual production of speech.[7]

The nonfluent/agrammatic and semantic variants are often grouped under the frontotemporal dementia syndromes, and the logopenic variant is frequently classified as an atypical variant of Alzheimer disease.

Etiology

Nonfluent/agrammatic variant of PPA (nvfPPA)

NfvPPA is most commonly associated with a form of FTD-4R tau.[8][9][10] Other reports indicate TDP-43-A pathology in nfvPPA.[8][9][11] and in some cases, associated with progranulin (PGRN) or chromosome 9 open reading frame 72 (C9ORF72) gene mutations.[12] Less frequently, AD pathology has also been reported in nfvPPA.[8][9] The three principal genes associated with frontotemporal lobar degeneration are Microtubule-associated protein tau (MAPT), Granulin (GRN), and C90rf72.[7] Frontotemporal lobar degeneration is frequently associated with nfvPPA; Interestingly, prospectively recruited cohorts of PPA suggest mutations are rarely the cause of nfvPPA.[13]

The nfvPPA is the most variable of the PPAs and lacks clinicopathologic associations.[7] GRN (granulin) gene mutations on chromosome 17q21.31, which encodes for a protein called progranulin, have been identified in two families with PPA.[14] These mutations have been associated with behavioral variants of frontotemporal lobe dementias.

Semantic Variant of PPA (svPPA)

SvPPA is nearly always associated with underlying TDP-43-C pathological aggregates (75–100% in clinicopathological correlation series), and for the remainder of patients, most often with FTD tau.[8][10]

Lopogenic variant of PPA (lvPPA)

LvPPA is most often caused by AD pathology in as many as 95% of cases.[8][10][15] It is considered one of the possible focal and early onset presentations of AD, even if other pathological profiles have been more rarely described, including Lewy body dementia, TDP-43, and tau.[16][10]

Epidemiology

The estimated prevalence of nfvPPA is approximately 0.5 to 3.9 per 100,000 people.[13] Men and women are affected equally, with an average age of about 60. No demographic, environmental, or socioeconomic risk factors have been identified. Approximately 56% to 86% of cases have coexisting apraxia of speech.[7]

Pathophysiology

The pathophysiology of nfvPPA is not clear and is still being investigated. However, there is always some involvement of the dominant inferior frontal lobe (Broca's area), and atrophy of the insular cortex in the dominant hemisphere can also be found.[17] This coincides with the brain regions involved with language output, sentence processing, and motor speech programming.

The high variability of nfvPPA relative to other PPAs is maintained histologically and remains a continued investigation subject. A large number of patients have been found to have some deposition of abnormal tau on post-mortem examination. TDP-43, or Alzheimer pathology, has also been found in a minority of patients.[8]

History and Physical

Patients with nfvPPA will often present with a gradual worsening of speech disturbances over the years. These aphasia symptoms should be the primary and initial presenting symptoms without significant cognitive, physical, or behavioral deficits. Specific speech disturbances can include worsening grammar, improper use of conjunctions, poor syntax, the omission of verbs, and reversal of binary terms such as "yes" and "no," with some attempts to correct themselves.[3] Speech sound errors may be apparent, and there is effortful, hesitant speech with frequent pauses or halting.[17]

Patients may complain of dropping words, or family members may be concerned about the patient using words out of order. Grammar is likewise affected in the written form. When analyzing the patient's emails or hand-written letters, it can often be found alongside choppy writing and misuse of functional morphemes (the plural -s, verb endings like -ing, -ed, and conjunctions).[7] Comprehension deficits can often be seen with synthetically and grammatically complex sentences. However, the repetition of phrases, single-word comprehension, and reading written words aloud is frequently spared. Apraxia may also be present as a symptom, which may obscure the line between the diagnosis of nfvPPA and primary progressive apraxia.[7] However, the more prominent symptom on presentation is often used to help distinguish the diagnosis between the two pathologies.

Patients will often express frustration and sometimes depression due to their retained insight into their condition. This can lead to family members expressing concern about the patient becoming less talkative and may even be the initial chief complaint that brings the patient for evaluation.[17] Patients can present with behavioral abnormalities along the disease course and may even meet behavior-variant frontotemporal dementia criteria. Patients with nfvPPA may also develop mild cognitive decline several years after the onset of aphasic symptoms.[7]

Physical examination, including the neurological exam, is usually normal. However, there have been reports of rare possible findings of mild ideomotor apraxia, parkinsonism, and increased reflexes.[7] Patients may also show mild frontal lobe dysfunction with impulsivity, perseveration, and attentional deficits.

Nonfluent/Agrammatic Variant of PPA (nvfPPA)

The hallmark clinical features of nfvPPA are effortful speech and agrammatism. Effortful speech is characterized by slow, labored speech production, mainly due to a speech motor planning deficit, i.e., apraxia of speech (AOS).[18] Speech sound errors, consisting of distortions, deletions, substitutions, insertions, or transpositions of speech sounds, are present. Distortions are considered phonetic errors and are caused by AOS, while deletions, substitutions, insertions, and transpositions are phonemic errors and can be caused by a motor speech impairment or a phoneme selection deficit.[19][20] However, there are some significant challenges in differentiating these two types of errors clinically, and both studies show higher rates of phonetic or phonemic errors.[21][20]

in nfvPPA patients have been reported. With the progression of the disease, other cognitive deficits may emerge, including a decline in attentional resources and verbal working memory, as well as executive functions, episodic memory, praxis, and behavioral symptoms.[22]

The current clinical criteria for nfvPPA include at least one of the following core features: (1) Agrammatism in language production; (2) Effortful, halting speech with inconsistent speech sound errors and distortions (AOS); and at least 2 of 3 of the following other features: (1) Impaired comprehension of syntactically complex sentences; (2) Spared single-word comprehension; (3) Spared object knowledge.[3]

Semantic Variant PPA

Patients with the svPPA progressively lose the meaning of words and usually present with severe, progressive anomia and impaired comprehension of single words.[3] In earlier stages, naming and single-word comprehension deficits are more prominent for low-frequency/familiarity items (e.g., "rhinoceros" vs. "dog").[23] Often, the patients replace less frequent words with more familiar ones, typically using the superordinate category (e.g., "animal" for "cat"). Anomia can also be observed in spontaneous speech that is often empty and not very informative.[24]

In the early stages, the inability to comprehend low-familiarity words can be the only symptom accompanying anomia, and patients frequently ask for the meaning of words. The progression of semantic deficits leads to impaired object recognition affecting all sensory modalities, including vision, touch, olfaction, and gustation. The ability to correctly identify objects is strongly influenced by familiarity with the object (e.g., "fork" is more familiar than "compass"). Additionally, individuals with svPPA appear to have disproportionate difficulty understanding concrete concepts relative to abstract concepts.[25]

Episodic memory is relatively preserved in svPPA, especially when tasks with minimal conceptual loading are used.[26] Behavioral abnormalities are typically present in mid-late phases, including disinhibition, irritability, and food taste changes (e.g., preference for sweet foods). Lack of empathy, mental inflexibility, and compulsions - including clockwatching and intense interest in jigsaws—are also frequently noted.[27]

The current diagnostic guidelines [3] identify anomia and single-word comprehension deficits as core features, both essential for diagnosis. At least 3 of the following other diagnostic features must also be present: (1) impaired object knowledge, particularly for low-frequency or low-familiarity items; (2) surface dyslexia or dysgraphia; (3) spared repetition; and 4. spared speech production (grammar and motor speech). 

Lopogenic Variant PPA

Patients with lvPPA typically present with word-finding difficulty, along with sentence repetition deficits and, as the disease progresses, impaired sentence comprehension. Phonological impairments and, specifically, a phonological short-term memory deficit have been suggested to be the core of the syndrome.[28] In accordance with this interpretation, repetition and comprehension of single words remain largely spared. Longitudinal studies have shown that cognitive decline is faster in lvPPA than in other variants and that this decline is not restricted to language functioning [29] but also visuospatial abilities.

Criteria for lvPPA require that both of the following core features must be present: impaired single-word retrieval in spontaneous speech and naming, along with the impaired repetition of sentences and phrases. At least 3 of the following other features must be present: (1) phonological errors in spontaneous speech and naming; (2) spared single-word comprehension and object knowledge; (3) spared motor speech; and (4) absence of frank agrammatism.[3]

Evaluation

The evaluation of a patient with progressive aphasia symptoms requires obtaining a detailed history and specific testing of the patient's speech and language. A more simplified 2-step process has been developed for standardization and eases clinical diagnosis.[3] The first step requires the patient to meet PPA requirements designed by Mesulam, involving a set of inclusion criteria that must all be answered positively and another set of exclusion criteria that must all be answered negatively.[30] This is followed by a group of diagnostic features developed by Gorno-Tempini that help differentiate the different types of PPA.[3]

Beyond the patient history, the Northwestern anagram test (NAT) is a commonly used grammar test, and patients with nfvPPA will have impaired performance. Additionally, the Montreal cognitive assessment (MoCA) can be utilized to evaluate cognitive performance or decline to differentiate from symptoms of dementia. However, the MoCA must be used with caution, as patients with nfvPPA may score lower on the examination only due to reduced spontaneous verbal output and developed apraxia of speech. Depression symptoms can also affect MoCA performance. Cognitive assessment in the context of detailed, careful speech/language examination is essential. After diagnosis, the progressive aphasia severity scale (PASS) allows clinicians to track progression and characterize symptoms, specifically in PPA patients.[31]

Imaging can also be helpful, as fludeoxyglucose positron emission tomography is often used in conjunction with brain magnetic resonance imaging to evaluate primary progressive aphasias. The dominant inferior frontal area (Broca's area) and the insular cortex are most affected in the nfvPPA; however, temporal and parietal hypometabolism is usually not seen.[7]

Neuroimaging Findings

Nonfluent/agrammatic variant of PPA: The left inferior frontal gyrus (pars opercularis) is considered the syndrome-specific epicenter in nfvPPA.[32][33] It is also associated with gray matter (GM) atrophy in the insula, premotor regions, SMA, and striatum.[8][34] Diffusion magnetic resonance imaging (MRI) techniques have shown that the dorsal language pathway of long-range white matter (WM) fibers connecting frontal, subcortical, and parietal areas are primarily involved in neurodegeneration in nfvPPA.[34]

The semantic variant of PPA: The anterior temporal lobes show bilateral atrophy and hypoperfusion in svPPA and are considered the syndrome-specific epicenter.[8][35] This focal anatomical damage makes neuroimaging a complementary tool in the diagnostic process for this PPA variant.[36] The damage is usually greater in the left hemisphere at the first stages of the disease.[37] 

Lopogenic variant PPA: Anatomical damage in lvPPA is typically located in the posterior superior temporal and middle temporal gyri and the inferior parietal lobule.[38] This pattern of atrophy is consistent with the classical anatomical model of the phonological loop.[28] This neurodegenerative pattern is very similar to the one observed in early-onset AD.[39]

Treatment / Management

There are no medications that have been proven beneficial for primary progressive aphasias. Proper treatment and management of PPA begin with a detailed history and analysis of the patient’s speech and language components. Referral to a speech and language pathologist is essential for properly diagnosing language disorders to plan the appropriate treatment regimen and strategy. Speech and language therapy is the most effective treatment of primary progressive aphasias, especially for symptoms of apraxia of speech.[7] 

Transcranial direct current stimulation (tDCS)has been identified as a promising intervention to augment behavioral treatment benefits in language therapy programs. The benefits of tDCS are its low expense, high safety profile, and non-invasive nature–which justify research on its use in PPA as a possible means to augment behavioral intervention effects and reduce the rate of decline in the language.[40]

Differential Diagnosis

Dementia: A patient may have aphasia components as part of a diagnosis of dementia, but nfvPPA will always have aphasia as the initial and primary symptom.

• Ischemic aphasia: An ischemic process will have symptoms of aphasia occurring more acutely. In nfvPPA, a gradually progressive process develops over the years.
• Brain tumor: A brain tumor located at a site affecting speech and language may cause aphasia in a progressive course as the lesion gradually grows. However, imaging would help differentiate a tumor from nfvPPA.
• Alzheimer's disease: Dementia is an initial and prominent sign of Alzheimer disease; nfvPPA will not have dementia at the onset of the disease process, as aphasia should be the primary and initial symptom.
• Frontotemporal dementia: Dementia may develop several years after diagnosing nfvPPA; however, nfvPPA will always have aphasia as the primary and initial symptom.

Prognosis

The disease is progressive, and as no cure currently exists, patients eventually lose the ability to speak and understand both written and spoken language. In the initial years from symptom onset, patients with nfvPPA are typically expected to have predominantly aphasic and apraxic symptoms. However, other cognitive and behavioral impairments are noted as the disease progresses, usually no earlier than eight to twelve years after the initial symptom onset.[41] Because of the heterogeneous variety of the disease process of nfvPPA, individual prognostication is somewhat unreliable.

Most patients with PPA live for 3 to 12 years after diagnosis. For nfvPPA, the median survival rate is approximately seven years.[13] Some rare cases have been described where patients with nfvPPA eventually developed corticobasal syndrome or progressive supranuclear palsy; however, these are often noted with concurrent apraxia.[7]

Complications

• Loss of the ability to speak and write
• Loss of the ability to understand written and spoken language
• Depression
• Poor judgment
• Inappropriate social behavior
• Parkinsonism, increased reflexes, or corticobasal syndrome may occur rarely

Consultations

• Neurologist
• Speech and language pathologist
• Speech therapist
• Social worker
• Psychologist

Deterrence and Patient Education

Because PPA may have an early onset (nvfPPA variant), with a progressive clinical course, patients and families risk developing depression symptoms. Patients with PPA are aware of their deficits, which can further frustrate their psyches. Psychological evaluation, education, and support conferences are often helpful for patients and family members to set expectations, develop coping mechanisms, and provide emotional support. With no cure available, patients may depend on social support for assistance with daily living activities.

Enhancing Healthcare Team Outcomes

Patients with nfvPPA are best managed with an interprofessional team approach. The relationship between the primary clinician, the neurologist, and the speech and language pathologist is critical. The precise evaluations provided by speech and language pathologists can more accurately diagnose a patient's presentation in a subject area with more fluid boundaries between particular diagnoses. The clinician can correlate the clinical findings with imaging findings to solidify the diagnosis. Treatment by speech and language pathologists provides the most significant potential for improvement. It also requires close communication with the clinician to better monitor development and new findings that may need to be addressed several years after the initial symptom presentation. In later stages, PPA may require psychological and psychiatric intervention for cases with significant depression.