PPA is a rare neurological syndrome characterized by the gradual and isolated decline of language function. Unlike aphasia resulting from a stroke, PPA is a neurodegenerative condition that worsens over time. When diagnosed, families often question the risk to other members. This article explores the nature of PPA and its hereditary component.
Defining Primary Progressive Aphasia
PPA is defined as a form of frontotemporal lobar degeneration (FTLD) where the first symptom is impaired communication skills. This difficulty progresses over at least two years, while other cognitive functions remain relatively intact initially. The diagnosis is clinical, based on a decline in the ability to speak, understand, read, or write.
The syndrome is divided into three main clinical variants, each associated with a distinct pattern of language decline. The nonfluent/agrammatic variant (nfvPPA) primarily affects speech production, making it effortful, halting, and often grammatically incorrect. The semantic variant (svPPA) results in the loss of word meaning, leading to trouble naming objects or understanding concepts despite fluent speech.
The logopenic variant (lvPPA) is marked by pronounced word-finding difficulties and frequent pauses in speech, though grammar and word meaning may be preserved early on. Distinguishing between these three variants is important because they often correlate with different underlying brain pathologies.
The Role of Genetics in PPA
The overwhelming majority of PPA cases are not hereditary. Although PPA is a subtype of frontotemporal dementia (FTD), which often has a strong hereditary link, most individuals with PPA have no family history of a similar disorder. However, a significant minority, estimated between 10 to 20% of cases, occur in individuals with a recognizable familial pattern.
In familial cases, PPA often follows an autosomal dominant inheritance pattern, meaning only one copy of the mutated gene is needed to develop the condition. The risk of inheriting the mutation from an affected parent is 50%, though the age of onset and the specific symptoms, known as penetrance, can vary greatly.
Key genetic mutations linked to this inherited risk include the C9orf72 expansion, a common cause of familial FTD and amyotrophic lateral sclerosis (ALS). Mutations in the GRN (progranulin) and MAPT (microtubule-associated protein tau) genes are also implicated. Genetic counseling and testing are recommended for individuals who have a strong family history of PPA, FTD, or ALS.
Understanding Sporadic PPA
The vast majority of PPA diagnoses (80 to 90%) are classified as sporadic, meaning they occur without a known genetic cause or family history. In these non-inherited cases, the condition is caused by an abnormal accumulation of proteins within brain cells, a process called proteinopathy. These protein aggregates lead to the progressive death of neurons in the language-dominant regions of the brain.
Different protein aggregates are found depending on the clinical variant. The semantic variant (svPPA) is most commonly associated with the accumulation of TDP-43 protein. Conversely, the nonfluent/agrammatic variant (nfvPPA) is frequently linked to abnormal deposits of the tau protein.
The logopenic variant (lvPPA) is often associated with amyloid-beta and tau proteins, the pathological hallmarks of Alzheimer’s disease. The specific proteinopathy determines the pattern of brain atrophy observed on neuroimaging and the resulting language symptoms. Sporadic PPA often manifests before the age of 65.
Diagnosis and Management
The diagnostic process for PPA is a multi-step evaluation designed to confirm language decline and exclude other potential causes, such as stroke or tumor. This involves a comprehensive neurological exam and detailed language testing performed by a speech-language pathologist to characterize the specific aphasia variant. Neuroimaging, using magnetic resonance imaging (MRI) or fluorodeoxyglucose positron emission tomography (FDG-PET) scans, is used to visualize the pattern of brain atrophy and hypometabolism.
These scans reveal the characteristic shrinking of the left hemisphere’s language areas. There is currently no cure for PPA, and no medication has been approved to halt its progression. Management focuses on maintaining communication function and quality of life for as long as possible.
Speech and language therapy (SLT) is the primary intervention, focusing on strategies to compensate for lost language skills and finding alternative methods of communication. Therapists work with individuals on maximizing their remaining abilities and also with caregivers to establish effective communication techniques. Ongoing research is exploring pharmacological interventions, particularly for the logopenic variant, which may respond to certain Alzheimer’s medications due to its underlying pathology.