Probing diffusion of water and metabolites to assess white matter microstructure in Duchenne muscular dystrophy.

Publisher: Wiley Country of Publication: England NLM ID: 8915233 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1099-1492 (Electronic) Linking ISSN: 09523480 NLM ISO Abbreviation: NMR Biomed Subsets: MEDLINE

Publication: Chichester : Wiley
Original Publication: London : Heyden & Son, 1988-

Muscular Dystrophy, Duchenne*/diagnostic imaging ; Muscular Dystrophy, Duchenne*/pathology ; Muscular Dystrophy, Duchenne*/metabolism ; White Matter*/diagnostic imaging ; White Matter*/metabolism ; White Matter*/pathology ; Diffusion Tensor Imaging*; Humans ; Male ; Adolescent ; Water ; Diffusion ; Child ; Diffusion Magnetic Resonance Imaging ; Female ; Creatine/metabolism ; Choline/metabolism ; Aspartic Acid/analogs & derivatives ; Aspartic Acid/metabolism ; Young Adult

Duchenne muscular dystrophy (DMD) is a progressive X-linked neuromuscular disorder caused by the absence of functional dystrophin protein. In addition to muscle, dystrophin is expressed in the brain in both neurons and glial cells. Previous studies have shown altered white matter microstructure in patients with DMD using diffusion tensor imaging (DTI). However, DTI measures the diffusion properties of water, a ubiquitous molecule, making it difficult to unravel the underlying pathology. Diffusion-weighted spectroscopy (DWS) is a complementary technique which measures diffusion properties of cell-specific intracellular metabolites. Here we performed both DWS and DTI measurements to disentangle intra- and extracellular contributions to white matter changes in patients with DMD. Scans were conducted in patients with DMD (15.5 ± 4.6 y/o) and age- and sex-matched healthy controls (16.3 ± 3.3 y/o). DWS measurements were obtained in a volume of interest (VOI) positioned in the left parietal white matter. Apparent diffusion coefficients (ADCs) were calculated for total N-acetylaspartate (tNAA), choline compounds (tCho), and total creatine (tCr). The tNAA/tCr and tCho/tCr ratios were calculated from the non-diffusion-weighted spectrum. Mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), and fractional anisotropy of water within the VOI were extracted from DTI measurements. DWS and DTI data from patients with DMD (respectively n = 20 and n = 18) and n = 10 healthy controls were included. No differences in metabolite ADC or in concentration ratios were found between patients with DMD and controls. In contrast, water diffusion (MD, t = -2.727, p = 0.011; RD, t = -2.720, p = 0.011; AD, t = -2.715, p = 0.012) within the VOI was significantly higher in patients compared with healthy controls. Taken together, our study illustrates the potential of combining DTI and DWS to gain a better understanding of microstructural changes and their association with disease mechanisms in a clinical setting.
(© 2024 The Author(s). NMR in Biomedicine published by John Wiley & Sons Ltd.)

Banihani R, Smile S, Yoon G, et al. Cognitive and neurobehavioral profile in boys with Duchenne muscular dystrophy. J Child Neurol. 2015;30(11):1472‐1482. doi:10.1177/0883073815570154.
Conway KC, Mathews KD, Paramsothy P, et al. Neurobehavioral concerns among males with dystrophinopathy using population‐based surveillance data from the Muscular Dystrophy Surveillance, Tracking, and Research Network. J Dev Behav Pediatr. 2015;36(6):455‐463. doi:10.1097/DBP.0000000000000177.
Darmahkasih AJ, Rybalsky I, Tian C, et al. Neurodevelopmental, behavioral, and emotional symptoms common in Duchenne muscular dystrophy. Muscle Nerve. 2020;61(4):466‐474. doi:10.1002/mus.26803.
Hendriksen JGM, Vles JSH. Neuropsychiatric disorders in males with Duchenne muscular dystrophy: frequency rate of attention‐deficit hyperactivity disorder (ADHD), autism spectrum disorder, and obsessive–compulsive disorder. J Child Neurol. 2008;23(5):477‐481. doi:10.1177/0883073807309775.
Hendriksen RGF, Vles JSH, Aalbers MW, Chin RFM, Hendriksen JGM. Brain‐related comorbidities in boys and men with Duchenne muscular dystrophy: a descriptive study. Eur J Paediatr Neurol. 2018;22(3):488‐497. doi:10.1016/J.EJPN.2017.12.004.
Lee AJ, Buckingham ET, Kauer AJ, Mathews KD. Descriptive phenotype of obsessive compulsive symptoms in males with Duchenne muscular dystrophy. J Child Neurol. 2018;33(9):572‐579. doi:10.1177/0883073818774439.
Pangalila RF, Van Den Bos GA, Bartels B, Bergen M, Stam HJ, Roebroeck ME. Prevalence of fatigue, pain, and affective disorders in adults with Duchenne muscular dystrophy and their associations with quality of life. Arch Phys Med Rehabil. 2015;96(7):1242‐1247. doi:10.1016/J.APMR.2015.02.012.
Ricotti V, Mandy WPL, Scoto M, et al. Neurodevelopmental, emotional, and behavioural problems in Duchenne muscular dystrophy in relation to underlying dystrophin gene mutations. Dev Med Child Neurol. 2016;58(1):77‐84. doi:10.1111/DMCN.12922.
Holder E, Maeda M, Bies RD. Expression and regulation of the dystrophin Purkinje promoter in human skeletal muscle, heart, and brain. Hum Genet. 1996;97(2):232‐239. doi:10.1007/BF02265272.
Muntoni F, Torelli S, Ferlini A. Dystrophin and mutations: one gene, several proteins, multiple phenotypes. Lancet Neurol. 2003;2(12):731‐740. doi:10.1016/S1474‐4422(03)00585‐4.
Lidov HGW, Selig S, Kunkel LM. Dp140: a novel 140 kDa CNS transcript from the dystrophin locus. Hum Mol Genet. 1995;4(3):329‐335. doi:10.1093/HMG/4.3.329.
Austin RC, Morris GE, Howard PL, Klamut HJ, Ray PN. Expression and synthesis of alternatively spliced variants of Dp71 in adult human brain. Neuromuscul Disord. 2000;10(3):187‐193. doi:10.1016/S0960‐8966(99)00105‐4.
Austin RC, Howard PL, D'Souza VN, Klamut HJ, Ray PN. Cloning and characterization of alternatively spliced isoforms of Dp71. Hum Mol Genet. 1995;4(9):1475‐1483. doi:10.1093/hmg/4.9.1475.
Fort PE, Sene A, Pannicke T, et al. Kir4.1 and AQP4 associate with Dp71‐and utrophin‐DAPs complexes in specific and defined microdomains of Muller retinal glial cell membrane. Glia. 2008;56(6):597‐610. doi:10.1002/glia.20633.
Lederfein D, Levy Z, Augier N, et al. A 71‐kilodalton protein is a major product of the Duchenne muscular dystrophy gene in brain and other nonmuscle tissues. Proc Natl Acad Sci USA. 1992;89(12):5346‐5350. doi:10.1073/PNAS.89.12.5346.
Tadayoni R, Rendon A, Soria‐Jasso LE, Cisneros B. Dystrophin Dp71: the smallest but multifunctional product of the Duchenne muscular dystrophy gene. Mol Neurobiol. 2012;45(1):43‐60. doi:10.1007/s12035‐011‐8218‐9.
Culligan K, Ohlendieck K. Diversity of the brain dystrophin–glycoprotein complex. J Biomed Biotechnol. 2002;2(1):31‐36. doi:10.1155/S1110724302000347.
Waite A, Brown SC, Blake DJ. The dystrophin–glycoprotein complex in brain development and disease. Trends Neurosci. 2012;35(8):487‐496. doi:10.1016/j.tins.2012.04.004.
Doorenweerd N, Mahfouz A, van Putten M, et al. Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy. Sci Rep. 2017;7(1):12575. doi:10.1038/s41598‐017‐12981‐5.
Naidoo M, Anthony K. Dystrophin Dp71 and the neuropathophysiology of Duchenne muscular dystrophy. Mol Neurobiol. 2020;57(3):1748‐1767. doi:10.1007/S12035‐019‐01845‐W.
Lange J, Gillham O, Alkharji R, et al. Dystrophin deficiency affects human astrocyte properties and response to damage. Glia. 2022;70(3):466‐490. doi:10.1002/GLIA.24116.
Doorenweerd N, Dumas EM, Ghariq E, et al. Decreased cerebral perfusion in Duchenne muscular dystrophy patients. Neuromuscul Disord. 2017;27(1):29‐37. doi:10.1016/j.nmd.2016.10.005.
Doorenweerd N, Straathof CS, Dumas EM, et al. Reduced cerebral gray matter and altered white matter in boys with Duchenne muscular dystrophy. Ann Neurol. 2014;76(3):403‐411. doi:10.1002/ANA.24222.
Tracey I, Thompson CH, Dunn JF, et al. Brain abnormalities in Duchenne muscular dystrophy: phosphorus‐31 magnetic resonance spectroscopy and neuropsychological study. Lancet. 1995;345(8960):1260‐1264. doi:10.1016/S0140‐6736(95)90923‐0.
Ronen I, Valette J. Diffusion‐weighted magnetic resonance spectroscopy. eMagRes. 2015;4:733‐750. doi:10.1002/9780470034590.emrstm1471.
Ronen I, Ercan E, Webb A. Axonal and glial microstructural information in white matter obtained with diffusion weighted magnetic resonance spectroscopy at 7T. Front Integr Neurosci. 2013;7:13. doi:10.3389/FNINT.2013.00013.
Palombo M, Shemesh N, Ronen I, Valette J. Insights into brain microstructure from in vivo DW‐MRS. NeuroImage. 2018;182:97‐116. doi:10.1016/j.neuroimage.2017.11.028.
Rae C, Scott RB, Thompson CH, et al. Brain biochemistry in Duchenne muscular dystrophy: a 1H magnetic resonance and neuropsychological study. J Neurol Sci. 1998;160(2):148‐157. doi:10.1016/S0022‐510X(98)00190‐7.
Doorenweerd N, Hooijmans M, Schubert SA, et al. Proton magnetic resonance spectroscopy indicates preserved cerebral biochemical composition in Duchenne muscular dystrophy patients. J Neuromuscul Dis. 2017;4(1):53‐58. doi:10.3233/JND‐160201.
Fu Y, Dong Y, Zhang C, et al. Diffusion tensor imaging study in Duchenne muscular dystrophy. Ann Transl Med. 2016;4(6):109. doi:10.21037/atm.2016.03.19.
Preethish‐Kumar V, Shah A, Kumar M, et al. In vivo evaluation of white matter abnormalities in children with Duchenne muscular dystrophy using DTI. Am J Neuroradiol. 2020;41(7):1271‐1278. doi:10.3174/ajnr.A6604.
Brooke MH, Fenichel GM, Griggs RC, et al. Clinical Investigation of Duchenne muscular dystrophy. Interesting results in a trial of prednisone. Arch Neurol. 1987;44(8):812‐817. doi:10.1001/archneur.1987.00520200016010.
Duan D, Goemans N, Takeda S, Mercuri E, Aartsma‐Rus A. Duchenne muscular dystrophy. Nat Rev Dis Primers. 2021;7(1):13. doi:10.1038/s41572‐021‐00248‐3.
Smith SM. Fast robust automated brain extraction. Hum Brain Mapp. 2002;17(3):143‐155. doi:10.1002/HBM.10062.
Zhang Y, Brady M, Smith S. Segmentation of brain MR images through a hidden Markov random field model and the expectation‐maximization algorithm. IEEE Trans Med Imaging. 2001;20(1):45‐57. doi:10.1109/42.906424.
Jenkinson M, Beckmann CF, Behrens TEJ, Woolrich MW, Smith SM. FSL. NeuroImage. 2012;62(2):782‐790. doi:10.1016/J.NEUROIMAGE.2011.09.015.
Provencher SW. Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med. 1993;30(6):672‐679. doi:10.1002/mrm.1910300604.
Govindaraju V, Young K, Maudsley AA. Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed. 2000;13(3):129‐153. doi:10.1002/1099‐1492(200005)13:3<129::AID‐NBM619>3.0.CO;2‐V.
Near J, Harris AD, Juchem C, et al. Preprocessing, analysis and quantification in single‐voxel magnetic resonance spectroscopy: experts' consensus recommendations. NMR Biomed. 2021;34(5):e4257. doi:10.1002/nbm.4257.
Leemans A, Jeurissen B, Sijbers J, Jones DK. ExploreDTI: a graphical toolbox for processing, analyzing, and visualizing diffusion MR data. Proc Int Soc Magn Reson Med. 2009;17:3537.
Wood ET, Ercan E, Sati P, Cortese ICM, Ronen I, Reich DS. Longitudinal MR spectroscopy of neurodegeneration in multiple sclerosis with diffusion of the intra‐axonal constituent N‐acetylaspartate. NeuroImage Clin. 2017;15:780‐788. doi:10.1016/j.nicl.2017.06.028.
Wood ET, Ronen I, Techawiboonwong A, et al. Investigating axonal damage in multiple sclerosis by diffusion tensor spectroscopy. J Neurosci. 2012;32(19):6665‐6669. doi:10.1523/JNEUROSCI.0044‐12.2012.
Kan HE, Techawiboonwong A, van Osch MJP, et al. Differences in apparent diffusion coefficients of brain metabolites between grey and white matter in the human brain measured at 7 T. Magn Reson Med. 2012;67(5):1203‐1209. doi:10.1002/mrm.23129.
Ellegood J, Hanstock CC, Beaulieu C. Trace apparent diffusion coefficients of metabolites in human brain using diffusion weighted magnetic resonance spectroscopy. Magn Reson Med. 2005;53(5):1025‐1032. doi:10.1002/mrm.20427.
Assaf Y, Pasternak O. Diffusion tensor imaging (DTI)‐based white matter mapping in brain research: a review. J Mol Neurosci. 2008;34(1):51‐61. doi:10.1007/s12031‐007‐0029‐0.
van der Meulen M, Amaya JM, Dekkers OM, Meijer OC. Association between use of systemic and inhaled glucocorticoids and changes in brain volume and white matter microstructure: a cross‐sectional study using data from the UK Biobank. BMJ Open. 2022;12(8):e062446. doi:10.1136/bmjopen‐2022‐062446.
van der Werff SJA, Andela CD, Nienke Pannekoek J, et al. Widespread reductions of white matter integrity in patients with long‐term remission of Cushing's disease. NeuroImage Clin. 2014;4:659‐667. doi:10.1016/j.nicl.2014.01.017.
Pires P, Santos A, Vives‐Gilabert Y, et al. White matter involvement on DTI‐MRI in Cushing's syndrome relates to mood disturbances and processing speed: a case–control study. Pituitary. 2017;20(3):340‐348. doi:10.1007/s11102‐017‐0793‐y.
Pires P, Santos A, Vives‐Gilabert Y, et al. White matter alterations in the brains of patients with active, remitted, and cured Cushing syndrome: a DTI study. Am J Neuroradiol. 2015;36(6):1043‐1048. doi:10.3174/ajnr.A4322.

Duchenne Parent Project; RA3/2079/1 Muscular Dystrophy UK; 10.13 Gratama Stichting; 847826 EU Horizon 2020 research and innovation programme

Keywords: Duchenne muscular dystrophy; MRI; brain; diffusion tensor imaging; diffusion‐weighted spectroscopy; multimodal; white matter

059QF0KO0R (Water)
MU72812GK0 (Creatine)
N91BDP6H0X (Choline)
997-55-7 (N-acetylaspartate)
30KYC7MIAI (Aspartic Acid)

Date Created: 20240715 Date Completed: 20241007 Latest Revision: 20241007

20241008

10.1002/nbm.5212

39005110