Greater extracellular free-water in first-episode psychosis predicts better neurocognitive functioning

Abstract

Free Water Imaging is a novel diffusion magnetic reasonance imaging (MRI) method that is able to separate changes affecting the extracellular space from those that reflect changes in neuronal cells and processes. A previous Free Water Imaging study in schizophrenia identified significantly greater extracellular water volume in the early stages of the disorder; however, it’s clinical and functional sequelae have not yet been investigated. Here, we applied Free Water Imaging to a larger cohort of 63 first-episode patients with psychosis and 70 healthy matched controls to better understand the functional significance of greater extracellular water. We used diffusion MRI data and the Tract-Based Spatial Statistics analytic pipeline to first analyze fractional anisotropy (FA), the most commonly employed metric for assessing white matter. This comparison was then followed by Free Water Imaging analysis, where two parameters, the fractional volume of extracellular free-water (FW) and cellular tissue FA (FA-t), were estimated and compared across the entire white matter skeleton between groups, and correlated with cognitive measures at baseline and following 12 weeks of antipsychotic treatment. Our results indicated lower FA across the whole brain in patients compared to healthy controls that overlap with significant increases in FW, with only limited decreases in FA-t. In addition, higher FW correlated with better neurocognitive functioning following 12 weeks of antipsychotic treatment. This is the first study to suggest that an extracellular water increase during the first-episode of psychosis, which may be indicative of an acute neuroinflammatory process, and/or cerebral edema may predict better functional outcome.

Amyloid burden accelerates white matter degradation in cognitively normal elderly individuals

“…Our findings are also congruent with previous studies illustrating distinct Aβ-related blood brain barrier and white matter damage at baseline and over time in preclinical and prodromal phases of AD (Iadecola, 2015;Montagne et al, 2015;Rieckmann et al, 2016). These findings further underscore the importance of the FW-correction method in differentiating tissue-associated from neuroinflammation-associated changes to enable a more precise interpretation of white matter alterations and their trajectory over time (Lyall et al, 2017;Pasternak et al, 2015).…”

“…Since FAt changes originate from tissue itself, it may be better associated with axonal and myelin sheath degeneration . These findings further underscore the importance of the FW-correction method in differentiating tissue-associated from neuroinflammation-associated changes to enable a more precise interpretation of white matter alterations and their trajectory over time (Lyall et al, 2017;Pasternak et al, 2015). Cumulatively, such processes may lead to altered homeostasis, inflammation and eventually synaptic dysfunction and cognitive deficits, reflecting a possible mechanism underlying the deleterious influence of high Aβ burden (Iadecola, 2015).…”

“…Recently, the free-water (FW) imaging method has been developed to eliminate partial volume with freely diffusing extracellular water molecules in diffusionweighted MRI (Pasternak, Sochen, Gur, Intrator, & Assaf, 2009;Pasternak, Westin, Dahlben, Bouix, & Kubicki, 2015). Accordingly FW changes can be sensitive to extracellular processes including atrophy, neuroinflammation and blood-brain barrier permeability modulation (Ji et al, 2017;Pasternak et al, 2012;Perez-Nievas et al, 2013), while FAt changes are more sensitive to alterations in white matter microstructural organization (Lyall et al, 2017;Montal et al, 2017;Pasternak et al, 2012Pasternak et al, , 2015. Accordingly FW changes can be sensitive to extracellular processes including atrophy, neuroinflammation and blood-brain barrier permeability modulation (Ji et al, 2017;Pasternak et al, 2012;Perez-Nievas et al, 2013), while FAt changes are more sensitive to alterations in white matter microstructural organization (Lyall et al, 2017;Montal et al, 2017;Pasternak et al, 2012Pasternak et al, , 2015.…”

“…The method allows separately identifying extracellular changes affecting the FW measure, from cellular changes influencing the FW-corrected fractional anisotropy measure (FAt). Accordingly FW changes can be sensitive to extracellular processes including atrophy, neuroinflammation and blood-brain barrier permeability modulation (Ji et al, 2017;Pasternak et al, 2012;Perez-Nievas et al, 2013), while FAt changes are more sensitive to alterations in white matter microstructural organization (Lyall et al, 2017;Montal et al, 2017;Pasternak et al, 2012Pasternak et al, , 2015.…”

Genetic load determines atrophy in hand cortico‐striatal pathways in presymptomatic Huntington's disease

“…However, in our experiments, the isotropic volume fraction outperforms both fractional anisotropy and mean diffusivity by demonstrating stronger correlation with age and CAG-repeats. We should note that, using a more advanced model of diffusion that incorporates multiple crossing fibers and an isotropic volume compartment lends increased specificity and sensitivity to the obtained results as seen in studies on other neurodegenerative disorders such as Parkinson’s disease (Planetta et al, 2016; Lyall et al, 2017). Our results indicate that the isotropic volume fraction could be a potential imaging maker for monitoring the progression of Huntington’s disease.…”