Diffusion-tensor imaging in aging and dementia - VRL …vis.cs.brown.edu/docs/ppt/Correia-2005-DTI.ppt · PPT file · Web view2005-04-22 · Diffusion-Tensor Imaging: ... MCI Petersen

Diffusion-Tensor Imaging: Diffusion-Tensor Imaging: Executive Function in Executive Function in

Subcortical Ischemic Vascular Subcortical Ischemic Vascular Disease and Mild Cognitive Disease and Mild Cognitive

ImpairmentImpairment Stephen Correia, Ph.D.Stephen Correia, Ph.D.

Dementia Research Fellow,Dementia Research Fellow,NeuropsychologyNeuropsychology

3 February 2005

Diffusion-Tensor Imaging Diffusion-Tensor Imaging MRI technique for MRI technique for in-vivoin-vivo characterization characterization

of 3D white matter microstructure. of 3D white matter microstructure. Measures magnitude and direction of water Measures magnitude and direction of water

diffusion in biological tissue in 3D.diffusion in biological tissue in 3D.More sensitive to white matter changes More sensitive to white matter changes

than conventional MRI sequences.than conventional MRI sequences.

DTI Basics – Water DiffusionDTI Basics – Water Diffusion

Isotropic Anisotropic

Adapted from: Beaulieu (2002). NMR in Biomed; 15:435-455

DTI Scalar ParametersDTI Scalar ParametersTraceTrace: The magnitude of diffusion in a : The magnitude of diffusion in a

voxel.voxel.

Fractional Anisotropy (FA)Fractional Anisotropy (FA): The extent to : The extent to which diffusion is directionally restricted.which diffusion is directionally restricted.

DTI Scalar MapsDTI Scalar Maps

T2-weighted

T2* & FA: Moseley et al. (2002) Brain & Cognition; 50;396-413.Trace: Molko et al. (2001) Stroke: 32(9) 2049-54

FA map Trace map

DTI Basics – White Matter IntegrityDTI Basics – White Matter Integrity

Lesioned white matter:Lesioned white matter: Increased diffusion (increased Trace)Increased diffusion (increased Trace)Decreased anisotropy (decreased FA)Decreased anisotropy (decreased FA)

Etiology of DTI changes unclearEtiology of DTI changes unclearAxon loss & membrane breakdownAxon loss & membrane breakdownDemyelinationDemyelinationGliosis/inflammationGliosis/inflammation

Why study frontal systems in SIVD Why study frontal systems in SIVD & MCI?& MCI?

Frontal-subcortical circuit disruption in SIVDFrontal-subcortical circuit disruption in SIVD Executive and behavioral impairment Executive and behavioral impairment Functional decline and dementia.Functional decline and dementia.

Executive impairment in MCI Executive impairment in MCI (CDR=0.5)(CDR=0.5) may may hasten conversion to dementia.hasten conversion to dementia.

Use DTI and cognitive testing as independent Use DTI and cognitive testing as independent probes of frontal systems integrity and function probes of frontal systems integrity and function to identify a subset of SIVD and MCI patients at to identify a subset of SIVD and MCI patients at greater risk for conversion to dementia.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.

Patient GroupsPatient Groups SIVD: Subcortical ischemic vascular disease SIVD: Subcortical ischemic vascular disease

Subcortical hyperintensities (SH) on T2-weighted Subcortical hyperintensities (SH) on T2-weighted MRI; lacunar infarction on T1MRI; lacunar infarction on T1

Gliosis and demyelination due to underlying small Gliosis and demyelination due to underlying small vessel disease.vessel disease.

70-year-old normal

52-year-old CADASIL

65-year-old CADASIL

Patient GroupsPatient GroupsCADASIL: CADASIL: CCerebral erebral aautosomal utosomal ddominant ominant

aarteriopathy with rteriopathy with ssubcortical ubcortical iinfarction and nfarction and lleukoencephalopathyeukoencephalopathy..Inherited form of SIVD.Inherited form of SIVD.

Effect on brain parenchyma same as in SIVD.Effect on brain parenchyma same as in SIVD.Relatively pure form of SIVD, excellent model.Relatively pure form of SIVD, excellent model.

MCIMCIPetersen criteria for Petersen criteria for amnestic amnestic MCIMCI

Normal controlsNormal controls

Prior Studies of DTIPrior Studies of DTI DTI in Aging: DTI in Aging:

Anterior – posterior gradient of DTI changes. Anterior – posterior gradient of DTI changes. (e.g., Pfefferbaum, (e.g., Pfefferbaum, 2000)2000)

Correlations w/executive function. Correlations w/executive function. (e.g.; O’Sullivan, 2001, Madden 2004)(e.g.; O’Sullivan, 2001, Madden 2004)

DTI in SIVD: DTI in SIVD: DTI abnormalities in normal appearing white matter (NAWM)DTI abnormalities in normal appearing white matter (NAWM) DTI in NAWM more strongly correlated w/executive function than DTI in NAWM more strongly correlated w/executive function than

DTI in SH. DTI in SH. (O’Sullivan 2004)(O’Sullivan 2004)

DTI in MCI:DTI in MCI: Little progression of anterior-posterior gradient found in normal Little progression of anterior-posterior gradient found in normal

aging aging (Head, 2004)(Head, 2004) DTI changes in regions expected for AD (left CSO, temporal DTI changes in regions expected for AD (left CSO, temporal

lobes, left HC) lobes, left HC) (Fellgeibel, 2004)(Fellgeibel, 2004) Association of DTI w/cognitive function not well studied.Association of DTI w/cognitive function not well studied.

ObjectivesObjectives

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.

HypothesesHypotheses

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.

MethodMethodSubjects recruited from Butler Hospital Subjects recruited from Butler Hospital

Memory & Aging Program @ BrownMemory & Aging Program @ BrownNC recruited from family members of NC recruited from family members of

patientspatientsMRI done generally within 2 months of MRI done generally within 2 months of

cognitive testing.cognitive testing.

Key inclusion criteria – SIVD Key inclusion criteria – SIVD n = 9 (4 CADASIL) n = 9 (4 CADASIL) Identified mainly on radiological grounds for protocol Identified mainly on radiological grounds for protocol

different than that of the MCI subjects.different than that of the MCI subjects. Greater than expected SH for age on a visual rating scale Greater than expected SH for age on a visual rating scale

((Vataja et al., 2003 Vataja et al., 2003 Eur J Neurol Eur J Neurol 10, 625-31)10, 625-31) Cognitive complaintCognitive complaint Consensus diagnosis of SIVD or genetically confirmed Consensus diagnosis of SIVD or genetically confirmed

CADASIL CADASIL MMSE ≥ 24MMSE ≥ 24 Global CDR ≥ 0.5Global CDR ≥ 0.5 ADL normal or only slightly impairedADL normal or only slightly impaired ExcludedExcluded: diagnosis of probable or possible AD: diagnosis of probable or possible AD

Key inclusion criteria – MCI Key inclusion criteria – MCI n = 9 n = 9 Documented memory complaintDocumented memory complaint MMSE ≥ 24MMSE ≥ 24 Global CDR = 0.5Global CDR = 0.5 ADL normal or only slightly impairedADL normal or only slightly impaired 1.5 SD below age-corrected mean on 1.5 SD below age-corrected mean on

HVLT-R delayed recall or % retainedHVLT-R delayed recall or % retained ExcludedExcluded: diagnosis of probable or possible : diagnosis of probable or possible

ADAD

Key inclusion criteria – NC Key inclusion criteria – NC Absence of significant memory complaintAbsence of significant memory complaint MMSE within normal limitsMMSE within normal limits CDR = 0CDR = 0 ADL normalADL normal Normal memory function for ageNormal memory function for age

DTI AcquisitionDTI Acquisition Siemens Symphony 1.5TSiemens Symphony 1.5T 3 acquisitions with offset in slice direction by 0.0mm, 1.7 3 acquisitions with offset in slice direction by 0.0mm, 1.7

mm and 3.4 mm, 5mm thick slicesmm and 3.4 mm, 5mm thick slices 0.1mm inter-slice spacing, 30 slices per acquisition0.1mm inter-slice spacing, 30 slices per acquisition matrix = 128 mm x128 mm; FOV = 21.7cm x 21.7cm, in-matrix = 128 mm x128 mm; FOV = 21.7cm x 21.7cm, in-

plane sample spacing was 0.85 mmplane sample spacing was 0.85 mm TR=7200, TE=156TR=7200, TE=156 b values: (0, 500, 1000 b values: (0, 500, 1000 mmmm22/s/s) or (0, 1000 mm) or (0, 1000 mm22/s) /s) 12 non-collinear directions, 12 non-collinear directions, The first three datasets were interleaved and zero-filled The first three datasets were interleaved and zero-filled

in the slice direction to form a fourth dataset with in the slice direction to form a fourth dataset with resulting inter-slice distance of 0.85 mm. resulting inter-slice distance of 0.85 mm.

FA and Trace maps derived.FA and Trace maps derived.

Additional MRI AcquisitionsAdditional MRI Acquisitions3D T1 volume (MPRAGE) for volumetric 3D T1 volume (MPRAGE) for volumetric

analysisanalysis3 interleaved FLAIR acquisitions 3 interleaved FLAIR acquisitions

concatenated into a concatenated into a pseudopseudo 3D volume for 3D volume for assessment of SH volumeassessment of SH volume

Voxel dimensions on MPRAGE & Voxel dimensions on MPRAGE & pseudo pseudo FLAIR match DTI.FLAIR match DTI.

Image AnalysisImage 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 (b=0)

images and transferred to FA and Trace maps for measurement

Recorded location as NAWM vs. SH; anterior vs. posterior

DTI in SIVD – ROI PlacementDTI in SIVD – ROI Placement

Image AnalysisImage 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

Cognitive TestsCognitive Tests

DRS I/PDRS I/P SDMTSDMT TMT A & BTMT A & B COWAT (FAS)COWAT (FAS)

Results – Demographics Results – Demographics

VariableVariable NCNC(n=8)(n=8)

SIVDSIVD(n=9)(n=9)

MCIMCI(n=9)(n=9)

OverallOverallpp

Age @ scan (yrs)Age @ scan (yrs) 68.0±14.868.0±14.8 58.6±10.758.6±10.7aa 76.7±8.476.7±8.4aa .011.011

Education (yrs)Education (yrs) 12.6±3.412.6±3.4 14.0±3.314.0±3.3 13.7±2.913.7±2.9 nsns

MMSEMMSE 29.0±1.629.0±1.6 28.6±1.228.6±1.2 27.3±1.527.3±1.5 nsns

% Female% Female 50.0% 50.0% 66.7%66.7% 55.6%55.6% nsns

SIVD group younger than MCI

All subsequent group analyses covaried for age @ scan

Results – Parenchymal & SH volumesResults – Parenchymal & SH volumes

VariableVariable NCNC(n=8)(n=8)

SIVDSIVD(n=9)(n=9)

MCIMCI(n=9)(n=9)

OverallOverallpp

Parenchymal Parenchymal (cm(cm33))

1099.9±96.281099.9±96.28 1184.2 ±191.1 1184.2 ±191.1 1103.7±153.81103.7±153.8 nsns

SH/parenchSH/parench .002±.002.002±.002aa .033±.025.033±.025a,ba,b .009±.009.009±.009bb .003.003

No significant differences across groups on estimated parenchymal volume.

SIVD had higher ratio of SH to parenchymal volume than NC or MCI

Results: SH FA & TraceResults: SH FA & TraceFA & Trace in SH

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

FA Trace

NC

SIVDMCI

No group differences in SH or Trace in regions of SH

(mm2/s x 10-3)

Results: NAWM FA & TraceResults: NAWM FA & Trace

NAWM FA & Trace (periventricular & centrum semiovale)

0.0

0.2

0.4

0.6

0.8

1.0

NAWM FA NAWM Trace

NC

SIVD

MCI

* *

* *

p=.126

(mm2/s x 10-3)

SIVD had lower FA vs. NC and higher trace vs. MCI

Results – NAWM Anterior/PosteriorResults – NAWM Anterior/Posterior

Estimated Marginal Means of A

AP_FA

21

Estim

ated

Mar

gina

l Mea

ns

.5

.4

.3

.2

1=NEC; 2=VCI; 3=MCI

1

2

3

Estimated Marginal Means of MEASURE_1

AP_TRACE

21

Estim

ated

Mar

gina

l Mea

ns

.0012

.0011

.0010

.0009

.0008

.0007

1=NEC; 2=VCI; 3=MCI

1

2

3

Results – DTI & Cognition Results – DTI & Cognition SH:

SDMT with SH/parenchymal ratio (r = .45, p = .02)SDMT with FA in SH (r = -.61, p = .01)

NAWMSDMT with NAWM FA (r = -.42, p < .04)SDMT with anterior NAWM FA (r = -.46, p < .02)SDMT with NAWM Trace (r = .40, p < .05)

No other significant correlations between tests/DTI variables

Conclusions Conclusions Consistent w/previous results showing DTI changes in Consistent w/previous results showing DTI changes in

NAWM in SIVD. NAWM in SIVD. NC and MCI were similar on DTINC and MCI were similar on DTI SIVD may alter the age-related gradient of anterior to SIVD may alter the age-related gradient of anterior to

posterior DTI changes. posterior DTI changes. Processing speed associated with DTI parameters in Processing speed associated with DTI parameters in

both NAWM and SH. both NAWM and SH. DTI may provide method for describing differential effect DTI may provide method for describing differential effect

of disorders on white matter and detect associations of disorders on white matter and detect associations between NAWM and cognitive function.between NAWM and cognitive function.

LimitationsLimitationsSmall nSmall nSIVD group younger than MCI SIVD group younger than MCI SIVD group radiographically SIVD group radiographically

characterized.characterized.Limited range of cognitive deficitsLimited range of cognitive deficitsCorrelation analyses exploratoryCorrelation analyses exploratoryROI analysis not capture DTI differences ROI analysis not capture DTI differences

in other regionsin other regions

Future DirectionsFuture DirectionsAdditional data collection underwayAssess differential impact of CADASIL vs.

SIVDDifferential contribution of SH volume vs.

DTI in these groups.Assess DTI correlation with experimental

working memory measures.

TractographyTractography

Zhang & Laidlaw: http://csdl.computer.org/comp/proceedings/vis/2004/8788/00/87880028p.pdf.

Superior view color fiber maps Lateral view color fiber maps

AcknowledgmentsAcknowledgments

Stephen SallowayStephen SallowayPaul MalloyPaul Malloy

David LaidlawDavid LaidlawSong ZhangSong Zhang

Thea Brennan-KrohnThea Brennan-KrohnErin SchlictingErin SchlictingJerome SanesJerome SanesLynn FanellaLynn Fanella

SupportSupportNIA AG020498-02

Alzheimer’s Association NIRG-03-6195Start-MH Grant

NIMH K08MH01487WThe Human Brain Project (NIBIB & NIMH)

Ittleson Fund at BrownP20 NCRR15578-01

Center for Translational Brain Research at Brown.

THANK YOUTHANK YOU

Results – DTI & CognitionResults – DTI & Cognition NC

SDMT with FA in NAWM FA (r = .-760, p < .03) SDMT with FA in ant. NAWM FA (r = .-750, p < .03)

Research FocusResearch Focus

Frontal Systems Disruption Frontal Systems Disruption ↓↓

Changes in Executive Cognition and BehaviorChanges in Executive Cognition and Behavior↓↓

Functional Disability/Conversion to DementiaFunctional Disability/Conversion to Dementia

Results: FA & Trace in Genu & SpleniumResults: FA & Trace in Genu & Splenium

FA: Genu & Splenium

0.0

0.2

0.4

0.6

0.8

1.0

FA genu FA splenium

NC

SIVD

MCI

No group differences in SH or Trace in regions of SH

Trace: Genu & Splenium

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

Trace genu Trace splenium

NCSIVDMCI

(mm2/s x 10-3)

Results: FA & Trace in Temporal Lobe Results: FA & Trace in Temporal Lobe White MatterWhite Matter

Trace: Temporal Lobe White Matter

0.0

0.2

0.4

0.6

0.8

1.0

1.2

TLWM-R TLWM-L

NC

SIVD

MCI

FA: Temporal Lobe White Matter

0.0

0.2

0.4

0.6

0.8

1.0

TLWM-R TLWM-L

NC

SIVD

MCI

(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.

Image AnalysisImage Analysis

Image AnalysisImage 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

Image AnalysisImage 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 b=0 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

Results – Corpus CallosumResults – Corpus Callosum VariableVariable ControlsControls

(n=8)(n=8)SIVDSIVD(n=9)(n=9)

MCIMCI(n=9)(n=9)

OverallOverallpp

FAFAGenuGenu .813±.041.813±.041 .720±.170 .720±.170 .769±.067.769±.067 nsns

SpleniumSplenium .811±.085.811±.085 .807±.097.807±.097 .815±.082.815±.082 nsns

TraceTrace (mm(mm22/s x 10/s x 10-3-3))

GenuGenu .730±.043.730±.043 .893±.259 .893±.259 .935±.517.935±.517 nsns

SpleniumSplenium .675±.046.675±.046 .747±.053.747±.053 .692±.076.692±.076 nsns

No group differences in FA or Trace in genu or splenium.

Results – Temporal Lobe White MatterResults – Temporal Lobe White Matter VariableVariable ControlsControls

(n=8)(n=8)SIVDSIVD(n=9)(n=9)

MCIMCI(n=9)(n=9)

OverallOverallpp

FAFATLWM – R TLWM – R .574±.052.574±.052a,ba,b .502±.053.502±.053aa .527±.039.527±.039bb .027.027

TLWM – L TLWM – L .551±.056.551±.056c,dc,d .445±.051.445±.051cc .487±.039.487±.039dd .001.001

TraceTrace (mm(mm22/s x 10/s x 10-3-3))

TLWM – R TLWM – R .768±.061.768±.061ee .855±.062.855±.062ee .796±.050.796±.050 .034.034

TLWM – L TLWM – L .785±.070.785±.070ff .920±.076.920±.076f,gf,g .823±.070.823±.070gg .001.001

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.

Results: Attention/ExecutiveResults: Attention/Executive

* *

* *

p=.126

(mm2/s x 10-

3)

Attention/Executive Measures (T scores)

0.0

20.0

40.0

60.0

80.0

100.0

SDMT TMT-A TMT-B COWA DRS I/P

NC

SIVD

MCI

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

Results: MemoryResults: Memory

* *

* *

p=.126

(mm2/s x 10-3)

Memory Measure (T scores)

0.0

20.0

40.0

60.0

80.0

100.0

HVLT TL HVLTDelay

HVLT %ret

HVLTDiscrim

DRSmem

NCSIVDMCI

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

Results – MemoryResults – MemoryVariableVariable ControlsControls

(n=8)(n=8)SIVDSIVD(n=9)(n=9)

MCIMCI(n=9)(n=9)

OverallOverallpp

HVLT-RHVLT-R

TotalTotal 24.88±4.6424.88±4.64aa 24.63±3.2524.63±3.25 14.44±4.5014.44±4.50aa .003.003

DelayDelay 9.50±2.079.50±2.07bb 7.50±3.127.50±3.12bb 2.33±2.182.33±2.18bb ..031031

% retn% retn 97.38±17.8297.38±17.82 74.13±24.3674.13±24.36 34.44±30.5434.44±30.54 nsns

DiscrmDiscrm 10.38±1.6910.38±1.69 9.88±2.649.88±2.64 6.22±2.196.22±2.19 nsns

DRS-MemDRS-Mem 24.00±1.3124.00±1.31 23.50±1.3123.50±1.31 21.89±2.8021.89±2.80 nsns

HVLT-R Total Learning: MCI lower than NC or SIVD HVLT-R Delayed Recall: Significant differences between all pairs

Results: Overall FA & TraceResults: Overall FA & Trace

Overall FA & Trace (all ROIs)

0.0

0.2

0.4

0.6

0.8

1.0

Overall FA Overall Trace

NC

SIVD

MCI

* *

* *

(mm2/s x 10-3)