Longitudinal follow-up of verbal span and processing speed in Duchenne muscular dystrophy

Neurocognitive deficits are frequently described in Duchenne muscular dystrophy (DMD), but it is unknown how these progress over time. Our aim was to longitudinally assess verbal span capacity and information processing speed in DMD and to explore a genotype-phenotype relation. Verbal span and processing speed scores were available of 28 males with DMD on two time-points, with a mean time interval of 28.34 months (SD = 16.09). The cohort contained of six patients missing only dystrophin isoform Dp427, sixteen missing Dp427 and Dp140, and six were undeterminable. A lower verbal span capacity was found at the first and second assessment, whereas processing speed was normal at both time-points. Post-hoc analyses suggested lower scores on verbal span and processing speed for patients missing Dp427 and Dp140. In DMD, a developmental stagnation in verbal span capacity, irrespective of normal processing speed, is detected through longitudinal follow-up. This appears more pronounced in patients missing Dp427 and Dp140. (C) 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved

Functional and structural impairment of transcallosal motor fibres in ALS: a study using transcranial magnetic stimulation, diffusion tensor imaging, and diffusion weighted spectroscopy

Imaging studies showed that the structure of the corpus callosum (CC) is affected in amyotrophic lateral sclerosis (ALS). Some clinical studies also suggest that interhemispheric connectivity is altered, since mirror movements seem to occur in ALS. Finally, reduced interhemispheric inhibition (IHI), studied by transcranial magnetic stimulation (TMS), has been reported. It is not known whether there is any association between these findings. Here, we studied the integrity of the CC in ALS on the morphological, the functional, the electrophysiological, and the clinical level. Twenty-seven right-handed ALS patients and 21 healthy right-handed controls were included. Mirror activity (MA) was quantified using surface EMG. Diffusion tensor imaging tractography was used to segment the CC and quantify fractional anisotropy (FA). We studied the diffusivity of the intra-axonal markers N-acetylaspartate+N-acetyl aspartyl glutamate D(tNAA) within the CC. IHI was studied as a marker of CC function using a double-pulse TMS protocol. ALS patients showed significantly decreased FA in the motor segment of the CC (p < 0.01), and IHI was significantly reduced compared to controls (p = 0.01). However, no differences were observed regarding D(tNAA) and MA. The morphological as well as the functional integrity of the CC are altered in ALS. IHI was reduced in ALS, associated with decreased FA in the motor CC. Patients did not exhibit increased MA. Also, no differences within the CC were observed using diffusion-weighted spectroscopy. IHI might serve as a marker of transcallosal pathway disruption in ALS, even before clinical deficits become apparent

Longitudinal follow-up of verbal span and processing speed in Duchenne muscular dystrophy

Neurocognitive deficits are frequently described in Duchenne muscular dystrophy (DMD), but it is unknown how these progress over time. Our aim was to longitudinally assess verbal span capacity and information processing speed in DMD and to explore a genotype-phenotype relation. Verbal span and processing speed scores were available of 28 males with DMD on two time-points, with a mean time interval of 28.34 months (SD = 16.09). The cohort contained of six patients missing only dystrophin isoform Dp427, sixteen missing Dp427 and Dp140, and six were undeterminable. A lower verbal span capacity was found at the first and second assessment, whereas processing speed was normal at both time-points. Post-hoc analyses suggested lower scores on verbal span and processing speed for patients missing Dp427 and Dp140. In DMD, a developmental stagnation in verbal span capacity, irrespective of normal processing speed, is detected through longitudinal follow-up. This appears more pronounced in patients missing Dp427 and Dp140. (C) 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved

Author Correction: Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy

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Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a muscular dystrophy with high incidence of learning and behavioural problems and is associated with neurodevelopmental disorders. To gain more insights into the role of dystrophin in this cognitive phenotype, we performed a comprehensive analysis of the expression patterns of dystrophin isoforms across human brain development, using unique transcriptomic data from Allen Human Brain and BrainSpan atlases. Dystrophin isoforms show large changes in expression through life with pronounced differences between the foetal and adult human brain. The Dp140 isoform was expressed in the cerebral cortex only in foetal life stages, while in the cerebellum it was also expressed postnatally. The Purkinje isoform Dp427p was virtually absent. The expression of dystrophin isoforms was significantly associated with genes implicated in neurodevelopmental disorders, like autism spectrum disorders or attention-deficit hyper-activity disorders, which are known to be associated to DMD. We also identified relevant functional associations of the different isoforms, like an association with axon guidance or neuron differentiation during early development. Our results point to the crucial role of several dystrophin isoforms in the development and function of the human brain.Pattern Recognition and Bioinformatic

Decreased cerebral perfusion in Duchenne muscular dystrophy patients

Duchenne muscular dystrophy is caused by dystrophin gene mutations which lead to the absence of the protein dystrophin. A significant proportion of patients suffer from learning and behavioural disabilities, in addition to muscle weakness. We have previously shown that these patients have a smaller total brain and grey matter volume, and altered white matter microstructure compared to healthy controls. Patients with more distal gene mutations, predicted to affect dystrophin isoforms Dp140 and Dp427, showed greater grey matter reduction. Now, we studied if cerebral blood flow in Duchenne muscular dystrophy patients is altered, since cerebral expression of dystrophin also occurs in vascular endothelial cells and astrocytes associated with cerebral vasculature. T1-weighted anatomical and pseudo-continuous arterial spin labeling cerebral blood flow images were obtained from 26 patients and 19 age-matched controls (ages 8-18 years) on a 3 tesla MRI scanner. Group comparisons of cerebral blood flow were made with and without correcting for grey matter volume using partial volume correction. Results showed that patients had a lower cerebral blood flow than controls (40.0 ± 6.4 and 47.8 ± 6.3 mL/100 g/min respectively, p = 0.0002). This reduction was independent of grey matter volume, suggesting that they are two different aspects of the pathophysiology. Cerebral blood flow was lowest in patients lacking Dp140. There was no difference in CBF between ambulant and non-ambulant patients. Only three patients showed a reduced left ventricular ejection fraction. No correlation between cerebral blood flow and age was found. Our results indicate that cerebral perfusion is reduced in Duchenne muscular dystrophy patients independent of the reduced grey matter volume