Lower Aβ-PET signal in white matter lesions relates to higher extracellular free water in mixed small vessel disease and Alzheimer's pathology

Ottoy, J.; Ozzoude, M.; Zukotynski, K.; Kang, M. S.; Adamo, S.; Scott, C.; Ramirez, J.; Swardfager, W.; Lam, B.; Bhan, A.; Mojiri, P.; Kiss, A.; Strother, S.; Bocti, C.; Borrie, M.; Chertkow, H.; Frayne, R.; Hsiung, R.; Laforce, R. J.; Noseworthy, M. D.; Prato, F. S.; Sahlas, D. J.; Smith, E. E.; Kuo, P. H.; Chad, J. A.; Pasternak, O.; Sossi, V.; Thiel, A.; Soucy, J.-P.; Tardif, J.-C.; Black, S. E.; Goubran, M.

doi:10.1101/2021.12.17.473211

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bioRxiv · 10.1101/2021.12.17.473211

Lower Aβ-PET signal in white matter lesions relates to higher extracellular free water in mixed small vessel disease and Alzheimer's pathology

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Abstract

White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (A{beta}-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered A{beta}-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to A{beta}-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy [FA]). We observed that, in regions of WMH, a decrease in A{beta}-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in A{beta}-PET related more closely to higher cortical A{beta} (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and A{beta}-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.

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Ottoy, J., Ozzoude, M., Zukotynski, K., Kang, M. S., Adamo, S., Scott, C., Ramirez, J., Swardfager, W., Lam, B., Bhan, A., Mojiri, P., Kiss, A., Strother, S., Bocti, C., Borrie, M., Chertkow, H., Frayne, R., Hsiung, R., Laforce, R. J., Noseworthy, M. D., Prato, F. S., Sahlas, D. J., Smith, E. E., Kuo, P. H., Chad, J. A., Pasternak, O., Sossi, V., Thiel, A., Soucy, J.-P., Tardif, J.-C., Black, S. E., Goubran, M.. 2021-12-21. Lower Aβ-PET signal in white matter lesions relates to higher extracellular free water in mixed small vessel disease and Alzheimer's pathology. https://doi.org/10.1101/2021.12.17.473211

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