CEREBRO-CEREBELLAR NETWORKS IN DMD CHILDREN: NEUROPSYCHOLOGICAL, GENETIC AND NEUROIMAGING ASPECTS

Several studies have reported cognitive difficulties and neuropsychological alterations in Duchenne muscular dystrophy (DMD) boys, which may be due to the lack of specific dystrophin isoforms in the brain, taking account of the possible involvement of cerebellum and of a complex cerebro-cerebellar network. The PhD project comes from the neuropsychological data collected before the beginning of the PhD in a multicenter setting by a group of Centres from the DMD Italian Network, including IRCCS Stella Maris Foundation, that produced two scientific reports, published during the second year of the PhD (Battini et al., 2018; Vicari et al., 2018). An impairment of multitasking, problem solving, inhibition and working memory (Battini et al., 2018) and an implicit learning deficit (Vicari et al., 2018) emerged in the analyzed DMD patients, supporting the hypothesis of a specific involvement of cerebellum as part of a more general involvement of the cerebellar-thalamo-cortical network. Starting from these results, in the PhD project we aimed to deepen the neuropsychological functioning of DMD boys without intellectual disability during school age, assessing longitudinally the subjects previously evaluated and extending the neuropsychological evaluation in another group of DMD Italian children. We wanted indeed to define the trend of impairments over time and to confirm the neuropsychological profile in a wider cohort of subjects than previously evaluated. Our overall findings confirm the impairment of some neuropsychological functions, in particular executive functions, in DMD boys, even without intellectual disability, and suggest the stability of the neuropsychological profile over time. As the results deriving from a specific questionnaire for DMD boys’parents show that neuropsychological deficits may be not completely recognized in the home environment, we believe that the detection of neuropsychological impairments in DMD boys without intellectual disability may be an important challenge. Actually, misdiagnosed neuropsychological deficits may have a negative impact on the global functioning of these children. We were also interested in analyzing possible correlations between neuropsychological findings and the site of mutations in DMD gene, according to the involvement of Dp140 dystrophin isoform. According to literature, possible genotype-neuropsychological phenotype correlations emerged both from the follow up and the total cohort assessment. Globally, the DMD boys who do not express Dp140 show greater difficulties in cognitive performances, in particular in the manipulation of stored information than children with a certain Dp140 dystrophin expression, while this last subgroup exhibits better performances in cognitive flexibility and in switching the tasks, and are more accurate in tasks requiring planning and problem solving. Since genetic mechanisms other than site of mutation have been widely described to explain variability in DMD clinical phenotype in terms of motor and cardiac outcome but not regarding neuropsychological functioning, as an ancillary genetic study, we wanted to verify the possible modifier effect of specific genetic loci (in LTBP4, SPP1, CD40 genes) for the neuropsychological variability in DMD. In fact, possible distribution of genetic modifiers and their protein products in the brain and their possible involvement in neuroprotection and in the pathogenesis of neurodegenerative disorders have been described in literature. The results suggest that some polymorphisms may play a role also in the modulation of the neuropsychological phenotype in DMD without intellectual disability, in particular regarding executive functioning as switching, planning and problem solving abilities. Eventually, in a functional neuroimaging pilot study, we explored structural connectivity in a small group of DMD boys. Because of the involvement of dystrophin in all dystrophinopathies, also a small cohort of Becker muscular dystrophy (BMD) children was enrolled. We focused in particular on cerebellar tracts and on tracts that have been described to be possibly involved in executive functions. Moreover, we explored possible correlations between altered scalar measures and neuropsychological functions in DMD and BMD groups. The results suggest that altered white matter connectivity and reduced fibre organization in cerebellar tracts, probably due to the lack of dystrophin in the brain, may render less efficient some neuropsychological functions in children affected by dystrophinopathies, identifying possible functional neuroimaging biomarkers for the neuropsychological profile of DMD without intellectual disability. In conclusion, our research confirms the hypothesis of the involvement of the cerebro-cerebellar network in DMD, which connects the neuropsychological, genetic and functional neuroimaging aspects, based on the localisation of dystrophin isoforms in normal brain.