Neuron-specific biomarkers predict hypo- and hyperalgesia in individuals with diabetic peripheral neuropathy

Abstract

Aims/hypothesis The individual risk of progression of diabetic peripheral neuropathy is difficult to predict for each individual. Mutations in proteins that are responsible for the process of myelination are known to cause neurodegeneration and display alteration in experimental models of diabetic neuropathy. In a prospective observational human pilot study, we investigated myelin-specific circulating mRNA targets, which have been identified in vitro, for their capacity in the diagnosis and prediction of diabetic neuropathy. The most promising candidate was tested against the recently established biomarker of neural damage, neurofilament light chain protein. Methods Schwann cells were cultured under high-glucose conditions and mRNAs of various myelin-specific genes were screened intra- and extracellularly. Ninety-two participants with type 2 diabetes and 30 control participants were enrolled and evaluated for peripheral neuropathy using neuropathy deficit scores, neuropathy symptom scores and nerve conduction studies as well as quantitative sensory testing at baseline and after 12/24 months of a follow-up period. Magnetic resonance neurography of the sciatic nerve was performed in 37 individuals. Neurofilament light chain protein and four myelin-specific mRNA transcripts derived from in vitro screenings were measured in the serum of all participants. The results were tested for associations with specific neuropathic deficits, fractional anisotropy and the progression of neuropathic deficits at baseline and after 12 and 24 months. Results In neuronal Schwann cells and human nerve sections, myelin protein zero was identified as the strongest candidate for a biomarker study. Circulating mRNA of myelin protein zero was decreased significantly in participants with diabetic neuropathy (p < 0.001), whereas neurofilament light chain protein showed increased levels in participants with diabetic neuropathy (p < 0.05). Both variables were linked to altered electrophysiology, fractional anisotropy and quantitative sensory testing. In a receiver-operating characteristic curve analysis myelin protein zero improved the diagnostic performance significantly in combination with a standard model (diabetes duration, age, BMI, HbA1c) from an AUC of 0.681 to 0.836 for the detection of diabetic peripheral neuropathy. A follow-up study revealed that increased neurofilament light chain was associated with the development of a hyperalgesic phenotype (p < 0.05), whereas decreased myelin protein zero predicted hypoalgesia (p < 0.001) and progressive loss of nerve function 24 months in advance (HR of 6.519). Conclusions/interpretation This study introduces a dynamic and non-invasive assessment strategy for the underlying pathogenesis of diabetic peripheral neuropathy. The diagnosis of axonal degeneration, associated with hyperalgesia, and demyelination, linked to hypoalgesia, could benefit from the usage of neurofilament light chain protein and circulating mRNA of myelin protein zero as potential biomarkers. Graphical abstract

Assessing Lumbar Plexus and Sciatic Nerve Damage in Relapsing-Remitting Multiple Sclerosis Using Magnetisation Transfer Ratio

“…It is therefore conceivable that the significantly lower MTR values identified in people with RRMS in the sciatic nerve (but not the lumbar plexus) in this study could be indicative of peripheral codemyelination, which is also in line with previous findings (3). Further multi-modal investigations may be needed to confirm the pathophysiological basis of the alterations in MTR identified in this study, for example with the use of diffusion-weighted imaging, as demonstrated in previous studies of peripheral neuropathy (29)(30)(31).…”

Fractional Anisotropy and Troponin T Parallel Structural Nerve Damage at the Upper Extremities in a Group of Patients With Prediabetes and Type 2 Diabetes – A Study Using 3T Magnetic Resonance Neurography

“…Moreover, the small sample size of our study does not allow a meaningful statistical assessment of differences between patients with and without DN. While this is a limitation, it should be considered that the development of DN has been shown to be a continuous process during which subclinical nerve damage can already be visualized and quantified with MRN imaging prior to the occurrence of clinical symptoms ( Groener et al, 2019 ; Morgenstern et al, 2021 ). In fact, the objective of this study was not to compare patients with and without DN, but to assess whether hsTNT is associated with a decrease in FA, that represents neurostructural deterioration mainly related to demyelination, and functional loss of proximal nerves at the upper limbs in patients with impaired glucose control.…”

Peripheral Neuropathy Phenotyping in Rat Models of Type 2 Diabetes Mellitus: Evaluating Uptake of the Neurodiab Guidelines and Identifying Future Directions

“…The molecular basis of this time-dependent dissociation between hyper- and hypoalgesia was recently studied in a prospective observational clinical study. Here, increased serum neurofilament light chain level (indicative of axonal injury) associated with hyperalgesia in T2DM patients with DPN while a decreased level of circulatory mRNA of myelin protein zero (indicative of demyelination) was associated with hypoalgesia [ 149 ]. Moreover, neurofilament light chain level correlated with quantitative sensory tests involving small unmyelinated C-fibers (warm detection, heat, and cold pain) whereas myelin protein zero mRNA level correlated with quantitative sensory tests involving myelinated A-δ and A-β fibers (mechanical sensitivity).…”