Aphasia is the inability to vocalize or understand the spoken or written language. 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. Although aphasia itself is usually the sudden onset of deficits in expressing or understanding language, such as in stroke, PPA involves the gradual impairment of these functions.
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 the expression of language, written or verbal, and are often associated with pathologies in the Broca's area of the brain. 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. It was initially called slowly progressive aphasia but later replaced by the PPA name.
Because of its close relation to Alzheimer disease and Pick disease, the classification and diagnosis of PPA can sometimes be controversial. However, PPA is primarily broken up into three main variants: nonfluent/agrammatic variant, semantic variant, and logopenic variant. 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.
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's disease. This article aims to review the nonfluent/agrammatic variant of PPA (nfvPPA).
The three principal genes associated with frontotemporal lobar degeneration are MAPT, GRN, and C90rf72. Frontotemporal lobar degeneration is frequently associated with nfvPPA; however, prospectively recruited cohorts of PPA suggest mutations are rarely the cause of nfvPPA. This variant is the most variable of the PPAs and lacks any tight clinicopathologic associations.
GRN (granulin) gene mutations on chromosome 17q21.31, which encodes for a protein called progranulin, have been identified in two families with PPA. These mutations have been associated with behavioral variants of frontotemporal lobe dementias.
The estimated prevalence of nfvPPA is approximately 0.5 to 3.9 per 100,000 people. Men and women are affected equally with an average age of onset of about 60 years. No demographic, environmental, or socioeconomic risk factors have been identified. Approximately 56% to 86% of cases have coexisting apraxia of speech.
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. 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's pathology have also been found in a minority of patients.
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 in the absence of 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. Speech sound errors may be apparent, and there is effortful, hesitant speech with frequent pauses or halting.
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. It can often be found alongside choppy writing and misuse of functional morphemes (the plural -s, verb endings like -ing, -ed, and conjunctions) when analyzing the patient’s emails or hand-written letters. 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. However, the more prominent symptom on presentation is often used to help make the diagnostic distinction 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. Patients can present with behavioral abnormalities along the disease course and may even meet the criteria for behavior variant frontotemporal dementia. Patients with nfvPPA may also develop mild cognitive decline several years after the initial onset of aphasic symptoms.
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. Patients may also show some mild frontal lobe dysfunction with impulsivity, perseveration, and attentional deficits.
The evaluation of a patient that presents with progressive symptoms of aphasia 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 more ease of clinical diagnosis. The first step requires the patient to meet PPA requirements developed 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. This is followed by a set of diagnostic features developed by Gorno-Tempini that help differentiate amongst the different types of PPA.
Beyond the patient history, the Northwestern anagram test (NAT) is a commonly used test of grammar, 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.
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.
There are no medications that have been proven beneficial for primary progressive aphasias. Proper treatment and management of nfvPPA begins 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.
The disease is progressive and, as no cure currently exists, patients are generally expected to eventually lose the ability to speak and understand both written and spoken language. In the initial years from symptom onset, patients with nfvPPA would typically be expected to have predominantly aphasic and apraxic symptoms. However, other cognitive and behavioral impairments can be seen in more terminal stages, usually no earlier than eight to twelve years after the initial symptom onset. Because of the heterogeneous variety of the disease process of nfvPPA, making 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. Some rare cases have been described where patients with nfvPPA eventually developed corticobasal syndrome or progressive supranuclear palsy; however, these are commonly seen in those patients with concurrent apraxia.
Because nfvPPA may have an early age onset, with a progressive clinical course, patients and families are at risk of developing depression symptoms. Patients with nfvPPA are aware of their deficits, which can add further frustration to their psyche. 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.
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 highly specific 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 initial symptom presentation. Psychological and psychiatric evaluation and management may be required for cases with significant depression.
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