Macromolecular proton fraction (MPF), the key two-pool MT model parameter, was established as a robust myelin-sensitive index, with clinical relevance in demyelinating diseases. However, as MPF assesses macromolecules relative to tissue water, its specificity to myelin is limited. i.e., MPF changes may occur independent of myelin, e.g., in the setting of inflammation and edema. Further, relating MPF to macromolecules may be ambiguous due to unequal concentrations of protons in macromolecular and water compartments. We demonstrate implications of these effects for MPF interpretation using phantom and ex-vivo experiments and propose a new macromolecular measure that explicitly accounts for tissue water effects.