Length‐dependent MRI of hereditary neuropathy with liability to pressure palsies

Abstract

ObjectiveHereditary neuropathy with liability to pressure palsies (HNPP) is caused by heterozygous deletion of the peripheral myelin protein 22 (PMP22) gene. Patients with HNPP present multifocal, reversible sensory/motor deficits due to increased susceptibility to mechanical pressure. Additionally, age‐dependent axonal degeneration is reported. We hypothesize that length‐dependent axonal loss can be revealed by MRI, irrespective of the multifocal phenotype in HNPP.MethodsNerve and muscle MRI data were acquired in the proximal and distal leg of patients with HNPP (n = 10) and matched controls (n = 7). More specifically, nerve magnetization transfer ratios (MTR) were evaluated to assay proximal‐to‐distal gradients in nerve degeneration, while intramuscular fat percentages (Fper) were evaluated to assay muscle fat replacement following denervation. Neurological disabilities were assessed via the Charcot‐Marie‐Tooth neuropathy score (CMTNS) for correlation with MRI.ResultsFper values were elevated in HNPP proximal muscle (9.8 ± 2.2%, P = 0.01) compared to controls (6.9 ± 1.0%). We observed this same elevation of HNPP distal muscles (10.5 ± 2.5%, P < 0.01) relative to controls (6.3 ± 1.1%). Additionally, the amplitude of the proximal‐to‐distal gradient in Fper was more significant in HNPP patients than controls (P < 0.01), suggesting length‐dependent axonal loss. In contrast, nerve MTR values were similar between HNPP subjects (sciatic/tibial nerves = 39.4 ± 2.0/34.2 ± 2.5%) and controls (sciatic/tibial nerves = 37.6 ± 3.8/35.5 ± 1.2%). Proximal muscle Fper values were related to CMTNS (r = 0.69, P = 0.03), while distal muscle Fper and sciatic/tibial nerve MTR values were not related to disability.InterpretationDespite the multifocal nature of the HNPP phenotype, muscle Fper measurements relate to disability and exhibit a proximal‐to‐distal gradient consistent with length‐dependent axonal loss, suggesting that Fper may be a viable biomarker of disease progression in HNPP.

Automation of Quantifying Axonal Loss in Patients with Peripheral Neuropathies through Deep Learning Derived Muscle Fat Fraction

“…Although volumetric muscle FF has been used as a monitoring biomarker in CMT1A, 11,15 its responsiveness may not be sufficient to show progression when FF is measured in early stage of diseases or over a short period 12,26 . Furthermore, the FF from a severely denervated muscle could be compromised by a “floor” effect, and would not be suitable for tracking the progression.…”

“…Consequently, muscle denervation causes muscle fiber degeneration that is replaced by intramuscular fat cells over time 10 . Therefore, the severity of intramuscular fat accumulation provides an indirect measure of axonal loss in motor nerves in patients with peripheral neuropathies, including CMT1A, 11 hereditary neuropathy with liability to pressure palsies (HNPP), 12 hereditary sensory neuropathy (HSN) 13 , and chronic inflammatory demyelinating polyneuropathy 14 …”

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

“…While results from MTC studies conducted in the central nervous system (CNS) are promising [27][28][29][30][31][32][33][34][35][36][37], data on the potential of MTC imaging in the peripheral nervous system are limited. 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].…”

Fatigue in patients with hereditary neuropathy with liability to pressure palsies

“…Our previous work has demonstrated a mild axonal loss in patients with HNPP using qMRI. 21 The axonal loss was quantified by the muscle FF. After axon degenerates, fat increases in denervated muscle.…”

“…After axon degenerates, fat increases in denervated muscle. 21 We therefore tested whether the axonal loss is related to the fatigue.…”