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Disrupted structural connectome and neurocognitive functions in Duchenne muscular dystrophy: classifying and subtyping based on Dp140 dystrophin isoform

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Abstract

Objective

Neurocognitive disabilities in Duchenne muscular dystrophy (DMD) children beginning in early childhood and distal DMD gene deletions involving disruption of Dp140 isoform are more likely to manifest significant neurocognitive impairments. MRI data analysis techniques like brain-network metrics can provide information on microstructural integrity and underlying pathophysiology.

Methods

A prospective study on 95 participants [DMD = 57, and healthy controls (HC) = 38]. The muscular dystrophy functional rating scale (MDFRS) scores, neuropsychology batteries, and multiplex ligand-dependent probe amplification (MLPA) testing were used for clinical assessment, IQ estimation, and genotypic classification. Diffusion MRI and network-based statistics were used to analyze structural connectomes at various levels and correlate with clinical markers.

Results

Motor and executive sub-networks were extracted and analyzed. Out of 57 DMD children, 23 belong to Dp140 + and 34 to Dp140- subgroup. Motor disabilities are pronounced in Dp140- subgroup as reflected by lower MDFRS scores. IQ parameters are significantly low in all-DMD cases; however, the Dp140- has specifically lowest scores. Significant differences were observed in global efficiency, transitivity, and characteristic path length between HC and DMD. Subgroup analysis demonstrates that the significance is mainly driven by participants with Dp140- than Dp140 + isoform. Finally, a random forest classifier model illustrated an accuracy of 79% between HC and DMD and 90% between DMD- subgroups.

Conclusions

Current findings demonstrate structural network-based characterization of abnormalities in DMD, especially prominent in Dp140-. Our observations suggest that participants with Dp140 + have relatively intact connectivity while Dp140- show widespread connectivity alterations at global, nodal, and edge levels. This study provides valuable insights supporting the genotype–phenotype correlation of brain-behavior involvement in DMD children.

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Availability of data and materials

Anonymized data not published within this article will be made available to any appropriately qualified investigator, based on a valid request through the corresponding author.

Code availability (software application or custom code)

Not Applicable.

Abbreviations

DMD:

Duchenne muscular dystrophy

MRI:

Magnetic resonance imaging

DTI:

Diffusion tensor imaging

FA:

Fractional anisotropy

MD:

Mean diffusivity

MLPA:

Multiplex ligation-dependent probe amplification

MDFRS:

Muscular dystrophy functional rating scale

NBS:

Network-based statistics

SC:

Structural connectome

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Acknowledgements

We acknowledge and convey our deepest gratitude to all the participants in this study including the young DMD boys, control subjects and their parents, who cooperated impeccably for MRI without even sedation. We also thank our radiographers who went out of the way to help complete the image acquisition of these children patiently even though busy doing regular clinical imaging services.

Funding

This study was partially supported by the educational grant from the “TVS-NIMHANS BURSARY” (grant support no.: TVSB/003/304/2015/00817).

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Author notes

  1. Jitender Saini and Madhura Ingalhalikar have equally contributed.

Authors and Affiliations

  1. Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India

    Veeramani Preethish-Kumar, Kiran Polavarapu, Seena Vengalil, Saraswati Nashi & Atchayaram Nalini

  2. Symbiosis Centre for Medical Image Analysis, Symbiosis International University, Mulshi, Pune, Maharashtra, India

    Apurva Shah, Apoorva Safai & Madhura Ingalhalikar

  3. Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bangalore, India

    Manoj Kumar & Jitender Saini

  4. Neuromuscular Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences, Bangalore, India

    Sekar Deepha & Periyasamy Govindaraj

  5. Department of Neuropsychology, National Institute of Mental Health and Neurosciences, Bangalore, India

    Mohammad Afsar & Jamuna Rajeswaran

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  1. Veeramani Preethish-Kumar
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All authors have contributed in this manuscript, reviewed and approved before submission. No authors have reported any conflict of interested related to this manuscript.

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Correspondence to Jitender Saini or Madhura Ingalhalikar.

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All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was carried out with consent from the appropriate Institutional ethics committee.

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Preethish-Kumar, V., Shah, A., Polavarapu, K. et al. Disrupted structural connectome and neurocognitive functions in Duchenne muscular dystrophy: classifying and subtyping based on Dp140 dystrophin isoform. J Neurol 269, 2113–2125 (2022). https://doi.org/10.1007/s00415-021-10789-y

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