Neural substrates of neuropsychological profiles in dystrophynopathies: A pilot study of diffusion tractography imaging

Abstract

Introduction Cognitive difficulties and neuropsychological alterations in Duchenne and Becker muscular dystrophy (DMD, BMD) boys are not yet sufficiently explored, although this topic could have a relevant impact, finding novel biomarkers of disease both at genetics and neuroimaging point of view. The current study aims to: 1) analyze the neuropsychological profile of a group of DMD and BMD boys without cognitive impairment with an assessment of their executive functions; 2) explore the structural connectivity in DMD, BMD, and age-matched controls focusing on cortico-subcortical tracts that connect frontal cortex, basal ganglia, and cerebellum via the thalamus; 3) explore possible correlations between altered structural connectivity and clinical neuropsychological measures. Materials and methods This pilot study included 15 boys (5 DMD subjects, 5 BMD subjects, and 5 age-matched typically developing, TD). They were assessed using a neuropsychological assessment protocol including cognitive and executive functioning assessment and performed a 1.5T MRI brain exam including advance Diffusion Weighted Imaging (DWI) method for tractography. Structural connectivity measurements were extracted along three specific tracts: Cortico-Ponto-Cerebellar Tract (CPCT), Cerebellar-Thalamic Tract (CTT), and Superior Longitudinal Fasciculus (SLF). Cortical-Spinal Tract (CST) was selected for reference, as control tract. Results Regarding intellectual functioning, a major impairment in executive functions compared to the general intellectual functioning was observed both for DMD (mean score = 86.20; SD = 11.54) and for BMD children (mean score = 88; SD = 3.67). Mean FA resulted tendentially always lower in DMD compared to both BMD and TD groups for all the examined tracts. The differences in FA were statistically significant for the right CTT (DMD vs BMD, p = 0.002, and DMD vs TD, p = 0.0015) and the right CPCT (DMD vs TD, p = 0.008). Concerning DMD, significant correlations emerged between FA-R-CTT and intellectual quotients (FIQ, p = 0.044; ρs = 0.821), and executive functions (Denomination Total, p = 0.044, ρs = 0.821; Inhibition Total, p = 0.019, ρs = 0.900). BMD showed a significant correlation between FA-R-CPCT and working memory index (p = 0.007; ρs = 0.949). Discussion and conclusion In this pilot study, despite the limitation of sample size, the findings support the hypothesis of the involvement of a cerebellar-thalamo-cortical loop for the neuropsychological profile of DMD, as the CTT and the CPCT are involved in the network and the related brain structures are known to be implied in executive functions. Our results suggest that altered WM 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. The wider multicentric study could help to better establish the role of cerebellar connectivity in neuropsychological profile for dystrophinopathies, identifying possible novel diagnostic and prognostic biomarkers.

Cognitive abnormalities in Becker muscular dystrophy: a mysterious link between dystrophin deficiency and executive functions

“…In agreement with our hypotheses, the neuropsychological profile of BMD subjects seems to be characterized by a selective deficit of Working Memory, the executive system that deals with the manipulation of temporarily stored information for the performance of cognitive tasks. This is in accordance with the emerging literature [ 13 , 14 ] that until now has preliminary assessed WM through the WM index of the Weschler Scale of Intelligence. This deficit in WM could be ascribed to the metabolic burden given by the presence of abnormal dystrophin.…”

“…Of note is the wide variability in the results at the Dual Task and PASAT (DS Dual Task 21.45, DS PASAT 11.94). A wide range in the scores has also been observed in studies investigating global intelligence [ 12 ] and BMD neuropsychological profile [ 14 ]. It could depend on the different degrees of expression of dystrophin and particularly of its brain isoforms.…”

“…The consensus is that, despite an increased risk of intellectual disability (7–25%) in children and adults affected by BMD, average QI does not differ from the general population. Only two studies to date aim to analyze the cognitive profile of BMD individuals, the works of Young et al [ 13 ] and the pilot study by Biagi et al [ 14 ]. Both works show a deficit in executive functions in BMD individuals, especially in working memory.…”

“…First of all, studies often include a population of both children and adults [ 12 ], reaching conflicting conclusions. Moreover, deficits in executive functions and working memory were inferred from verbal subtests of WISC-III and not using specific tests assaying executive functions [ 13 , 14 ]. Finally, the studies confront the intellectual functions of children whose motor impairment and general frailty affect social relationships and psychological equilibrium with those of children in normal living conditions.…”

Brain Abnormalities in Becker Muscular Dystrophy: Evaluation by Voxel-Based DTI and Morphometric Analysis

“…10,12 However, the existing neuroimaging studies of BMD are limited to a visual-assessment study on brain atrophy and a DTI study using ROI methodology. 6,13 No quantitative evaluation of whole-brain morphology and microstructures in BMD has been reported.…”