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. 2023 Jan;270(1):328-339.
doi: 10.1007/s00415-022-11336-z. Epub 2022 Sep 6.

Muscle quantitative MRI as a novel biomarker in hereditary transthyretin amyloidosis with polyneuropathy: a cross-sectional study

Elisa Vegezzi #  1   2 , Andrea Cortese #  3   4 , Niels Bergsland  5   6 , Roberta Mussinelli  7 , Matteo Paoletti  8 , Francesca Solazzo  9 , Riccardo Currò  1   10 , Lucia Ascagni  11 , Ilaria Callegari  12 , Ilaria Quartesan  1 , Alessandro Lozza  7 , Xeni Deligianni  13   14 , Francesco Santini  13   14 , Enrico Marchioni  2 , Giuseppe Cosentino  1   15 , Enrico Alfonsi  15 , Cristina Tassorelli  1   16 , Stefano Bastianello  1   8 , Giampaolo Merlini  7   17 , Giovanni Palladini  7   17 , Laura Obici #  7 , Anna Pichiecchio #  1   8
Affiliations

Muscle quantitative MRI as a novel biomarker in hereditary transthyretin amyloidosis with polyneuropathy: a cross-sectional study

Elisa Vegezzi et al. J Neurol. 2023 Jan.

Abstract

Background: The development of reproducible and sensitive outcome measures has been challenging in hereditary transthyretin (ATTRv) amyloidosis. Recently, quantification of intramuscular fat by magnetic resonance imaging (MRI) has proven as a sensitive marker in patients with other genetic neuropathies. The aim of this study was to investigate the role of muscle quantitative MRI (qMRI) as an outcome measure in ATTRv.

Methods: Calf- and thigh-centered multi-echo T2-weighted spin-echo and gradient-echo sequences were obtained in patients with ATTRv amyloidosis with polyneuropathy (n = 24) and healthy controls (n = 12). Water T2 (wT2) and fat fraction (FF) were calculated. Neurological assessment was performed in all ATTRv subjects. Quantitative MRI parameters were correlated with clinical and neurophysiological measures of disease severity.

Results: Quantitative imaging revealed significantly higher FF in lower limb muscles in patients with ATTRv amyloidosis compared to controls. In addition, wT2 was significantly higher in ATTRv patients. There was prominent involvement of the posterior compartment of the thighs. Noticeably, FF and wT2 did not exhibit a length-dependent pattern in ATTRv patients. MRI biomarkers correlated with previously validated clinical outcome measures, Polyneuropathy Disability scoring system, Neuropathy Impairment Score (NIS) and NIS-lower limb, and neurophysiological parameters of axonal damage regardless of age, sex, treatment and TTR mutation.

Conclusions: Muscle qMRI revealed significant difference between ATTRv and healthy controls. MRI biomarkers showed high correlation with clinical and neurophysiological measures of disease severity making qMRI as a promising tool to be further investigated in longitudinal studies to assess its role at monitoring onset, progression, and therapy efficacy for future clinical trials on this treatable condition.

Keywords: ATTR; Biomarker; Magnetic resonance imaging (MRI); Outcome measure; Polyneuropathy.

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Conflict of interest statement

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Figures

Fig. 1
Fig. 1
Thigh and calf single muscle ROIs and compartments. Thigh (A) and calf (B) single muscle ROI of a healthy control superimposed on multi-echo spin-echo (ME-SE) sequence (1st echo) to extract water T2 values and on multi-echo gradient-echo (ME-GRE) sequence (1st echo) to obtain fat fraction maps. Thigh and calf compartments are reported on the right
Fig. 2
Fig. 2
Muscle quantitative MRI imaging: thigh and calf compartments in ATTRv patients and healthy controls. Overall thigh and calf fat fraction (FF) and water T2 (wT2) are significantly higher in ATTRv compared to healthy controls. Boxes represent median and IQR and whiskers show range
Fig. 3
Fig. 3
Correlation of muscle quantitative MRI measures with functional rating scales in ATTRv amyloidosis. Representative examples of T1-weighted (T1w) and short tau inversion recovery (STIR) sequences of the thighs and calves of two patients affected by ATTRv amyloidosis with moderate (left) and severe (right) disease. The patient with greater disability (right) has more prominent fat infiltration and a higher water T2 content (A). Moderate to strong positive correlation was observed between mean fat fraction (FF) and water T2 (wT2) at thigh (purple) and calf (blue) level and Polyneuropathy Disability (PND) score (B), Neuropathy Impairment Score (NIS) (C), and NIS-lower limb (NIS-LL) (D)
Fig. 4
Fig. 4
Correlation of muscle quantitative MRI measures with NCS parameters in ATTRv amyloidosis. Negative correlation between NCS parameters namely peroneal nerve compound muscle action potential (CMAP) (pink), tibial nerve CMAP (green), and sural nerve sensory nerve action potential (SNAP) (light-blue) and water T2 (wT2) and fat fraction (FF) at thigh (A) and calf (B) level
Fig. 5
Fig. 5
Muscle quantitative MRI imaging: thigh and calf compartments in ATTRv amyloidosis. Fat fraction (FF) and water T2 (wT2) were not significantly different between thigh and calf level (A). Fat substitution prevailed in the medio-posterior thigh compartment compared to the anterior region while no difference was seen at calf between the antero-lateral and posterior region (B)
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Supplementary concepts