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Diffusion-Tensor Imaging: Executive Function in Subcortical Ischemic Vascular Disease and Mild Cognitive Impairment

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Diffusion-Tensor Imaging: Executive Function in Subcortical Ischemic Vascular Disease and Mild Cognitive Impairment Stephen Correia, Ph.D. Dementia Research Fellow, – PowerPoint PPT presentation

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Title: Diffusion-Tensor Imaging: Executive Function in Subcortical Ischemic Vascular Disease and Mild Cognitive Impairment


1
Diffusion-Tensor Imaging Executive Function in
Subcortical Ischemic Vascular Disease and Mild
Cognitive Impairment
  • Stephen Correia, Ph.D.
  • Dementia Research Fellow,
  • Neuropsychology

3 February 2005
2
Diffusion-Tensor Imaging
  • MRI technique for in-vivo characterization of 3D
    white matter microstructure.
  • Measures magnitude and direction of water
    diffusion in biological tissue in 3D.
  • More sensitive to white matter changes than
    conventional MRI sequences.

3
DTI Basics Water Diffusion
Isotropic
Anisotropic
Adapted from Beaulieu (2002). NMR in Biomed
15435-455
4
DTI Scalar Parameters
  • Trace The magnitude of diffusion in a voxel.
  • Fractional Anisotropy (FA) The extent to which
    diffusion is directionally restricted.

5
DTI Scalar Maps
T2-weighted
FA map
Trace map
T2 FA Moseley et al. (2002) Brain
Cognition 50396-413. Trace Molko et al. (2001)
Stroke 32(9) 2049-54
6
DTI Basics White Matter Integrity
  • Lesioned white matter
  • Increased diffusion (increased Trace)
  • Decreased anisotropy (decreased FA)
  • Etiology of DTI changes unclear
  • Axon loss membrane breakdown
  • Demyelination
  • Gliosis/inflammation

7
Why study frontal systems in SIVD MCI?
  • Frontal-subcortical circuit disruption in SIVD
  • Executive and behavioral impairment
  • Functional decline and dementia.
  • Executive impairment in MCI (CDR0.5) may hasten
    conversion to dementia.
  • Use DTI and cognitive testing as independent
    probes of frontal systems integrity and function
    to identify a subset of SIVD and MCI patients at
    greater risk for conversion to dementia.

Almkvist (2000), The matter of white matter,
81-95. Albert et al. (2001), JINS 7(5)
631-5. Chen et al (2000), Neurology 55(12)
1847-53.
8
Patient Groups
  • SIVD Subcortical ischemic vascular disease
  • Subcortical hyperintensities (SH) on T2-weighted
    MRI lacunar infarction on T1
  • Gliosis and demyelination due to underlying small
    vessel disease.

70-year-old normal
52-year-old CADASIL
65-year-old CADASIL
9
Patient Groups
  • CADASIL Cerebral autosomal dominant
    arteriopathy with subcortical infarction and
    leukoencephalopathy.
  • Inherited form of SIVD.
  • Effect on brain parenchyma same as in SIVD.
  • Relatively pure form of SIVD, excellent model.
  • MCI
  • Petersen criteria for amnestic MCI
  • Normal controls

10
Subcortical Ischemic Vascular Disease (SIVD)
  • Subcortical hyperintensities (SH) on T2-weighted
    MRI lacunar infarction
  • Gliosis and demyelination due to underlying small
    vessel disease.

70-year-old normal
52-year-old CADASIL
65-year-old CADASIL
11
Impact of SIVD
  • Mental flexibility
  • Speed of processing
  • Complex attention
  • Executive functioning working memory
  • Apathy

12
Prior Studies of DTI
  • DTI in Aging
  • Anterior posterior gradient of DTI changes.
    (e.g., Pfefferbaum, 2000)
  • Correlations w/executive function. (e.g.
    OSullivan, 2001, Madden 2004)
  • DTI in SIVD
  • DTI abnormalities in normal appearing white
    matter (NAWM)
  • DTI in NAWM more strongly correlated w/executive
    function than DTI in SH. (OSullivan 2004)
  • DTI in MCI
  • Little progression of anterior-posterior gradient
    found in normal aging (Head, 2004)
  • DTI changes in regions expected for AD (left CSO,
    temporal lobes, left HC) (Fellgeibel, 2004)
  • Association of DTI w/cognitive function not well
    studied.

13
Objectives
  1. To assess white matter integrity in patients with
    SIVD vs. MCI vs. normal controls using DTI.
  2. To determine the association between DTI
    parameters in white matter and attention/executive
    function and processing speed.

14
Hypotheses
  1. Increased FA and decreased Trace in SIVD MCI
    vs. NC.
  2. FA and Trace in NAWM will correlate significantly
    with performance on tests of attention/executive
    function and psychomotor processing speed.

15
Method
  • Subjects recruited from Butler Hospital Memory
    Aging Program _at_ Brown
  • NC recruited from family members of patients
  • MRI done generally within 2 months of cognitive
    testing.

16
Key inclusion criteria SIVD
  • n 9 (4 CADASIL)
  • Identified mainly on radiological grounds for
    protocol different than that of the MCI subjects.
  • Greater than expected SH for age on a visual
    rating scale (Vataja et al., 2003 Eur J Neurol
    10, 625-31)
  • Cognitive complaint
  • Consensus diagnosis of SIVD or genetically
    confirmed CADASIL
  • MMSE 24
  • Global CDR 0.5
  • ADL normal or only slightly impaired
  • Excluded diagnosis of probable or possible AD

17
Key inclusion criteria MCI
  • n 9
  • Documented memory complaint
  • MMSE 24
  • Global CDR 0.5
  • ADL normal or only slightly impaired
  • 1.5 SD below age-corrected mean on HVLT-R
    delayed recall or retained
  • Excluded diagnosis of probable or possible AD

18
Key inclusion criteria NC
  • Absence of significant memory complaint
  • MMSE within normal limits
  • CDR 0
  • ADL normal
  • Normal memory function for age

19
DTI Acquisition
  • Siemens Symphony 1.5T
  • 3 acquisitions with offset in slice direction by
    0.0mm, 1.7 mm and 3.4 mm, 5mm thick slices
  • 0.1mm inter-slice spacing, 30 slices per
    acquisition
  • matrix 128 mm x128 mm FOV 21.7cm x 21.7cm,
    in-plane sample spacing was 0.85 mm
  • TR7200, TE156
  • b values (0, 500, 1000 mm2/s) or (0, 1000 mm2/s)
  • 12 non-collinear directions,
  • The first three datasets were interleaved and
    zero-filled in the slice direction to form a
    fourth dataset with resulting inter-slice
    distance of 0.85 mm.
  • FA and Trace maps derived.

20
Additional MRI Acquisitions
  • 3D T1 volume (MPRAGE) for volumetric analysis
  • 3 interleaved FLAIR acquisitions concatenated
    into a pseudo 3D volume for assessment of SH
    volume
  • Voxel dimensions on MPRAGE pseudo FLAIR match
    DTI.

21
Image Analysis
  • Describing DTI parameters in NAWM, SH, and in
    anterior and posterior white matter.
  • Analyze AVW 5.0, 6.0 (Mayo Clinic)
  • ROI 5 x 5 square voxels
  • Periventricular white matter
  • Centrum semiovale
  • ROIs were placed on T2-weighted images (b0)
    images and transferred to FA and Trace maps for
    measurement
  • Recorded location as NAWM vs. SH anterior vs.
    posterior

22
DTI in SIVD ROI Placement
23
Image Analysis
  • Parenchymal volume estimation
  • Performed on MPRAGE sequences
  • Voxel estimation tool in Analyze following skull
    stripping.
  • SH volume
  • Performed on pseudo-3D FLAIR images
  • SH thresholding following skull stripping
    w/operator correction
  • Sum of all voxels with intensity levels within SH
    threshold range

24
Cognitive Tests
  • DRS I/P
  • SDMT
  • TMT A B
  • COWAT (FAS)

25
Results Demographics
Variable NC (n8) SIVD (n9) MCI (n9) Overall p
Age _at_ scan (yrs) 68.014.8 58.610.7a 76.78.4a .011
Education (yrs) 12.63.4 14.03.3 13.72.9 ns
MMSE 29.01.6 28.61.2 27.31.5 ns
Female 50.0 66.7 55.6 ns
  • SIVD group younger than MCI
  • All subsequent group analyses covaried for age _at_
    scan

26
Results Parenchymal SH volumes
Variable NC (n8) SIVD (n9) MCI (n9) Overall p
Parenchymal (cm3) 1099.996.28 1184.2 191.1 1103.7153.8 ns
SH/parench .002.002a .033.025a,b .009.009b .003
  • No significant differences across groups on
    estimated parenchymal volume.
  • SIVD had higher ratio of SH to parenchymal
    volume than NC or MCI

27
Results SH FA Trace
(mm2/s x 10-3)
  • No group differences in SH or Trace in regions
    of SH

28
Results NAWM FA Trace


p.126


(mm2/s x 10-3)
  • SIVD had lower FA vs. NC and higher trace vs. MCI

29
Results NAWM Anterior/Posterior
30
Results DTI Cognition
  • SH
  • SDMT with SH/parenchymal ratio (r .45, p .02)
  • SDMT with FA in SH (r -.61, p .01)
  • NAWM
  • SDMT with NAWM FA (r -.42, p lt .04)
  • SDMT with anterior NAWM FA (r -.46, p lt .02)
  • SDMT with NAWM Trace (r .40, p lt .05)
  • No other significant correlations between
    tests/DTI variables

31
Conclusions
  • Consistent w/previous results showing DTI changes
    in NAWM in SIVD.
  • NC and MCI were similar on DTI
  • SIVD may alter the age-related gradient of
    anterior to posterior DTI changes.
  • Processing speed associated with DTI parameters
    in both NAWM and SH.
  • DTI may provide method for describing
    differential effect of disorders on white matter
    and detect associations between NAWM and
    cognitive function.

32
Limitations
  • Small n
  • SIVD group younger than MCI
  • SIVD group radiographically characterized.
  • Limited range of cognitive deficits
  • Correlation analyses exploratory
  • ROI analysis not capture DTI differences in other
    regions

33
Future Directions
  • Additional data collection underway
  • Assess differential impact of CADASIL vs. SIVD
  • Differential contribution of SH volume vs. DTI in
    these groups.
  • Assess DTI correlation with experimental working
    memory measures.

34
Tractography
Superior view color fiber maps
Lateral view color fiber maps
Zhang Laidlaw http//csdl.computer.org/comp/pro
ceedings/vis/2004/8788/00/87880028p.pdf.
35
Acknowledgments
  • Stephen Salloway
  • Paul Malloy
  • David Laidlaw
  • Song Zhang
  • Thea Brennan-Krohn
  • Erin Schlicting
  • Jerome Sanes
  • Lynn Fanella

36
Support
  • NIA AG020498-02
  • Alzheimers Association NIRG-03-6195
  • Start-MH Grant
  • NIMH K08MH01487W
  • The Human Brain Project (NIBIB NIMH)
  • Ittleson Fund at Brown
  • P20 NCRR15578-01
  • Center for Translational Brain Research at Brown.

37
THANK YOU
38
Results DTI Cognition
  • Whole Sample (partial correlations controlled for
    age)
  • SDMT with FA in SH (r .54, p .03)
  • Bivariate group analyses
  • SIVD
  • DRS I/P with FA in NAWM FA (r .706, p lt .03)
  • DRS I/P with Trace in ant. NAWM (r -.685, p lt
    .04)
  • MCI
  • TMT-B with FA in ant. NAWM FA (r .-681, p lt
    .04)
  • COWAT with SH/parench ratio (r -.792, p lt .01)

39
Results DTI Cognition
  • NC
  • SDMT with FA in NAWM FA (r .-760, p lt .03)
  • SDMT with FA in ant. NAWM FA (r .-750, p lt .03)

40
Research Focus
  • Frontal Systems Disruption
  • ?
  • Changes in Executive Cognition and Behavior
  • ?
  • Functional Disability/Conversion to Dementia

41
Results FA Trace in Genu Splenium
(mm2/s x 10-3)
  • No group differences in SH or Trace in regions
    of SH

42
Results FA Trace in Temporal Lobe White Matter
(mm2/s x 10-3)
  • FA Lower in SIVD and MCI groups vs. NC
    bilaterally.
  • Trace Higher in SIVD vs. NC on right and
    higher in SIVD than both NC and MCI on left.

43
Image Analysis
44
Image Analysis
  • Temporal lobe white matter rectangular ROI (6 x
    3) in left right temporal stem
  • 10 consecutive coronal slices starting at the
    mamillary bodies and proceeding posteriorly.
  • Corpus callosum square (3 x 3) ROI in left
    right genu and splenium on 5 consecutive slices.
  • Placed directly on FA or Trace maps
  • No classification of SH vs. NAWM

45
Image Analysis
  • Analyze AVW 5.0, 6.0 (Mayo Clinic)
  • Periventricular white matter 3 ROIs (5 x 5)
    around each horn, 2 axial slices.
  • Centrum semiovale Up to 5 ROIs (5 x 5) in each
    hemisphere in NAWM and SH, 2 axial slices
  • ROIs were placed on b0 images and transferred to
    FA and Trace maps for measurement
  • FLAIR and MPRAGE used for guidance.
  • Recorded location as NAWM vs. SH anterior vs.
    posterior

46
Results DTI Cognition
  • Age _at_ scan
  • SDMT (r -.45, plt.05)
  • TMT-B (r .58, plt.05)
  • All HVLT-R (r .41 - .69, plt.05)
  • Education none
  • Parenchymal volume
  • SDMT (r -.42, plt.05)
  • TMT-B (r -.53, plt.05)
  • DRS-Memory (r .43, plt.05)
  • SH ratio None

47
Results NAWM
Variable Variable Variable Controls (n8) SIVD (n9) MCI (n9) Overall p
FA FA FA FA
NAWM NAWM .438.045e .438.045e .408.035e .409.030 .043
Trace (mm2/s x 10-3) Trace (mm2/s x 10-3) Trace (mm2/s x 10-3) Trace (mm2/s x 10-3)
NAWM .761.045c .761.045c .761.045c .824.052c,d .797.047d .013
  • SIVD had lower NAWM FA than NC
  • SIVD had higher NAWM Trace than either NC or MCI
  • No differences between NC and MCI in NAWM FA or
    Trace
  • No group differences in FA or Trace in regions
    of SH (not shown)

48
Results Corpus Callosum
Variable Controls (n8) SIVD (n9) MCI (n9) Overall p
FA
Genu .813.041 .720.170 .769.067 ns
Splenium .811.085 .807.097 .815.082 ns
Trace (mm2/s x 10-3) Trace (mm2/s x 10-3)
Genu .730.043 .893.259 .935.517 ns
Splenium .675.046 .747.053 .692.076 ns
  • No group differences in FA or Trace in genu or
    splenium.

49
Results Temporal Lobe White Matter
Variable Controls (n8) SIVD (n9) MCI (n9) Overall p
FA
TLWM R .574.052a,b .502.053a .527.039b .027
TLWM L .551.056c,d .445.051c .487.039d .001
Trace (mm2/s x 10-3) Trace (mm2/s x 10-3)
TLWM R .768.061e .855.062e .796.050 .034
TLWM L .785.070f .920.076f,g .823.070g .001
  • FA Lower in SIVD and MCI groups vs. NC
    bilaterally.
  • Trace Higher in SIVD vs. NC on right and
    higher in SIVD than both NC and MCI on left.

50
Image Analysis
Skull stripping and parenchymal volume estimation
51
Results Attention/Executive
Variable Controls (n8) SIVD (n9) MCI (n9) Overall p
SDMT 44.009.04 45.0020.52 32.3313.90 ns
TMT-A 29.257.13a 40.3815.65 53.5616.70a .015
TMT-B 88.3849.50 101.1345.02 180.6778.99 .057
COWA 40.2514.14 35.5012.62 31.4411.22 ns
DRS I/P 35.002.88 35.882.80 33.332.96 ns
  • TMT-A NC better than MCI trend (p .058) for
    NC better than SIVD
  • TMT-B NC better than MCI

52
Results Attention/Executive



p.126
  • SIVD intermediate on all measures except DRS I/P
  • TMT-A NC better than SIVD and MCI MCI and SIVD
    not different.
  • TMT-B NC better than MCI no other pair-wise
    differences

(mm2/s x 10-3)
53
Results Memory



p.126
  • SIVD intermediate on all measures
  • MCI significantly worse than NC on all measures
  • MCI significantly worse than SIVD on all
    measures except HVLT-R Total Learning

(mm2/s x 10-3)
54
Results Attention/Executive (T scores)
Variable Controls (n8) SIVD (n9) MCI (n9) Overall p
SDMT 47.007.75 51.8813.49 54.444.00 ns
TMT-A 42.508.33a,b 58.0013.81a 63.2216.35b .013
TMT-B 46.7511.89c 58.2515.12 72.119.68c .013
COWA 46.3715.41 52.7514.63 56.1114.63 ns
DRS I/P 51.639.53 48.759.45 57.339.84 ns
  • TMT-A NC better than SIVD and MCI MCI and
    SIVD not different.
  • TMT-B NC better than MCI no other pair-wise
    differences

55
Results Memory
Variable Controls (n8) SIVD (n9) MCI (n9) Overall p
HVLT-R
Total 24.884.64a 24.633.25 14.444.50a .003
Delay 9.502.07b 7.503.12b 2.332.18b .031
retn 97.3817.82 74.1324.36 34.4430.54 ns
Discrm 10.381.69 9.882.64 6.222.19 ns
DRS-Mem 24.001.31 23.501.31 21.892.80 ns
  • HVLT-R Total Learning MCI lower than NC or
    SIVD
  • HVLT-R Delayed Recall Significant differences
    between all pairs

56
Results Memory (T scores)
Variable Controls (n8) SIVD (n9) MCI (n9) Overall p
HVLT-R
Total 53.008.26a 58.117.37 74.2211.95a lt.001
Delay 49.758.83b 62.2212.87b 78.2211.22b lt.001
retn 45.889.20c 61.5613.27c 80.0019.22c lt.001
Discrm 53.7515.09d 58.5617.02e 76.8916.57d,e .017
DRS-Mem 46.756.11f 49.115.71g 61.5613.22f,g .005
  • HVLT-R Total Learning NC better than MCI
  • HVLT-R Delayed Recall Significant differences
    between all pairs
  • HVLT-R retained Significant differences
    between all pairs
  • HVLT-R Discrim NC better than MCI, SIVD better
    than MCI
  • DRS-Memory NC and SIVD both better than MCI

57
Results Overall FA Trace




(mm2/s x 10-3)
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