Accurate free‐water estimation in white matter from fast diffusion MRI acquisitions using the spherical means technique

AbstractWhite-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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P.0757 White-matter free-water diffusion MRI in schizophrenia: a systematic review and meta-analysis

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2021.10.821 ◽

2021 ◽

Vol 53 ◽

pp. S551-S552

Author(s):

I. Carreira Figueiredo ◽

F. Borgan ◽

O. Pasternak ◽

F.E. Turkheimer ◽

O. Howes

Keyword(s):

Systematic Review ◽

White Matter ◽

Diffusion Mri ◽

Meta Analysis ◽

Free Water ◽

Water Diffusion

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A longitudinal analysis of brain extracellular free water in HIV infected individuals

Scientific Reports ◽

10.1038/s41598-021-87801-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Md Nasir Uddin ◽

Abrar Faiyaz ◽

Lu Wang ◽

Yuchuan Zhuang ◽

Kyle D. Murray ◽

...

Keyword(s):

White Matter ◽

Antiretroviral Therapy ◽

Diffusion Mri ◽

Temporal Evolution ◽

Free Water ◽

Combination Antiretroviral Therapy ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Cd4 Counts

AbstractInitiation of combination antiretroviral therapy (cART) reduces inflammation in HIV-infected (HIV+) individuals. Recent studies demonstrated that diffusion MRI based extracellular free water (FW) modeling can be sensitive to neuroinflammation. Here, we investigate the FW in HIV-infection, its temporal evolution, and its association with blood markers, and cognitive scores. Using 96 age-matched participants, we found that FW was significantly elevated in grey and white matter in cART-naïve HIV+ compared to HIV-uninfected (HIV−) individuals at baseline. These increased FW values positively correlated with neurofilament light chain (NfL) and negatively correlated with CD4 counts. FW in grey and white matter, as well as NfL decreased in the HIV+ after 12 weeks of cART treatment. No significant FW differences were noted between the HIV+ and HIV− cohorts at 1 and 2-year follow-up. Results suggest that FW elevation in cART-naïve HIV+ participants is likely due to neuroinflammation. The correlation between FW and NfL, and the improvement in both FW and NfL after 12 weeks of cART treatment further reinforces this conclusion. The longer follow-up at 1 and 2 years suggests that cART helped control neuroinflammation as inferred by FW. Therefore, FW could be used as a biomarker to monitor HIV-associated neuroinflammation.

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In vivo microstructural heterogeneity of white matter lesions in Alzheimer’s disease using tissue compositional analysis of diffusion MRI data

10.1101/623124 ◽

2019 ◽

Cited By ~ 3

Author(s):

Remika Mito ◽

Thijs Dhollander ◽

Ying Xia ◽

David Raffelt ◽

Olivier Salvado ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

White Matter ◽

Diffusion Mri ◽

Classification Scheme ◽

Free Water ◽

Imaging Biomarkers ◽

White Matter Microstructure ◽

Periventricular Lesions

AbstractWhite matter hyperintensities (WMH) are commonly observed in elderly individuals, and are typically more prevalent in Alzheimer’s disease subjects than in healthy subjects. These lesions can be identified on fluid attenuated inversion recovery (FLAIR) MRI, on which they are hyperintense compared to their surroundings. These MRI-visible lesions appear homogeneously hyperintense despite known heterogeneity in their pathological underpinnings, and are commonly regarded as surrogate markers of small vessel disease in in vivo studies. Consequently, the extent to which these lesions contribute to Alzheimer’s disease remains unclear, likely due to the somewhat limited way in which these lesions are assessed in vivo. Diffusion MRI is sensitive to white matter microstructure, and might thus be used to investigate microstructural changes within WMH. In this study, we applied a method called single-shell 3-tissue constrained spherical deconvolution, which models white matter microstructure while also accounting for other tissue compartments, to investigate WMH in vivo. Diffusion MRI data and FLAIR images were obtained from Alzheimer’s disease (n = 48) and healthy elderly control (n = 94) subjects from the Australian Imaging, Biomarkers and Lifestyle study of ageing. WMH were automatically segmented and classified as periventricular or deep lesions from FLAIR images based on their continuity with the lateral ventricles, and the 3-tissue profile of different classes of WMH was characterised by three metrics, which together characterised the relative tissue profile in terms of the white matter-, grey matter-, and fluid-like characteristics of the diffusion signal. Our findings revealed that periventricular and deep lesion classes could be distinguished from one another, and from normal-appearing white matter based on their 3-tissue profile, with substantially higher free water content in periventricular lesions than deep. Given the higher lesion load of periventricular lesions in Alzheimer’s disease patients, the 3-tissue profile of these WMH could be interpreted as reflecting the more deleterious pathological underpinnings that are associated with disease. However, when alternatively classifying lesion sub-regions in terms of distance contours from the ventricles to account for potential heterogeneity within confluent lesions, we found that the highest fluid content was present in lesion areas most proximal to the ventricles, which were common to both Alzheimer’s disease subjects and healthy controls. We argue that whatever classification scheme is used when investigating WMH, failure to account for heterogeneity within lesions may result in classification-scheme dependent conclusions. Future studies of WMH in Alzheimer’s Disease would benefit from inclusion of microstructural information when characterising lesions.

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Modern Technology in Multi-Shell Diffusion MRI Reveals Diffuse White Matter Changes in Young Adults With Relapsing-Remitting Multiple Sclerosis

Frontiers in Neuroscience ◽

10.3389/fnins.2021.665017 ◽

2021 ◽

Vol 15 ◽

Author(s):

Ann-Marie Beaudoin ◽

François Rheault ◽

Guillaume Theaud ◽

Frédéric Laberge ◽

Kevin Whittingstall ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Diffusion Mri ◽

Free Water ◽

Cerebral White Matter ◽

Fiber Density ◽

White Matter Changes ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

ObjectiveTo characterize microstructural white matter changes related to relapsing-remitting multiple sclerosis using advanced diffusion MRI modeling and tractography. The association between imaging data and patient’s cognitive performance, fatigue severity and depressive symptoms is also explored.MethodsIn this cross-sectional study, 24 relapsing-remitting multiple sclerosis patients and 11 healthy controls were compared using high angular resolution diffusion imaging (HARDI). The imaging method includes a multi-shell scheme, free water correction to obtain tissue-specific measurements, probabilistic tracking algorithm robust to crossing fibers and white matter lesions, automatic streamlines and bundle dissection and tract-profiling with tractometry. The neuropsychological evaluation included the Symbol Digit Modalities Test, Paced Auditory Serial Addition Test, Modified Fatigue Impact Scale and Beck Depression Inventory-II.ResultsBundle-wise analysis by tractometry revealed a difference between patients and controls for 11 of the 14 preselected white matter bundles. In patients, free water corrected fractional anisotropy was significantly reduced while radial and mean diffusivities were increased, consistent with diffuse demyelination. The fornix and left inferior fronto-occipital fasciculus exhibited a higher free water fraction. Eight bundles showed an increase in total apparent fiber density and four bundles had a higher number of fiber orientations, suggesting axonal swelling and increased organization complexity, respectively. In the association study, depressive symptoms were associated with diffusion abnormalities in the right superior longitudinal fasciculus.ConclusionTissue-specific diffusion measures showed abnormalities along multiple cerebral white matter bundles in patients with relapsing-remitting multiple sclerosis. The proposed methodology combines free-water imaging, advanced bundle dissection and tractometry, which is a novel approach to investigate cerebral pathology in multiple sclerosis. It opens a new window of use for HARDI-derived measures and free water corrected diffusion measures. Advanced diffusion MRI provides a better insight into cerebral white matter changes in relapsing-remitting multiple sclerosis, namely diffuse demyelination, edema and increased fiber density and complexity.

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Lower Aβ-PET signal in white matter lesions relates to higher extracellular free water in mixed small vessel disease and Alzheimer's pathology

10.1101/2021.12.17.473211 ◽

2021 ◽

Author(s):

Julie Ottoy ◽

Miracle Ozzoude ◽

Katherine Zukotynski ◽

Min Su Kang ◽

Sabrina Adamo ◽

...

Keyword(s):

White Matter ◽

Diffusion Mri ◽

Small Vessel Disease ◽

Free Water ◽

Partial Least Square ◽

Least Square ◽

Amyloid Pet ◽

Tissue Specific ◽

Vessel Disease ◽

Partial Least Square Analysis

Background and Objectives: Positron emission tomography (PET) with amyloid-ligands recently gained interest for evaluating white matter (WM) pathology. Here, we investigated the neurobiological underpinnings of the amyloid-PET signal in the WM using free water (FW) diffusion MRI in a mixed cohort of small vessel disease (SVD) and Alzheimer's disease (AD) pathology. Methods: We included data from two large cohort imaging studies, including MITNEC-C6 with moderate-to-severe white matter hyperintensity (WMH) burden and ADNI-2 with mild-to-moderate WMH burden, covering the spectrum of cognitively normal to dementia. Subjects underwent diffusion MRI, 18F-AV45 amyloid-PET, and cognitive testing. We calculated WM diffusion metrics including fractional anisotropy (FA) and mean diffusivity (MD). In addition, we applied a bi-tensor diffusion MRI model that differentiates between extracellular (FW fraction) and tissue-specific (FW-adjusted FA) compartments of the WM. We tested associations of all diffusion metrics with 18F-AV45 SUVR in regions of WMH vs. normal-appearing WM (NAWM), and with cognition. We further performed partial-least-square analysis to investigate how the diffusion metrics as well as age, sex, education, WMH volume, and cortical 18F-AV45 SUVR covary with WM 18F-AV45 SUVR. Results: 18F-AV45 SUVR was significantly lower in regions of WMH compared to NAWM (t=25.08, P<0.0001, n=115 subjects). Within WMH, lower 18F-AV45 SUVR was associated with higher FW (β=-0.36±0.13, P=0.005) and lower FA (β=+0.24±0.12, P=0.046), but not with the tissue-specific metric FW-adjusted FA. Partial-least-square analysis further confirmed that FW had the most influence on 18F-AV45 SUVR in regions of WMH. In contrast, FW-adjusted FA had more influence on 18F-AV45 SUVR in NAWM. Last, correlation with cognitive impairment was higher for FW than FW-adjusted FA, both in regions of WMH (MMSE: βFW=-0.40±0.13, P=0.003; βFW-adjustedFA=0.14±0.09, P=0.11) and NAWM (MMSE: βFW=-0.30±0.11, P=0.01; βFW-adjustedFA=0.21±0.09, P=0.02. Conclusion: In a cohort representative of the more common AD population, reduced amyloid-PET uptake in WM lesions may largely reflect the appearance of extracellular FW, while changes in NAWM may associate with tissue-specific damage. Ultimately, our findings may support FW and amyloid-PET as markers of WM abnormalities in SVD and AD.

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Altered Cellular White Matter But Not Extracellular Free Water on Diffusion MRI in Individuals at Clinical High Risk for Psychosis

American Journal of Psychiatry ◽

10.1176/appi.ajp.2019.18091044 ◽

2019 ◽

Vol 176 (10) ◽

pp. 820-828 ◽

Cited By ~ 5

Author(s):

Yingying Tang ◽

Ofer Pasternak ◽

Marek Kubicki ◽

Yogesh Rathi ◽

Tianhong Zhang ◽

...

Keyword(s):

White Matter ◽

High Risk ◽

Diffusion Mri ◽

Free Water ◽

Clinical High Risk

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Linking Neuroinflammation and Extracellular Free Water in HIV Infection: A Longitudinal Study

10.21203/rs.3.rs-121836/v2 ◽

2020 ◽

Author(s):

Md Nasir Uddin ◽

Abrar Faiyaz ◽

Lu Wang ◽

Yuchuan Zhuang ◽

Kyle D Murray ◽

...

Keyword(s):

White Matter ◽

Hiv Infection ◽

Diffusion Mri ◽

Temporal Evolution ◽

Free Water ◽

Combination Antiretroviral Therapy ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Cd4 Counts

Abstract Initiation of combination antiretroviral therapy (cART) reduces inflammation in HIV-infected (HIV+) individuals. Recent studies demonstrated that diffusion MRI based extracellular free water (FW) modeling can be sensitive to neuroinflammation. Here, we investigate the FW in HIV-infection, its temporal evolution, and its association with blood markers, and cognitive scores. Using 96 age-matched participants, we found that FW was significantly elevated in grey and white matter in cART-naïve HIV+ compared to healthy controls (HIV-) at baseline. Similarly, at baseline, HIV+ participants had increased neurofilament light chain (NfL) values that correlated with FW and CD4 counts. FW in grey and white matter, as well as NfL decreased in the HIV+ after 12 weeks of cART treatment. No significant FW differences were noted between the HIV+ and HIV- cohorts at 1 and 2-year follow-up. Results suggest that FW elevation in cART-naïve HIV+ participants is likely due to neuroinflammation. The correlation between FW and NfL and the improvement in both FW and NfL after 12 weeks of cART treatment further reinforces this conclusion. The longer follow-up at 1 and 2 years suggests that cART helped control neuroinflammation as inferred by FW. Therefore, FW could be used as a biomarker to monitor HIV-associated neuroinflammation.

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

10.1101/867606 ◽

2019 ◽

Author(s):

Manon Edde ◽

Guillaume Theaud ◽

François Rheault ◽

Bixente Dilharreguy ◽

Catherine Helmer ◽

...

Keyword(s):

White Matter ◽

Verbal Fluency ◽

Diffusion Mri ◽

White Matter Hyperintensities ◽

Free Water ◽

Partial Volume ◽

Cingulum Bundle ◽

Partial Volume Effects ◽

Age Related ◽

Water Elimination

AbstractDiffusion MRI is extensively used to investigate changes in white matter microstructure. However, diffusion measures within white matter tissue can be affected by partial volume effects due to cerebrospinal fluid and white matter hyperintensities, especially in the aging brain. In previous aging studies, the cingulum bundle that plays a central role in the architecture of the brain networks supporting cognitive functions has been associated with cognitive deficits. However, most of these studies did not consider the partial volume effects on diffusion measures. The aim of this study was to evaluate the effect of free water elimination on diffusion measures of the cingulum in a group of 68 healthy elderly individuals. We first determined the effect of free water elimination on conventional DTI measures and then examined the effect of free water elimination on verbal fluency performance over 12 years. The cingulum bundle was reconstructed with a tractography pipeline including a white matter hyperintensities mask to limit the negative impact of hyperintensities on fiber tracking algorithms. We observed that free water elimination improved the sensitivity of conventional DTI measures to detect associations between tissue-specific diffusion measures of the cingulum and changes in verbal fluency in older individuals. Moreover, free water content measured along the cingulum was independently strongly associated with changes in verbal fluency. These observations suggest the importance of using free water elimination when studying brain aging and indicate that free water itself could be a relevant marker for age-related cingulum white matter modifications and cognitive decline.

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