Cerebral white matter free water

Abstract

ObjectiveTo determine whether free water (FW) content, initially developed to correct metrics derived from diffusion tensor imaging and recently found to be strongly associated with vascular risk factors, may constitute a sensitive biomarker of white matter (WM) microstructural differences associated with cognitive performance but remains unknown.MethodsFive hundred thirty-six cognitively diverse individuals, aged 77 ± 8 years, received yearly comprehensive clinical evaluations and a baseline MRI examination of whom 224 underwent follow-up MRI. WM microstructural measures, including FW, fractional anisotropy, and mean diffusivity corrected for FW and WM hyperintensity burden were computed within WM voxels of each individual. Baseline and change in MRI metrics were then used as independent variables to explain baseline and change in episodic memory (EM), executive function (EF), and Clinical Dementia Rating (CDR) scores using linear, logistic, and Cox proportional-hazards regressions.ResultsHigher baseline FW and WM hyperintensity were associated with lower baseline EM and EF, higher baseline CDR, accelerated EF and EM decline, and higher probability to transition to a more severe CDR stage (p values <0.01). Annual change in FW was also found to be associated with concomitant change in cognitive and functional performance (p values <0.01).ConclusionsThis study finds cross-sectional and longitudinal associations between FW content and trajectory of cognitive and functional performance in a large sample of cognitively diverse individuals. It supports the need to investigate the pathophysiologic process that manifests increased FW, potentially leading to more severe WM territory injury and promoting cognitive and functional decline.

Diffusion MRI free water is a sensitive marker of age-related changes in the cingulum

“…The observed association is consistent with previous studies that evidenced the involvement of the cingulum bundle in executive functioning (Bettcher et al, 2016;Gyebnár et al, 2018;Metzler-Baddeley et al, 2012;Seiler et al, 2018) and with studies showing that higher free water fraction was associated with poorer cognitive performance in older adults (Maillard et al, 2019) and in clinical populations (Bergamino et al, 2017;Ji et al, 2017Ji et al, , 2019Maillard et al, 2017). Indeed, in a recent longitudinal study on 224 elderly subjects, Maillard and colleagues showed that free water increased was not only associated with reduced performance in executive function but was also the most robust predictor of cognitive decline (Maillard et al, 2019). Ji and colleagues showed in sample of 85 subjects with Alzheimer's Disease or vascular dementia that high free water fraction was associated with the symptom severity (Clinical Dementia Rating) and poor cognitive performance (Ji et al, 2017).…”

“…In our group of elderly participants, we observed a non-zero value of free water fraction in the cingulum bundle that showed no difference according to the WMH groups. This suggests that free water fraction was unaffected by the WMH burden, supporting previous studies (Dumont et al, 2019;Ji et al, 2017) but in contrast to others (Maillard et al, 2019;Promjunyakul et al, 2016) emphasizing the need for additional studies. Moreover, this non-zero value of free water suggests that despite its distance from the ventricles there is an accumulation of free water in the extracellular space within the cingulum bundle.…”

“…The prevalence and severity of these white matter signal abnormalities as observed on a T2-weighted MRI scan, increase with age and more than 90% of older adults (>60 years old) exhibit WMH (Habes et al, 2016;Leeuw et al, 2001). In older adults, WMH have been associated with a diverse set of inter-related metabolic, inflammatory and vascular factors that affect brain integrity in healthy adults (Arvanitakis et al, 2016;Habes et al, 2018;Jagust, 2013;Wiseman et al, 2018) and related to cognitive impairments, especially in memory and executive functions (Maillard et al, 2019;Svärd et al, 2017;Meike W. Vernooij et al, 2009).…”

An IL-18-centered inflammatory network as a biomarker for cerebral white matter injury

“…DTI free water is an emerging MR metric that indirectly measures leakage of extracellular fluid into white matter and precedes the development of T2/FLAIR white matter hyperintensities. DTI free water is associated with vascular risk factors including systolic blood pressure and arterial stiffness [11] and more recently has been shown to be associated with cognitive decline [13]. Exactly what DTI free water is measuring in tissue is unknown, however one hypothesis is that excess extracellular fluid results from blood-brain barrier leakage with leaking serum proteins damaging myelin and axons.…”

“…In the context of cSVD, WMH are thought to be evidence of irreversible white matter injury with axonal and myelin damage [9,10]. Recent studies using diffusion tensor imaging (DTI), found that DTI-derived measures, including fractional anisotropy (FA) and extracellular free water (FW), constitute sensitive biomarkers of early-stage white matter injury resulting from cSVD that occurs in advance of the lasting tissue injury measured by WMH [11][12][13]. However, MRI scans are costly and not indicated in the absence of neurologic symptoms, therefore limiting the ability to prevent or intervene in early cSVD to prevent cognitive decline late in life.…”