Results from a study out of Portugal suggested that there may be early pathological involvement of the central nervous system (CNS) in patients with hereditary transthyretin amyloidosis (hATTR), and they identified a sequential pattern in amyloid protein deposition.

“Our findings suggest a distinct sequence of CNS involvement, with leptomeninges and subarachnoid vessels affected earlier, followed by perforating cortical vessels and subpial deposition, and finally subependymal deposition and involvement of basal ganglia vessels near the ependymal lining,” the researchers wrote in Acta Neuropathologica.

The researchers analyzed postmortem human brains from 16 patients with hATTR. Cortical amyloid deposition was restricted to the meningocortical penetrating vessels. Meningeal and subpial amyloid deposits in the brainstem and spinal cord were frequently found near cranial and spinal nerves rather than intranerve.

Moreover, subpial amyloid deposits were associated with astrocytosis. Subependymal amyloid deposition was more frequent in the third and fourth ventricles and in the basal ganglia region of the lateral ventricles.

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In contrast, the authors did not observe parenchymal amyloid deposits in the cortex or white matter, fibrinoid necrosis, or capillary cerebral amyloid angiopathy. Vascular lesions were not frequent and occurred relatively late in the disease course. Mild superficial cortical siderosis was observed in only 2 cases, 1 of which was homozygous for the Val30Met mutation in the transthyretin (TTR) gene.

Fifteen of the 16 patients had the Val30Met mutation in the TTR gene, and 1 had a Ser52Pro mutation. Neuropathological findings were similar regardless of the mutation. The study included 1 homozygous patient for the the Val30Met mutation, but clinical and pathological features were similar to heterozygous patients. All patients experienced neuropathy as the earliest and predominant manifestation of the disease.

Despite the study’s limitations, including the limited number of patients and its retrospective nature, it has uncovered potential early pathogenic events that might begin in the presymptomatic stages of hATTR.

Reference

Taipa R, Sousa L, Pinto M, et al. Neuropathology of central nervous system involvement in TTR amyloidosis. Acta Neuropathol. Published online October 6, 2022. doi:10.1007/s00401-022-02501-9