Functional and structural Functional and structural imaging in imaging in

neurodegenerative neurodegenerative diseasesdiseases

Caroline SagePromotor: Prof. Dr. Stefan Sunaert

Co-promotor: Prof. Dr. Wim Robberecht

OverviewOverview

• Introduction

• Aims and methods

• Results

• Future directions

OverviewOverview

• Introduction

• Aims and methods

• Results

• Future directions

IntroductionIntroduction

• Neurodegenerative diseases

– Alzheimer’s disease– Parkinson’s disease– Multiple sclerosis– Huntington’s

disease– Pick’s disease– Prion diseases– Amyotrophic lateral

sclerosis

IntroductionIntroduction

• Amyotrophic Lateral Sclerosis (ALS)

– Cause is poorly understood

• 5-10% familial ALS (fALS)• 90-95% sporadic ALS

(sALS)

– Loss of motor neurons (MN)

• Upper MN signs• Lower MN signs

– Spectrum disease?

IntroductionIntroduction

• Research in ALS

– Cell cultures & molecular research• Neuronal cells: motor neurons• Non-neuronal cells: astrocytes, oligodendrocytes, microglia• Agents for survival and neuronal protection (VEGF,...)

– Animal studies• Mutant SOD1 mice and rats: overexpression of mutant SOD1

– Pathological mechanisms: glutamate excitotoxicity, impaired axonal transport,...

– Rescue experiments

– Human studies• Ex-vivo: autopsy of brain and/or spinal cord• Tissue studies: blood analysis, CSF analysis• In-vivo: PET, TMS, 1H-MRS, MRI

Pubmed search dd 26/06/2007: 4568 scientific publications, in English, over the

last 10 years!

IntroductionIntroduction

• Magnetic resonance imaging (MRI) in ALS

– Conventional MRI• PD/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)

OverviewOverview

• Introduction

• Aims and methods

• Results

• Future directions

AimsAims

• Research 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 settings– Improve diagnosis– Provide prognosis– Monitor newly developed therapies

WM architecture

Diffusion tensor

imaging (DTI)

Neuronal function

fMRI motor tasks

Cerebral vasculature/perfusion

Dynamic contrast-enhanced

T2*w imaging

(PWI)

Cerebral vasoreactivity

fMRI vasoreactivity

(VASC)

OverviewOverview

• Introduction

• Aims and methods

• Results

• Future directions

DTIDTI

DTI - introductionDTI - introduction

• DTI

– Diffusion Tensor Imaging

– Assess Brownian motion of water molecules

free diffusion

restricted diffusion

isotropy

anisotropy

myelinaxonal membrane neurofilament

microtubule

axon

D(//)

D()

DTI - introductionDTI - introduction

• Data 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 fitting

S = S0 e-bD

DTI - introductionDTI - introduction

non diffusion-weighted

image (b0) + ≥ 6 diffusion

weighted images

Dxx Dxy Dxz

Dyx Dyy Dyz

Dzx Dzy Dzz

λ1 0 0

0 λ2 0

0 0 λ3

DTI - introductionDTI - introduction

• Derive quantitative diffusion parameters

– Dav : amount of directionally averaged diffusion (in mm²/s)

– FA : scalar measure of amount of anisotropy (0 = isotropic; 1 = diffusion in 1 specific direction only)

Dav =

FA =

DTI - introductionDTI - introduction

DTI - introductionDTI - introduction

Mori et al., 1999

DTI - aimDTI - aim

• Study white matter integrity in the brain of ALS patients by means of DT-MRI

– Fibertracking of CST– Spatial interpolation of tract data– Voxel-based analysis of whole brain white matter– Correlation of disease severity with diffusion

parameters

• Quantitative comparison of diffusion parameters between ALS patients and controls

– FA– Dav

DTI - material & methodsDTI - material & methods

• Subjects

– Patients (PA, n = 28)• Sex: 14 female, 14 male• Age = 58.9 +/- 11.8 years • ALS-FRS= 39.7 +/- 6.3

– Controls (CT, n = 26)• Age = 53.7 +/- 11.8 years• Sex: 15 female, 11 male

• Imaging (3T)

– DTI• 16 directions; b= 800 mm²/s; 2mm isotropic resolution

– 3D-TFE

DTI - fibertrackingDTI - fibertracking

• Check integrity of corticospinal tract (CST)

– Motor part -> precentral gyrus– Sensory part -> postcentral gyrus

Reconstruct ‘mean’ CST + separate parts Compare mean FA/Dav values between

patients and controls

DTI - DTI - Fibertracking Fibertracking

Prec

entr

al

Postcentra

l

Stats FA p-value Dav p-value

MWU FA_mean_L 0,0028 Dav_mean_L 0,0043

FA_mean_R 0,0007 Dav_mean_R 0,0041

Stats FA p-value Dav p-value

MWU FA_mean_L 0,4150 Dav_mean_L 0,2273

FA_mean_R 0,0016 Dav_mean_R 0,6211

CST_precentral

0.3

0.35

0.4

0.45

0.5

0.55

FA_R FA_L Dav_R Dav_L

FA

/ x1

0-3m

m2/s

CT

PA

* *

* *

CST_postcentral

0.3

0.35

0.4

0.45

0.5

0.55

FA_R FA_L Dav_R Dav_L

FA

/ x1

0-3m

m2/s

CT

PA

* n.s.

n.s.

n.s.

CST_mean

0.3

0.35

0.4

0.45

0.5

0.55

FA_R FA_L Dav_R Dav_L

FA

/ x

10-3m

m2/s

CT

PA

* *

* *

Stats FA p-value Dav p-value

MWU FA_mean_L 0.0041 Dav_mean_L 0.0206

FA_mean_R <0.0001 Dav_mean_R 0.0243

DTI – interpolation of tract DTI – interpolation of tract datadata

• Assess 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 DTI - Interpolation of tract datadata

Tract dataSelect part of CST between pons and subcortical WM

z

Interpolation of individual data in z-direction

Measure FA/Dav over z-direction of interpolated data

$

$ 76 « new » z-coordinates

*

*

* *

FA

Dav

DTI – voxel-based analysisDTI – voxel-based analysis

• Assess WM integrity of whole brain

– Normalize FA/Dav maps

– Smooth warped maps

Voxel-by-voxel comparison of FA/Dav values in whole brain

DTI – voxel-based analysisDTI – voxel-based analysis

t-test t-test

X 28 ALS patients X 26 controls X 28 ALS patients X 26 controls

Test in each voxel

T-valueof test FA inPA < CT

T-valueof test Dav inPA > CT

DTI – voxel-based analysisDTI – voxel-based analysis

• CST• Orbitofrontal• Prefrontal • Hippocampal formations

• Insular regions• Parietal regions• WM underneath PMC• WM underneath SMA

p<0.05, FWE corrected

DTI - correlation analysisDTI - correlation analysis

• Study effect of patients’ scores on ALS-FRS on FA/Dav

– ALS-FRS: questionnaire of 12 questions to assess « functional integrity » of patients

• Questions relate to day-to-day activities• max. score = 48

• Add individual score as a covariate in a voxel-based correlation analysis

A

DTI - correlation analysisDTI - correlation analysis

CST_ALSFRS_FA_positiveFrontal_ALSFRS_FA_positive

DTI - summaryDTI - summary

• Significant impairment of CST in ALS patients– Limited to the precentral part of the CST– Mostly in cranial parts of the CST

• White matter impairment is not limited to the motor system– Areas involved in voluntary motor control– Proprioceptive areas– Frontal/temporal/hippocampal structures

• Strong correlation of ALS-FRS and FA– In CST– Especially in orbitofrontal cortex

This 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

OverviewOverview

• Introduction

• Aims and methods

• Results

• Future directions

Future directions - DTIFuture directions - DTI

• Non-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 Thank you for your attentionattention

Questions?