Diffusion MRI derived free-water imaging measures in patients with schizophrenia and their non-psychotic siblings

Free-water imaging is a diffusion MRI technique that separately models water diffusion hindered by fiber tissue and water that disperses freely in the extracellular space. Studies using this technique have shown that schizophrenia is characterized by a lower level of fractional anisotropy of the tissue compartment (FAt) and higher free-water fractional volume (FW). It is unknown, however, whether such abnormalities are an expression of pre-existing (genetic) risk for schizophrenia or a manifestation of the illness. To investigate the contribution of familial risk factors to white matter abnormalities, we used the free-water imaging technique to assess FAt and FW in a large cohort of 471 participants including 161 patients with schizophrenia, 182 non-psychotic siblings, and 128 healthy controls. In this sample, patients did not show significant differences in FAt as compared to controls, but did exhibit a higher level of FW relative to both controls and siblings in the left uncinate fasciculus, superior corona radiata and fornix / stria terminalis. This increase in FW was found to be related to, though not solely explained by, ventricular enlargement. Siblings did not show significant FW abnormalities. However, siblings did show a higher level of FAt as compared to controls and patients, in line with results of a previous study on the same data using conventional DTI. Taken together, our findings suggest that extracellular free-water accumulation in patients is likely a manifestation of established disease rather than an expression of familial risk for schizophrenia and that super-normal levels of FAt in unaffected siblings may reflect a compensatory process. •Free-water imaging models white matter fractional anisotropy (FAt) and extracellular free-water (FW).•Schizophrenia patients show a higher level of FW compared to their unaffected siblings and controls.•Unaffected siblings do not show FW changes, but exhibit an overall higher FAt than controls and patients.•Higher FW is likely to be a disease status marker, rather than an expression of familial risk for schizophrenia.