functional and structural imaging in neurodegenerative diseases caroline sage promotor: prof. dr....
TRANSCRIPT
![Page 1: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/1.jpg)
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
![Page 2: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/2.jpg)
OverviewOverview
• Introduction
• Aims and methods
• Results
• Future directions
![Page 3: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/3.jpg)
OverviewOverview
• Introduction
• Aims and methods
• Results
• Future directions
![Page 4: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/4.jpg)
IntroductionIntroduction
• Neurodegenerative diseases
– Alzheimer’s disease– Parkinson’s disease– Multiple sclerosis– Huntington’s
disease– Pick’s disease– Prion diseases– Amyotrophic lateral
sclerosis
![Page 5: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/5.jpg)
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?
![Page 6: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/6.jpg)
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!
![Page 7: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/7.jpg)
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)
![Page 8: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/8.jpg)
OverviewOverview
• Introduction
• Aims and methods
• Results
• Future directions
![Page 9: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/9.jpg)
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
![Page 10: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/10.jpg)
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)
![Page 11: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/11.jpg)
OverviewOverview
• Introduction
• Aims and methods
• Results
• Future directions
![Page 12: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/12.jpg)
DTIDTI
![Page 13: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/13.jpg)
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()
![Page 14: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/14.jpg)
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
![Page 15: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/15.jpg)
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
![Page 16: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/16.jpg)
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 =
![Page 17: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/17.jpg)
DTI - introductionDTI - introduction
![Page 18: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/18.jpg)
DTI - introductionDTI - introduction
Mori et al., 1999
![Page 19: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/19.jpg)
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
![Page 20: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/20.jpg)
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
![Page 21: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/21.jpg)
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
![Page 22: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/22.jpg)
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
![Page 23: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/23.jpg)
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
![Page 24: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/24.jpg)
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
![Page 25: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/25.jpg)
*
*
* *
FA
Dav
![Page 26: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/26.jpg)
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
![Page 27: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/27.jpg)
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
![Page 28: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/28.jpg)
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
![Page 29: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/29.jpg)
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
![Page 30: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/30.jpg)
A
DTI - correlation analysisDTI - correlation analysis
CST_ALSFRS_FA_positiveFrontal_ALSFRS_FA_positive
![Page 31: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/31.jpg)
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
![Page 32: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/32.jpg)
OverviewOverview
• Introduction
• Aims and methods
• Results
• Future directions
![Page 33: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/33.jpg)
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)
![Page 34: Functional and structural imaging in neurodegenerative diseases Caroline Sage Promotor: Prof. Dr. Stefan Sunaert Co-promotor: Prof. Dr. Wim Robberecht](https://reader036.vdocuments.mx/reader036/viewer/2022081516/56649cc45503460f9498db1e/html5/thumbnails/34.jpg)
Thank you for your Thank you for your attentionattention
Questions?