Diffusion-Tensor Imaging: Diffusion-Tensor Imaging:

Frontal Executive Function in Frontal Executive Function in Vascular Cognitive ImpairmentVascular Cognitive Impairment

Stephen Salloway, MDStephen Salloway, MDStephen Correia, PhDStephen Correia, PhD

Paul Malloy, PhDPaul Malloy, PhDWilliam Heindel, PhDWilliam Heindel, PhDDavid Laidlaw, PhDDavid Laidlaw, PhD

19 April 2005

CTBR Symposium 2005

Goal Goal

To develop diffusion-tensor imaging as an To develop diffusion-tensor imaging as an imaging biomarker of white matter integrity imaging biomarker of white matter integrity

in aging and dementiain aging and dementia

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

Frontal Systems: Frontal Systems: Subcortical-thalamic connectionsSubcortical-thalamic connections

dorsomedial

Striatum

Globus Pallidus/Substantia Nigra

Frontal Cortex

Thalamus

The prefrontal cortex is connected The prefrontal cortex is connected to the striatum and thalamus in to the striatum and thalamus in parallel but separate circuits that parallel but separate circuits that help regulate behaviorhelp regulate behavior

Topographic mapping of caudate Topographic mapping of caudate and thalamusand thalamus

Subcortical white matter Subcortical white matter connectionsconnections Long tractsLong tracts Cortical U-fibersCortical U-fibers

Injury anywhere in a circuit can Injury anywhere in a circuit can produce a major deficit and small produce a major deficit and small small subcortical lesions can mimic small subcortical lesions can mimic large cortical lesionslarge cortical lesions

Frontal Systems FunctionFrontal Systems Function

Processing speedProcessing speed Mental flexibilityMental flexibility PlanningPlanning SequencingSequencing Decision-makingDecision-making Working memoryWorking memory Behavioral regulation, self-monitoringBehavioral regulation, self-monitoring Motivation, drive, interestMotivation, drive, interest

White Matter Changes in AgingWhite Matter Changes in Aging

Volume lossVolume lossGreater than grey matter lossGreater than grey matter lossGreater in frontal lobesGreater in frontal lobes

Loss of myelinLoss of myelinWallerian degenerationWallerian degenerationSubcortical ischemic vascular changesSubcortical ischemic vascular changesSelective vulnerability of frontal regionsSelective vulnerability of frontal regions Increased interstitial fluidIncreased interstitial fluid

Peters, A. (2002) J. Neurocyt. 31: 581-93; Jernigan et al. (2001) Neurobiol Aging 22(4): 581-94; Guttman et al. (1998) Neurology 50(4): 972-8

Subcortical HyperintensitiesSubcortical Hyperintensities

None Mild Moderate Severe

Malloy & Correia, The Clinical Neuropsychologist, in press

Vascular Cognitive ImpairmentVascular Cognitive Impairment

Cognitive impairment due to cerebrovascular Cognitive impairment due to cerebrovascular diseasedisease

Subcortical Ischemic Vascular Disease (SIVD)Subcortical Ischemic Vascular Disease (SIVD) Most common formMost common form Increases with age & cardiovascular risk factorsIncreases with age & cardiovascular risk factors

Features of SIVD:Features of SIVD: Impaired executive function/mental flexibilityImpaired executive function/mental flexibility Cognitive slowingCognitive slowing Apathy & depressionApathy & depression

Diffusion-Tensor Imaging Diffusion-Tensor Imaging

MRI technique that provides MRI technique that provides in-vivoin-vivo characterization of 3D white matter characterization of 3D white matter microstructure. 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.Detects changes in normal-appearing white Detects changes in normal-appearing white

matter (NAWM) that correlate w/cognitionmatter (NAWM) that correlate w/cognition

DTI BasicsDTI Basics

Rosenbloom M, et al. (July 2004). NIAA pubs; http://www.niaaa.nih.gov/publications/arh27-2/146-152.htm

DTI BasicsDTI Basics

Measures water diffusion in at least 6 directions Measures water diffusion in at least 6 directions – we use 12 for better resolution– we use 12 for better resolution

1.5T magnet or greater capable of diffusion 1.5T magnet or greater capable of diffusion encodingencoding

Echo-planar imaging (fast acquisition)Echo-planar imaging (fast acquisition) Collecting small voxels, scanning takes about 14 Collecting small voxels, scanning takes about 14

minutesminutes Off-line post-processing (Laidlaw lab)Off-line post-processing (Laidlaw lab) Image analysis: Butler Hospital Quantitative Image analysis: Butler Hospital Quantitative

Imaging LabImaging Lab

DTI – Tractography DTI – Tractography

Bammer, 2003

DTI Scalar ParametersDTI Scalar Parameters

TraceTrace: Magnitude of : Magnitude of diffusion in a voxel.diffusion in a voxel. Increases in damaged white Increases in damaged white

mattermatter

Fractional Anisotropy (FA)Fractional Anisotropy (FA): : Measure of directionally-Measure of directionally-restricted diffusion.restricted diffusion. Decreases in damaged white Decreases in damaged white

mattermatter

Rosenbloom M, et al. (July 2004). NIAA pubs; http://www.niaaa.nih.gov/publications/arh27-2/146-152.htm

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, 2000)(e.g., Pfefferbaum, 2000)Correlations w/executive function. Correlations w/executive function. (e.g.; O’Sullivan, (e.g.; O’Sullivan,

2001, Madden 2004)2001, Madden 2004)

DTI in SIVD: DTI in SIVD: DTI abnormalities in normal appearing white DTI abnormalities in normal appearing white

matter (NAWM)matter (NAWM)Those DTI changes more strongly correlated Those DTI changes more strongly correlated

w/executive function than DTI in SH. w/executive function than DTI in SH. (O’Sullivan (O’Sullivan 2004)2004)

AIMSAIMS

To determine the integrity of anterior vs. To determine the integrity of anterior vs. posterior normal appearing white matter posterior normal appearing white matter (NAWM) in VCI vs. controls using DTI.(NAWM) in VCI vs. controls using DTI. H: VCI will show poorer anterior & posterior NAWM H: VCI will show poorer anterior & posterior NAWM

integrity than controls on DTIintegrity than controls on DTI

To determine the association between anterior To determine the association between anterior DTI parameters in NAWM and executive DTI parameters in NAWM and executive function and processing speed.function and processing speed. H: DTI parameters in anterior NAWM will correlate H: DTI parameters in anterior NAWM will correlate

with executive functioning and processing speedwith executive functioning and processing speed

SubjectsSubjects

6 VCI (scanned 9)6 VCI (scanned 9)SIVD (sporadic or genetic forms [CADASIL])SIVD (sporadic or genetic forms [CADASIL]) Impaired executive function &/or memoryImpaired executive function &/or memoryMMSE MMSE >> 24 24No cortical strokesNo cortical strokesNo dementiaNo dementia

6 Normal elderly controls (NEC) (scanned 6 Normal elderly controls (NEC) (scanned 10)10)

MethodMethod

Structural MRI, DTIStructural MRI, DTIPrimary imaging outcomes:Primary imaging outcomes:

DTI: FA & TraceDTI: FA & TraceStructural: parenchymal & SH volumesStructural: parenchymal & SH volumes

Cognitive batteryCognitive batteryExecutive functionExecutive function

DRS I/P, TMT-B, COWADRS I/P, TMT-B, COWAProcessing SpeedProcessing Speed

TMT-A, Symbol-digitTMT-A, Symbol-digit

Analysis: ANOVA, chi-square, correlationAnalysis: ANOVA, chi-square, correlation

ResultsResults

NEC NEC

(n=6)(n=6)

VCI VCI

(n = 6)(n = 6) pp

Age (yrs)Age (yrs) 64.83 64.83 ± 7.89± 7.89 62.13 62.13 ± 11.40± 11.40 nsns

Education (yrs)Education (yrs) 15.17 15.17 ± 4.12± 4.12 14.00 14.00 ± 4.00± 4.00 nsns

# Female# Female 22 44 nsns

MMSEMMSE 28.83 28.83 ± 1.62± 1.62 28.17 28.17 ± 1.33± 1.33 nsns

Correia S (2005) 33rd INS meeting; St. Louis, MO

Brennan-Krohn, T (2004) ISMRM Workshop; Boston, MA

Correia, S (2004) 9th ICAD; Philadelphia, PA

Laidlaw, L (2004) 12th ISMRM meeting; Kyoto, Japan

DTI Analysis – ROI PlacementDTI Analysis – ROI Placement

Imaging ResultsImaging Results

VCI group had higher estimated SH VCI group had higher estimated SH volume (volume (pp = .040) = .040)

Estimated parenchymal volume not Estimated parenchymal volume not different across groups (different across groups (pp = .378) = .378)

DTI: No significant differences in FA or DTI: No significant differences in FA or Trace in SH Trace in SH

DTI – TraceDTI – TraceAnterior-Posterior Trace in NAWM

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Anterior Posterior

NEC

VCI

Trace units: x 10-3 mm2/s

p = .033 p = .033

DTI – FADTI – FA

p = .033 p = .033

Anterior-Posterior FA in NAWM

0

0.1

0.2

0.3

0.4

0.5

0.6

Anterior Posterior

NEC

VCI

p = ns p <.001

Processing SpeedProcessing Speed

0

10

20

30

40

50

60

70

80

Sym-Dig

# co

rrec

t (9

0s)

NEC

VCI

0

10

20

30

40

50

60

70

TMT-A

Tim

e to

co

mp

lete

(s)

NEC

VCI

p = .052p = ns

Executive MeasuresExecutive Measures

0

10

20

30

40

50

60

70

COWA

To

tal w

ord

s -

3 tr

ials

NEC

VCI

p = ns

0

10

20

30

40

50

60

DRS I/P

To

tal c

orr

ect

NEC

VCI

p = ns

Executive MeasuresExecutive Measures

0

20

40

60

80

100

120

140

160

TMT-B

Tim

e to

co

mp

lete

(s)

NEC

VCI

p = .003

CorrelationsCorrelations

DTI in NAWMDTI in NAWM: : TMT A & B: TMT A & B:

Inversely correlated with anterior & posterior FAInversely correlated with anterior & posterior FA Positively correlated with anterior & posterior TracePositively correlated with anterior & posterior Trace all all pp < .05 < .05

DTI in SHDTI in SH: : TMT A &B not correlated with FA or Trace (TMT A &B not correlated with FA or Trace (pp > 0.5) > 0.5)

SH VolumeSH Volume: : TMT A & B correlate inversely with SH volume (TMT A & B correlate inversely with SH volume (rr = =

-.70, -.70, pp < .05) < .05)

ConclusionsConclusions

Patients with VCI preform more poorly than NEC Patients with VCI preform more poorly than NEC on tests of processing speed and executive on tests of processing speed and executive functioning.functioning.

VCI alters anterior and posterior NAWM.VCI alters anterior and posterior NAWM. Processing speed and executive functioning Processing speed and executive functioning

correlate with DTI parameters in NAWM but not correlate with DTI parameters in NAWM but not in SH.in SH.

DTI in NAWM may predict executive/processing DTI in NAWM may predict executive/processing speed better than SH volumespeed better than SH volume

Future DirectionsFuture Directions

Successful R03 to study furtherSuccessful R03 to study furtherContinue data collection and analysisContinue data collection and analysisCompare with amnestic MCI & ADCompare with amnestic MCI & ADProgression of white matter changes as Progression of white matter changes as

imaging biomarker in clinical trialsimaging biomarker in clinical trialsDTI in cerebrovascular risk factors (HTN, DTI in cerebrovascular risk factors (HTN,

DM).DM).TractographyTractography

Fiber ClusteringFiber Clustering

Courtesy of Song Zhang

Courtesy of Stephanie Lee, Laidlaw Lab, Brown University

Courtesy of Stephanie Lee, Laidlaw Lab, Brown University

AcknowledgmentsAcknowledgments

Stephen CorreiaStephen CorreiaPaul MalloyPaul Malloy

David LaidlawDavid LaidlawSong ZhangSong Zhang

Thea Brennan-KrohnThea Brennan-KrohnErin SchlictingErin SchlictingJerome SanesJerome SanesLynn FanellaLynn FanellaDavid TateDavid Tate

Stephanie LeeStephanie Lee

SupportSupport

Center for Translational Brain ResearchNIA AG020498-02

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

NIMH K08MH01487WThe Human Brain Project (NIBIB & NIMH)

Ittleson Fund at BrownP20 NCRR15578-01

Brown VP for Research Seed Funds

THANK YOU THANK YOU CTBRCTBR!!

Threshold to DementiaThreshold to Dementia

Cognitive Continuum

Functional Continuum

Normal

Mild Cognitive Impairment

Dementia

Adapted from Petersen

MCI not a unitary constructMCI not a unitary construct

Petersen, 2003

Why study frontal systems in VCI?Why study frontal systems in VCI?

Independent probes of frontal systems: Independent probes of frontal systems: Tests of executive function & processing Tests of executive function & processing

speedspeedDTIDTI

The combination may help identify patients The combination may help identify patients at greatest risk for dementiaat greatest risk for dementia

Image AnalysisImage Analysis

Skull stripping and parenchymal volume estimation

Image AnalysisImage Analysis

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

RegressionRegression

Exploratory regressionExploratory regression IV: SH volume, anterior & posterior FA, TraceIV: SH volume, anterior & posterior FA, TraceDV: TMT A & BDV: TMT A & B

ResultsResultsPosterior FA significantly predicted TMT A & Posterior FA significantly predicted TMT A &

B; SH volume, anterior FA did not.B; SH volume, anterior FA did not.Trace: overall model significant only.Trace: overall model significant only.

DTI ResultsDTI ResultsAnterior-Posterior Trace in NAWM

0.7

0.8

0.9

1

1.1

Anterior Posterior

NEC

VCI

Trace units: 10-3 mm2/s

Between subjects effect: p = .032Within subjects effect: p = .025Interaction effect: p = .057

DTI ResultsDTI Results

Between subjects effect: p = .012Within subjects effect: p = .058Interaction effect: p < .001

Anterior-Posterior FA in NAWM

0.3

0.4

0.5

0.6

Anterior Posterior

NEC

VCI

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 Acquisitions

3D T1 volume (MPRAGE) for volumetric 3D T1 volume (MPRAGE) for volumetric analysisanalysis

3 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.