1. INFLUENCE OF FRACTIONAL ANISOTROPY THRESHOLD FOR TRACT BASED DIFFUSION TENSOR ANALYSIS OF UNCINATE FASCICLES IN ALZHEIMER DISEASE Toshiaki Taoka, Toshiaki Akashi, Toshiteru Miyasaka,Hiroyuki Nakagawa, Masayuki Morikawa,Kuniaki Kiuchi, Toshifumi Kishimoto, Kimihiko Kichikawa Nara Medical University, Kashihara, JAPAN

2. Background Alzheimer’s disease (AD) is the most common cause of dementia. Surrogate markers of disease progression are required for measuring treatment effects of the therapies in development. The surrogate biomarker should be able to detect a fundamental feature of Alzheimer’s neuropathology, be diagnostically sensitive and specific through validation in confirmed cases.

3. Background A variety of methods have been used to quantify the changes in structural brain MRI –Region-of-interest measurements of the hippocampus (Frisoni et al., Neurology1999;52:91–100) –Voxel-based morphometry (Whitwell JLet al., Brain 2007;130:1777–1786 / Karas G et al. AJNR 2008;29:944-9) –Tract based diffusion tensor analysis (Taoka T et al., AJNR 2009;30:1700-3 / Taoka T et al., AJNR 2006;27:1040-5.)

4. Background Tract-based analysis of white matter is a useful method to analyze pathological changes in selected fiber tracts, especially in degenerative diseases. Increased diffusivity and decreased fractional anisotropy (FA) in the uncinate fascicles are reported to reflect progression of histopathological changes in Alzheimer disease (AD). T Taoka et al. AJNR2006;27:1040-1045

5. Background T Taoka et al. AJNR2006;27:1040-1045 The patients with AD had significantly lower mean FA than the controls at both sides of the uncinate fasciculus and at the left side of the inferior occipitofrontal fasciculus. There were no significant differences in FA along Meyer’s loop Comparison of mean FA between patients with AD and controls.

6. Background T Taoka et al. AJNR2006;27:1040-1045 The patients with AD had significantly higher mean ADC than the controls at both sides of the uncinate fasciculus and inferior occipitofrontal fasciculus. There were no significant differences in ADC along Meyer’s loop Comparison of mean ADC between patients with AD and controls.

7. Background FA threshold ： 0.1 FA threshold ： 0.25 For actual measurement of tract- based analyses, tractography of the required fiber bundle has to be performed. Selection of the FA threshold is critical to determine the size and location of tractography for the uncinate fascicles. Our hypothesis for the current study is that the selection of the FA influences the measurement of diffusion tensor parameters of the uncinate fascicle.

8. Purpose The purpose of the current study is to evaluate the influence of the FA threshold to measured FA and apparent diffusion coefficient (ADC) values in tract-based analysis for the cases with Alzheimer disease.

9. Subjects Patients with AD :25 (64 to 82 years ;mean 72). Severe:5 Moderate:7 Mild:6 Mild cognitive impairment [MCI] :7 Normal controls. :10 (65 to 78 years; mean 71)

10. Methods Imaging: 1.5-T clinical MR unit (Magnetom Sonata, Siemens AG, Erlangen, Germany). Diffusion-tensor images : EPI sequence TR = 2300 ms, TE = 122 ms, b = 1000 sec/mm 2, 6-axis encoding, FOV = 230 mm, matrix = 128 × 128, 50 slices, slice thickness = 3 mm, averaging = 6

11. Methods Post-processing-Tractography of uncinate fasciculus Seed area:White matter of the substantia-innominata and external capsule just cranial to the MCA Target area:White matter of the temporal lobe just caudal to the MCA Seed Target

12. Analysis Tractographies of uncinate fasciculus were acquired using different FA thresholds (0.1, 0.15, 0.2, 0.25). For different FA thresholds, FA and ADC along uncinate fasciculus were measured and the values were compared between AD cases and control subjects, and were evaluated statistical difference by ANOVA. FA threshold:0.10.150.20.25

13. 0.25 0.20 0.10 0.15 Result-FA Distribution of measured mean FA within the tracts of the uncinate fascicles under four different FA thresholds in correlation with MMSE score. FA threshold: 0.1 FA threshold: 0.15 FA threshold: 0.2 FA threshold: 0.25

14. Result-FA FA FA Threshold ： 0.10 0.15 0.20 0.25 Severe Moderate Mild MCI Normal Severe Moderate Mild MCI Normal Severe Moderate Mild MCI Normal Severe Moderate Mild MCI Normal ANOVA:p<0.01 p<0.01 p<0.01 p<0.01 ： Include cases in which tractography could not drawn ： p<0.05 ： p<0.01

15. 0.25 0.20 0.10 0.15 Result-ADC Distribution of measured mean ADC within the tracts of the uncinate fascicles under four different FA thresholds in correlation with MMSE score. FA threshold: 0.1 FA threshold: 0.15 FA threshold: 0.2 FA threshold: 0.25

16. Result-ADC FA Threshold ： 0.10 0.15 0.20 0.25 ADC(10 -3 sec/mm 2 ) Severe Moderate Mild MCI Normal Severe Moderate Mild MCI Normal Severe Moderate Mild MCI Normal Severe Moderate Mild MCI Normal ： Include cases in which tractography could not drawn ： p<0.05 ： p<0.01 ANOVA:p<0.01 p<0.01 p<0.01 p<0.01

17. Discussion Selection of the FA did influence the measured diffusion tensor parameters. For the measurement of the diffusion tensor parameter along the uncinate fascicles, a higher FA threshold resulted in a lower mean ADC value and a higher FA value along the uncinate fasciculus. In every FA threshold, the mean FA value was higher in normal cases and lower in severe AD. ADC value was lower in normal cases and higher in severe AD. This means that as far as using a constant FA threshold, the essence of the results are not influenced.

18. Discussion FA threshold of 0.10 and 0.25 showed less discrimination between groups with different severities of AD. An FA threshold as low as 0.10 might result in contamination from voxels outside the uncinate fascicles. In contrast, a threshold as high as 0.25 might overly restrict the number of voxels and result in decreased statistical power. For the uncinate fascicles, an FA threshold between 0.15 and 0.20 may be optimal for evaluation of diffusion tensor parameters.

19. Discussion Distribution of the FA of uncinate fascicles seems to be concentric, with a higher FA in the center. The ellipsoids near the center of the fascicles tend to have smaller diffusivity and larger anisotropy. FA ＞ 0.1 FA ＞ 0.25 FA

20. Conclusion For the measurement of the diffusion tensor parameter along the uncinate fascicles, a higher FA threshold resulted in lower mean ADC values and higher mean FA values along the uncinate fasciculus. Although the relative order was not affected, the FA threshold influenced the measured values of mean FA and mean ADC along the tract. For tract-based analysis of degenerative diseases such as AD, appropriate selection of the FA threshold for tractography is important. T. Taoka et al. AJNR 2009