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?