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Diffuse alterations in grey and white matter associated with cognitive impairment in Shwachman-Diamond syndrome: evidence from a multimodal approach.
Neuroimage Clin 2015; 7:721-31NC

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).

Authors+Show Affiliations

Cystic Fibrosis Centre, Azienda Ospedaliera Universitaria, Piazzale Stefani, 1-37126 Verona, Italy.Neuroradiology Department, Azienda Ospedaliera Universitaria, Piazzale Stefani, 1-37126 Verona, Italy.Neuroradiology Department, Azienda Ospedaliera Universitaria, Piazzale Stefani, 1-37126 Verona, Italy.Laboratory of Molecular Pathology, Laboratory of Clinical Chemistry and Haematology, Azienda Ospedaliera Universitaria, Piazzale Stefani, 1-37126 Verona, Italy.Neuroradiology Department, Azienda Ospedaliera Universitaria, Piazzale Stefani, 1-37126 Verona, Italy.Cystic Fibrosis Centre, Azienda Ospedaliera Universitaria, Piazzale Stefani, 1-37126 Verona, Italy.Cystic Fibrosis Centre, Azienda Ospedaliera Universitaria, Piazzale Stefani, 1-37126 Verona, Italy.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25844324

Citation

Perobelli, Sandra, et al. "Diffuse Alterations in Grey and White Matter Associated With Cognitive Impairment in Shwachman-Diamond Syndrome: Evidence From a Multimodal Approach." NeuroImage. Clinical, vol. 7, 2015, pp. 721-31.
Perobelli S, Alessandrini F, Zoccatelli G, et al. Diffuse alterations in grey and white matter associated with cognitive impairment in Shwachman-Diamond syndrome: evidence from a multimodal approach. Neuroimage Clin. 2015;7:721-31.
Perobelli, S., Alessandrini, F., Zoccatelli, G., Nicolis, E., Beltramello, A., Assael, B. M., & Cipolli, M. (2015). Diffuse alterations in grey and white matter associated with cognitive impairment in Shwachman-Diamond syndrome: evidence from a multimodal approach. NeuroImage. Clinical, 7, pp. 721-31. doi:10.1016/j.nicl.2015.02.014.
Perobelli S, et al. Diffuse Alterations in Grey and White Matter Associated With Cognitive Impairment in Shwachman-Diamond Syndrome: Evidence From a Multimodal Approach. Neuroimage Clin. 2015;7:721-31. PubMed PMID: 25844324.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Diffuse alterations in grey and white matter associated with cognitive impairment in Shwachman-Diamond syndrome: evidence from a multimodal approach. AU - Perobelli,Sandra, AU - Alessandrini,Franco, AU - Zoccatelli,Giada, AU - Nicolis,Elena, AU - Beltramello,Alberto, AU - Assael,Baroukh M, AU - Cipolli,Marco, Y1 - 2015/02/27/ PY - 2014/04/22/received PY - 2015/02/05/revised PY - 2015/02/22/accepted PY - 2015/4/7/entrez PY - 2015/4/7/pubmed PY - 2016/1/15/medline KW - BA, Brodmann area KW - BOLD, blood oxygen level-dependent KW - CTA, cortical thickness analysis KW - Cognitive impairment KW - DTI, diffusion tensor imaging KW - Diffusion tensor imaging KW - EPI, Echo-planar Imaging KW - FA, fractional anisotropy KW - FDT, Diffusion Toolbox KW - Functional MRI KW - GLM, General Linear Model KW - ICA, independent component analysis KW - MD, mean diffusivity KW - PD, parallel diffusivity KW - PT, probabilistic tractography KW - RD, radial diffusivity KW - SDS, Shwachman–Diamond syndrome KW - Shwachman–Diamond syndrome KW - Structural MRI KW - TBSS, Tract-based Spatial Statistics. KW - Tract-based Spatial Statistics KW - rs-fMRI, resting state fMRI SP - 721 EP - 31 JF - NeuroImage. Clinical JO - Neuroimage Clin VL - 7 N2 - 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). SN - 2213-1582 UR - https://www.unboundmedicine.com/medline/citation/25844324/Diffuse_alterations_in_grey_and_white_matter_associated_with_cognitive_impairment_in_Shwachman_Diamond_syndrome:_evidence_from_a_multimodal_approach_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2213-1582(15)00032-7 DB - PRIME DP - Unbound Medicine ER -