Magnetization transfer ratio quantifies polyneuropathy in hereditary transthyretin amyloidosis

Abstract

Objective: To quantify peripheral nerve lesions in symptomatic and asymptomatic hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PNP) by analyzing the magnetization transfer ratio (MTR) of the sciatic nerve, and to test its potential as a novel biomarker for macromolecular changes. Methods: Twenty-five patients with symptomatic ATTRv-PNP, 30 asymptomatic carriers of the mutant transthyretin gene (mutTTR), and 20 age-/sexmatched healthy controls prospectively underwent magnetization transfer contrast imaging at 3 Tesla. Two axial three-dimensional gradient echo sequences with and without an off-resonance saturation rapid frequency pulse were conducted at the right distal thigh. Sciatic nerve regions of interest were manually drawn on 10 consecutive axial slices in the images without off-resonance saturation, and then transferred to the corresponding slices that were generated by the sequence with the off-resonance saturation pulse. Subsequently, the MTR and cross-sectional area (CSA) of the sciatic nerve were evaluated. Detailed neurologic and electrophysiologic examinations were conducted in all ATTRv-PNP patients and mutTTR-carriers. Results: Sciatic nerve MTR and CSA reliably differentiated between ATTRv-PNP, mutTTR-carriers, and controls. MTR was lower in ATTRv-PNP (26.4 AE 0.7; P < 0.0001) and in mutTTR-carriers (32.6 AE 0.8; P = 0.0005) versus controls (39.4 AE 2.1), and was also lower in ATTRv-PNP versus mutTTR-carriers (P = 0.0009). MTR correlated negatively with the NIS-LL and positively with CMAPs and SNAPs. CSA was higher in ATTRv-PNP (34.3 AE 1.7 mm 3 ) versus mutTTR-carriers (26.0 AE 1.1 mm 3 ; P = 0.0005) and versus controls (20.4 AE 1.2 mm 3 ; P < 0.0001). CSA was also higher in mutTTR-carriers versus controls. Interpretation: MTR is a novel imaging marker that can quantify macromolecular changes in ATTRv-PNP and differentiate between symptomatic ATTRv-PNP and asymptomatic mutTTRcarriers and correlates with electrophysiology.

Magnetization transfer ratio: a quantitative imaging biomarker for 5q spinal muscular atrophy

“…To date, there have been two studies that applied MTC imaging in patients with peripheral neuropathies, but their results were controversial: while one study found that MTR does not differentiate between patients with hereditary neuropathy with liability to pressure palsies (HNPP) and controls, the other study demonstrated a strong correlation between decreasing sciatic nerve MTR values and higher grades of disability in patients with Charcot-Marie-Tooth disease [38,39]. The latter finding is supported by a recent study from our group, in which we found evidence that sciatic nerve MTR is decreased in patients with hereditary transthyretin amyloidosis with polyneuropathy and correlates well with electrophysiologic results and the Neuropathy Impairment Score of the Lower Limb [40].…”

Reliability and reproducibility of sciatic nerve magnetization transfer imaging and T2 relaxometry

“…5 Bland-Altman plots for assessment of interreader reliability of magnetization transfer ratio (MTR) (a), transverse relaxation time T2 (b), and proton spin density (PSD) (c) of the sciatic nerve. The black continuous line represents the mean of all differences (bias), grey dotted lines show the 95% limits of agreement from 3.4 to 13%, and in three out of four studies a difference of over 4.7% was observed (Table 4) [11,12,14,24]. Notably, the mean MTR of our cohort was lower than in most of the control groups listed in Table 4.…”

“…While T2 relaxometry and MTI are increasingly studied as quantitative MRN techniques, they have not been implemented in clinical routine yet [ 11 – 14 , 24 , 26 ]. Before interpreting MRN biomarkers in individual patients, assessment of reliability is required not only in qualitative categories but particularly by precise quantification of measurement error.…”

“…These techniques offer additional information about nerve microstructure or tissue composition and provide quantitative biomarkers. In addition to DTI-which has been well evaluated [10]-T2 relaxometry and magnetization transfer imaging (MTI) have increasingly been applied as novel quantitative MRN techniques in recent investigations [11][12][13][14].…”

Progressive brachial plexus enlargement in hereditary transthyretin amyloidosis

“…The former issue is required also for monitoring the response to treatment, while the latter is crucial for early diagnosis and timely therapy [3][4][5]. Previous findings suggest that subtle nerve abnormalities may precede the clinical or neurophysiological demonstration of polyneuropathy [6][7][8], but the time-course of the early abnormalities in pre-symptomatic carriers has never been addressed. Recently, we have demonstrated at nerve ultrasound (US), an enlargement of brachial plexus in ATTRv-PN patients, but no in pre-symptomatic carriers, pointing to brachial plexus enlargement as a possible morphological biomarker of the disease [9].…”