White-matter free-water diffusion MRI in schizophrenia: a systematic review and meta-analysis

Abstract

White-matter abnormalities, including increases in extracellular free-water, are implicated in the pathophysiology of schizophrenia. Recent advances in diffusion magnetic resonance imaging (MRI) enable free-water levels to be indexed. However, the brain levels in patients with schizophrenia have not yet been systematically investigated. We aimed to meta-analyse white-matter free-water levels in patients with schizophrenia compared to healthy volunteers. We performed a literature search in EMBASE, MEDLINE, and PsycINFO databases. Diffusion MRI studies reporting free-water in patients with schizophrenia compared to healthy controls were included. We investigated the effect of demographic variables, illness duration, chlorpromazine equivalents of antipsychotic medication, type of scanner, and clinical symptoms severity on free-water measures. Ten studies, including five of first episode of psychosis have investigated free-water levels in schizophrenia, with significantly higher levels reported in whole-brain and specific brain regions (including corona radiata, internal capsule, superior and inferior longitudinal fasciculus, cingulum bundle, and corpus callosum). Six studies, including a total of 614 participants met the inclusion criteria for quantitative analysis. Whole-brain free-water levels were significantly higher in patients relative to healthy volunteers (Hedge’s g = 0.38, 95% confidence interval (CI) 0.07–0.69, p = 0.02). Sex moderated this effect, such that smaller effects were seen in samples with more females (z = −2.54, p < 0.05), but antipsychotic dose, illness duration and symptom severity did not. Patients with schizophrenia have increased free-water compared to healthy volunteers. Future studies are necessary to determine the pathological sources of increased free-water, and its relationship with illness duration and severity.

Free‐Water Imaging in Friedreich Ataxia Using Multi‐Compartment Models

“…Increased free-water in the extracellular space surrounding axons accompanies neurodegeneration and/or prolonged neuroinflammation in response to pathology. 4,15,30,[39][40][41] In the current study, elevated free-water was observed in key gray and white-matter regions of the brainstem and cerebellum, consistent with patterns of atrophy observed in volumetric studies in FRDA. 3,42 These findings are also in line with increased [ 18 F]-FEMPA binding, a measure of neuroinflammation, in the dentate nuclei, cerebellar cortex, brainstem, and SCP in people with FRDA.…”

“…Increased free‐water in the extracellular space surrounding axons accompanies neurodegeneration and/or prolonged neuroinflammation in response to pathology 4,15,30,39‐41 . In the current study, elevated free‐water was observed in key gray and white‐matter regions of the brainstem and cerebellum, consistent with patterns of atrophy observed in volumetric studies in FRDA 3,42 .…”

Free-water volume fraction increases non-linearly with age in the white matter of the healthy human brain

“…This part of the study gathers two previously known effects that have been studied separately: (1) the change of diffusion metrics with age: when single-component DTI is considered, diffusion measures in the healthy WM of the human brain present a curvilinear U-form across the lifespan. FA shows a rapid growth in childhood and adolescence and then a systematic decline, while MD reveals the opposite trend (Westlye et al, 2010; Lebel et al, 2012; Beck et al, 2021); (2) the effect of the FWVF on DTI-based measures has also been studied previously (Pasternak et al, 2009; Metzler-Baddeley et al, 2012; Chad et al, 2018; Rydhög et al, 2017; Kubicki et al, 2019), with some preliminary research on differences with age (Metzler-Baddeley et al, 2012; Chad et al, 2018; Kubicki et al, 2021), and under the impact of neurodegenerative diseases (Bergamino et al, 2021; Carreira Figueiredo et al, 2022).…”

“…The free-water fraction has become a relevant biomarker in neuroimaging, especially for modeling various types of brain damage (Ofori et al, 2015; Bergamino et al, 2021; Carreira Figueiredo et al, 2022). With its proven importance in age-related pathologies and aging processes (Chad et al, 2018; Edde et al, 2020, Berger et al 2022), the evolution of this parameter across the adult lifespan has not been studied in detail.…”

“…Changes in the FWVF may also reflect the response to pathological processes that modify the interstitial extracellular spaces (Chad et al, 2018). Examples of conditions leading to increased FWVF values include parenchymal edema, such as those around tumors (Pasternak et al, 2009), Parkinson’s disease (Ofori et al, 2015), first-episode of psychosis (Lyall et al, 2018), Alzheimer’s disease (Bergamino et al, 2021) and schizophrenia (Carreira Figueiredo et al, 2022). The main implication of recovering FWVF information is related to the palliation of partial volume effects created by free-water diffusion (Metzler-Baddeley et al, 2012), given that DTI-based metrics are often contaminated with such, and its elimination results in the reduction in the number of false-positive streamlines in DTI-based tractography (Pasternak et al, 2009) and an improvement of the metrics’ reproducibility (Albi et al, 2017).…”