Dottorato in PLASTICITÀ NEUROSENSORIALE

Titolo della tesi: Neuromuscular imaging as a biomarker for disease diagnosis and progression

Preface Diagnosis of neuromuscular diseases (NMDs) was historically made on the basis of the clinical picture, neurological examination and neurophysiological and pathological studies. Over the last 20 years, the development of innovative imaging methods has shown the possibility to study nerve and muscle structures in detail, analyse the severity and distribution of damage and identify specific patterns of involvement [1,2], making a strong contribution to early diagnosis and, therefore, to early treatment of patients. In general, neuromuscular diseases are rare diseases, and a high level of standardization of imaging methods is required to compare individual patient data across different imaging centres. To achieve this target, standardized evaluation and innovative methods of quantification have emerged [3]. Moreover, emerging innovative therapies for hereditary and acquired diseases have renewed the interest in studying the natural history of these diseases, the degree of damage progression and, finally, the therapeutic response [4], topics to which imaging techniques have made a useful contribution. On these bases, both high-resolution ultrasound (HRUS) and magnetic resonance imaging (MRI) have progressively become essential tools to support the clinician in diagnosing peripheral neuropathies and muscle diseases [5]. HRUS may provide information about morphological abnormalities in nerve and muscles, contributing, together with EDx study, in the diagnosis of neuropathies and myopathies. . HRUS enhances the ability to detect focal nerve entrapment, as well as pathological nerve enlargements in genetic and acquired neuropathies [6]. To date, US has been introduced as supportive diagnostic criteria for CIDP diagnosis [7]. Furthermore, muscle fibrosis and fat replacement can potentially be detected by HRUS and used as a biomarker for muscular dystrophies and motor neuron disorders [8,9]. Sometimes, in the clinical practice, it can also guide needle placement for therapeutic injections (i.e. botulinum toxin), for electromyographic examination and suggest the site for muscle/nerve biopsy. Last, but not least, HRUS is inexpensive and well tolerated. Potential limitations of HRUS include an inability to image deeper structures and its reliability and replicability (it is frequently based on an operator-dependent interpretation) especially among different centres. MRI has already demonstrated to be a useful tool for the diagnosis of a wide variety of primary muscle disorders including both acquired and inherited myopathies. It can provide complementary information to clinical, histologic, genetic, and laboratory findings for the identification of specific muscular tissue alterations [10]. Muscle MRI allows the identification of oedema and fat replacement of muscle tissue through conventional MRI sequences such as T1-weighted and STIR and can be helpful for diagnosis of inherited and inflammatory myopathies that exhibit distinctive patterns of muscle involvement, especially when they are not yet clinically observable [11]. Muscle MRI can also increase sensitivity and specificity of muscle biopsy; finally, there is growing interest in using muscle MRI to assess disease progression and evolution overtime, also for monitoring the response to treatment both in clinical trials and in clinical practice. Peripheral nerve MRI can add information especially about nerve roots and deep nerves that cannot be studied through US, and for alterations that could be detected with post-contrast acquisitions [7,12]. However, high costs and low availability do not allow an extensive use of MRI in clinical practice. To date, even if diagnostic role of HRUS and MRI in neuromuscular diseases is well known [3], less is known about modification of nerves and muscles over-time in different disorders, also with respect to treatments, and about comparison between the two techniques. This dissertation summarizes the results obtained during these years in our centre for neuromuscular and rare diseases, focused on diagnosis and follow-up of inherited and acquired rare neuromuscular diseases, as well as comparison between the US and MRI techniques. It is divided in four sections: the first three about published results and the third one about ongoing and future projects.