Neuropathology of central nervous system involvement in TTR amyloidosis.

Hereditary transthyretin amyloidosis (ATTRv) is a systemic disease caused by the accumulation of misfolded transthyretin (TTR). It usually presents with an adult-onset progressive axonal peripheral neuropathy and cardiomyopathy. In the central nervous system (CNS), variant TTR is produced by the choroid plexus and accumulates in the leptomeninges. CNS symptoms have been increasingly recognized in this population, including transient focal neurological episodes and stroke, particularly in patients with the V30M mutation and longstanding disease. The prevalence, pathophysiology, and progression of CNS involvement remain to be clarified. The present work explores if there is a recognizable sequence of CNS TTR deposition in ATTRv. We studied the topographical and severity distribution of TTR deposition in 16 patients with ATTRv, aged 27-69 years and with a mean disease duration of 10.9 years (range: 3-29). Our results suggest that CNS pathological involvement in V30M ATTRv occurs early in the disease course, probably starting in pre-symptomatic phases, and follows a distinct sequence. Leptomeninges and subarachnoid meningeal vessels are affected earlier, then followed by perforating cortical vessels and subpial deposition, and finally by deposition in the subependymal and basal ganglia vessels near the ependymal lining. Brainstem and spinal cord show early and severe involvement, with amyloid subpial deposition already seen in initial stages. Despite massive superficial amyloid deposition, no parenchymal deposition outside subpial or subependymal regions was found. Additionally, vascular lesions or superficial cortical siderosis were not frequent. Future studies with more patients from different populations and TTR mutations will be important to confirm these findings. Defining stages of TTR pathology in the CNS may be useful to better understand pathogenic mechanisms leading to symptoms and to interpret neuroimaging biomarkers.