Objective: To apply a novel neuroimaging method, Coordinate-based Network Mapping (CNM)¹, to localise heterogeneous neuroimaging findings in multiple system atrophy (MSA) into a functionally connected brain network with focal hubs most central to symptom generation.

Background: MSA is a progressive neurodegenerative disorder characterised by parkinsonism, cerebellar ataxia and autonomic dysfunction². Life expectancy after diagnosis is between 6-10 years³ and misdiagnosis rates are high⁴. Prominent symptoms define two subtypes, MSA-P (parkinsonism) and MSA-C (cerebellar-ataxia)². Whilst brainstem and cerebellar atrophy are well characterised, studies have reported abnormalities in multiple other regions that vary from study to study^5,6.

Method: Literature was systematically searched to identify whole-brain neuroimaging studies reporting coordinates demonstrating significant brain abnormalities in MSA patients compared to healthy controls. CNM was conducted in three steps: 1) peak coordinate locations in individual studies were combined to create ‘study-specific combined seeds’. 2) Brain regions functionally connected to sites of reported abnormality were identified using a dataset of resting state fMRI data (N = 1000)^7,8. 3) Functional connectivity maps from each study were binarised (connected=t>7, not connected=t<7), and overlaid, identifying regions significantly connected to all or most of the included studies’ combined seeds. This process was conducted across all included studies, and MSA-C and MSA-P separately assessing subtype specific localisations.

Results: 19 studies including 471 patients, 465 controls and 351 peak coordinates were included. Peak coordinates from published studies were distributed throughout the brain. However, results of CNM revealed >15/19 studies were commonly functionally connected to the basal ganglia, midbrain and cerebellum. Interestingly, results in MSA-C and MSA-P identified sets of regions functionally connected to all included studies (6/6, 8/8), with hubs within the cerebellum and putamen, respectively.

Conclusion: Examining brain regions functionally connected to previously reported sites of abnormality demonstrates that previously heterogeneous neuroimaging findings in MSA localise to a network of specific brain regions. MSA-C and MSA-P networks align with diagnostic markers and neuropathological examination^2,9. Localisation of these brain networks may guide targeted treatments.

References: [1] Darby R. R., Joutsa, J., & Fox, M.D. (2018). Network localization of heterogeneous neuroimaging findings. Brain, 142(1), 70-79. https://doi.org/10.1093/brain/awy292
[2] Gilman, S., Wenning, G. K., Low, P. A., Brooks, D. J., Mathias, C. J., Trojanowski, J. Q., … & Kaufmann, H. (2008). Second consensus statement on the diagnosis of multiple system atrophy. Neurology, 71(9), 670-676. https://doi.org/10.1212/01.wnl.0000324625.00404.15
[3] Jellinger, K. A. (2018). Multiple system atrophy: an oligodendroglioneural synucleinopathy. Journal of Alzheimer’s Disease, 62(3) 1141-1179. https://doi.org/10.3233/JAD-170397
[4] Joutsa, J., Gardberg, M., Röyttä, M., & Kaasinen, V. (2014). Diagnostic accuracy of parkinsonism syndromes by general neurologists. Parkinsonism & Related Disorders, 20(8), 840-844. https://doi.org/10.1016/j.parkreldis.2014.04.019
[5] Fiorenzato, E., Weis, L., Seppi, K., Onofrj, M., Cortelli, P., Zanigni, S., … & Krismer, F. (2017). Brain structural profile of multiple system atrophy patients with cognitive impairment. Journal of Neural Transmission, 124(3), 293-302. https://doi.org/10.1007/s00702-016-1636-0
[6] Grimaldi, S., Boucekine, M., Witjas, T., Fluchère, F., Renaud, M., Azulay, J. P., Guedj, E., & Eusebio, A. (2019). Multiple System Atrophy: Phenotypic spectrum approach coupled with brain 18-FDG PET. Parkinsonism and Related Disorders, 67(September), 3–9. https://doi.org/10.1016/j.parkreldis.2019.09.005
[7] Holmes, A. J., Hollinshead, M. O., O’Keefe, T. M., Petrov, V. I., Fariello, G. R., Wald, L. L., Wald, L. L., Fischl, B., Rosen, B. R., Mair, R. W., Roffman, L. J, Buckner, R. L., & Smoller, J. W. (2015). The organization of the human cerebral cortex estimated by intrinsic functional connectivity. Scientific Data, 2, 150031. https://doi.org/10.1038/sdata.2015.31
[8] Yeo, B. T., Krienen, F. M., Sepulcre, J., Sabuncu, M. R., Lashkari, D., Hollinshead, M., … & Fischl, B. (2011). The organization of the human cerebral cortex estimated by intrinsic functional connectivity. Journal of Neurophysiology, 106(3), 1125-1165. https://doi.org/10.1152/jn.00338.2011
[9] Dickson, D. W. (2012). Parkinson’s disease and parkinsonism: neuropathology. Cold Spring Harbor Perspectives in Medicine, 2(8), a009258. https://doi.org/10.1101/cshperspect.a009258

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MDS Abstracts - https://www.mdsabstracts.org/abstract/network-localisation-of-multiple-system-atrophy/