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The first issue raised is primarily based on a technical misunderstanding of definitions. There is a difference between “water uptake per volume of brain” (our bioimaging marker for time interval between stroke onset and admission computed tomographic [CT] imaging) and “absolute increase of fractional brain water content”; these quantities are directly related but not equivalent. For that reason, the critique by Kauppinen and Knight misinterprets data of prior studies examining lesion water changes in stroke animal models as being inconsistent with our study results in humans, although, upon careful consideration, they are perfectly in line. CT density changes linearly with percentage change of fractional brain water content. For each percentage point increase in fractional water content, the CT density will decrease proportionally in a linear fashion and will reach 0 Hounsfield units (HU) at 100%. However, it is important to realize that each percentage point rise of fractional brain water to a theoretical maximum of 100% requires an exponential increase in net water uptake to a theoretical limit of infinity. It is evident that, pathophysiologically, only relatively small changes in absolute fractional water content are realistic, because the required amount of net water uptake per brain volume will increase exponentially with each percentage point increase of brain water content.
The following example relates the studies we cited (which reported a 1–2% increase in brain water content within 4.5 hours of ischemia) to our results. A representative 100ml volume of brain with typical 80% fractional tissue water content contains 80ml pure water. An increase in brain water content by 1% to reach 81% requires 5ml of water uptake per final volume of 105ml ischemic brain (4.8% water uptake). An increase by 2% to reach 82% brain water content requires 11ml of net water uptake per final volume of 111ml ischemic brain (9.9% water uptake), and so on.
Accordingly, the findings of Dzialowski et al,1 for example, are perfectly in line with our results. The mean CT attenuation in the ischemic hemisphere in rats after 4 hours of middle cerebral artery occlusion significantly decreased from 75 to 72HU, and the directly measured percentage water content by wet–dry weight increased from 77.5% to 78.5% within the hemisphere. This 1% increase of hemispheric water content requires a water uptake of 4.4% with respect to the final ischemic hemispheric volume, a value that is well within the range of our derived water uptake w based on the preischemic and ischemic hemispheric density values in their study.
There is a specific reason for defining the biomarker of “water uptake per volume” instead of “absolute change in water content” to determine lesion age. For any mixed body consisting of pure water and dry matter (as brain tissue), the mean CT value will be a linear function of each contributing part.2 Because the CT value of water is calibrated to 0, the following principle is therefore always true: the product between a volume of a body and its mean density remains constant regardless of the total amount of water uptake (and this is what we have shown in the calibration experiment). Because of this principle, net volume of water uptake per volume of tissue, in contrast to absolute change of brain water content, can be calculated by density measurements alone independent of the inherent and variable tissue‐specific preischemic water content, which remains unknown for each voxel in CT.
With respect to the second issue raised by Kauppinen and Knight, we agree that an exact operational definition of how measurements are acquired in the mirror region as normal reference is important. However, such a definition is provided in our article.
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