Post on 09-Jan-2016
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Functional and structural imaging in neurodegenerative diseasesCaroline SagePromotor: Prof. Dr. Stefan SunaertCo-promotor: Prof. Dr. Wim Robberecht
OverviewIntroduction
Aims and methods
Results
Future directions
OverviewIntroduction
Aims and methods
Results
Future directions
IntroductionNeurodegenerative diseases
Alzheimers diseaseParkinsons diseaseMultiple sclerosisHuntingtons diseasePicks diseasePrion diseasesAmyotrophic lateral sclerosis
IntroductionAmyotrophic Lateral Sclerosis (ALS)
Cause is poorly understood5-10% familial ALS (fALS)90-95% sporadic ALS (sALS)
Loss of motor neurons (MN)Upper MN signsLower MN signs
Spectrum disease?
IntroductionResearch in ALS
Cell cultures & molecular researchNeuronal cells: motor neuronsNon-neuronal cells: astrocytes, oligodendrocytes, microgliaAgents for survival and neuronal protection (VEGF,...)
Animal studiesMutant SOD1 mice and rats: overexpression of mutant SOD1Pathological mechanisms: glutamate excitotoxicity, impaired axonal transport,...Rescue experiments
Human studiesEx-vivo: autopsy of brain and/or spinal cordTissue studies: blood analysis, CSF analysisIn-vivo: PET, TMS, 1H-MRS, MRIPubmed search dd 26/06/2007: 4568 scientific publications, in English, over the last 10 years!
IntroductionMagnetic resonance imaging (MRI) in ALS
Conventional MRIPD/T2w/FLAIR: non specific markers (Cheung et al., 1995; Hecht et al., 2001; Hecht et al., 2002)T1w: loss of GM volume and to a lesser degree also loss of WM volume, especially in patients with cognitive deficits (Ellis et al., 1999; Abrahams et al., 2005; Grosskreutz et al., 2006)
Functional MRI (fMRI)Motor tasks: recruitment of motor and non-motor areas in ALS patients (Konrad et al., 2002; Schoenfeld et al., 2005)Cognitive tasks: cognitive deficits in ALS patients, especially in ALS patients with concomittant frontotemporal lobe dementia (Abrahams et al., 2006)
Diffusion tensor imaging (DTI)Impairment of the corticospinal tract: reduction of FA and/or increase of Dav (Ellis et al., 2001; Toosy et al., 2003; Graham et al., 2004; Hong et al., 2004; Sach et al., 2004; Abe et al., 2005)
OverviewIntroduction
Aims and methods
Results
Future directions
AimsResearch questions
Are there structural MRI changes in the brain of ALS patients?
Are there functional MRI changes in the brain of ALS patients?
Search for radiological correlates of structural and/or functional deficits in ALS patients by comparing ALS patients with a group of healthy age- and sex-matched controls
Design scan protocol of different tests for use in clinical settingsImprove diagnosisProvide prognosisMonitor newly developed therapies
Diffusion tensor imaging (DTI)fMRI motor tasksDynamic contrast-enhanced T2*w imaging (PWI)fMRI vasoreactivity (VASC)
OverviewIntroduction
Aims and methods
Results
Future directions
DTI
DTI - introductionDTI
Diffusion Tensor Imaging
Assess Brownian motion of water molecules
free diffusionrestricted diffusionisotropyanisotropy
DTI - introductionData acquisition
Apply magnetic field gradients in multiple non-collinear directions during MRI data acquisition -> signal loss due to diffusion (Stejskal and Tanner, 1965)
Determine diffusion coefficient D in each voxel by varying b-value In case of highly ordered structures: model diffusion by estimation of diffusion tensor D using multivariate fittingS = S0 e-bD
DTI - introductionnon diffusion-weighted image (b0) + 6 diffusion weighted images
DTI - introductionDerive quantitative diffusion parameters
Dav : amount of directionally averaged diffusion (in mm/s)
FA : scalar measure of amount of anisotropy (0 = isotropic; 1 = diffusion in 1 specific direction only)Dav =FA =
DTI - introduction
DTI - introductionMori et al., 1999
DTI - aimStudy white matter integrity in the brain of ALS patients by means of DT-MRI
Fibertracking of CSTSpatial interpolation of tract dataVoxel-based analysis of whole brain white matterCorrelation of disease severity with diffusion parameters
Quantitative comparison of diffusion parameters between ALS patients and controls
FADav
DTI - material & methodsSubjects
Patients (PA, n = 28)Sex: 14 female, 14 maleAge = 58.9 +/- 11.8 years ALS-FRS= 39.7 +/- 6.3
Controls (CT, n = 26)Age = 53.7 +/- 11.8 yearsSex: 15 female, 11 male
Imaging (3T)
DTI16 directions; b= 800 mm/s; 2mm isotropic resolution3D-TFE
DTI - fibertrackingCheck integrity of corticospinal tract (CST)
Motor part -> precentral gyrusSensory part -> postcentral gyrus
Reconstruct mean CST + separate parts Compare mean FA/Dav values between patients and controls
DTI - Fibertracking
StatsFAp-valueDavp-valueMWUFA_mean_L0,4150Dav_mean_L0,2273FA_mean_R0,0016Dav_mean_R0,6211
StatsFAp-valueDavp-valueMWUFA_mean_L0.0041Dav_mean_L0.0206FA_mean_R
DTI interpolation of tract dataAssess local variation of FA/Dav values over course of CST
Interpolation of tract data to spatially normalize tract data Compare mean FA/Dav values between patients and controls
DTI - Interpolation of tract dataTract dataSelect part of CST between pons and subcortical WMInterpolation of individual data in z-directionMeasure FA/Dav over z-direction of interpolated data$$ 76 new z-coordinates
**FADav
DTI voxel-based analysisAssess WM integrity of whole brain
Normalize FA/Dav mapsSmooth warped maps
Voxel-by-voxel comparison of FA/Dav values in whole brain
DTI voxel-based analysisTest in each voxel
DTI voxel-based analysisCSTOrbitofrontalPrefrontal Hippocampal formationsInsular regionsParietal regionsWM underneath PMCWM underneath SMA
DTI - correlation analysisStudy effect of patients scores on ALS-FRS on FA/Dav
ALS-FRS: questionnaire of 12 questions to assess functional integrity of patientsQuestions relate to day-to-day activitiesmax. score = 48
Add individual score as a covariate in a voxel-based correlation analysis
DTI - correlation analysisCST_ALSFRS_FA_positiveFrontal_ALSFRS_FA_positive
DTI - summarySignificant impairment of CST in ALS patientsLimited to the precentral part of the CSTMostly in cranial parts of the CSTWhite matter impairment is not limited to the motor systemAreas involved in voluntary motor controlProprioceptive areasFrontal/temporal/hippocampal structuresStrong correlation of ALS-FRS and FAIn CSTEspecially in orbitofrontal cortexThis study provides support for the view of ALS as being a multisystem degenerative disease, in which abnormalities of extra-motor play an important role in the in vivo physiopathology Sage et al., 2007
Other
OtherNext experiment: Is the cerebral vasculature impaired in ALS?
Basal perfusion -> PWI
Reactivity to respiratory stress conditions -> VASC
PWI - introductionStudy baseline cerebral perfusion
Is a fundamental characteristic of brain tissueReflects baseline vascular integrity
Is needed for correct BOLD response
Is altered in numerous pathological processes
Impairment of baseline perfusion could possibly contribute to physiopathology of ALS
PWI - materials and methods This study: use dynamic susceptibility contrast-enhanced T2*-weighted imaging
Administer bolus of paramagnetic contrast agent
Signal intensity drop at the time of first passageSignal loss is roughly proportional to log[contrast]Estimate [contrast] within each voxel and plot it against scan time
PWI - materials and methods Use arterial input function (AIF) to deconvolve signal and generate individual quantitative maps
rCBFrCBVMTT
Use these maps for statistical group comparisonsKeston et al, 2003
CVR - introductionCVR?
Dynamic autoregulation is a term that describes the moment-to-moment adjustment of arterial vascular resistance to meet the demands of sudden changes in arterial blood pressure
The physiologic response of vasomotor tone to vasodilatory stress from either functional activation or pharmacologic manipulation is one of the prime features of intact cerebral perfusion
Fall in perfusion pressure is counterbalanced by vasodilation of cerebral arteries to maintain an adequate CBFAaslid et al., 1989
VASC - materials and methodsfMRI
120 dynamics (TE = 33ms; TR = 3000ms; 34 slices; voxel size = 2x2x4mm)
Paradigm: 21s of hyperventilation (HV) alternated with 21s breath-hold (BH)
Induce BOLD response (~ SI) without specific taskHV -> PaCO2 -> vasoconstriction -> T2*w-signalBH -> PaCO2 -> vasodilation -> T2*w-signal
VASC - materials and methods1st level analysis: Make VASC map for each subject
Use global intensity changes to model the paradigm
Create contrast image containing desired contrast
2nd level analysis: Make VASC map for groups and make group comparisons
Take contrast images from 1st level analysis
Create contrast images containing group differences (PAvsCT; CTvsPA)
OverviewIntroduction
Aims and methods
Results
Future directions
Future directions - DTINon-rigid coregistration of DTI data in cooperation with UZ Antwerpen (W. Van Hecke)
To reference
To atlas
Tract-based spatial statistics (TBSS, S. Smith et al., 2006)
Thank you for your attentionQuestions?