Multimodal Magnetic Resonance Imaging for the identification of early Multiple System Atrophy biomarkers

Background. Multiple system atrophy (MSA) is a rare, sporadic disease characterized by autonomic failure and a various combination of parkinsonism and cerebellar dysfunction. Currently, development of new treatment strategies in MSA is hampered by the lack of reliable diagnostic and disease-progression biomarkers. The aim of this study was to investigate brain microstructural abnormalities in MSA through diffusion and neuromelanin-sensitive magnetic resonance imaging (MRI) and their relationship with clinical manifestations. Methods. Clinical evaluation and MRI were performed on 11 MSA patients, 19 Parkinson’s Disease (PD) and 18 healthy controls (HC). MRI scans included structural, diffusion (dMRI) and neuromelanin-sensitive sequences. dMRI was applied through a novel technique, neurite orientation dispersion and density imaging (NODDI). Compared to previous dMRI techniques, NODDI allows the simultaneous evaluation of the integrity of the intracellular and extracellular compartments, while gathering information on the orientation of axons and dendrites. Neuromelanin-sensitive MRI was used to quantitively investigate the integrity of substantia nigra (SN) and locus coeruleus (LC). Results. Median duration of symptoms in MSA patients was 3 years (range 1-6). Age was not significantly different across subgroups. Compared to PD, MSA patients had reduced neurite density index (NDI) in the middle cerebellar peduncle (MCP) and in the pons (Mann-Whitney U=44.0, p=0.019 and U=52.0, p=0.050), indicating white matter degeneration in these locations, and increased free water fraction (FWF), indicating grey matter loss, in the putamen, caudate and cerebellar lobule VI grey matter (U=146.0, p=0.019; U=145.0, p=0.021; U=154.0, p=0.006 respectively). Neuromelanin content was not different in SN and LC between PD and MSA, although this was reduced in the posterior SN and intermediate part of LC compared to HCs (Kruskal Wallis H=11.363, p=0.003 and H=13.788, p=0.001), indicating similar, significant degeneration of these nuclei in both conditions. No significant correlations were found between motor scores and MRI parameters in the SN, putamen, and MCP and pons. LC neuromelanin loss in the rostral and/or intermediate sections was significantly associated with greater cognitive, depressive and REM sleep behaviour disorder (RBD) symptoms scores in MSA. Symptoms of dysautonomia were not associated with diffusion or neuromelanin content measures. Conclusion. Multimodal MRI with diffusion and neuromelanin evaluation may help define structural abnormalities in the early stages of MSA. NODDI seems a promising technique to simultaneously evaluate multiple microstructural parameters in critical locations of MSA pathology, such as the basal ganglia, cerebellum, and pons. Neuromelanin content evaluation is useful for defining SN and LC degeneration, although this occurs similarly in MSA and PD. In MSA, LC degeneration is associated with greater depressive, cognitive and RBD symptoms. Longitudinal investigations are needed to establish whether these MRI parameters may serve as disease-progression biomarkers.