Elevated Extracellular Free-Water in a Multicentric First-Episode Psychosis Sample, Decrease During the First 2 Years of Illness

Bergé, Daniel; Mané, Anna; Lesh, Tyler A.; Bioque, Miquel; Barcones, Fe; González‐Pinto, Ana; Parellada, Mara; Vieta, Eduard; Castro‐Fornieles, Josefina; Rodríguez‐Jiménez, Roberto; García-Portilla, María Paz; Usall, Judith; Carter, Cameron S.; Cabrera, Bibiana; Bernardo, Miguel; Janssen, Joost

doi:10.1093/schbul/sbz132

Cited by 15 publications

(20 citation statements)

References 36 publications

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“…These data suggest that the earlier stages of illness in schizophrenia may be characterized by pathologies that affect the extracellular space. Our work directly aligns with previous reports and a recent meta-analysis [34] showing widespread FW elevations in early course schizophrenia populations [9,10,12,13] and an attenuated FW pathology in individuals with a longer duration of illness [14][15][16][17][18]. This study expands upon those previous studies using our well-matched sample of healthy controls and participants with schizophrenia, thus enabling us to characterize the relationships between FW, age and duration of illness, separately.…”

Section: Discussionsupporting

confidence: 88%

“…Since then, four additional studies have identified increased FW in independent early psychosis cohorts [10][11][12][13], thereby calling into question whether the biological changes taking place in the early stages of illness are in fact driven by structural changes in white matter, as previously assumed by earlier DTI studies [1][2][3][4][5]. All five published studies have observed FW increases in cerebral white matter [9][10][11][12][13], with two studies also observing FW elevations in gray matter [9,11]. Moreover, two of these studies, Guo et al…”

Section: Introductionmentioning

confidence: 92%

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Characterization of Extracellular Free Water Pathologies in Schizophrenia Using Multi-Site Diffusion MRI Harmonization

Cetin-Karayumak

Lyall

Biase³

et al. 2022

Preprint

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Studies applying Free Water Imaging have consistently reported significant global increases in extracellular FW in populations of individuals with early psychosis. However, these published studies focused on homogenous clinical participant groups (e.g., only first episode or chronic), thereby limiting our understanding of the time course of free water (FW) elevations across illness stages. Moreover, the relationship between FW and duration of illness has yet to be directly tested. Leveraging our multi-site diffusion magnetic resonance imaging(dMRI) harmonization approach, we analyzed dMRI scans collected by 12 international sites from 441 healthy controls and 434 individuals diagnosed with schizophrenia-spectrum disorders who represent different illness stages and ages (15–58 years). We characterized the pattern of age-related FW changes by assessing whole brain white matter in individuals with schizophrenia and healthy controls. Quadratic and non-parametric curves were used to model between-group FW differences in averaged whole brain white matter. In individuals with schizophrenia, whole brain FW was higher than in controls across all ages, with the greatest FW values observed from 15 to 23 years of age (effect size range= [0.70-0.87]). Following this peak, FW exhibited a monotonic decrease until reaching a minima at the age of 39 years. After 39 years of age, an attenuated monotonic increase in FW was observed, but with markedly lower effect sizes when compared to younger patients (effect size range = [0.32-0.43]). Importantly, FW was found to be negatively associated with duration of illness in schizophrenia (p=0.006), independent of the effects of age. In summary, our study finds in a large, age-diverse sample that participants with schizophrenia with a shorter duration of illness showed higher FW values compared to participants with more prolonged illness. Our findings indicate that FW might be a reliable imaging marker of acute, extracellular processes which appear to occur predominantly in the early stages of schizophrenia.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 92%

Characterization of Extracellular Free Water Pathologies in Schizophrenia Using Multi-Site Diffusion MRI Harmonization

Cetin-Karayumak

Lyall

Biase³

et al. 2022

Preprint

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“…of patients Patient age, Mean (SD), y Patient gender, % male DSM diagnoses Disease status (FEP, CSZ) Duration of illness (months), Mean (SD) PANSS total score Mean (SD) No. of controls CPZ equivalent, Mean (SD) Type of scanner Neuroimaging ROIs Pasternak et al [ 24 ] United States of America (USA) 18 21.6 (4.3) 77.8 Schizophrenia, schizoaffective, or schizophreniform FEP 6.2 (4.3) 79(20) 20 472.2 (651.3) 3 T Whole-brain Berge et al [ 34 ] Spain, The Netherlands 59 22.1 (5.9) 64.4 Schizophrenia, schizoaffective, or schizophreniform FEP 4.6 (3.3) 82.3 (27.6) 101 527.5 (409.4) 3 T, 1.5 T Whole-brain Lesh et al [ 29 ] USA 36 21.4 (3.4) 69.4 Schizophrenia, schizoaffective, or schizophreniform FEP Not reported 84 (19) 40 226.6 (168.7) 3 T Whole-brain Lyall et al [ 35 ] USA 63 21.4 (4.9) 73 Schizophrenia, schizoaffective, or schizophreniform FEP Not reported 79 (14) 70 Not reported 3 T Whole-brain Mandl et al [ 30 ] The Netherlands/USA 40 26.8 (5.8) 92.5 Schizophrenia CSZ 25.1 (17.4) 62.3 (15.8) 40 Not reported 1.5 T Bilateral uncinate, bilateral arcuate fasciculus, bilateral inferior lo...…”

Section: Resultsmentioning

confidence: 99%

“…Focusing on the studies that included patients with the diagnosis of first episode of psychosis, three studies [ 24 , 34 , 35 ] found differences in FW levels between early onset patients and healthy volunteers. The only study that did not find a difference [ 33 ] used a scanner with a lower magnetic field (1.5 T), which may have reduced the sensitivity to detect differences.…”

Section: Resultsmentioning

confidence: 99%

“…In regards to possible medication effects, we did not find a relationship with CPZ equivalent dose, suggesting antipsychotics are not substantially influencing our findings. However, since four studies did not report the number of unmedicated patients in the sample [ 16 , 29 , 34 , 36 ], we were unable to account for this in our meta-analysis. Therefore, differences in the use of medications may have contributed to high levels of heterogeneity across studies [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

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

Figueiredo

Borgan

Pasternak

et al. 2022

Neuropsychopharmacol.

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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.

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Schizophrenia spectrum disorders

Wijtenburg¹,

Rowland²

2023

Advances in Magnetic Resonance Technology and Applications

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Elevated Extracellular Free-Water in a Multicentric First-Episode Psychosis Sample, Decrease During the First 2 Years of Illness

Cited by 15 publications

References 36 publications

Characterization of Extracellular Free Water Pathologies in Schizophrenia Using Multi-Site Diffusion MRI Harmonization

Characterization of Extracellular Free Water Pathologies in Schizophrenia Using Multi-Site Diffusion MRI Harmonization

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

Schizophrenia spectrum disorders

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