Primary Progressive Aphasia

Primary progressive aphasia is a neurodegenerative syndrome in which language impairment is the most prominent early feature and the main cause of loss of daily function for the first 2 years. It has three main variants: semantic, nonfluent and logopenic.

The prevalence is about 3 in every 100,000 people, and it is probably under recognised. Onset is usually between 50 and 70 years, with a similar distribution in both sexes.

Causes. Frontotemporal lobar degeneration (tau or TDP-43 pathology) accounts for most nonfluent and semantic cases, and Alzheimer disease for most logopenic cases. A minority have familial disease, such as GRN and C9orf72 variants.

Course. Language decline over years, with later spread to behaviour, motor function or memory. Median survival is about 10 to 12 years from onset and depends on variant and pathology.

Pathophysiology.

Focal neurodegeneration of the dominant hemisphere language network, with inferior frontal, anterior temporal or temporoparietal involvement by variant, causes progressive loss of language.

The pathology spreads along connected networks over time.

• Insidious word finding difficulty, hesitant or effortful speech, loss of word meaning, or impaired repetition.
• Preserved memory, behaviour and visuospatial function early, with isolated language impairment.
• Reading and writing difficulty, and errors in grammar or sound structure by variant.
• Anxiety, frustration and withdrawal as communication fails; later behavioural change, parkinsonism or motor neurone disease signs.

Red flags.

• Sudden onset (stroke) or rapid progression over weeks (prion disease, tumour, encephalitis).
• Seizures, headache, focal weakness or visual field loss.
• Prominent motor neurone disease or parkinsonism features, or family history of dementia.

• Clinical diagnosis by consensus criteria: language impairment as the main deficit, with the variant identified from speech and language testing (naming, repetition, comprehension, grammar, motor speech).
• Neuropsychology and speech and language assessment.
• MRI of the brain (left perisylvian, anterior temporal or inferior frontal atrophy by variant), FDG-PET and amyloid biomarkers (PET or cerebrospinal fluid) to define Alzheimer pathology.
• Genetic testing when family history is present; EEG when seizures or encephalitis are suspected.
• Exclude stroke, tumour, infection and metabolic causes.

Differential diagnosis. Stroke, tumour, Alzheimer disease with language onset, behavioural variant frontotemporal dementia, corticobasal syndrome, dysarthria or apraxia of speech from other causes, depression and functional language disorder.

• Speech and language therapy early, with strategies to maintain communication (word retrieval, script training, communication aids and augmentative devices); family training.
• Treatment follows the variant and the likely pathology: logopenic variant (Alzheimer pathology) may benefit from donepezil; semantic and nonfluent variants do not usually benefit and may worsen with cholinesterase inhibitors.
• Donepezil for logopenic variant or confirmed Alzheimer pathology: 5 mg orally once daily at night for 4 to 6 weeks, then 10 mg once daily. Maximum 10 mg daily. Monitor heart rate, weight, nausea, diarrhoea and syncope. Avoid in bradycardia, sick sinus syndrome, heart block and active peptic ulcer; use caution in asthma and seizures; no renal adjustment.
• Treat depression, anxiety and compulsions: sertraline 50 mg orally once daily, increased by 50 mg every 1 to 2 weeks as needed to 100 to 200 mg daily. Maximum 200 mg daily. Monitor mood and suicidal thoughts, sodium, bleeding and serotonin toxicity. Reduce dose (or use alternate days) in hepatic impairment; avoid with monoamine oxidase inhibitors.
• Swallowing assessment, nutrition and advance care planning while the person can take part in decisions.
• Occupational therapy, carer support, driving and work review; psychological support.
• Genetic counselling for familial disease.

Monitoring. Review every 6 months; track language, behaviour, swallowing and carer strain.

Referral and escalation. Cognitive neurology and speech and language therapy; palliative care in later stages.

Special groups. Younger patients: employment, finances and family counselling.