Extent and Distribution of White Matter Hyperintensities in Normal Aging, Mild Cognitive Impairment and Alzheimer’s Disease Mitsuhiro Yoshita, Evan Fletcher,

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Extent and Distribution of White Matter Hyperintensities in Normal Aging, Mild Cognitive Impairment and Alzheimer’s Disease Mitsuhiro Yoshita, Evan Fletcher, Oliver Martinez, Mario Ortega, Oliver Martinez, Mario Ortega, Bruce Reed, Dan Mungas and Charles DeCarli Department of Neurology and Center for Neuroscience University of California at Davis

Object & Background How different in Extent and Distribution (NA) (MCI) (AD) Mild Cognitive Impairment Normal Aging White Matter Hyperintensites (WMH) Alzheimer’s Disease

Subject Demographics Number (F/M) 26 (16/10) 29 (12/17) 33 (23/10) Age (y) 79.6 ± 6.8 * 74.6 ± ± 8.1 range Education (y) 11.7 ± ± ± 5.8 range MMSE 19.5 ± 6.8 a 26.6 ± ± 2.7 range Vascular risk score range Brain volume (%) 77.3 ± 4.2 b 80.7 ± ± 4.3 WMH volume (%) 1.33 ± 1.30 c 0.92 ± ± 0.67 Data represented as mean ± standard deviation. * p < 0.01 between AD and NA, a p < between AD and others. b p < 0.01 between AD and others, c p < between AD and NA. AD MCI NA

Methods Image Analysis Schema for WMH segmentation and nonlinear transformation for mapping DeCarli C, et al. Stroke APAP Composite image APAP

ROI on 3-D WMH maps Cg: genu of corpus callosum, Cs: splenium of corpus callosum, Pa: anterior periventricular region, Pb: body of periventricular region, Pp: posterior periventricular region, Po: occipital periventricular region. Abbreviations: ROI volume (mm 3 ) : Cg: 263, Cs: 205, Pa: 1325, Pb: 3190, Pp: 2385, Po: 983. We computed the number of voxel of WMH in each ROI, and calculated percentage of voxel which have WMH in each ROI of each subject. (B) Cg Cs Pa Pb Pp Po (A) Pp Pa Cg Po Pb Cs

Statistical Analysis 1. Groups were compared using analysis of variance (ANOVA) or Kruskal-Wallis test as appropriate according to the distribution of the data, with post hoc analysis. 2. Correlations were evaluated by Spearman’s ranks correlation test. 3. Results are expressed as mean values ± standard deviation. 4. A p value less than 0.05 was considered significant. 5. Data were analyzed using the Statistical Package for Social Sciences (SPSS for Windows, version 12.0; SPSS Inc, Chicago, IL).

X= 21 (A-1) X= 2 (A-2) Z= 28 (B-1) Z= 22 (B-2) Y= -4 (C-1) Y= -26 (C-2) A P (D) WMH frequency maps in all subjects

3-D WMH frequency maps in each group (A) (B)(C) Three-dimensional reconstruction of the WMH (orange) and ventricular (grey) maps. Orange color indicate the frequency of voxels containing the WMH more than 10%. (A): group of NA (B): group of MCI (C): group of AD

Group difference of WMH severity in each ROI Error bars indicate standard deviation of the mean. (B) : Corpus callosum region : AD : MCI : NA (%) GenuSplenium 70 * * ** * p < 0.05, ** p < (A): Periventricular region AnteriorBodyPosteriorOccipital (%) * ** *

Correlations between age, MMSE and WMH severity in each ROI Pa: anterior periventricular region Pb: body of periventricular region Pp: posterior periventricular region Po: occipital periventricular region Cg: genu of corpus callosum Cs: splenium of corpus callosum Abbreviations: AD Pa Pb Pp Po Cg Cs * 0.553** * 0.394* Age MCI NA MMSE AD MCI NA * p < 0.05, ** p < 0.01 corrected.

We believe the methods developed here conclusively show the difference of WMH distribution of each cognitive stage. These observations also support the notion of both a common ischemic etiology and Wallerian degeneration as a mechanism of WMH in each cognitive stage. Our study shows that measurements of the extent and distribution of WMH in both corpus callosum and periventricular area are suitable for assessment for NA, MCI and AD. Conclusion

Thanks Student: Ryan Berthold, Ryan Berthold, Chris Davies, Chris Davies, Alex Early, Alex Early, Marty Greenia, Marty Greenia, Evan Lloyd Evan LloydStaff: Lauren Cibattari, Lauren Cibattari, Krista Garcia, Krista Garcia, Oliver Martinez, Oliver Martinez, Mario Ortega, Mario Ortega, Baljeet Singh, Baljeet Singh, Laura Whiteside, Laura Whiteside, Sky Raptentsetsang Sky Raptentsetsang