Diffusion Tensor Scalars Vary with Age and Across Spinal Levels in Children

Transcription

1 Reserch Article imedpub Journls JOURNAL OF NEUROLOGY AND NEUROSCIENCE ISSN DOI: / Abstrct Diffusion Tensor Sclrs Vry with Age nd Across Spinl Levels in Children Purpose: 1) To evlute the mturtionl evolution of the pprent diffusion coefficient (ADC) nd frctionl nisotropy (FA) of the norml peditric cervicl s well s upper thorcic cord, 2) to evlute whether ADC nd FA vlues vry t different levels within the spinl cord [upper cervicl (UC), lower cervicl (LC) nd upper thorcic (UT)]. Methods: Norml peditric MRI nd diffusion tensor imging (DTI) studies of the spinl cord obtined with 1.5 Tesl MR scnner were retrospectively nlyzed. ADC nd FA mps were reconstructed from the DTI dt. Regions of interest were mnully plced t the center of the cervicl nd upper thorcic cord t the intervertebrl disk levels in mid-sgittl plne. The ADC nd FA vlues were nlyzed by liner regression nd generl liner model with repeted mesures. Results: Forty-seven subjects rnged in ge from 2 months-17.5 yers (men ± stndrd devition: 74.3 ± 61.1 months) were included in the study. At ll spinl cord levels sttisticlly significnt decrese in ADC nd increse in FA with incresing child s ge ws evident. The ADC vlues of the UC/LC levels were higher thn those of UT while the FA vlues did not show significnt differences. Conclusion: DTI sclrs vry with ge, likely due to ongoing mturtionl processes, nd ADC vlues vry cross levels of the spinl cord. Consequently when quntittive DTI of the spinl cord is undertken in children; n ge nd levelmtched normtive dt should be used to ccurtely interpret the quntittive results. Keywords: Apprent Diffusion Coefficient (ADC), Frctionl Anisotropy (FA), Diffusion Tensor Imging (DTI) Received: July 21, ; Accepted: December 04; ; Published: December 07, Izlem Izbudk 1, Netsiri Dumrongpisutikul 2, Crol B Thompson 3, Aylin Tekes 1, Mjd Thurnher 4 nd Thierry AGM Huismn 1 1 Division of Peditric Neurordiology, The Russell H. Morgn Deprtment of Rdiology nd Rdiologicl Science, Johns Hopkins School of Medicine, Bltimore, MD, USA 2 Deprtment of Rdiology, Fculty of Medicine, King Chullongkorn Memoril Hospitl, Pthumwn, Bngkok, Thilnd 3 Biosttistics Center, Johns Hopkins Bloomberg School of Public Helth, MD, USA 4 Deprtment of Neurordiology, University Hospitl, Vienn, Austri Corresponding uthor: Izlem Izbudk iizbud1@jhmi.edu Assistnt Professor, Neurordiology, The Russell H. Morgn Deprtment of Rdiology nd Rdiologicl Science, Johns Hopkins Hospitl, 600 N. Wolfe Street, Phipps B-126-B, Bltimore. Tel: Fx: Introduction Diffusion tensor imging (DTI) is non-invsive, dvnced imging modlity tht hs helped in understnding the pthophysiology of white mtter diseses t microstructure level in the brin nd might be n importnt dditionl tool for the quntittive evlution of the spinl cord. The spinl cord DTI studies in the literture re limited in number compred to brin DTI studies nd mostly re performed in dults nd focused on the cervicl spinl cord [1-10]. This is due to inherent technicl chllenges of the spinl cord DTI; relted to smll cord volume, susceptibility rtifcts creted by different tissue interfces such s bone, soft tissue, CSF; s well s CSF pulstion, respirtory nd crdic Under License of Cretive Commons Attribution 3.0 License This rticle is vilble in: Cittion: Izbudk I, Dumrongpisutikul N, Thompson CB. Diffusion Tensor Sclrs Vry with Age nd Across Spinl Levels in Children. J Neurol Neurosci. 2016, 6:4. motion rtifcts. These rtifcts ffect the thorcic cord the most t mid thorcic level, therefore the mjority of the prior studies focused on cervicl spine or even upper cervicl spine. There re even less studies in children nd hrdly ny normtive dt [5,6,11,12]. Age-specific normtive dt re necessry to identify nd grde spinl cord pthology in developing children. Similr to the brin, mny ongoing mturtionl processes 1

2 (myelintion, fiber pcking, networking, sprouting of synpses, etc.) re expected to lter the DTI sclrs of the spinl cord [13,14]. Another spect of spinl cord is potentil differences cross spinl levels [15]. Only recently Brkt et l. in 25 norml children ged 7 to 21 yers showed vrition in DTI metrics between C1 nd T1 levels [5]. The gols of this study were two-fold. 1) To evlute the gedependent evolution of the ADC nd FA vlues of the norml peditric cervicl spinl cord s well s upper thorcic cord, nd 2) to evlute whether there re sttisticlly significnt differences of ADC nd FA vlues between upper cervicl, lower cervicl nd upper thorcic levels in developing children. Mterils nd Methods Subjects All children studied by MRI nd DTI of the cervicl nd upper thorcic cord were retrospectively evluted. Children 0 to 21 yers old with good qulity spinl MRI nd DTI imges were included in this study. Exclusion criteri were 1) cliniclly confirmed pthology or disese of the spinl cord or centrl nervous system, 2) positive MRI nd DTI findings for disese of the spinl cord, 3) non-dignostic imge qulity nd 4) incomplete clinicl nd imging informtion. The cut-off ge of 2 (30 months to be precise) ws chosen s it is widely-ccepted milestone for erly mturtion including myelintion in the corticospinl trcts which neurodevelopmentlly correltes to independent wlking nd effective hnd control (reching nd grsping). The study ws pproved by the institutionl review bord of our hospitl with permission to ccess the ptients dtbse. Imging Techniques All MRI studies were performed on clinicl 1.5 Tesl MR scnner (Avnto, Siemens Helthcre, Erlngen, Germny) using stndrd 4-element neck mtrix coil nd stndrd 24-element spine mtrix coil. Routine conventionl sequences of the spine were performed including xil nd sgittl T1- nd T2- weighted turbo spin echo imging nd sgittl short [inversion time (TI)] inversion recovery (STIR) sequences. We obtined sgittl DTI of the cervicl nd upper thorcic spinl cord using single-shot, interleved, multi-slice, spin-echo EPI pulse sequence in combintion with prllel imging with n ccelertion (ipat) fctor of two. Cervicl nd upper thorcic cord could be included in single FOV with miniml rtifcts s detiled bove. DTI imges were cquired using the following prmeters: TR: 2400 ms; TE: 100 ms; field-of-view: 220 mm; slice thickness: 1.9 mm; imging mtrix: 192x192 with n in-plne resolution of 1.1x1.1 mm. Blnced pirs of diffusion grdients were used, centered round the 180 pulse, to minimize eddy current effects. The tensor of the diffusion ws smpled by diffusion grdients oriented in 20 non-colliner directions in spce using two b-vlues (0 nd 750 mm 2 /s). No respirtory or crdic gting ws performed. Diffusion weighted imges, s well s ADC, FA nd color-coded FA mps, were creted using the stndrd vendor- 2 specific softwre (Siemens Neuro3D). Dt nlysis The conventionl MRI imges nd post-processed DTI mps (ADC nd FA mps) were visully evluted for qulity nd for ny incidentl pthology by 2 experienced peditric neurordiologists. Any spinl cord level which showed distortion, rtifcts or inhomogeneity of the signl intensities ws excluded. Regions of interest (ROI) were mnully plced t the center of the cervicl nd upper thorcic spinl cord t every intervertebrl disk level defined on sgittlly reconstructed trce-imge. Meticulous ROI-plcement to void the prtil volume verging effect with the CSF ws performed t mid-sgittl imges. Sizes of the ROIs rnged between 2-9 mm 2 to include the mximum cord re while voiding the CSF verging (Figure 1). Averge ADC nd FA vlues were collected over the selected ROIs t every intervertebrl disc level concurrently with the minimum nd mximum vlues nd stndrd devitions. Any mesurement which showed more thn 30% stndrd devition ws not included in the nlyses. The upper cervicl level (UC) ws defined from the crnio-cervicl junction to C3/4 intervertebrl disc level. The spinl cord ROIs t C4/5-C7/T1 were clssified s lower cervicl level (LC) nd T1/2-T4/5 were clssified s upper thorcic level (UT). Ech of UC, LC, UT levels ws comprised of up to 4 mesurements nd for tht reson there were up to 12 mesurements per child. Sttisticl nlysis Sttisticl nlysis ws performed with STATA version 11.1 (STATA Corportion, 2010; College Sttion, Texs). Liner regression ws used to evlute the reltionship between ge nd ADC nd FA. The subjects were lso clssified into two groups by ge less thn or greter thn 2 yers (specificlly 30 months). The ADC nd FA vlues were compred between the two ge groups cross the Figure 1 T2 weighted sgittl (A) color coded FA mp of sgittl DTI (B) showing ROI plcements in the spinl cord This rticle is vilble in:

3 Vol. 6 No. 4 :47 levels UC, LC, nd UT using generl liner model with repeted mesures. Up to 12 mesurements (excluding those with more thn 30% stndrd devition) were used for ech child in mixed effects model with fixed effects of re (LC, UC, UT) nd level (4). This generl liner model used the vilble mesurements s repeted mesures for ech child to compre the three res for FA nd ADC individully. A two-tiled p-vlue <0.05 ws considered sttisticlly significnt. Results Forty-seven subjects were included (23 mle, 24 femle) with men ± stndrd devition (SD) ge of 74.3 ± 61.1 months (rnge 2 months-17.5 yers). Using cut-off ge of 2 yers (30 months), there were 16 subjects <2 yers of ge (34%) nd 31 subjects older thn 2 yers (66%). Across the 47 scns, fter exclusion of the levels with significnt rtifcts; there were 176 ADC mesurements (men ± SD: 3.7 ± 0.6 per scn) t the UC level, 180 ADC mesurements ( per scn) t the LC level, nd 139 mesurements (3.0 ± 1.2 per scn) t the UT level. Across the 47 scns, there were 178 FA mesurements (men ± SD: 3.8 ± 0.5 per scn) t the UC level, 179 FA mesurements (3.8 ± 0.4 per scn) t the LC level, nd 142 mesurements (3.0 ± 1.2 per scn) t the UT level. ADC nd FA demonstrted sttisticlly significnt reltionships with ge for ll three spinl levels, decresing nd incresing, respectively (Tble 1 nd Figure 2). The men ADC vlues for ges 2 yers were significntly greter thn for ges >2 yers t ech of the three levels (Tble 2 nd Figure 3). The men FA vlues for ges 2 yers were significntly less thn for ges >2 yers t ll three levels (Tble 3 nd Figure 4). When compring levels within ech ge ctegory, UT hs significntly lower ADC vlues thn either UC or LC (Tble 4 nd Figure 3). No significnt differences between levels were found for FA vlues within ech ge ctegory (Figure 4). Discussion MRI diffusion tensor metrics; ADC nd FA in this study; t cervicl nd upper thorcic cord; showed reltionships with ge in children of ges from 2 months to 17.5 yers. ADC vlues decresed nd FA vlues incresed with incresing ge. This result correltes with the previous DTI studies which showed n ge-relted ADC decrese nd FA increse in the brin [14,16,17]. Recently Singhi et l. showed ge-relted ADC decrese nd FA increse in the Tble 1 Slope nd 95% confidence intervls (CI) for pprent diffusion coefficient (ADC) nd frctionl nisotropy (FA) vlues with ge for three spinl cord levels ADC FA Level b Slope c (95%CI) Slope (95%CI) UC (-19.1, -6.4) (0.007, 0.016) LC (-12.9, -3.0) (0.006, 0.014) UT (-22.8, -7.3) (0.003, 0.012) 10-6 mm 2 /s; b UC-Upper Cervicl, LC-Lower Cervicl, UT-Upper Thorcic; c Slope represent chnge in ADC/FA for ech yer increse in ge Under License of Cretive Commons Attribution 3.0 License Figure 2 Figure 3 Assocition of pprent diffusion coefficient (ADC) (x10-6 mm 2 /s) nd frctionl nisotropy (FA) with ge by spinl cord level (UC-upper cervicl, LC-lower cervicl, UTupper thorcic). Tble 2 Comprison of the ADC vlues by ge ctegories split t two yers (30 months) for three spinl cord levels. ADC vlue x10-6 mm 2 /s (95% CI c ) Level b 2 yers (n=16) > 2 yers (n=31) p-vlue UC (1021,1150) (923, 1018) LC (988, 1117) (872, 966) UT (914, 1046) (785, 887) ADC-Apprent Diffusion Coefficient; b UC-Upper Cervicl, LC-Lower Cervicl, UT-Upper Thorcic; c CI-Confidence Intervl Men nd 95% confidence intervl (CI) of frctionl nisotropy (FA)) vlues by spinl cord level (UC upper cervicl, LC lower cervicl, UT upper thorcic) nd ge ctegory (where two yers represent 30 months of ge). UC spinl cord in 41 norml children [11]. Otherwise there re no previous studies, to our knowledge, tht investigted the norml diffusion metrics of the spinl cord in children from infncy to dulthood. A grdul decrese in ADC nd grdul increse in 3

4 Tble 3 Comprison of the FA vlue by ge ctegories split t two yers (30 months) for three spinl cord levels. FA vlue (95% CI c ) Level b 2 yers (n=16) > 2 yers (n=31) p-vlue UC (0.469,0.548) (0.585, 0.642) < LC (0.444,0.524) (0.554, 0.611) < UT (0.473,0.554) (0.564, 0.626) FA-Frctionl Anisotropy; b UC-Upper Cervicl, LC-Lower Cervicl, UT- Upper Thorcic; c CI-Confidence Intervl FA with incresing ge reflects CNS mturtion process in the spinl cord which includes myelintion of the xons, membrne prolifertion, decresing extr xonl spce nd decresing overll wter content mong other things tht re not yet well known [14]. When the study cohort ws divided into two groups, the ADC vlues were significntly lower nd FA vlues were significntly higher t ll levels in children older thn 2 yers of ge compred to children equl to or younger thn 2 yers of ge. The cutoff ge of 2 (30 months to be precise) ws chosen s widelyccepted milestone for erly mturtion including myelintion in the corticospinl trcts which neurodevelopmentlly correltes to independent wlking nd effective hnd control (reching nd grsping). Altmn J nd Byer S.A. demonstrted this 4 Figure 4 Men nd 95% confidence intervl (CI) of pprent diffusion coefficient (ADC) vlues (x10-6mm2/s) by spinl cord level (UC upper cervicl, LC lower cervicl, UT upper thorcic) nd ge ctegory (where two yers represent 30 months of ge). Tble 4 Comprison of the ADC vlues between levels for ech ge group. Men difference of the ADC vlue x10-6 mm 2 /s (95% CI c ) Level b 2 yers (n=16) p-vlue > 2 yers (n=31) p-vlue LC-UC (-108, 42) (-106, 3) UT-UC (-182, -30) (-193, -76) < UT-LC (-149, 3) (-141, -25) ADC-Apprent Diffusion Coefficient; b UC-Upper Cervicl, LC-lower Cervicl, UT-Upper Thorcic; c CI-Confidence Intervl developmentl process from fetl life to the 2 nd yer of life by mcroscopic nd microscopic nlysis of preserved humn spinl cord specimens [13]. The uthors showed n orthogrde (crniocudl) mturtion of the lterl nd ventrl corticospinl trcts in the first 2 yers of life. A lrger norml popultion between 0 to 2 yers of ge nd xil DTI cquisition with high resolution cn enble mesurements of specific corticospinl trcts nd would probbly demonstrte the sme orthogonl mturtion by using DTI. The UT cord showed significntly lower ADC vlues thn either the UC or LC in both ge groups in our study. A recent cervicl spinl cord DTI study in developing children lso showed grdul decrese in men diffusivity (MD) (synonymous to ADC) in crniocudl direction (C1 to T1) [5]. This is ttributed to the decresing number of xons in the spinl cord from cervicl to thorcic direction, which ws lso mentioned in dult DTI studies [2,18]. Interestingly the sme study showed grdul decrese in FA from superior to inferior direction wheres in our study FA did not show sttisticlly significnt differences cross spinl cord levels. Mjor white mtter trcts re highly ordered nd course in single direction (crniocudl or cudcrnil) in the humn spinl cord. Even without myelintion of the xons there is high nisotropy long the longitudinl xis of the cord; on the contrry to the brin where there re innumerble crossing fibers. We think the decresing number of xons crniocudlly result in decresed diffusion in both xil nd rdil diffusion keeping the FA constnt [14]. Secondly, the previously published dt represents the ge rnge from 7 yers to 85 yers wheres our cohort includes 31 children between 2 months nd 6 yers of ge which might hve ffected the FA results differently. The potentil effect of gry mtter inclusion on sgittl DTI mkes understnding the simultneously ongoing mturtionl processes nd chnges in FA nd ADC metrics more difficult. There re some limittions of our study. First, crdic or respirtory gting ws not used during MR scnning. The thorcic levels re the most sensitive to respirtory nd crdic motion. Therefore some crdic nd respirtory rtifcts my hve bised our results. This might be reflected on smller number of mesurements of good qulity DTI dt in UT compred to cervicl cord. However gting increses the scnning time nd our gol ws to keep scnning time to resonble minimum for clinicl MRI in this peditric popultion (the used DTI sequence tkes pproximtely five minutes). Secondly, by mesuring ADC nd FA t mid-sgittl plne we hve most likely included both gry nd white mtter in the voxel, however this is n inherent limittion of sgittl DTI technique nd the mesured vlues represent n overll diffusion chrcteristics t the individul cord levels. Sgittl DTI cquisition ws chosen s it took shorter scn time compred to xil cquisition nd llowed scnning of the entire cervicl nd upper thorcic cord in single cquisition. Thirdly, due to limittions of DTI technique in pplying to the spinl cord especilly t the upper thorcic cord level s listed before; we hd to exclude dt with rtifcts nd this resulted in vrying numbers of smples for ech three spinl cord levels. This rticle is vilble in:

5 Vol. 6 No. 4 :47 Lstly, this is retrospective study nd prospective lrger multi institutionl popultion bsed studies would be the idel study design. Conclusion Our study shows tht developmentl differences in mturing peditric spinl cord exist nd it should be tken into ccount when MR imging with DTI is undertken in children. We recommend hving n ge nd level-mtched normtive dt for more ccurte interprettion of the DTI results. A quntittive in vivo method of spinl cord imging is importnt in young children with spinl cord injury. Conflicts of Interest nd Source of Funding Relted to the Study No conflicts of interest nd no funding ws received for this study. Under License of Cretive Commons Attribution 3.0 License 5

6 References 1 Ducreux D, Fillrd P, Fcon D (2007) Diffusion tensor mgnetic resonnce imging nd fiber trcking in spinl cord lesions: current nd future indictions. Neuroimging clinics of North Americ 17: Song T, Chen WJ, Yng B (2011) Diffusion tensor imging in the cervicl spinl cord. Europen spine journl : officil publiction of the Europen Spine Society, the Europen Spinl Deformity Society, nd the Europen Section of the Cervicl Spine Reserch Society 20: Wheeler-Kingshott CA, Hickmn SJ, Prker GJ (2002) Investigting cervicl spinl cord structure using xil diffusion tensor imging. NeuroImge 16: Clrk CA, Werring DJ (2002) Diffusion tensor imging in spinl cord: methods nd pplictions - review. NMR in biomedicine 15: Brkt N, Mohmed FB, Hunter LN (2012) Diffusion tensor imging of the norml peditric spinl cord using n inner field of view echoplnr imging sequence. AJNR. Americn journl of neurordiology 33: Mohmed FB, Hunter LN, Brkt N (2011) Diffusion tensor imging of the peditric spinl cord t 1.5T: preliminry results. AJNR. Americn journl of neurordiology 32: Mulchey MJ, Smdni A, Gughn J (2012) Diffusion tensor imging in peditric spinl cord injury: preliminry exmintion of relibility nd clinicl correltion. Spine 37: Qin W, Chn Q, Mk H (2011) Quntittive ssessment of the cervicl spinl cord dmge in neuromyelitis optic using diffusion tensor imging t 3 Tesl. Journl of mgnetic resonnce imging: JMRI 33: Renoux J, Fcon D, Fillrd P, Huynh I, Lsjunis P, et l. (2006) MR diffusion tensor imging nd fiber trcking in inflmmtory diseses of the spinl cord. AJNR. Americn journl of neurordiology 27: Wng KY, Idowu O, Thompson CB () Trct-Specific Diffusion Tensor Imging in Cervicl Spondylotic Myelopthy Before nd After Decompressive Spinl Surgery: Preliminry Results. Clinicl neurordiology. 11 Singhi S, Tekes A, Thurnher M (2012) Diffusion tensor imging of the mturing peditric cervicl spinl cord: from the neonte to the young dult. Journl of neurordiology. Journl de neurordiology 39: Brkt N, Shh P, Fro SH () Inter- nd intr-rter relibility of diffusion tensor imging prmeters in the norml peditric spinl cord. World journl of rdiology 7: Altmn J, Byer, Shirley A (2001) Development of the humn spinl cord: An interprettion bsed on experimentl studies in nimls. Englnd: Oxford ; New York : Oxford University Press. 14 Dubois J, Dehene LG, Perrin M (2008) Asynchrony of the erly mturtion of white mtter bundles in helthy infnts: quntittive lndmrks reveled noninvsively by diffusion tensor imging. Humn brin mpping 29: Izbudk I, Dumrongpisutikul N, Thompson CB (2011) Trends nd differences in DTI metrics cross ges nd spinl cord levels in norml children. Pper presented t: Interntionl Society of Mgnetic Resonnce in Medicine; Montrel, Quebec, Cnd. 16 Sksen S, Husin N, Mlik GK (2008) Comprtive evlution of the cerebrl nd cerebellr white mtter development in peditric ge group using quntittive diffusion tensor imging. Cerebellum 7: Mukherjee P, Miller JH, Shimony JS (2002) Diffusion-tensor MR imging of gry nd white mtter development during norml humn brin mturtion. AJNR. Americn journl of neurordiology 23: Ellingson BM, Ulmer JL, Kurpd SN, Schmit BD (2008) Diffusion tensor MR imging of the neurologiclly intct humn spinl cord. AJNR. Americn journl of neurordiology 29: This rticle is vilble in: