Nonfluent Variant Primary Progressive Aphasia

Nonfluent variant primary progressive aphasia (progressive nonfluent aphasia) is a neurodegenerative syndrome with effortful, halting speech from apraxia of speech or agrammatism, with preserved single word comprehension. It is caused by degeneration of the left inferior frontal and insular regions.

It accounts for about 20 to 25% of frontotemporal dementia. The prevalence is about 1 to 3 in every 100,000 people, with onset typically between 55 and 70 years and a slight female predominance.

Pathology. Frontotemporal lobar degeneration with tau (progressive supranuclear palsy or corticobasal degeneration) in most, and TDP-43 or Alzheimer disease in a few. GRN variants cause familial cases.

Course. Progression over 6 to 10 years, with spread to mutism, dysphagia, parkinsonism, limb apraxia and falls in many.

Pathophysiology.

Degeneration of the left posterior inferior frontal gyrus, premotor cortex and insula impairs motor speech planning and syntactic processing.

Spread to the basal ganglia and brainstem explains later motor and swallowing features.

• Effortful, halting speech with sound distortions and errors (apraxia of speech), slow rate and prosodic loss.
• Agrammatism: short, simple sentences with omitted function words, and difficulty understanding complex sentences.
• Preserved single word comprehension and object knowledge.
• Dysarthria, buccofacial apraxia, dysphagia, and later mutism.
• Parkinsonism, limb rigidity, apraxia, falls and vertical gaze limitation in some.

Red flags.

• Sudden onset (stroke) or rapid decline (prion disease, tumour).
• Weakness, wasting or fasciculations (motor neurone disease).
• Dysphagia with weight loss or aspiration.

• Clinical diagnosis by consensus criteria: apraxia of speech or agrammatism with at least 2 of impaired comprehension of complex sentences, spared single word comprehension and spared object knowledge.
• Speech and language assessment; neuropsychology; swallowing evaluation.
• MRI shows left inferior frontal and insular atrophy; FDG-PET shows left frontal hypometabolism; tau PET or amyloid biomarkers in selected cases.
• Genetic testing (GRN, MAPT, C9orf72) for family history.
• Exclude stroke and tumour; neurological examination for parkinsonism and motor neurone disease.

Differential diagnosis. Stroke, tumour, logopenic variant, corticobasal syndrome, progressive supranuclear palsy, motor neurone disease, functional dysarthria and apraxia of speech from other causes.

• No disease modifying treatment exists; management is supportive and multidisciplinary.
• Speech and language therapy early: strategies for motor speech (slowed rate, gestures), augmentative and alternative communication (writing, picture boards, tablet based devices), and training for family partners.
• Swallowing assessment, texture modification and nutrition; gastrostomy discussion in advance disease.
• Physiotherapy and occupational therapy for parkinsonism, falls and limb apraxia; aids and home safety.
• Cholinesterase inhibitors and memantine have little benefit and may worsen behaviour; they are not used.
• Treat depression and anxiety: 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; no renal adjustment; avoid with monoamine oxidase inhibitors.
• Carer support, advance care planning, driving and legal review.
• Genetic counselling for familial disease.

Monitoring. Review every 6 months; track speech, swallowing, motor signs, weight and carer strain.

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

Special groups. Younger patients: work, finance and family support.