Continuing Education Activity

Aphasia is the inability to understand, formulate, or vocalize 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.

Classic aphasia typically arises suddenly, as seen in stroke. In contrast, PPA develops gradually, impairing language functions over time. The condition can be classified as semantic, nonfluent agrammatic, or logopenic, depending on the patient's predominant deficits. PPA has no cure, and the condition progresses with time. However, depending on disease subtype and individual factors, the appropriate management approach can help maintain functional abilities and enhance quality of life for patients with PPA and their caregivers.

This activity for healthcare workers enhances learners' proficiency in evaluating and managing PPA. The activity aims to improve participants' understanding of the condition's neuroanatomical and neuropathological bases, subtypes, diagnostic criteria, evaluation strategies, and treatment options. Learners become equipped to contribute meaningfully to an interprofessional team caring for patients with PPA.

Objectives:

• Identify the signs and symptoms suggestive of primary progressive aphasia.

• Create a clinically appropriate diagnostic plan for an individual with suspected primary progressive aphasia.

• Develop a personalized management plan for a patient diagnosed with primary progressive aphasia.

• Apply effective strategies to improve care coordination among interprofessional team members to facilitate positive outcomes for patients with primary progressive aphasia.

Introduction

Primary Progressive Aphasia Overview

Aphasia is a language disorder arising from damage to a specific brain area controlling language comprehension, formulation, and expression. Primary progressive aphasia (PPA) refers to a group of neurodegenerative diseases in which gradual speech and language impairment are the primary presenting symptoms, unaccompanied by marked cognitive, physical, or behavioral changes.[1] Classic aphasia occurring after conditions such as stroke develops abruptly, but PPA has a gradual onset. 

PPA characterization and differentiation based on linguistic and nonlinguistic profiles are now easier to accomplish due to extensive research. Advanced neuroimaging techniques like diffusion-weighted imaging (DWI) and resting-state functional magnetic resonance imaging (fMRI) allow healthcare providers to go beyond distinct focal gray matter atrophy patterns to a deeper understanding of PPA's effects on structural and functional connectivity changes. However, despite significant diagnostic advances, a clear consensus on its pathology remains elusive. Nevertheless, improved PPA characterization may positively impact patient management.

Fluent aphasia refers to deficits related to comprehension and is usually associated with Wernicke brain area pathologies. In contrast, nonfluent aphasias produce a failure in written or verbal language expression and are often associated with Broca brain area lesions. The general concept of a primary progressive language impairment disease process without cognitive effects was first described in the 1890s by Pick and Serieux. However, Mesulam is presently credited for exploring "slowly progressive aphasia" and coining its name in the 1980s.[2] "Slowly progressive aphasia" was later renamed in the literature as "primary progressive aphasia."[3]

PPA is closely related to Alzheimer and Pick diseases. Thus, PPA classification and diagnosis can sometimes be controversial.[4] PPA's 3 main variants are nonfluent/agrammatic (nfvPPA), semantic (svPPA), and logopenic (lvPPA).[5] PPA presents similarly to primary progressive apraxia, a gradual, degenerative disorder affecting the planning, programming, and execution of sensorimotor commands required for speech production.[6] Pathologically, nfvPPA is grouped under the frontotemporal dementia (FTD) syndromes. In contrast, the logopenic variant is frequently classified as an atypical Alzheimer disease form.

Anatomical Considerations for PPA

In PPA, neuroanatomical changes primarily affect brain regions associated with language processing. The specific areas vary depending on the PPA subtype, but commonly involved brain regions affect left-hemisphere language functions. The Broca area within the left inferior frontal gyrus' posterior portion is responsible for language production and grammar. The Wernicke area within the left superior temporal gyrus' posterior aspect is involved in language comprehension. The angular gyrus at the parietal, temporal, and occipital lobe junction is implicated in semantic processing and reading. The left temporal lobe is crucial in language processing, including semantic memory and word retrieval. Damage to these areas can lead to word-finding and semantic knowledge deficits.

The frontal lobes, especially the left inferior frontal gyrus, are involved in language production, grammar, and articulation. Injury to these areas results in nonfluent or agrammatic speech. The parietal lobes, including the angular gyrus, contribute to language processing, particularly in reading and semantic comprehension. Damage to these regions can impair reading comprehension and semantic processing. Some PPA cases may also affect posterior language areas beyond the traditional language cortex. These areas include regions involved in visual processing and multisensory integration, impacting reading and comprehension abilities. Understanding PPA's neuroanatomical basis is crucial for accurate diagnosis, prognosis estimation, and developing targeted interventions tailored to individual patients' specific language deficits and affected brain regions.

Etiology

PPA is a group of neurodegenerative disorders primarily affecting the language (dominant) areas of the brain. The disorder is usually considered an FTD subtype. Since 2011, FTD has been classified clinically and pathologically into the more common behavioral variant (bvFTD) and primary progressive aphasia (PPA).[7] The 3 PPA variants arise from neurodegenerative changes in different brain areas. The semantic and nonfluent variants are related to FTD, while the logopenic type resembles Alzheimer disease more closely. The semantic variant mainly affects the anterior temporal region. The nonfluent variant impacts the inferior frontal gyrus and precentral cortex regions. The logopenic variant involves the left posterior superior and middle temporal gyri and inferior parietal lobule.[8] The etiology in each type is detailed below.

Nonfluent or Agrammatic PPA Variant

NfvPPA is most commonly associated with an FTD-4R tau protein form.[9][10][11] Other reports indicate TDP-43-A pathology in nfvPPA. Some nfvPPA cases are associated with progranulin (PGRN) or chromosome 9 open reading frame 72 (C9orf72) gene mutations.[12] Less frequently, Alzheimer disease pathology has also been reported in nfvPPA. The 3 genes primarily associated with FTD are microtubule-associated protein tau (MAPT), granulin (GRN), and C9orf72. Frontotemporal lobar degeneration is frequently associated with nfvPPA. Interestingly, prospectively recruited cohorts of PPA suggest mutations are rarely the cause of nfvPPA.[13]

NfvPPA is the most variable of the PPAs and lacks clinicopathologic associations. GRN gene mutations on chromosome 17q21.31, which encodes for a protein called "progranulin," have been identified in 2 families with PPA.[14] These mutations are associated with bvFTD.

Semantic PPA Variant

SvPPA is nearly always associated with underlying TDP-43-C pathological aggregates found in 75–100% of cases in clinicopathological correlation series. This variant is most often associated with FTD tau in the remainder of patients. SvPPA is most consistently associated with left (dominant) temporal lobe pathology.[15]

Logopenic PPA Variant

LvPPA is most often caused by Alzheimer disease pathology in as many as 95% of cases.[16] This condition is recognized as one of the potential focal and early-onset presentations of Alzheimer disease, although other pathological profiles such as Lewy body dementia, TDP-43, and tau have been less commonly reported.[17]

Epidemiology

PPA's prevalence is estimated to be 3 to 4 per 100,000 population.[18] A recent registry study revealed that this condition's incidence was around 1.14 per 100,000 person-years, compared with 35.7 per 100,000 person-years for Alzheimer disease.[19] The nfvPPA's prevalence is approximately 0.5 to 3.9 per 100,000 people. Men and women are equally affected, with an average age of about 60. No demographic, environmental, or socioeconomic risk factors have been identified. Approximately 56% to 86% of individuals with PPA have coexisting speech apraxia. A recent study showed that bvFTD was more common in men, whereas PPA was more common in women.[20]

Pathophysiology

The pathology underlying svPPA mainly involves the atrophy and hypometabolism of the anterior temporal lobes, particularly the temporal poles, with a notable left-sided predominance. In 80% of cases, svPPA exhibits aggregates of TAR DNA-binding protein 43kDa (TDP-43), similar to the pathological features observed in FTD and amyotrophic lateral sclerosis.

The pathophysiology of nfvPPA remains under investigation. This condition exhibits more pathology and disease progression variability than other PPA types. However, involvement of the dominant inferior frontal lobe (Broca area) is consistently observed, with atrophy of the insular cortex in the dominant hemisphere also common.[21] This condition's variability coincides with brain regions associated with language output, sentence processing, and motor speech programming. The pronounced variability of nfvPPA compared to other variants persists histologically and remains a subject of investigation. Many patients exhibit abnormal tau deposition upon postmortem examination, while a minority may show signs of TDP-43 or Alzheimer pathology.

Meanwhile, lvPPA is most commonly an aphasic Alzheimer disease variant. Patients most frequently develop the typical clinical Alzheimer disease features. The pathology is similar to Alzheimer disease but with more left-sided perisylvian or parietal atrophy. Similar to Alzheimer disease, lvPPA also has amyloid and hyperphosphorylated tau accumulation.

History and Physical

Most individuals with PPA have progressive cognitive impairment or dementia with aphasia as the dominant symptom during the first couple of years of the disease course. This presentation differs from other dementia forms, which often have language involvement as a late symptom. Obtaining the history of a progressive language problem that worsens over time is crucial. The symptom differs from acute stroke, which has a sudden onset and is nonprogressive.

The neurologic examination in patients with PPA focuses on assessing language comprehension, expression, and fluency, including verbal and written communication skills. Additionally, cognitive functions such as memory, executive function, and visuospatial abilities are evaluated to rule out other neurodegenerative disorders. Motor function, sensory perception, and reflexes are also assessed to exclude neurological conditions mimicking PPA.

The clinical features and exam findings of each PPA variant are explained below.

History and Physical Examination Features of NfvPPA

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, ie, apraxia of speech (AOS).[22] Speech sound or phonemic errors, such as distortions, deletions, substitutions, insertions, and transpositions, may be present. Distortions are phonetic errors caused by AOS. Deletions, substitutions, insertions, and transpositions are phonemic errors that may arise from a motor speech impairment or phoneme selection deficit.[23][24] However, these 2 error types are often difficult to distinguish clinically. Research shows higher phonetic or phonemic error rates in patients with nfvPPA.[25] Other cognitive deficits may emerge as the disease progresses, including a decline in attentional resources, verbal working memory, executive functions, episodic memory, and praxis. Behavioral changes may also appear.[26]

The clinical criteria for diagnosing nfvPPA require at least 1 core feature, either agrammatism or effortful speech with inconsistent errors. Additionally, at least 2 of the following must be present: impaired comprehension of complex sentences, preserved single-word comprehension, and preserved object knowledge.

History and Physical Examination Features of SvPPA

Individuals with svPPA typically experience a gradual decline in their ability to understand and use words correctly, resulting in severe and progressive difficulties in word retrieval (anomia) and comprehension of single words. The patients' speech output is fluent. Naming and single-word comprehension deficits are more prominent for low-frequency or low-familiarity items (eg, "rhinoceros" vs. "dog") in the illness' earlier stages.[27] Patients often replace less frequent words with more familiar ones, typically using the superordinate category (eg, "animal" for "cat"). Anomia may also be observed in spontaneous speech, often empty and not very informative.[28]

Early in the disease course, patients with svPPA may struggle to understand unfamiliar words, often leading to anomia. These individuals frequently ask for the meaning of words as a symptom. The progression of semantic deficits leads to impaired object recognition affecting all sensory modalities, including vision, touch, olfaction, and gustation. Object familiarity strongly influences the ability to correctly identify objects, eg, a fork may be more familiar to the patient than a compass. Additionally, individuals with svPPA appear to have disproportionate difficulty understanding concrete concepts relative to abstract concepts.[29]

Episodic memory is relatively preserved in svPPA, especially when tasks with minimal conceptual loading are used.[30] Behavioral abnormalities are typically present in mid-to-late phases, including disinhibition, irritability, and food taste changes (eg, developing a preference for sweet foods). Lack of empathy, mental inflexibility, and compulsions, including clockwatching and intense interest in jigsaw puzzles, are also frequently noted.[31]

The current diagnostic guidelines identify anomia and single-word comprehension deficits as core features, and both are essential for diagnosis. At least 3 of the following diagnostic features must also be present: impaired object knowledge (especially for less common items), surface dyslexia or dysgraphia, intact repetition, and preserved speech production (grammar and motor skills).

History and Physical Examination Features of LvPPA

Patients with lvPPA typically present with word-finding difficulty, 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.[32] Single-word repetition and comprehension remain largely spared. Longitudinal studies indicate faster cognitive decline in lvPPA than other variants, impacting not only language but also visuospatial abilities.[33] 

To diagnose lvPPA, impairments in both single-word retrieval (in spontaneous speech and naming) and sentence repetition are required. At least 3 of the following features must also be present: phonological errors in spontaneous speech and naming, preserved single-word comprehension and object knowledge, intact motor speech, and absence of clear agrammatism.

The clinical features of the 3 PPA variants are summarized as follows: 

Evaluation

Evaluating a patient with PPA symptoms involves obtaining a detailed history and specific speech and language testing. A simplified 2-step process has been developed for standardization and ease of clinical diagnosis. The first step requires the patient to meet PPA requirements designed by Mesulam, which include a set of inclusion and exclusion criteria. Afterward, the diagnostic features crafted by Gorno-Tempini aid in distinguishing between the various types of PPA.[34] 

The Northwestern anagram test assesses grammar, often revealing impaired performance in patients with nfvPPA. The Montreal Cognitive Assessment test aids in evaluating cognitive decline, distinguishing it from dementia symptoms, but it must be used cautiously. Reduced verbal output and AOS in nfvPPA may lower Montreal Cognitive Assessment scores, as can depression symptoms. Cognitive assessment alongside detailed speech and language examination is crucial. Following diagnosis, the progressive aphasia severity scale helps clinicians track progression and symptom characterization in people with PPA.[35]

Imaging may also be helpful. Fludeoxyglucose positron emission tomography (FDG-PET) is often used with brain MRI to evaluate primary progressive aphasias. The Broca area and insular cortex are most affected in the nfvPPA, though temporal and parietal hypometabolism are usually absent.

Neuroimaging Findings

Brain MRI and FDG-PET scans are the most important neuroimaging studies for PPA. The findings in each PPA variant are explained below (see Image. Primary Progressive Aphasia Variants).

Neuroimaging for NfvPPA

Patients with nfvPPA typically exhibit more atrophy and hypometabolism, primarily affecting the dominant posterior frontal lobe. The left inferior frontal gyrus (pars opercularis) is considered the syndrome-specific epicenter in nfvPPA.[36][37] Additionally, the condition is associated with gray matter atrophy in the insula, premotor regions, supplementary motor area, and striatum. DWI reveals involvement of the dorsal language pathway, primarily comprising long-range white-matter fibers connecting frontal, subcortical, and parietal areas, in nfvPPA neurodegeneration.[38] Brain MRI has a low sensitivity at 29% but a high specificity at 91%. On the other hand, FDG-PET has roughly 67% sensitivity and 92% specificity.

Neuroimaging for SvPPA

Brain MRI and FDG-PET show atrophy and hypometabolism in the anterior temporal lobes, especially the temporal poles in patients with svPPA.[39] This focal anatomical damage makes neuroimaging a complementary tool in the diagnostic process for this PPA variant.[40] Brain MRI has good sensitivity (98%) and specificity (93%). By comparison, FDG-PET has close to 100% sensitivity and specificity. The damage is usually more significant in the left hemisphere during the disease's first stages.[41] 

Neuroimaging for LvPPA

Anatomical damage in lvPPA is typically located in the posterior superior temporal and middle temporal gyri and the inferior parietal lobule.[42] This atrophy pattern is consistent with the classical anatomical model of the phonological loop. The condition's neurodegenerative pattern is highly similar to the one observed in early-onset Alzheimer disease.[43] Brain MRI has a low sensitivity at 57% but good specificity at 95%. FDG-PET is more sensitive at 92% and specific at 94%.

Treatment / Management

No medication has proven beneficial for PPA. Proper management of this condition begins with a detailed history and analysis of the patient’s speech and language components. Contrary to previous beliefs, speech and language therapy may be considerably beneficial. Referral to a speech and language pathologist is essential for properly diagnosing language disorders and planning the appropriate treatment strategy. Speech and language therapy is the most effective PPA intervention, especially for AOS symptoms.[44]

Transcranial direct current stimulation is seen as a promising intervention to enhance language therapy outcomes in PPA. This treatment's low cost, high safety, and noninvasiveness justify research into its potential to augment behavioral interventions and slow language decline in PPA.[45]

Differential Diagnosis

The most important conditions that must be ruled out when considering PPA include the following:

• Dementia: A patient may or may not have aphasia as part of dementia. In contrast, PPA always has aphasia as the initial and primary symptom.
• Ischemic aphasia: An ischemic process will have symptoms of aphasia occurring more acutely. PPA has a slower course that can take years.
• Brain tumor: A brain tumor located at a site affecting speech and language may cause aphasia progressively as the lesion grows. Other complaints may include headache and sensorimotor weakness, both of which are often absent in PPA. Imaging can also differentiate a tumor from PPA.
• Alzheimer disease: Dementia is an initial and prominent sign of this condition. PPA rarely has dementia at the onset of the disease process but has aphasia as the primary and initial symptom.
• FTD: Dementia is the initial presenting symptom of FTD. In contrast, PPA always has aphasia as the primary and initial manifestation. Dementia may develop, though late in the illness course.

A thorough history, physical examination, and diagnostic testing can help differentiate PPA from these clinical entities.

Prognosis

PPA is progressive, and no cure currently exists. Thus, patients eventually lose the ability to speak and understand both written and spoken language. Individuals with PPA are typically expected to have predominantly aphasic and apraxic symptoms initially. However, other cognitive and behavioral impairments develop as the disease progresses, usually no earlier than 8 to 12 years after initial symptom onset.[46] Individual prognostication is somewhat unreliable because of PPA's heterogeneity.

Most patients with PPA live for 3 to 12 years after diagnosis. The mean survival from symptom onset for svPPA is 12 years, nfvPPA is 7.1 years, and lvPPA is 7.6 years. The most frequent cause of death is aspiration pneumonia.[47]

Complications

PPA's complications include the following: 

• 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, hyperreflexia, and corticobasal syndrome may occur but rarely

Managing this condition's complications requires a multidisciplinary approach involving speech-language therapy, cognitive rehabilitation, psychosocial support, and caregiver education to optimize patient care and quality of life.

Consultations

Consultation with a neurologist, speech and language pathologist, speech therapist, social worker, and psychologist is necessary to optimize patient outcomes.

Deterrence and Patient Education

Primary preventive measures for PPA focus on reducing the risks associated with neurodegenerative diseases and promoting brain health. These measures include maintaining a healthy lifestyle with a proper diet, regular exercise, and mental stimulation through activities like reading and puzzle-solving. Managing cardiovascular risk factors like hypertension, diabetes, and obesity is crucial, as cardiovascular health is closely linked to brain health. Additionally, protecting against head injuries and maintaining social connections can help preserve cognitive function and reduce the risk of cognitive decline.

Secondary preventive measures for PPA involve early detection and management of underlying medical conditions potentially contributing to cognitive decline. Seeking medical advice if experiencing memory loss or language difficulties can lead to early diagnosis and intervention, which may help slow the progression of PPA and other neurodegenerative diseases. Regular medical check-ups and screenings can aid in detecting and managing risk factors such as hypertension, diabetes, and hypercholesterolemia.

Patients with PPA and their families have an increased depression risk due to the condition's potentially earlier onset and progressive nature compared to Alzheimer disease. Patients' awareness of their deficits can exacerbate psychological distress. Psychological evaluation, education, and support conferences can assist patients and families in managing expectations, developing coping strategies, and receiving emotional support. Without a cure, patients may rely on social support for assistance with daily activities. Early intervention with appropriate treatment and support services can improve outcomes for people with PPA and their caregivers.

Pearls and Other Issues

PPA presents a unique set of diagnostic and management challenges. Diagnosing this condition requires a comprehensive evaluation, including detailed language assessments and neuroimaging studies to identify specific neurodegenerative patterns. Subtyping PPA into its 3 main variants—nfvPPA, svPPA, and lvPPA—is crucial for tailoring interventions and predicting disease progression.

Semantic memory deficits and fluent but empty speech characterize svPPA. Interventions focus on augmenting residual semantic knowledge through strategies like semantic cueing and categorization tasks. In contrast, nfvPPA manifests with effortful, agrammatic speech, often accompanied by AOS. Treatment for nfvPPA may involve speech therapy targeting grammatical structures and articulatory planning alongside compensatory strategies like using simplified language. LvPPA, typified by word-finding difficulties and impaired phonological processing, benefits from interventions that enhance phonological awareness and word retrieval, including phonological cueing and repetition exercises.

Managing PPA requires a multidisciplinary approach. Collaborative efforts are essential for developing individualized treatment plans, providing support to patients and caregivers, and facilitating communication strategies to maintain functional abilities and quality of life throughout the disease course.

Enhancing Healthcare Team Outcomes

Patients with PPA are best managed with an interprofessional team approach. The relationships among the primary clinician, neurologist, and speech and language pathologist are 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. Proper management 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. PPA may require psychological and psychiatric intervention for patients who develop significant depression later in the illness course.