Diffuse alterations in grey and white matter associated with cognitive impairment in Shwachman-Diamond syndrome: evidence from a multimodal approach

Abstract

Shwachman-Diamond syndrome is a rare recessive genetic disease caused by mutations in SBDS gene, at chromosome 7q11. Phenotypically, the syndrome is characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal dysplasia and variable cognitive impairments. Structural brain abnormalities (smaller head circumference and decreased brain volume) have also been reported. No correlation studies between brain abnormalities and neuropsychological features have yet been performed. In this study we investigate neuroanatomical findings, neurofunctional pathways and cognitive functioning of Shwachman-Diamond syndrome subjects compared with healthy controls. To be eligible for inclusion, participants were required to have known SBDS mutations on both alleles, no history of cranial trauma or any standard contraindication to magnetic resonance imaging. Appropriate tests were used to assess cognitive functions. The static images were acquired on a 3 × 0 T magnetic resonance scanner and blood oxygen level-dependent functional magnetic resonance imaging data were collected both during the execution of the Stroop task and at rest. Diffusion tensor imaging was used to assess brain white matter. The Tract-based Spatial Statistics package and probabilistic tractography were used to characterize white matter pathways. Nine participants (5 males), half of all the subjects aged 9-19 years included in the Italian Shwachman-Diamond Syndrome Registry, were evaluated and compared with nine healthy subjects, matched for sex and age. The patients performed less well than norms and controls on cognitive tasks (p = 0.0002). Overall, cortical thickness was greater in the patients, both in the left (+10%) and in the right (+15%) hemisphere, significantly differently increased in the temporal (left and right, p = 0.04), and right parietal (p = 0.03) lobes and in Brodmann area 44 (p = 0.04) of the right frontal lobe. The greatest increases were observed in the left limbic-anterior cingulate cortex (≥43%, p < 0.0004). Only in Broca's area in the left hemisphere did the patients show a thinner cortical thickness than that of controls (p = 0.01). Diffusion tensor imaging showed large, significant difference increases in both fractional anisotropy (+37%, p < 0.0001) and mean diffusivity (+35%, p < 0.005); the Tract-based Spatial Statistics analysis identified six abnormal clusters of white matter fibres in the fronto-callosal, right fronto-external capsulae, left fronto-parietal, right pontine, temporo-mesial and left anterior-medial-temporal regions. Brain areas activated during the Stroop task and those active during the resting state, are different, fewer and smaller in patients and correlate with worse performance (p = 0.002). Cognitive impairment in Shwachman-Diamond syndrome subjects is associated with diffuse brain anomalies in the grey matter (verbal skills with BA44 and BA20 in the right hemisphere; perceptual skills with BA5, 37, 20, 21, 42 in the left hemisphere) and white matter connectivity (verbal skills with alterations in the fronto-occipital fasciculus and with the inferior-longitudinal fasciculus; perceptual skills with the arcuate fasciculus, limbic and ponto-cerebellar fasciculus; memory skills with the arcuate fasciculus; executive functions with the anterior cingulated and arcuate fasciculus).

Keywords: BA, Brodmann area; BOLD, blood oxygen level-dependent; CTA, cortical thickness analysis; Cognitive impairment; DTI, diffusion tensor imaging; Diffusion tensor imaging; EPI, Echo-planar Imaging; FA, fractional anisotropy; FDT, Diffusion Toolbox; Functional MRI; GLM, General Linear Model; ICA, independent component analysis; MD, mean diffusivity; PD, parallel diffusivity; PT, probabilistic tractography; RD, radial diffusivity; SDS, Shwachman–Diamond syndrome; Shwachman–Diamond syndrome; Structural MRI; TBSS, Tract-based Spatial Statistics.; Tract-based Spatial Statistics; rs-fMRI, resting state fMRI.

Fig. 1

Differences in cortical thickness between groups and hemispheres. A) Right and left hemispheres, 3D reconstruction in SDS and control subjects. Upper row: lateral views. Lower row: mesial views. Colourimetric maps show differences in cortical thickness between groups and hemispheres (dark blue: 0.5 mm; green: 5 mm). B) The graphs show the mean values of the cortical thickness registered in all the Brodmann areas (BAs) in SDS and in controls. The following BA resulted to be significantly increased in SDS: in the frontal lobe—right BA44 +12% (p = 0.04); in the parietal lobe—right BA2 +18% (p = 0.03), BA3 +30% (p = 0.005), BA5 +26% (p = 0.02), BA39 +20% (p = 0.03), BA40 +39% (p = 0.03); in the temporal lobe—right BA20 +24% (p = 0.007), BA21 +27% (p = 0.007), BA37 +17% (p = 0.02), BA42 +36% (p = 0.02); in the temporal lobe—left BA21 +22% (p = 0.01), BA22 +29% (p = 0.02), BA37 +14% (p = 0.01), BA42 +33% (p = 0.02); in the occipital lobe—left BA18 +16% (p = 0.04); and in the limbic—left BA23 +33% (p = 0.0001), BA31 +22% (p = 0.003), BA32 +49% (0.0001), BA33 +43% (0.0004). Only in the frontal lobe—left BA45 showed a thinner cortical thickness in SDS subjects (−18%, p = 0.01), than that in controls.

Fig. 2

SDS vs. control subject pattern of activation in the Stroop effect and in resting state. fMRI maps superimposed on 3D T1 weighted anatomical images (p < 0.05) (radiological view: R = L). I. The upper row represents findings of random effect group analysis (SDS vs. controls) in SDS subjects, i.e. brain activation in the middle left frontal gyrus, left precuneus and left hippocampus. In the lower panel random effect group analysis (controls vs. SDS) in control subjects shows brain activation in the anterior cingulate cortex, in the orbital cortex and in the left inferior frontal gyrus. II. The panel represents findings of independent component analysis (ICA) of BOLD fMRI signal in resting state activity (panel A: SDS; panel B: controls). ICA maps are superimposed on a T1 weighted anatomical template. SDS subjects show different and reduced functional connectivity networks within the default mode network (DMN) in resting state activity (p < 0.001).

Fig. 3

Diffusion tensor imaging (DTI) and Tract-based Spatial Statistics (TBSS) analyses. A. DTI analysis: differences in fractional anisotropy (FA) and mean diffusivity (MD) between SDS and control groups (LH = left hemisphere; RH = right hemisphere). B. a) TBSS analysis showing the mean FA skeleton (green) and regions with statistically significant differences between SDS and control groups (red), displayed on the MNI152 brain (radiological view: R = L). b) Detailed view. c) Slices showing the connectivity distribution of fibres originating from each of the areas of FA difference shown immediately above. Connectivity maps representing the paths extending to and from each cluster identified in the TBSS analysis. Fibre paths are displayed on the representative target FA image to which all other images are registered. 1) The cluster in the fronto-callosal region [anterior cingulated, peak (x,y,z) 17,31,16; k 785, p < 0.02] formed part of the bilateral white matter connections in the pre-frontal regions, through the genu of the corpus callosum and the anterior cingulum. 2) The cluster in the right frontal–external capsulae [fronto-occipital fasciculus, peak (x,y,z) 23,35,−1; k 4435, p < 0.02] formed part of the pathways interconnecting the ipsilateral frontal and occipital regions through the fronto-occipital fasciculus. 3) The cluster in the left fronto-parietal region [arcuate fasciculus, peak (x,y,z) −42,−44,32; k 375, p < 0.03] formed part of the pathways interconnecting the frontal and temporal lobes, which give rise to the arcuate fasciculus. 4) The cluster in the right pontine region [ponto-cerebellar fasciculus, peak (x,y,z) 18,−32,−32; k 785, p < 0.03] formed part of the pathway interconnecting the right cerebellar hemisphere through the ponto-cerebellar fasciculus. 5) The clusters in the anterior medial temporal lobes [inferior longitudinal fasciculus, peak (x,y,z) −29,−3,−24; k 139, p < 0.03] formed part of the pathways interconnecting the hippocampus, the amygdala and the inferior longitudinal fasciculus. 6) The cluster in the left anterior medial temporal lobe [limbic, peak (x,y,z) −27,−4,−23; k 139, p < 0.02] formed part of the pathway interconnecting the hippocampus and amygdala to the ipsilateral thalamus.