• Yoshiki Sekijima and Luísa Sousa.
• Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan.
• Amyloid. 2024 Dec 3: 1121-12.

AbstractThe clinical efficacy of transthyretin (TTR) tetramer stabilisers and TTR gene silencers in addition to liver transplantation has been established for hereditary ATTR (ATTRv) amyloidosis. Accordingly, non-central nervous system (CNS) systemic amyloidosis manifestations, such as peripheral neuropathy and cardiomyopathy, are now being overcome. However, emerging disease-modifying therapeutics have limited effects on CNS amyloidosis since they target the blood-circulating TTR produced in the liver, and not the cerebral spinal fluid (CSF) TTR synthesised in the choroid plexus. CNS involvement is therefore becoming the most common and severe complication in patients with ATTRv amyloidosis, including transient focal neurologic episodes, haemorrhagic and ischaemic stroke, cognitive decline, and cranial nerve dysfunction. Pathologically, extensive amyloid depositions are observable in the leptomeninges and leptomeningeal vessels, which are in direct contact with the CSF. Amyloid positron emission tomography is a useful biomarker for the early detection and treatment evaluation of early-onset ATTRv amyloidosis with the V30M (p.V50M) variant. Treatment-wise, blood-brain barrier-permeable stabilisers, intrathecal injection of silencers, and monoclonal antibodies against misfolded TTR and/or ATTR amyloid may potentially ameliorate CNS ATTR amyloidosis. The development of novel imaging/CSF biomarkers and disease-modifying therapies are the greatest unmet medical need in ATTRv amyloidosis and require further clinical trials.

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