Reduced cerebral gray matter and altered white matter in boys with <scp>D</scp>uchenne muscular dystrophy

Doorenweerd, N.; Straathof, C.S.M.; Dumas, Eve M.; Spitali, Pietro; Ginjaar, Ieke B.; Wokke, B.H.A.; Schrans, D.G.M.; Bergen, J.C. van den; Zwet, Erik W. van; Webb, Andrew; Buchem, Mark A. van; Verschuuren, Jan J.; Hendriksen, Jos G.M.; Niks, Erik H.; Kan, Hermien E.

doi:10.1002/ana.24222

Cited by 99 publications

(146 citation statements)

References 41 publications

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“…Further, reduced cerebral blood flow [27] and a global reduction in cerebral gray matter [36] has been reported in boys with DMD.…”

Section: Discussionmentioning

confidence: 89%

“…Fourteen of the patients had deletion mutations between exons 45 and 48, which put them at risk of being deficient in the Dp140 isoform localized to the central nervous system. This has been associated with changes in CBF and cognitive deficits [5,27]. The design was a randomized double-blind, placebo-controlled, crossover study of two 4-week treatments with either placebo (lactose monohydrate oral in gelatin capsules, 3 times daily) or sildenafil 20 mg [Revatio in gelatin capsules (Pfizer, New York, NY, USA), p.o., 3 times daily], with the treatments separated by a washout period of 2 weeks.…”

Section: Subjectsmentioning

confidence: 99%

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Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy

et al. 2017

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Patients suffering from Becker muscular dystrophy (BMD) have dysfunctional dystrophin proteins and are deficient in neuronal nitric oxide synthase (nNOS) in muscles. This causes functional ischemia and contributes to muscle wasting. Similar functional ischemia may be present in brains of patients with BMD, who often have mild cognitive impairment, and nNOS may be important for the regulation of the microvascular circulation in the brain. We hypothesized that treatment with sildenafil, a phosphodiesterase type 5 inhibitor that potentiates nitric oxide responses, would augment both the blood oxygen level-dependent (BOLD) response and cerebral blood flow (CBF) in patients with BMD. Seventeen patients (mean ± SD age 38.5 ± 10.8 years) with BMD were included in this randomized, double-blind, placebo-controlled, crossover trial. Twelve patients completed the entire study. Effects of sildenafil were assessed by 3 T magnetic resonance (MR) scanning, evoked potentials, somatosensory task-induced BOLD functional MR imaging, regional and global perfusion, and angiography before and after 4 weeks of sildenafil, 20 mg (Revatio in gelatine capsules, oral, 3 times daily), or placebo treatment.Sildenafil increased the event-related sensory and visual BOLD response compared with placebo (p < 0.01). However, sildenafil did not alter CBF, measured by MR phase contrast mapping, or the arterial diameter of the middle cerebral artery, measured by MR angiography. We conclude that nNOS may play a role in event-related neurovascular responses. Further studies in patients with BMD may help clarify the roles of dystrophin and nNOS in neurovascular coupling in general, and in patients with BMD in particular.

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“…Further, reduced cerebral blood flow [27] and a global reduction in cerebral gray matter [36] has been reported in boys with DMD.…”

Section: Discussionmentioning

confidence: 89%

Section: Subjectsmentioning

confidence: 99%

Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy

et al. 2017

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“…Structural abnormalities in the brain have been recently described: changes in the cerebral grey matter volume and white matter microstructure in males with DMD have been described using quantitative magnetic resonance imaging. 35 Previous studies using magnetic resonance spectroscopy have indicated altered phosphorus metabolite ratios in the cerebral cortex of 19 males with DMD. 36 In an animal model, disrupted cerebral diffusivity was demonstrated to be associated with lack of dystrophin.…”

Section: Discussionmentioning

confidence: 98%

Neurodevelopmental, emotional, and behavioural problems in Duchenne muscular dystrophy in relation to underlying dystrophin gene mutations

Ricotti¹,

Mandy²,

Scoto³

et al. 2015

Develop Med Child Neuro

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280

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ABBREVIATIONS 3Di-svDevelopmental, Diagnostic and Dimensional Interview -short version ASD Autistic spectrum disorder CBCL Child Behavior Checklist DMD Duchenne muscular dystrophy SCDC Social Communication Disorder Checklist AIM Duchenne muscular dystrophy (DMD) is associated with neuropsychiatric disorders. The aim of the study was to characterize the DMD neuropsychiatric profile fully and to explore underlying genotype/phenotype associations.METHOD One hundred and thirty males with DMD (mean age 9y 10mo, range 5-17y) in four European centres were included and completed IQ assessment and a neurodevelopmentalscreening questionnaire. Of these, 87 underwent comprehensive neuropsychiatric assessment using structured diagnostic interview and parent-reported questionnaires. RESULTSThe overall mean score on the neurodevelopmental questionnaire was significantly abnormal compared with the general population of children (p<0.001). On average, intelligence was below the population mean, with intellectual disability observed in 34 males (26%). Autistic spectrum disorder was identified in 18 (21%), hyperactivity in 21 (24%), and inattention in 38 (44%). Clinical levels of internalizing and externalizing problems were observed in 21 (24%) and 13 (15%) respectively. Over a third of males scored more than two measures of emotional, behavioural, or neurodevelopmental problems. Males with mutations at the 3 0 end of the DMD gene affecting all protein isoforms had higher rates of intellectual disability and clusters of symptoms.INTERPRETATION Males with DMD are at very high risk of neuropsychiatric disturbance, and this risk appears to increase with mutations at the 3 0 end of the gene. Patterns of symptom clusters suggest a DMD neuropsychiatric syndrome, which may require prompt evaluation and early intervention.Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder affecting one in 5000 live male births, which causes progressive muscle weakness leading to loss of ambulation in the mid-adolescent years. Affected males generally present in the first few years of life with motor symptoms and enlarged calves. However, neurodevelopmental disorders are increasingly recognized features and can be the initial presenting symptoms. 1,2 DMD occurs as a result of mutations in the dystrophin gene. The large dystrophin gene contains 79 exons plus seven promoters. These tightly regulated internal promoters generate a range of different protein isoforms, with diverse expression in tissues. Mutations in the 5 0 end of the gene (i.e. mutations from exons 1-31) only affect the three longest isoforms, Dp427M, Dp427C, and Dp427P, which are expressed in skeletal and cardiac muscles, in the neurons in the cortex, and in cerebellar Purkinje cells respectively. However, mutations progressively further along the gene affect increasingly more isoforms. Mutations between exons 31 and 44, in addition to disrupting expression of the long isoforms, will also disrupt Dp260 (expressed mostly in the retina); mutations between exons 4...

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“…Secondly, since dystrophin mainly exists in the cerebral cortex, hippocampus, and cerebellar neurons, its absence may result in changes in WM tracts connected to homologous brain gray matter (GM). Doorenweerd et al using voxel-based morphometry found that DMD patients have a significantly smaller occipital cortex and significantly lower WM FA in the occipital lobe (37). Thirdly, during neural development, dystrophin is expressed within the neural tube and selected areas of the embryonic and postnatal neuraxis, and may regulate distinct © Annals of Translational Medicine.…”

Section: Discussionmentioning

confidence: 99%

Diffusion tensor imaging study in Duchenne muscular dystrophy

Fu¹,

Dong²,

Zhang³

et al. 2016

Ann. Transl. Med.

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Background: Duchenne muscular dystrophy (DMD) is a progressive muscle disorder associated with an intellectual deficit which is non-progressive. The aim of this study was to investigate brain microstructural changes in DMD and to explore the relationship between such changes and cognitive impairment.Methods: All participants (12 DMD patients, 14 age-matched healthy boys), intelligence quotients (IQs) [both full (FIQ) and verbal (VIQ)] were evaluated using the Wechsler intelligence scale for children China revised (WISC-CR) edition, and brain gray matter (GM) and white matter (WM) changes were mapped using diffusion tensor imaging (DTI) with fractional anisotropy (FA). The differences between groups were analyzed using the t-test and the association of cognition with neuroimaging parameters was evaluated using Pearson's correlation coefficient. Conclusions: There were microstructural changes of splenium of CC in DMD patients, which was associated with cognitive impairment.

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Reduced cerebral gray matter and altered white matter in boys with Duchenne muscular dystrophy

Abstract: Both gray and white matter is affected in boys with DMD at a whole brain level. Differences between the DMD_Dp140(-) subgroup and controls indicate an important role for the Dp140 dystrophin isoform in cerebral development.

Cited by 99 publications

References 41 publications

Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy

Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy

Neurodevelopmental, emotional, and behavioural problems in Duchenne muscular dystrophy in relation to underlying dystrophin gene mutations

Diffusion tensor imaging study in Duchenne muscular dystrophy

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