The Study Of Central Nervous System Changes Of Hereditary Spastic Paraplegia Type 5 And The Related Mechanisms Using Multiparametric MR Imaging

Part 1: Structural MR imaging in the study of the central nervous system morphological and signal changes in hereditary spastic paraplegia type 5Purpose: Conventional and structural MRI techniques were applied to characterize and quantify the signal and morphological changes of the spinal cord and brain in patients with hereditary spastic paraplegias type 5(SPG5).The correlations between the structural MRI metrics and clinical data were further analyzed.Material and methods: We prospectively recruited 17 SPG5 patients from the neuroscience institute in our university,and 17 age-gender matched healthy controls(HCs).Clinical and MRI data of 34 participants were collected.The spinal cord and brain were characterized and quantified by conventional MRI(T2WI,T1 WI,T2-FLAIR,MEDCI,PDWI,and SWI)and structural MRI(3D-T1W-MPRAGE and 3DT2W-SPACE).Disease duration and disease severity(spastic paraplegia rating scale,SPRS)were recorded in the patients with SPG5;the levels of 27-hydroxycholesterol(27-OHC)derived from plasma were also tested.For the first time,we defined the scoring criteria for the spinal cord “cross signs”.To grade the severity of this sign,we set up a scoring scale(cross-sign scores)in the cervical spinal cords.We quantitatively analyzed the cervical spinal cord(C2-C7 intervertebral disk levels)“cross signs” on the MEDIC sequences.Compared to the HCs,morphological indicators(cross-sectional area,left-right diameter,and anteroposterior diameter)of the spinal cord(C1-T9 segments)in SPG5 patients were quantitatively analyzed using the Spinal Cord Toolbox(SCT).The brain volume of SPG5 patients was analyzed by visual rating scales and voxel morphometry(VBM).The correlations between the structural MRI data(spinal cord areas and the total scores of “cross signs”)and clinical data(SPRS scores and disease duration)and plasma 27-OHC in SPG5 patients was investigated.Results: Seventeen SPG5 patients(11 men,6 women;average age,29±11 years;median disease duration,16 years)and seventeen age-gender matched HCs(11 men,6 women;average age,29±10 years)were enrolled.T2 hyperintensities with "+" form(cross sign)in the atrophic spinal cord were found among all SPG5 patients.Total cross-sign scores in the spinal cord of MEDIC sequence showed a positive correlation with disease duration(r=0.742,P=0.002)and SPRS scores(r=0.545,P=0.035).No correlation was found between total cross-sign scores and the plasma levels of 27-OHC(P=0.976).No "cross sign" was observed in the cervical spinal cord of HCs.Although total spinal cord area was reduced(cervical levels:-11 ?-21%;thoracic levels:-29?-38%),no correlation was found between spinal cord atrophy and disease severity or disease duration.No brain atrophy was observed in SPG5 patients.Plasma 27-OHC was not correlated with disease duration(P=0.679)or SPRS scores(P=0.397).Conclusion: The spinal cord atrophy without brain atrophy in the SPG5 patients.Cross sign of the spinal cord was established as a potential diagnostic biomarker linked to SPG5.Moreover,the cross-sign scoring scale is more sensitive than spinal cord atrophy and plasma 27-OHC for monitoring the disease progress in SPG5.Part 2: Diffusion tensor imaging and T1 Mapping in the study of the microstructural changes and related pathological mechanisms in spastic paraplegia type 5Purpose: To explore the white matter microstructural changes of the spinal cord and brain and related pathological mechanisms in spastic paraplegia type 5(SPG5)using diffusion tensor imaging(DTI)and T1 Mapping sequences.Material and methods: In this prospective study,seventeen patients with SPG5 and seventeen age-gender matched healthy controls(HCs)were enrolled.Fractional anisotropy(FA),mean diffusivity(MD),radial diffusivity(RD),axial diffusivity(AD),and T1 values were obtained using tract-based spatial statistics(TBSS),tractography analysis,and atlas-based analyses.Disease severity(SPRS)and disease duration were both recorded.Neurofilament light(NF-L)and myelin basic protein(MBP)in the cerebrospinal fluid(CSF)were measured.The differences of MRI metrics(FA,AD,MD,RD,and T1 values)in the central nervous system(brain and spinal cord)and biochemical data(the levels of MBP and NF-L)in the CSF between SPG5 and HCs were compared using the Mann-Whitney U-test and student t-test with Bonferroni adjustment to correct for multiple comparisons.The Pearson correlations between clinical data(disease duration and SPRS score)and MRI data were explored.Results: In 17 SPG5,a widespread reduction of FA values,an elevation of MD,T1,and RD values in the white matter;AD values changed only in some spinal cord levels and brain regions,but not in the grey matter.The differences of FA,RD,and T1 values were more pronounced between SPG5 and HCs in the internal capsule,corona radiata,subcortical white matter,C2,C3,T4,and T5 segments of spinal cord.The levels of NF-L(HC vs SPG5: 265 pg/m L vs 617 pg/m L)and MBP(HC vs SPG5: 127 pg/m L vs 3507 pg/m L)in the CSF were higher in SPG5 than that in HCs(P<0.05).DTI metrics and T1 values in the brain and spinal cord were not correlated with SPRS scores and disease duration(P>0.05).Conclusions: The DTI parameters and T1 values of MRI could well show the microstructural impairment of the brain and spinal cord in SPG5 and can be mutually verified with the CSF biochemical indexes(NF-L and MBP),suggesting that the pathological characteristics of SPG5 may be demyelination(mainly)with axonal loss in the brain and spinal cord.Part 3: Resting-state functional magnetic resonance imaging analysis in spastic paraplegia type 5Purpose: To investigate the changes of resting-state brain network in patients with spastic paraplegia type 5(SPG5)using independent component analysis(ICA).Material and methods: In this prospective study,seventeen patients with SPG5 and seventeen age-gender matched healthy controls(HCs)were scanned with 3.0T MRI,the resting-state functional magnetic resonance imaging(rs-f MRI)data were collected.Eight classical resting-state brain function networks were extracted by ICA: sensorimotor network(SMN),default mode network(DMN),visual network and auditory network,bilateral frontoparietal network,salience network,dorsal attention network.Student t-test was used to compare the differences of functional connectivity in each RSN network between HCs and the SPG5.Pearson correlation was used to analyze the correlations between the average Z value(average functional connectivity strength)and clinical indicators(SPRS,MMSE,and disease duration).Results: Compared to HC,SPG5 showed reduced activation in the bilateral precentral and posterior central gyrus(BA3 and 4)of the SMN.No statistically significant differences were found in the other seven RSNs.No statistically significant correlation was found between the mean Z value in the SMN and the clinical indicators(SPRS,MMSE,and disease duration)in the patients with SPG5.Conclusions: The results of the resting state brain network based on ICA suggested that the brain network damage in SPG5 patients was mainly limited to SMN,while other RSN damage was not apparent,which helped to deepen the understanding of the pathogenesis of SPG5.Part 4: The longitudinal study of central nervous system changes of hereditary spastic paraplegia type 5 using multiparameter MRIPurpose: To explore the longitudinal image changes of the central nervous system in SPG5 patients in one-year follow-up,based on multi-parameter MRI.Material and methods: A cohort of SPG5 patients was revisited one year later for MRI scan and neurological evaluation.Conventional MRI(T2-FLAIR and MEDIC sequences),structural MRI(3D-T1W-MPRAGE and 3D-T2W-SPACE sequences),DTI,and T1 Mapping data of brain and spinal cord were collected.Clinical data of SPG5 patients were followed up: 1-year medical history,spastic paraplegia rating scale(SPRS).The morphological and signal changes of the central nervous system in SPG5 patients at baseline and 12 months follow-up were compared using conventional MRI sequences.Spinal cord cross-sectional area,left-right diameter,anteroposterior diameter,DTI parameters,and T1 values of SPG5 patients were quantitatively analyzed using Spinal Cord Toolbox(SCT).The differences of spinal cord MRI data were compared between baseline and 12-month follow-up.Results: Six patients with SPG5 were lost to follow-up,eleven SPG5 patients(median age:29 years;8 men,3 women)were finally complete the MRI follow-up.Conventional MRI showed that the signal characteristics of the brain and the “cross sign” of the spinal cord were the same in 12 months follow-up.There were no statistically significant differences in the spinal cord cross-sectional area,anteroposterior diameter,left-right diameter,DTI parameters,and T1 values between the one-year follow-up and baseline.The specific FA values of one-year follow-up in most cervical spinal cords were lower than baseline,while RD and MD values were higher than baseline.Conclusion: The multi-parameter MRI and clinical results of one-year follow-up suggested that SPG5 was a neurodegenerative disease with slow progression.