Higher free water fraction in deep white matter was associated with lower likelihood of functional independence at 3 months after intracerebral hemorrhage, and greater relative white matter hyperintensity volume was significantly associated with increased free water in deep white matter, though neither free water association remained statistically significant after FDR correction.
Key Findings
Results
Higher free water fraction in deep white matter was associated with a lower likelihood of functional independence at 3 months after intracerebral hemorrhage in fully adjusted logistic regression models.
OR = 0.59; 95% CI, 0.36–0.98; p = 0.041
Functional independence was defined as a 3-month modified Rankin Scale score of 0–2
The association was consistent across sequential models
However, neither FW association remained statistically significant after FDR correction
The FW-outcome association was also nonsignificant after adjustment for WMH burden
Results
Greater relative white matter hyperintensity (WMH) volume was significantly associated with increased free water in deep white matter.
β = 0.143; 95% CI, 0.008–0.277; p = 0.038 in linear regression analyses
This association did not remain statistically significant after FDR correction
The study included 70 patients with acute supratentorial ICH who underwent diffusion tensor imaging
Results
Greater relative WMH volume was significantly associated with smaller relative perivascular space (PVS) volume in fully adjusted models.
This was identified through linear regression analyses
Relative PVS volume was one of three glymphatic-related imaging parameters derived from MRI
The other glymphatic parameters assessed were DTI-ALPS and free water (FW) fraction
Results
An exploratory mediation analysis showed no statistically significant indirect effect of WMH burden mediating the relationship between free water and functional outcome.
The mediation analysis was described as exploratory
The FW-outcome association became nonsignificant after adjustment for WMH burden
These findings leave the independent prognostic and mediating roles of free water unestablished
Results
Contralateral free water showed nominal associations with functional outcome and WMH burden, potentially reflecting diffuse CSVD-related white matter injury.
Contralateral FW associations were described as 'nominal' rather than robust
Authors interpreted this as possibly reflecting diffuse cerebral small vessel disease-related white matter injury rather than purely perilesional effects
The independent prognostic and mediating roles of contralateral FW remain unestablished and require validation in larger longitudinal studies
Methods
The study assessed glymphatic function using three MRI-derived imaging markers in 70 patients with acute supratentorial intracerebral hemorrhage who underwent diffusion tensor imaging.
Glymphatic markers included DTI-ALPS, free water (FW) fraction, and relative perivascular space (PVS) volume
CSVD burden was assessed using relative WMH volume and number of lacunes
Sample size was 70 patients
All patients had acute supratentorial ICH
What This Means
This research suggests that the brain's waste-clearance system, called the glymphatic system, may play a role in recovery after a type of stroke called intracerebral hemorrhage (ICH), where bleeding occurs within the brain. The researchers used a special type of brain scan (diffusion tensor MRI) to measure three markers related to how well the glymphatic system is working in 70 patients who had experienced an ICH. They found that patients with higher levels of 'free water' — loose water molecules in the deep white matter of the brain, which can indicate tissue damage — were less likely to have good functional recovery three months after their stroke.
The study also found that patients with more white matter damage visible on brain scans (called white matter hyperintensities, a marker of small vessel disease) tended to have higher free water levels and smaller perivascular spaces (channels that are part of the glymphatic drainage system). These connections suggest that long-standing small vessel disease of the brain, rather than just the acute bleed itself, may be an important factor linking glymphatic dysfunction to poor recovery. However, the researchers note important caveats: these associations did not hold up after applying stricter statistical corrections for multiple comparisons, and a mediation analysis did not find a statistically significant pathway from white matter disease through free water to functional outcome.
This research suggests that glymphatic imaging markers could be useful tools for understanding brain health after ICH, but the findings are preliminary. The study was limited by its small sample size of 70 patients, and the authors call for larger, longer-term studies to confirm whether free water and other glymphatic markers can independently predict recovery or serve as targets for future treatments aimed at improving outcomes after brain hemorrhage.
Hu X, Li Z, Wang Z, Zhang Y, Zhang M, Liu S, et al.. (2026). Association of Glymphatic Imaging Markers With Clinical Outcomes and Cerebral Small Vessel Disease Burden After Intracerebral Hemorrhage.. Brain and behavior. https://doi.org/10.1002/brb3.71856