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Microstructural characterization of Unidentified Bright Objects in Neurofibromatosis type 1Can DKI and T2 relaxometry refineour understanding of tissue microstructure in NF1 related T2 hyperintensities?Tuesday 23 april at 13:30, Computer 54Thibo BillietE-poster nr. 3654

Microstructural characterization of Unidentified Bright Objects in Neurofibromatosis type 1Thibo Billiet1, Louise Emsell1, Burkhard Maedler2, Felice D'Arco3, Sabine Deprez1, Judith Verhoeven1, Ellen Plasschaert4, Ronald Peeters1, Alexander Leemans5, Bea Van den Bergh6, Mathieu Vandenbulcke7, Eric Legius4, and Stefan Sunaert1

1 Translational MRI, Imaging and Pathology dpt., KU Leuven, Leuven, Belgium Radiology, University Hospitals Leuven, Leuven, Belgium Leuven research Institute for Neuroscience & Disease, Leuven, Belgium Medical Imaging Research Center, KU Leuven & UZ Leuven, Leuven, BelgiumDivision of Stereotaxy and MR-Based Operative Techniques, Department of Neurosurgery, Bonn University Hospital, Bonn, GermanyRadiology, University Federico II of Naples, Naples, ItalyHuman Genetics, KU Leuven, Leuven, BelgiumImage Sciences Institute, University Medical Center Utrecht,Utrecht, The NetherlandsPsychology, KU Leuven, Leuven, BelgiumPsychiatry, KU Leuven, Leuven, BelgiumConclusionDTI & DKI resultsResearch questionWhat are UBOs?Materials & methodsMWI resultsDiscussion

ConclusionDTI & DKI resultsResearch questionWhat are UBOs?Materials & methodsMWI resultsDiscussion

Unidentified Bright Objects are NF1-related T2 hyperintensities

Basal ganglia and hypothalamiMesencephalonCerebellar white matter

Neurofibromatosis type 1:

Hereditary genetic disorderPrevalence 1 in 3000Peripheral nerve tumoursLearning difficulties in children(transient) hyperintensities on T2-weighted MRI scans

Unidentified Bright Objects can be transient

UBO volume vs. ageUBO number vs. ageCerebellar WMCerebellar WMGlobus Pallidus / Internal CapsuleGlobus Pallidus / Internal CapsuleKraut M.A., Gerring J.P. et al., A.J.M.G. 129A:113-119 (2004)

The histopathological basis of UBOs remains unclear

1H MR SpectroscopyNAA: UBO < contralateral NAWMCholine: UBO > contralateral NAWMJones, Gunawardena et al. 2001

Apparent Diffusion Coefficient (ADC)UBO > contralateral NAWMTognini, Ferrozzi et al. 2005Alkan, Sigirci et al. 2005UBO > healthy control WMEastwood, Fiorella et al. 2001Van Engelen, Krab et al. 2008

Fractional Anisotropy (FA)UBO < healthy control WMZamboni, Loenneker et al. 2007Ferraz-Filho, da Rocha et al. 2011Filippi, Bos et al. 2012

Magnetization Transfer Ratio (MTR)UBO < healthy control WMMargariti et al. 2007Hamartomas?Braffman, Bilaniuk et al. 1988

Heterotopias?Bognanno, Edwards et al. 1988

Regions of abnormal myelination/demyelination?Smirniotopoulos and Murphy 1992

Intramyelinic vacuolization/astroglial cell proliferation?DiPaolo et al. 1995

A hamartoma[2] is a benign,[3] focal malformation that resembles a neoplasm in the tissue of its origin. This is not a malignant tumor, and it grows at the same rate as the surrounding tissues.

In medicine, "heterotopia" refers to presence of a particular tissue type at a non-physiological site, but usually co-existing with original tissue in its the correct anatomical location. In other words, it implies ectopic tissue, in addition to retention of the original tissue type. In neuropathology, for example, gray matter heterotopia, is the presence of gray matter within the cerebral white matter or ventricles.7

The histopathological basis of UBOs remains unclear

1H MR SpectroscopyNAA: UBO < contralateral NAWMCholine: UBO > contralateral NAWMJones, Gunawardena et al. 2001

Apparent Diffusion Coefficient (ADC)UBO > contralateral NAWMTognini, Ferrozzi et al. 2005Alkan, Sigirci et al. 2005UBO > healthy control WMEastwood, Fiorella et al. 2001Van Engelen, Krab et al. 2008

Fractional Anisotropy (FA)UBO < healthy control WMZamboni, Loenneker et al. 2007Ferraz-Filho, da Rocha et al. 2011Filippi, Bos et al. 2012

Magnetization Transfer Ratio (MTR)UBO < healthy control WMMargariti et al. 2007Hamartomas?Braffman, Bilaniuk et al. 1988

Heterotopias?Bognanno, Edwards et al. 1988

Regions of abnormal myelination/demyelination?Smirniotopoulos and Murphy 1992

Intramyelinic vacuolization/astroglial cell proliferation?DiPaolo et al. 1995

Current hypothesisA hamartoma[2] is a benign,[3] focal malformation that resembles a neoplasm in the tissue of its origin. This is not a malignant tumor, and it grows at the same rate as the surrounding tissues.

In medicine, "heterotopia" refers to presence of a particular tissue type at a non-physiological site, but usually co-existing with original tissue in its the correct anatomical location. In other words, it implies ectopic tissue, in addition to retention of the original tissue type. In neuropathology, for example, gray matter heterotopia, is the presence of gray matter within the cerebral white matter or ventricles.8ConclusionDTI & DKI resultsResearch questionWhat are UBOs?Materials & methodsMWI resultsDiscussion

Can novel MRI techniques refine our understanding of UBO microstructure?

UBO vs. cNAWM

Pairwise comparison?

DTI and DKIMWI

male/female: ; age range 9.08 16.66 years; mean 12.6 years; SD 3.4 10ConclusionDTI & DKI resultsResearch questionWhat are UBOs?Materials & methodsMWI resultsDiscussion

Radial diffusionMean diffusionAxial diffusionFractional AnisotropyRadial kurtosisMean kurtosisAxial kurtosisKurtosis AnisotropyNo boundaries:Free diffusion

Excess Kurtosis = 0Diffusion Tensor ImagingKurtosis Tensor Imaging

Excess Kurtosis = 0.5Excess Kurtosis = 5Diffusion Tensor Imaging & Diffusion Kurtosis ImagingMyelin Water Imaging

A: the fraction of water with T2 relaxation time 10-40 ms correlates with the myelin content. This is the Myelin Water Fraction (MWF)B: The water having medium T2 (40-200 ms) is the intra- and extracellular water fraction (IEF). Note: The T2 time of CSF is even longer and not shown in this graph.C: the sum of all T2 fractions gives the total water content (TWC).D: the geometric mean T2 of the MWF peak (M-gmT2)E: the geometric mean T2 of total water content (T-gmT2)F: the geometric mean T2 of the IEF peak (IE-gmT2)G: the peak width of the IEF peak (IE-pw)

MWI sequence

3D GraSE32 echoes (TE1 = 10 ms, TE = 10 ms) TR = 800 ms32 slices (thickness 1mm)FOV= 240 x 240 x 64mm3data matrix= 240 x 240 x 32EPI read-out factor = 3

Madler and MacKay 2007Prasloski, Rauscher et al. 2012

Data acquisitionDKI sequence

SE-EPI3 b0-imagesB-shells:700 s/mm2 x 25 directions1000 s/mm2 x 40 directions2800 s/mm2 x 75 directions/ = 20ms/48.3msTR/TE= 7800ms/90msuniform voxel size= 2.5 mmFOV= 240 x 240 x 125 mm3data matrix= 96 x 96 x 50SENSE factor = 2 in the anteroposterior direction

Poot, den Dekker et al. 2010

T2w-FLAIR

TR = 11000 msTI = 2800 msTE = 120 msSlice thickness 4 mmFOV 230 x 184 x 119 mm3Data matrix 240 x 138 x 16

Subjects

7 NF1 patients (4 girls, 3 boys, mean age 12.6 years, SD 3.4 years)21 UBO-cNAWM pairs (DKI) / 10 UBO-cNAWM pairs (MWI)

ConclusionDTI & DKI resultsResearch questionWhat are UBOs?Materials & methodsMWI resultsDiscussion

DTI results

RDMDFA

Increased diffusivity in radial direction is the main contributor to decreased FA and increased MD in UBOs

No changes in axial directionRDMD FA

AD --

DKI results

Decreased kurtosis in radial direction is the main contributor to decreased KA and decreased MK in UBOs

No changes in axial directionUBOradial compartmentalizationcNAWMradial compartmentalizationRKMK KA

AK -- RKMK KAConclusionDTI & DKI resultsResearch questionWhat are UBOs?Materials & methodsMWI resultsDiscussion

MWI results

In UBOs:

1) Longer overall T2 relaxation time UBOcNAWM

MWI results

In UBOs:

1) Longer overall T2 relaxation time 2) Longer intra-and extracellular water T2 UBOcNAWM

MWI results

In UBOs:

1) Longer overall T2 relaxation time 2) Longer intra-and extracellular water T2 3) Extended range of T2 times in intra-and extracellular water UBOcNAWM

MWI results

In UBOs:

1) Longer overall T2 relaxation time 2) Longer intra-and extracellular water T2 3) Extended range of T2 times in intra-and extracellular water 4) No changes in myelin water fraction (MWF) or intra-and extracellular water fraction (IEWF)UBOcNAWMConclusionDTI & DKI resultsResearch questionWhat are UBOs?Materials & methodsMWI resultsDiscussion

What can MWI teach us about the T2 hyperintensities (UBOs)?T2 hyperintensities arise in the intra- and extracellular spaceLonger T2 relaxation timesExtended range of T2 times

Edema? Barnes et al. 1987 (T2 and cerebral edema), Margariti et al. 2007 (MTR in UBOs), Vacuolization? Laule, Vavasour et al. 2007 (T2 and MS lesions)Astroglial cell proliferation? DiPaolo et al. 1995 (diffuse proliferation of protoplasmic astroglia in UBOs)

Unaltered MWF

No demyelination? DiPaolo et al. 1995 (no effect on myelin stain in UBOs)

UBOcNAWM

What is the added value of DTI & DKI?

UBOcNAWM

Axial direction: no changes

intact axons? DiPaolo et al. 1995 (no axonal damage in UBOs)

Radial direction: Increased diffusivity + decreased kurtosis

Intramyelinic vacuolization? DiPaolo et al. 1995 (spongiotic myelin in UBOs)MWI results: T2 hyperintensities arise in the intra- and extracellular space

ConclusionDTI & DKI resultsResearch questionWhat are UBOs?Materials & methodsMWI resultsDiscussion

Conclusion

UBO vs. cNAWM

Pairwise comparison

DTI and DKIMWI

cNAWMUBODiPaolos hypothesis confirmed:

No demyelinationNo axonal damageIntramyelinic vacuolizationAstroglial cell proliferationmale/female: ; age range 9.08 16.66 years; mean 12.6 years; SD 3.4 27

Stefan SunaertRonald PeetersLouise EmsellSabine DeprezMarjolein VerlySilvia KovacsSofie Van CauterTranslational MRI Advanced Neuroradiology

Thank you for your attention