Magnetic resonance neurography and diffusion tensor imaging of the sciatic nerve in hereditary transthyretin amyloidosis polyneuropathy

Abstract

The therapeutic advance in hereditary transthyretin amyloidosis (ATTRv amyloidosis) requires quantitative biomarkers of nerve involvement in order to foster early diagnosis and monitor therapy response. We aimed at quantitatively assessing Magnetic Resonance Neurography (MRN) and Diffusion Tensor Imaging (DTI) properties of the sciatic nerve in subjects with ATTRv-amyloidosis-polyneuropathy (ATTRv-PN) and pre-symptomatic carriers (ATTRv-C). Twenty subjects with pathogenic variants of the TTR gene (mean age 62.20 ± 12.04 years), 13 ATTRv-PN, and 7 ATTRv-C were evaluated and compared with 20 healthy subjects (mean age 60.1 ± 8.27 years). MRN and DTI sequences were performed at the right thigh from the gluteal region to the popliteal fossa. Cross-sectional-area (CSA), normalized signal intensity (NSI), and DTI metrics, including fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivity (RD) of the right sciatic nerve were measured. Increased CSA, NSI, RD, and reduced FA of sciatic nerve differentiated ATTRv-PN from ATTRv-C and healthy subjects at all levels (p < 0.01). NSI differentiated ATTRv-C from controls at all levels (p < 0.05), RD at proximal and mid-thigh (1.04 ± 0.1 vs 0.86 ± 0.11 p < 0.01), FA at mid-thigh (0.51 ± 0.02 vs 0.58 ± 0.04 p < 0.01). According to receiver operating characteristic (ROC) curve analysis, cutoff values differentiating ATTRv-C from controls (and therefore identifying subclinical sciatic involvement) were defined for FA, RD, and NSI. Significant correlations between MRI measures, clinical involvement and neurophysiology were found. In conclusion, the combination of quantitative MRN and DTI of the sciatic nerve can reliably differentiate ATTRv-PN, ATTRv-C, and healthy controls. More important, MRN and DTI were able to non-invasively identify early subclinical microstructural changes in pre-symptomatic carriers, thus representing a potential tool for early diagnosis and disease monitoring.

Keywords: ATTRv amyloidosis; Amyloidotic polyneuropathy; Diffusion tensor imaging; Magnetic resonance neurography; Transthyretin amyloidosis.

Fig. 1

Quantitative MRN markers. Mean and SD values of sciatic nerve cross-sectional area (CSA) and normalized signal intensity (NSI) are plotted for controls, ATTRv-C, and symptomatic ATTRv-PN patients at proximal (P), mid (M), and distal (D) thigh. Sciatic nerve CSA was higher in symptomatic ATTRv-PN patients, with no significant differences between ATTRv-C and controls. NSI was significantly increased in ATTRv-C and ATTRv-PN compared to healthy controls, with no significant difference between ATTRv-C and ATTRv-PN. Significant differences are indicated by p values

Fig. 2

Quantitative DTI metrics. Mean and SD values of sciatic nerve Fractional Anisotropy (FA) and Radial diffusivity (RD) are plotted for healthy controls, ATTRv-C and ATTRv-PN patients at proximal (P), mid (M), and distal (D) thigh. Sciatic nerve FA reached the highest values in healthy controls, decreased in ATTRv-C, and further decreased in ATTRv-PN patients. Sciatic nerve RD was highest in ATTRv-PN patients and decreased in pre-symptomatic carriers, reaching the lowest values in healthy controls. FA at mid-thigh and RD at proximal and mid-thigh were able to differentiate pre-symptomatic carriers from healthy controls. Significant differences are indicated by p values

Fig. 3

Receiver operating characteristic (ROC) curves of the sensitivity and specificity of DTI values (FA and RD) and NSI in the sciatic nerve at mid-thigh to distinguish ATTRv-C from controls

Fig. 4

Receiver operating characteristic (ROC) curves of the sensitivity and specificity of DTI (FA and RD) and CSA of the sciatic nerve at mid-thigh, to distinguish ATTRv-PN from ATTRv-C

Fig. 5

Scatter plots relating FA and RD of the sciatic nerve at mid-thigh and mean FA values derived from DTI tractography with nerve conduction studies of the fibular and sural nerve

Fig. 6

ATTRv-PN. MR Neurography, sciatic nerve at mid-thigh. B DWI trace-weighted image (b = 700), C FA, D AD, E RD, F MD maps, G sciatic nerve tractography at thigh. Sciatic nerve CSA 82.7 mm², NSI = 2, FA = 0.41, AD = 2.29 10^–3 mm²/s, RD = 1.26 10^–3 mm²/s, ADC = 1.6 10^–3 mm²/s. Increased signal intensity and size of the sciatic nerve, with significant reduction of FA

Fig. 7

ATTRv-C. MR Neurography, sciatic nerve at mid-thigh. B DWI trace-weighted image (b = 700), C FA, D AD, E) RD, F MD maps, G sciatic nerve tractography at thigh. Sciatic nerve CSA = 42.6 mm², NSI = 1.70, FA = 0.51, AD = 2.44 10^–3 mm²/s, RD = 1.08 10^–3 mm²/s, ADC = 1.53 10^–3 mm²/s. Increased size and signal intensity of the fascicles of the sciatic nerve with no significant changes of CSA and FA

Fig. 8

Healthy control. A MR Neurography, sciatic nerve at mid-thigh. B DWI trace-weighted image (b = 700), C FA, D AD, E RD, F MD maps, G sciatic nerve tractography at thigh. Sciatic nerve CSA 48 mm², NSI = 1.16, FA = 0.54, AD = 1.84 10^–3 mm²/s, RD = 0.82 10^–3 mm²/s, ADC = 1.16 10^–3 mm²/s