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

3. DTI Basics – Water Diffusion IsotropicAnisotropic Adapted from: Beaulieu (2002). NMR in Biomed; 15:435-455

4. DTI Scalar Parameters Trace: The magnitude of diffusion in a voxel. Trace: The magnitude of diffusion in a voxel. Fractional Anisotropy (FA): The extent to which diffusion is directionally restricted. Fractional Anisotropy (FA): The extent to which diffusion is directionally restricted.

5. DTI 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 mapTrace map

6. DTI 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 unclear Etiology of DTI changes unclear Axon loss & membrane breakdown Axon loss & membrane breakdown Demyelination Demyelination Gliosis/inflammation Gliosis/inflammation

7. Why study frontal systems in SIVD & MCI? Frontal-subcortical circuit disruption in SIVD Frontal-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 (CDR=0.5) may hasten conversion to dementia. Executive impairment in MCI (CDR=0.5) 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. 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 SIVD: Subcortical ischemic vascular disease Subcortical hyperintensities (SH) on T2-weighted MRI; lacunar infarction on T1 Subcortical hyperintensities (SH) on T2-weighted MRI; lacunar infarction on T1 Gliosis and demyelination due to underlying small vessel disease. 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. CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy. 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. MCI MCI Petersen criteria for amnestic MCI Petersen criteria for amnestic MCI Normal controls Normal controls

10. Subcortical Ischemic Vascular Disease (SIVD) Subcortical hyperintensities (SH) on T2- weighted MRI; lacunar infarction Subcortical hyperintensities (SH) on T2- weighted MRI; lacunar infarction Gliosis and demyelination due to underlying small vessel disease. 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 Mental flexibility Speed of processing Speed of processing Complex attention Complex attention Executive functioning & working memory Executive functioning & working memory Apathy Apathy

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

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

14. Hypotheses 1. 1. Increased FA and decreased Trace in SIVD & MCI vs. NC. 2. 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 @ Brown Subjects recruited from Butler Hospital Memory & Aging Program @ Brown NC recruited from family members of patients NC recruited from family members of patients MRI done generally within 2 months of cognitive testing. MRI done generally within 2 months of cognitive testing.

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

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

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

19. DTI Acquisition Siemens Symphony 1.5T Siemens Symphony 1.5T 3 acquisitions with offset in slice direction by 0.0mm, 1.7 mm and 3.4 mm, 5mm thick slices 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 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 matrix = 128 mm x128 mm; FOV = 21.7cm x 21.7cm, in- plane sample spacing was 0.85 mm TR=7200, TE=156 TR=7200, TE=156 b values: (0, 500, 1000 mm 2 /s) or (0, 1000 mm 2 /s) b values: (0, 500, 1000 mm 2 /s) or (0, 1000 mm 2 /s) 12 non-collinear directions, 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. 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. FA and Trace maps derived.

20. Additional MRI Acquisitions 3D T1 volume (MPRAGE) for volumetric analysis 3D T1 volume (MPRAGE) for volumetric analysis 3 interleaved FLAIR acquisitions concatenated into a pseudo 3D volume for assessment of SH volume 3 interleaved FLAIR acquisitions concatenated into a pseudo 3D volume for assessment of SH volume Voxel dimensions on MPRAGE & pseudo FLAIR match DTI. 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 (b=0) 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 DRS I/P SDMT SDMT TMT A & B TMT A & B COWAT (FAS) COWAT (FAS)

25. Results – Demographics VariableNC(n=8)SIVD(n=9)MCI(n=9)Overallp Age @ scan (yrs) 68.0±14.8 58.6±10.7 a 76.7±8.4 a.011 Education (yrs) 12.6±3.414.0±3.313.7±2.9ns MMSE29.0±1.628.6±1.227.3±1.5ns % Female 50.0%66.7%55.6%ns  SIVD group younger than MCI  All subsequent group analyses covaried for age @ scan

26. Results – Parenchymal & SH volumes VariableNC(n=8)SIVD(n=9)MCI(n=9)Overallp Parenchymal (cm 3 ) 1099.9±96.28 1184.2 ±191.1 1103.7±153.8ns SH/parench.002±.002 a.033±.025 a,b.009±.009 b.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  No group differences in SH or Trace in regions of SH (mm 2 /s x 10 -3 )

28. Results: NAWM FA & Trace * * * * p=.126 (mm 2 /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 <.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

31. Conclusions Consistent w/previous results showing DTI changes in NAWM in SIVD. Consistent w/previous results showing DTI changes in NAWM in SIVD. NC and MCI were similar on DTI NC and MCI were similar on DTI SIVD may alter the age-related gradient of anterior to posterior DTI changes. SIVD may alter the age-related gradient of anterior to posterior DTI changes. Processing speed associated with DTI parameters in both NAWM and SH. 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. 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 Small n SIVD group younger than MCI SIVD group younger than MCI SIVD group radiographically characterized. SIVD group radiographically characterized. Limited range of cognitive deficits Limited range of cognitive deficits Correlation analyses exploratory Correlation analyses exploratory ROI analysis not capture DTI differences in other regions 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 Zhang & Laidlaw: http://csdl.computer.org/comp/proceedings/vis/2004/8788/00/87880028p.pdf.http://csdl.computer.org/comp/proceedings/vis/2004/8788/00/87880028p.pdf Superior view color fiber mapsLateral view color fiber maps

35. Acknowledgments Stephen Salloway Paul Malloy David Laidlaw Song Zhang Thea Brennan-Krohn Erin Schlicting Jerome Sanes Lynn Fanella

36. Support NIA AG020498-02 Alzheimer’s 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 <.03) DRS I/P with Trace in ant. NAWM (r = -.685, p <.04) MCI TMT-B with FA in ant. NAWM FA (r =.-681, p <.04) COWAT with SH/parench ratio (r = -.792, p <.01)

39. Results – DTI & Cognition NC SDMT with FA in NAWM FA (r =.-760, p <.03) SDMT with FA in ant. NAWM FA (r =.-750, p <.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  No group differences in SH or Trace in regions of SH (mm 2 /s x 10 -3 )

42. Results: FA & Trace in Temporal Lobe White Matter (mm 2 /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. 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 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

46. Results – DTI & Cognition Age @ scan SDMT (r = -.45, p<.05) TMT-B (r =.58, p<.05) All HVLT-R (r =.41 -.69, p<.05) Education: none Parenchymal volume SDMT (r = -.42, p<.05) TMT-B (r = -.53, p<.05) DRS-Memory (r =.43, p<.05) SH ratio: None

47. Results – NAWM VariableControls(n=8)SIVD(n=9)MCI(n=9)Overallp FA NAWM.438±.045 e.408±.035 e.409±.030.043 Trace (mm 2 /s x 10 -3 ) NAWM.761±.045 c.824±.052 c,d.797±.047 d.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 VariableControls(n=8)SIVD(n=9)MCI(n=9)Overallp FA Genu.813±.041.720±.170.769±.067ns Splenium.811±.085.807±.097.815±.082ns Trace (mm 2 /s x 10 -3 ) Genu.730±.043.893±.259.935±.517ns Splenium.675±.046.747±.053.692±.076ns  No group differences in FA or Trace in genu or splenium.

49. Results – Temporal Lobe White Matter VariableControls(n=8)SIVD(n=9)MCI(n=9)Overallp FA TLWM – R.574±.052 a,b.502±.053 a.527±.039 b.027 TLWM – L.551±.056 c,d.445±.051 c.487±.039 d.001 Trace (mm 2 /s x 10 -3 ) TLWM – R.768±.061 e.855±.062 e.796±.050.034 TLWM – L.785±.070 f.920±.076 f,g.823±.070 g.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 VariableControls(n=8)SIVD(n=9)MCI(n=9)Overallp SDMT44.00±9.0445.00±20.5232.33±13.90ns TMT-A 29.25±7.13 a 40.38±15.65 53.56±16.70 a.015 TMT-B88.38±49.50101.13±45.02180.67±78.99.057 COWA40.25±14.1435.50±12.6231.44±11.22ns DRS I/P 35.00±2.8835.88±2.8033.33±2.96ns  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 (mm 2 /s x 10 - 3 )  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

53. Results: Memory * * * * p=.126 (mm 2 /s x 10 -3 )  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

54. Results: Attention/Executive (T scores) VariableControls(n=8)SIVD(n=9)MCI(n=9)Overallp SDMT47.00±7.7551.88±13.4954.44±4.00ns TMT-A 42.50±8.33 a,b 58.00±13.81 a 63.22±16.35 b.013 TMT-B 46.75±11.89 c 58.25±15.12 72.11±9.68 c.013 COWA46.37±15.4152.75±14.6356.11±14.63ns DRS I/P 51.63±9.5348.75±9.4557.33±9.84ns  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 VariableControls(n=8)SIVD(n=9)MCI(n=9)Overallp HVLT-R Total 24.88±4.64 a 24.63±3.25 14.44±4.50 a.003 Delay 9.50±2.07 b 7.50±3.12 b 2.33±2.18 b.031 % retn 97.38±17.8274.13±24.3634.44±30.54ns Discrm10.38±1.699.88±2.646.22±2.19ns DRS-Mem24.00±1.3123.50±1.3121.89±2.80ns  HVLT-R Total Learning: MCI lower than NC or SIVD  HVLT-R Delayed Recall: Significant differences between all pairs

56. Results: Memory (T scores) VariableControls(n=8)SIVD(n=9)MCI(n=9)Overallp HVLT-R Total 53.00±8.26 a 58.11±7.37 74.22±11.95 a <.001 Delay 49.75±8.83 b 62.22±12.87 b 78.22±11.22 b <.001 % retn 45.88±9.20 c 61.56±13.27 c 80.00±19.22 c <.001 Discrm 53.75±15.09 d 58.56±17.02 e 76.89±16.57 d,e.017 DRS-Mem 46.75±6.11 f 49.11±5.71 g 61.56±13.22 f,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 * * * * (mm 2 /s x 10 -3 )