Beyond β-amyloid: transthyretin cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) is most commonly associated with β-amyloid deposition, but other amyloid proteins may accumulate in leptomeningeal and superficial cortical vessels. We report a man first evaluated neurologically at 44 years of age after approximately one year of recurrent upper-limb and perioral sensory symptoms with speech disturbance, retrospectively considered transient focal neurological episodes (TFNEs). During follow-up, he developed bilateral vitritis and progressive behavioral, psychiatric, and cognitive impairment. Brain computed tomography showed diffuse linear and serpiginous leptomeningeal hyperdensities, consistent with calcified amyloid deposits with focal cortical subarachnoid hemorrhagic lesions SAH); angiography showed no underlying vascular abnormality. Follow-up neuroimaging demonstrated persistent leptomeningeal abnormalities and hemorrhagic lesions. Leptomeningeal biopsy revealed Congo red- and thioflavin S-positive vascular and meningeal amyloid deposits, with negative β-amyloid and amyloid A immunohistochemistry. A subcutaneous adipose tissue biopsy supported systemic amyloid deposition, and genetic testing identified the heterozygous TTR c.265T > C, p.(Tyr89His) variant. Electroneurography showed no large-fiber peripheral neuropathy. An off-label trial of tolcapone produced no clinical benefit. The patient subsequently developed severe cognitive and functional disability and progressive hydrocephalus, and died at 55 years of age from acute respiratory failure. This case highlights TTR-related cerebral amyloid angiopathy (TTR-CAA) as an important non-β-amyloid cause of TFNEs, calcified leptomeningeal infiltration, focal superficial hemorrhage, and progressive neuropsychiatric decline.