Loss of White Matter Microstructural Integrity Is Associated with Adverse Neurological Outcome in Tuberous Sclerosis Complex

doi:10.1016/j.acra.2011.08.016

Academic Radiology

Volume 19, Issue 1, January 2012, Pages 17-25

https://doi.org/10.1016/j.acra.2011.08.016 Get rights and content

Rationale and Objectives

Tuberous sclerosis complex (TSC) is a genetic neurocutaneous syndrome in which cognitive and social-behavioral outcomes for patients vary widely in an unpredictable manner. The cause of adverse neurologic outcome remains unclear. The aim of this study was to investigate the hypothesis that disordered white matter and abnormal neural connectivity are associated with adverse neurologic outcomes.

Materials and Methods

Structural and diffusion magnetic resonance imaging was carried out in 40 subjects with TSC (age range, 0.5–25 years; mean age, 7.2 years; median age, 5 years), 12 of whom had autism spectrum disorders (ASD), and in 29 age-matched controls. Tractography of the corpus callosum was used to define a three-dimensional volume of interest. Regional averages of four diffusion scalar parameters of the callosal projections were calculated for each subject. These were the average fractional anisotropy (AFA) and the average mean, radial, and axial diffusivity.

Results

Subjects with TSC had significantly lower AFA and higher average mean, radial, and axial diffusivity values compared to controls. Subjects with TSC and ASD had significantly lower AFA values compared to those without ASD and compared to controls. Subjects with TSC without ASD had similar AFA values compared to controls.

Conclusion

Diffusion tensor scalar parameters provided measures of properties of the three-dimensional callosal projections. In TSC, changes in these parameters may reflect microstructural changes in myelination, axonal integrity, or extracellular environment. Alterations in white matter microstructural properties were associated with TSC, and larger changes were associated with TSC and ASD, thus establishing a relationship between altered white matter microstructural integrity and brain function.

Section snippets

Subjects

Forty patients (age range, 0.5–25 years) with established diagnoses of TSC and 29 age-matched control subjects were imaged using 3-T MRI. Control subjects underwent imaging as part of their routine care or as part of this research study. Each MRI study was reviewed by a pediatric neuroradiologist S.P.P., and all controls had normal MRI results and normal neurologic examination results. Controls did not undergo neuropsychological evaluation as part of this study. Recruitment of subjects and data

Patients

Forty subjects (24 male, 16 female; mean age, 7.2 years; age range, 0.5–25 years; median age, 5.0 years) underwent MRI. Only one patient had normal results on MRI. Twenty-four had clinically significant developmental delays or intellectual disabilities, and 12 had ASD (note that six patients aged < 1.5 years were not considered for formal diagnosis of ASD). Thirty patients had genetic confirmation of their clinical diagnoses with abnormalities in the Tsc1 (n = 8) and Tsc2 (n = 22) regions; in

Relation between White Matter Microstructure and the Development of Brain Function

Our study provides the first imaging data that identify an association between altered white matter microstructure and abnormal brain function in the TSC population. Moreover, a reduction in white matter integrity is seen in patients with worse neurodevelopmental outcomes (ie, in those who have ASD; Fig 3).

Several recent studies have reported DTI abnormalities in TSC of the normal-appearing white matter, indicating foci of microstructural abnormalities, depending on sample size and technique 8,

Conclusions

Our novel method of streamline density–weighted calculation of mean DTI scalar parameters allows for the incorporation of all white matter projections while compensating for volume averaging, resulting in average DTI measures of a white matter structure defined by tractography rather than by its voxels. Using streamline density weighting, we found a relation between alterations in white matter microstructure and neurologic outcomes in TSC.

The finding of decreased AFA and increased AAD, AMD, and

Acknowledgments

Thanks go to Sarah Spence, MD, PhD for critical reading of the manuscript. We gratefully acknowledge the contribution of MRI scans from John Gilmore and Martin Styner, supported by grant P50 MH064065 from the National Institutes of Health. We are indebted to the children and families who have participated in this study.

References (51)

P. Curatolo et al.
Tuberous sclerosis
Lancet
(2008)
M.L. Krishnan et al.
Diffusion features of white matter in tuberous sclerosis with tractography
Pediatr Neurol
(2010)
A.L. Alexander et al.
Diffusion tensor imaging of the corpus callosum in Autism
Neuroimage
(2007)
N.I. Weisenfeld et al.
Automatic segmentation of newborn brain MRI
Neuroimage
(2009)
J. Ruiz-Alzola et al.
Nonrigid registration of 3D tensor medical data
Med Image Anal
(2002)
S.B. Vos et al.
Partial volume effect as a hidden covariate in DTI analyses
Neuroimage
(2011)
M. Kubicki et al.
Stochastic tractography study of Inferior Frontal Gyrus anatomical connectivity in schizophrenia
Neuroimage
(2011)
H.W. Powell et al.
Hemispheric asymmetries in language-related pathways: a combined functional MRI and tractography study
Neuroimage
(2006)
P.J. Basser et al.
Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI
J Magn Reson B
(1996)
S.K. Song et al.
Demyelination increases radial diffusivity in corpus callosum of mouse brain
Neuroimage
(2005)

D.H. Geschwind et al.

Autism spectrum disorders: developmental disconnection syndromes

Curr Opin Neurobiol

(2007)

Y. Zhang et al.

Atlas-guided tract reconstruction for automated and comprehensive examination of the white matter anatomy

Neuroimage

(2010)

J. Dauguet et al.

Comparison of fiber tracts derived from in-vivo DTI tractography with 3D histological neural tract tracer reconstruction on a macaque brain

Neuroimage

(2007)

V. Wong

Study of the relationship between tuberous sclerosis complex and autistic disorder

J Child Neurol

(2006)

F.E. Jansen et al.

Cognitive impairment in tuberous sclerosis complex is a multifactorial condition

Neurology

(2008)

S. Clifford et al.

Autism spectrum phenotype in males and females with fragile X full mutation and premutation

J Autism Dev Disord

(2007)

Y.J. Choi et al.

Tuberous sclerosis complex proteins control axon formation

Genes Dev

(2008)

L. Meikle et al.

A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival

J Neurosci

(2007)

D. Nie et al.

Tsc2-Rheb signaling regulates EphA-mediated axon guidance

Nat Neurosci

(2010)

S. Arulrajah et al.

Magnetic resonance imaging and diffusion-weighted imaging of normal-appearing white matter in children and young adults with tuberous sclerosis complex

Neuroradiology

(2009)

M.I. Makki et al.

Characteristics of abnormal diffusivity in normal-appearing white matter investigated with diffusion tensor MR imaging in tuberous sclerosis complex

AJNR Am J Neuroradiol

(2007)

G. Simao et al.

Diffusion tensor imaging of commissural and projection white matter in tuberous sclerosis complex and correlation with tuber load

AJNR Am J Neuroradiol

(2010)

T.A. Keller et al.

A developmental study of the structural integrity of white matter in autism

Neuroreport

(2007)

E.S. Roach et al.

Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria

J Child Neurol

(1998)

American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed, text rev. Arlington,...

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Tuberous sclerosis complex (TSC) patients may have different specific neuropsychological deficits related to the location of the tubers. Autism spectrum disorders (ASD) are common in TSC patients but the relationship between these diagnoses has not been formally explored. In this study we sought to examine brain Magnetic Resonance Imaging (MRI) findings in TSC patients with ASD.
We evaluated 34 TSC patients on the basis of DSM-V diagnostic criteria for ASD, Wechsler Intelligence Scale for Children (WISC-R), psychiatrist’s examination and also structured parent interviews. The number and localization of the tubers, postcontrast signal characteristics of the tubers, SWI findings, DWI findings on brain MRI were recorded. Demographic features, epilepsy histories, number of antiseizure medications, cognitive status were eveluated also. Patients were divided into two groups: ASD group, which represented group 1 and group 2 consisting of patients without any ASD symptoms.
In our study, the mean number of tuber count was 21.8 in patients with ASD patients (Group 1, n = 13) and 12.4 in other TSC patients without ASD (Group 2, n = 21). Rate of tubers in prefrontal cortex/whole tubers (0.51) in patients with ASD was determined to be higher in group 1 (p = 0.003). Also a significant difference was detected between generalize epileptiform activities on EEG and the rate of DRE (p = 0.002; p = 0.001) between groups. Cognitive disturbances and infantile spasm history were similar between groups. TSC2 mutations have been identified in 29 (86%) patients.
The mean of total tuber count and the rate of the location in the prefrontal cortex were determined to be higher in TSC patients with ASD. Specific areas on brain MRI may help understanding the development of ASD in TSC patients.
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Tuberous sclerosis complex (TSC) is a genetic multisystem disease due to the mutation in one of the two genes TSC1 and TSC2, affecting several organs and systems and carrying a significant risk of early onset and refractory seizures. The pathogenesis of this complex disorder is now well known, with most of TSC-related manifestations being a consequence of the overactivation of the mammalian Target of Rapamycin (mTOR) complex. The discovery of this underlying mechanism paved the way for the use of a class of drugs called mTOR inhibitors including rapamycin and everolimus and specifically targeting this pathway. Rapamycin has been widely used in different animal models of TSC-related epilepsy and proved to be able not only to suppress seizures but also to prevent the development of epilepsy, thus demonstrating an antiepileptogenic potential. In some models, it also showed some benefit on neuropsychiatric manifestations associated with TSC. Everolimus has recently been approved by the US Food and Drug Administration and the European Medical Agency for the treatment of refractory seizures associated with TSC starting from the age of 2 years. It demonstrated a clear benefit when compared to placebo on reducing the frequency of different seizure types and exerting a higher effect in younger children. In conclusion, mTOR cascade can be a potentially major cause of TSC-associated epilepsy and neurodevelopmental disability, and additional research should investigate if early suppression of abnormal mTOR signal with mTOR inhibitors before seizure onset can be a more efficient approach and an effective antiepileptogenic and disease-modifying strategy in infants with TSC.
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Citation Excerpt :
Diffusion imaging has been successfully applied in TSC to assess white matter microstructure, with findings converging on dysconnectivity due to structurally compromised and disorganised axons (Im et al., 2016; Taoka et al., 2020; Peters et al., 2012). In particular, TSC participants display reduced fractional anisotropy and increased mean diffusivity in numerous white matter tracts (Peters et al., 2012; Im et al., 2016; Krishnan et al., 2010), consistent with a reduced capacity for efficient information transfer between disparate regions. These metrics appear to be particularly altered in regions with cortical tubers and other lesions (Tsai et al., 2021).
Tuberous sclerosis complex is a rare genetic multisystem condition that is associated with a high prevalence of neurodevelopmental disorders such as autism and attention-deficit/hyperactivity disorder. The underlying neural mechanisms of the emergence of these symptom domains in tuberous sclerosis complex remain unclear.
Here, we use fixel-based analysis of diffusion-weighted imaging, which allows for the differentiation between multiple fibre populations within a voxel, to compare white matter properties in 16 participants with tuberous sclerosis complex (aged 11–19) and 12 age and sex matched control participants. We further tested associations between white matter alterations and autism and inattention symptoms as well as cognitive ability in participants with tuberous sclerosis complex.
Compared to controls, participants with tuberous sclerosis complex showed reduced fibre density cross-section (FDC) in the dorsal branch of right superior longitudinal fasciculus and bilateral inferior longitudinal fasciculus, reduced fibre density (FD) in bilateral tapetum, and reduced fibre cross-section (FC) in the ventral branch of right superior longitudinal fasciculus. In participants with tuberous sclerosis complex, the extent of FDC reductions in right superior longitudinal fasciculus was significantly associated with autism traits (social communication difficulties and restricted, repetitive behaviours), whereas FDC reductions in right inferior longitudinal fasciculus were associated with inattention. The observed white matter alterations were unrelated to cognitive ability.
Our findings shed light on the fibre-specific biophysical properties of white matter alterations in tuberous sclerosis complex and suggest that these regional changes are selectively associated with the severity of neurodevelopmental symptoms.
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Diffusion Tensor Imaging (DTI) enabled the investigation of brain White Matter (WM), both qualitatively to study the macrostructure, and quantitatively to study the microstructure. The quantitative analyses are mostly performed at the whole-tract level, i.e., providing one measure of interest per tract; however, along-tract approaches may provide finer details of the quality of the WM tracts. In this study, using the DWI data collected from 40 young and 40 old individuals, we compared the DTI measures of FA, MD, AD, and RD, estimated by both whole-tract and along-tract approaches in 18 WM bundles, between the two groups. The results of the whole-tract quantitative analysis showed a statistically significant (p-FWER < 0.05) difference between the old and young groups in 6 tracts for FA, 8 tracts for MD, 1 tract for AD, and 7 tracts for RD. On the contrary, the along-tract approach showed differences between the two groups in 10 tracts for FA, 14 tracts for MD, 8 tracts for AD, and 11 tracts for RD. All the differences between the along-tract measures of the two groups had a large effect size (Cohen’d > 0.80). This study showed that the along-tract approach for the analysis of brain WM reveals changes in some WM tracts which had not shown any changes in the whole-tract approach, and therefore this finding emphasizes the utilization of the along-tract approach along with the whole-tract method for a more accurate study of the brain WM.

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: Dr Sahin is supported in part by the John Merck Fund and a Junior Investigator Award from the Children’s Hospital Boston Translational Research Program. Dr Nelson is supported by grant R01 DC010290 from the National Institutes of Health (Bethesda, MD). This investigation was supported in part by grants R01 RR021885, R01 LM010033, R03 EB008680, and UL1 RR025758 from the National Institutes of Health.

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Original investigationLoss of White Matter Microstructural Integrity Is Associated with Adverse Neurological Outcome in Tuberous Sclerosis Complex

Rationale and Objectives

Materials and Methods

Results

Conclusion

Section snippets

Subjects

Patients

Relation between White Matter Microstructure and the Development of Brain Function

Conclusions

Acknowledgments

Lancet

Pediatr Neurol

Neuroimage

Neuroimage

Med Image Anal

Neuroimage

Neuroimage

Neuroimage

J Magn Reson B

Neuroimage

Curr Opin Neurobiol

Neuroimage

Neuroimage

Study of the relationship between tuberous sclerosis complex and autistic disorder

J Child Neurol

Cognitive impairment in tuberous sclerosis complex is a multifactorial condition

Neurology

Autism spectrum phenotype in males and females with fragile X full mutation and premutation

J Autism Dev Disord

Tuberous sclerosis complex proteins control axon formation

Genes Dev

A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival

J Neurosci

Tsc2-Rheb signaling regulates EphA-mediated axon guidance

Nat Neurosci

Magnetic resonance imaging and diffusion-weighted imaging of normal-appearing white matter in children and young adults with tuberous sclerosis complex

Neuroradiology

Characteristics of abnormal diffusivity in normal-appearing white matter investigated with diffusion tensor MR imaging in tuberous sclerosis complex

AJNR Am J Neuroradiol

Diffusion tensor imaging of commissural and projection white matter in tuberous sclerosis complex and correlation with tuber load

AJNR Am J Neuroradiol

A developmental study of the structural integrity of white matter in autism

Neuroreport

Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria

J Child Neurol

Original investigation
Loss of White Matter Microstructural Integrity Is Associated with Adverse Neurological Outcome in Tuberous Sclerosis Complex