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Unaccounted exchange may even blur microstructural or other characteristics of multicompartmental systems studied by MR methods. Despite the growing interest in diffusion\u2010exchange studies of complex systems, comparative studies remain scarce. Most existing investigations have applied different diffusion MR methods to different biological samples under varying experimental conditions, making direct comparisons difficult. Moreover, the lack of a gold standard for exchange rate measurements further complicates efforts to validate and interpret results. To address these challenges, we employed two diffusion NMR\u2010based methods\u2014the constant\u2010gradient pulsed\u2010field gradient (CG\u2010PFG) and the recently introduced filter\u2010exchange NMR spectroscopy (FEXSY)\u2014to investigate apparent water exchange in yeast cells and optic nerves, both before and after fixation. We first evaluated the effect of the  values on the extracted indices and then evaluated the repeatability and reproducibility of the measurements. The CG\u2010PFG and FEXSY experiments were collected on the same sample to allow comparison of the results. The intracellular mean residence times (MRTs) () extracted from the log\u2010linear fit of the CG\u2010PFG NMR experiments were found to be  and  for yeast cells before and after fixation, respectively. The respective  values extracted from the FEXSY experiments before and after fixation were found to be  and . Despite the difference in absolute values of MRTs, the same qualitative behavior is observed in the two methodologies, and both could be analyzed using the bicompartmental K\u00e4rger model. The same methodologies were then used to study exchange in the more complex porcine optic nerves. There, the bicompartmental K\u00e4rger model analysis is shown to be inadequate. Extensive Monte Carlo simulations are used to narrow down on the most possible explanation, suggesting that optic nerves are multicompartmental systems where not all spins are free to undergo exchange. Supporting theoretical calculations point to the existence of at least one additional nonexchanging restricted compartment. Thus, a tricompartmental model is derived and used to analyze the data. The new model fits the data significantly better and results in dramatically different exchange rates when used on white matter (WM) data: CG\u2010PFG experiments were found to be  and  for optic nerves before and after fixation, respectively. The respective  values extracted from the FEXSY experiments before and after fixation were found to be  and . These values are considerably lower than the values previously reported. Finally, we use simulations to show that the quantitative discrepancy between CG\u2010PFG and FEXSY can be attributed, at least partially, to the difference in  values between the intracellular and extracellular compartments. We thus encourage the pairing of exchange and spin\u2013spin relaxation measurements in future studies. We end with a discussion on the current state of the diffusion\u2010exchange field, where we attempt to put a spotlight on essential corner stones that are still missing despite the great advance of recent years: experimental standardization, method comparison, and adequate modeling.<\/jats:p>","DOI":"10.1002\/nbm.70224","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T04:42:05Z","timestamp":1770612125000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Quantifying Transmembrane Water Exchange by Diffusion NMR Methods: From Yeast Cells to Optic Nerve Ex\u00a0Vivo"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8020-2352","authenticated-orcid":false,"given":"Yuval","family":"Scher","sequence":"first","affiliation":[{"name":"School of Chemistry Raymond and Beverly Sackler Faculty of Exact Sciences  Tel Aviv Israel"},{"name":"The Center for 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