Dynamic susceptibility contrast MR imaging was performed to determine the local cerebral blood flow and blood volume.

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1 RSNA, /radiol Appendix E1 Neuropsychological Tests All patients underwent a battery of neuropsychological tests. This included the Rey auditory verbal learning test (34), the digit span of the Wechsler adult intelligence scale third edition (35,36), the letter digit substitution test (37), and a verbal fluency test (38). The mean raw scores and standard deviation are displayed in Table E1. Image Analysis T1-weighted and fluid-attenuated inversion recovery images were used for automated, manually adjusted tissue classification of total WM, total GM, deep GM, and cortex (FreeSurfer software package combined with FAST, FMRIB s Automated Segmentation Tool). WM hyperintensity segmentation was performed by using a semiautomatic method, and was used to determine the WM hyperintensity volume relative to the intracranial volume and the normal-appearing WM (39). The Fazekas score and medial temporal lobe atrophy rating were determined by an experienced researcher blinded to the subject groups (S.B., with 7 years of experience) (40,41). Motion correction and image registration of the dynamic series were performed by using a six degrees of freedom linear transformation with an averaged unenhanced image as reference (FMRIB linear image registration tool, fsl.fmrib.ox.ac.uk/fsl/fslwiki). Further analysis was performed by using custom-made software with a technical computing language (Matlab; Mathworks, Natick, Mass). To account for the nonlinear relationship between signal enhancement and relatively high contrast agent concentration of the vascular input function, the signal conversion was implemented by using in vitro data (diluted manganese chloride stock solution with different concentrations of gadobutrol [1 40 mmol/l], baseline T1 relaxation time of 1650 msec, comparable to that of human blood [42]). Conversion to contrast agent concentration in the tissue was performed assuming a linear relationship and a contrast agent relaxivity of 3.3 sec 1 mmol/l 1 (43). Dynamic Susceptibility Contrast MR Imaging Dynamic susceptibility contrast MR imaging was performed to determine the local cerebral blood flow and blood volume. Acquisition The dynamic susceptibility contrast MR imaging was performed with a three-dimensional gradient-echo principles of echo shifting with a train of observations sequence (44) with a repetition time msec/echo time msec, 20/30; flip angle, 8 ; voxel size, mm 3 ; matrix size, ; dynamic imaging interval of 1.56 seconds with 75 volumes, resulting in a total imaging time of 117 seconds. Contrast agent (gadobutrol, 0.1 mm/kg, injected by using a power injector with a flow rate of 3 ml/sec, followed by a 20-mL saline flush) was Page 1 of 5

2 injected at the 11th dynamic sequence. The dynamic susceptibility contrast MR imaging sequence was performed after the dynamic contrast-enhanced MR imaging sequence. Analysis The motion correction was performed by using the mean of the precontrast images as reference. The raw signal-time series were converted to concentration by using the following equation: C t 1 S t k ln, TE S 0 where C (t) is the contrast agent concentration over time, k is the proportionality constant for MR imaging in brain tissue, TE is the echo time, S (t) is the signal at time t, and S 0 is the baseline signal before contrast agent arrival. The proportionality constant k was set to 1 in this study, under the assumption that the transverse relaxivity (r 2 *) of tissue and blood is equal, and a change in contrast agent concentration gives a linear increase on the transverse relaxation rate (R 2 *). An individual vascular input function (VIF) was chosen in or near the anterior cerebral artery. Cerebral blood volume (CBV) was calculated by using the following equation: a 1 H CBV l a 1 H VIF s 0 C t dt 0 t dt where H l and H s are the hematocrit values in the large and small blood vessels, respectively, is the brain mass density, and a is the time point at which the contrast agent concentration reaches baseline again after the initial injection peak. The total correction factor (1 H l )/ (1 H s ) was set as cm 3 /g (45). Voxels with CBV values greater than 10% were considered to represent large blood vessels and were discarded for all further analyses. The CBF was calculated by solving the following equation: C t CBF R t VIF, where R(t) is the tissue residue function and denotes the convolution operator (46). The deconvolution was performed by using a block-circulant singular value decomposition method with a cutoff value of 10%, meaning that singular values less than 10% of the maximal singular value were set to zero (46,47). Statistics Independent two-sided Student t tests were used to test group differences in CBF and CBV in two steps; first the differences between the groups in the total WM and GM were tested, and in the second step, the normal-appearing WM, deep GM, cortex, and WM hyperintensities. To test whether CBF and BBB leakage were correlated, the Pearson correlation coefficient between CBF and BBB leakage rate K i and v L was calculated in every region throughout all subjects by using the same two-step approach. Results, Page 2 of 5

3 An overview of the results is given in Table 2. In short, there were no significant differences in CBF or CBV between the patients and control subjects in any of the investigated regions. No significant correlations were found between the CBF and the BBB leakage measures. Conclusion Both the CBF and the CBV values are comparable to those reported in the literature (48,49). By using dynamic susceptibility contrast MR imaging, patients with early AD and healthy control subjects had comparable CBF and CBV values and CBF did not correlate with BBB leakage. References 34. Rey A. L examen clinique en psychologie. Paris, France: Presse Universitaires de Paris; Wechsler D. WAIS-III/WMS-III Technical Manual Update. 3rd ed. San Antonio, Texas: Psychological Corporation, Borkowski JG, Benton AL, Spreen O. Word fluency and brain damage. Neuropsychologia 1967;5(2): van der Elst W, van Boxtel MP, van Breukelen GJ, Jolles J. The Letter Digit Substitution Test: normative data for 1,858 healthy participants aged from the Maastricht Aging Study (MAAS): influence of age, education, and sex. J Clin Exp Neuropsychol 2006;28(6): Van der Elst W, Van Boxtel MPJ, Van Breukelen GJP, Jolles J. Normative data for the animal, profession and letter M naming verbal fluency tests for Dutch speaking participants and the effects of age, education, and sex. J Int Neuropsychol Soc 2006;12: de Boer R, Vrooman HA, van der Lijn F, et al. White matter lesion extension to automatic brain tissue segmentation on MRI. Neuroimage 2009;45(4): Fazekas F, Kleinert R, Offenbacher H, et al. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology 1993;43(9): Scheltens P, Leys D, Barkhof F, et al. Atrophy of medial temporal lobes on MRI in probable Alzheimer s disease and normal ageing: diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry 1992;55(10): Lu H, Clingman C, Golay X, van Zijl PC. Determining the longitudinal relaxation time (T1) of blood at 3.0 Tesla. Magn Reson Med 2004;52(3): Pintaske J, Martirosian P, Graf H, et al. Relaxivity of Gadopentetate Dimeglumine (Magnevist), Gadobutrol (Gadovist), and Gadobenate Dimeglumine (MultiHance) in human blood plasma at 0.2, 1.5, and 3 Tesla. Invest Radiol 2006;41(3): Liu G, Sobering G, Duyn J, Moonen CT. A functional MRI technique combining principles of echo-shifting with a train of observations (PRESTO). Magn Reson Med 1993;30(6): Knutsson L, Lindgren E, Ahlgren A, et al. Dynamic susceptibility contrast MRI with a prebolus contrast agent administration design for improved absolute quantification of perfusion. Magn Reson Med 2014;72(4): Page 3 of 5

4 41. Willats L, Calamante F. The 39 steps: evading error and deciphering the secrets for accurate dynamic susceptibility contrast MRI. NMR Biomed 2013;26(8): Wu O, Østergaard L, Weisskoff RM, Benner T, Rosen BR, Sorensen AG. Tracer arrival timing-insensitive technique for estimating flow in MR perfusion-weighted imaging using singular value decomposition with a block-circulant deconvolution matrix. Magn Reson Med 2003;50(1): Hauser T, Schönknecht P, Thomann PA, et al. Regional cerebral perfusion alterations in patients with mild cognitive impairment and Alzheimer disease using dynamic susceptibility contrast MRI. Acad Radiol 2013;20(6): Engvall C, Ryding E, Wirestam R, et al. Human cerebral blood volume (CBV) measured by dynamic susceptibility contrast MRI and 99mTc-RBC SPECT. J Neurosurg Anesthesiol 2008;20(1): Rey A. L examen clinique en psychologie. Paris, France: Presse Universitaires de Paris; Wechsler D. WAIS-III/WMS-III Technical Manual Update. 3rd ed. San Antonio, Texas: Psychological Corporation, Borkowski JG, Benton AL, Spreen O. Word fluency and brain damage. Neuropsychologia 1967;5(2): van der Elst W, van Boxtel MP, van Breukelen GJ, Jolles J. The Letter Digit Substitution Test: normative data for 1,858 healthy participants aged from the Maastricht Aging Study (MAAS): influence of age, education, and sex. J Clin Exp Neuropsychol 2006;28(6): Table E1. Overview of Neuropsychological Test Scores of the Patients Neuropsychological test Cognitive Domain Mean Score RAVLT immediate recall (words)* RAVLT delayed recall (words)* RAVLT recognition (words)* Digit span WAIS-III-forward* Digit span WAIS-III-backward* LDST (correct items after 90 sec)* LDST (wrong items after 90 sec)* Episodic 24.7 ± 5.3 Episodic 2.0 ± 2.0 Episodic 20.1 ± 5.7 Attention 7.4 ± 1.3 Working memory 4.4 ± 1.3 Processing speed 29.1 ± 12.2 Processing speed 0.1 ± 0.4 Fluency (named animals) Language 15.1 ± 5.7 Note. Data are means ± standard deviation. RAVLT = Rey auditory verbal learning test (13) (episodic memory), WAIS-III = Wechsler adult intelligence scale third edition (14,15), LDST = letter digit substitution test (16). * Data missing for two subjects. Data missing for one (other) subject. Table E2. Regional Comparison of Dynamic Susceptibility Contrast MR Imaging Measures and Correlation with Blood-Brain Barrier Leakage Region of Interest CBF (ml/100 g/min) CBV ( 10 2 ) Correlation CBF and K i Correlation CBF and Patients Control Subjects P Value Patients Control Subjects P Value Pearson r P Value Pearson r P Value WM 53.0 ± ± ± ± v L Page 4 of 5

5 GM 84.7 ± ± ± ± 1.5 > Normal-appearing 53.4 ± ± ± ± WM Deep GM 84.6 ± ± ± ± Cortex 84.8 ± ± ± ± 1.5 > Areas of WM hyperintensity 42.0 ± ± ± ± Note. All data (other than P values) are mean ± one standard deviation. Page 5 of 5