Longitudinal multimodal assessment of peripheral nerve involvement in wild-type transthyretin amyloidosis

INTRODUCTION: Wild-type transthyretin amyloidosis (ATTRwt) is a progressive disease marked by extracellular transthyretin amyloid deposition, predominantly causing cardiomyopathy. Neurological manifestations are known in hereditary ATTR but remain comparatively understudied in ATTRwt. METHODS: Patients with ATTRwt cardiomyopathy were prospectively evaluated at baseline and after 1 year, alongside healthy controls. Neurological assessment included Neuropathy Impairment Score Lower Limb (NIS-LL), nerve conduction studies, quantitative sensory testing (QST), serum neurofilament light chain (sNfL), and intra-epidermal nerve fiber density (IENFD) from skin biopsies. Symptoms and fatigue were assessed using Norfolk-QoL-DN and Chalder Fatigue scale. RESULTS: Twenty-three patients were included and compared to controls. Pathological IENFD occurred in 47.8% of patients vs. 4.3% of controls (p=0.002). In ATTRwt, except cold detection, all QST parameters were abnormal. Sensory-predominant axonal polyneuropathy was present in 82.6%, with higher NIS-LL and symptom burden (p<0.001). sNfL levels were similar between groups. Carpal tunnel syndrome was frequent (82.7%). Polyneuropathy with CTS was more common in ATTRwt (p=0.025). At follow-up, we observed no clinical or electrophysiological progression, and no newly diagnosed cases of polyneuropathy. CONCLUSIONS: ATTRwt is associated with mixed fiber neuropathy and frequent entrapment neuropathies which should raise suspicion for ATTRwt. We found subtle clinical progression over 13 months.