Increased extracellular fluid is associated with white matter fiber degeneration in CADASIL: in vivo evidence from diffusion magnetic resonance imaging

Abstract Background White matter hyperintensities (WMHs) are one of the hallmarks of cerebral small vessel disease (CSVD), but the pathological mechanisms underlying WMHs remain unclear. Recent studies suggest that extracellular fluid (ECF) is increased in brain regions with WMHs. It has been hypothesized that ECF accumulation may have detrimental effects on white matter microstructure. To test this hypothesis, we used cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as a unique CSVD model to investigate the relationships between ECF and fiber microstructural changes in WMHs. Methods Thirty-eight CADASIL patients underwent 3.0 T MRI with multi-model sequences. Parameters of free water (FW) and apparent fiber density (AFD) obtained from diffusion-weighted imaging (b = 0 and 1000 s/mm2) were respectively used to quantify the ECF and fiber density. WMHs were split into four subregions with four levels of FW using quartiles (FWq1 to FWq4) for each participant. We analyzed the relationships between FW and AFD in each subregion of WMHs. Additionally, we tested whether FW of WMHs were associated with other accompanied CSVD imaging markers including lacunes and microbleeds. Results We found an inverse correlation between FW and AFD in WMHs. Subregions of WMHs with high-level of FW (FWq3 and FWq4) were accompanied with decreased AFD and with changes in FW-corrected diffusion tensor imaging parameters. Furthermore, FW was also independently associated with lacunes and microbleeds. Conclusions Our study demonstrated that increased ECF was associated with WM degeneration and the occurrence of lacunes and microbleeds, providing important new insights into the role of ECF in CADASIL pathology. Improving ECF drainage might become a therapeutic strategy in future.

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Venous disruption affects white matter integrity through increased interstitial fluid in cerebral small vessel disease

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20904840 ◽

2020 ◽

Vol 41 (1) ◽

pp. 157-165

Author(s):

Ruiting Zhang ◽

Peiyu Huang ◽

Yeerfan Jiaerken ◽

Shuyue Wang ◽

Hui Hong ◽

...

Keyword(s):

White Matter ◽

Interstitial Fluid ◽

Diffusion Tensor ◽

Small Vessel Disease ◽

Free Water ◽

Cerebral Small Vessel Disease ◽

White Matter Integrity ◽

Small Vessel ◽

White Matter Damage ◽

Vessel Disease

Deep medullary veins (DMVs) participate in the drainage of surrounding white matter. In cerebral small vessel disease (CSVD), disrupted DMVs were often observed together with damaged white matter, but the phenomenon lacked validation and explanation. We hypothesized that venous disruption might cause white matter damage through increased interstitial fluid resulting from hemodynamic alteration, and we designed a comprehensive multi-modality MRI study to testify our hypothesis. Susceptibility-weighted imaging was used to investigate the characteristics of DMVs and derive DMVs scores. Free water elimination diffusion tensor imaging model was used to analyze interstitial fluid fraction (fraction of free water, fFW) and white matter integrity (tissue fractional anisotropy, FAt). Totally, 104 CSVD patients were included. Total DMVs score was associated with FAt of DMVs drainage area. The effect of total DMVs score on FAt was mediated by fFW, after controlling for age, sex, hypertension, regional cerebral blood flow and lacune numbers. The relationships between DMVs score, fFW and FAt were also significant in most DMVs drainage subregions. Therefore, we discovered the DMVs disruption – increased interstitial fluid – white matter damage link in CSVD patients, which was independent of arterial perfusion variations.

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Retrospective analysis of hemispheric structural network change as a function of location and size of glioma

Brain Communications ◽

10.1093/braincomms/fcaa216 ◽

2020 ◽

Author(s):

Shawn D’Souza ◽

Lisa Hirt ◽

David R Ormond ◽

John A Thompson

Keyword(s):

Diffusion Tensor Imaging ◽

White Matter ◽

Temporal Lobe ◽

Diffusion Tensor ◽

Brain Regions ◽

Structural Network ◽

Tumour Location ◽

The Impact ◽

Tractography Data ◽

Diffusion Tensor Imaging Tractography

Abstract Gliomas are neoplasms that arise from glial cell origin and represent the largest fraction of primary malignant brain tumours (77%). These highly infiltrative malignant cell clusters modify brain structure and function through expansion, invasion and intratumoral modification. Depending on the growth rate of the tumour, location and degree of expansion, functional reorganization may not lead to overt changes in behaviour despite significant cerebral adaptation. Studies in simulated lesion models and in patients with stroke reveal both local and distal functional disturbances, using measures of anatomical brain networks. Investigations over the last two decades have sought to use diffusion tensor imaging tractography data in the context of intracranial tumours to improve surgical planning, intraoperative functional localization, and post-operative interpretation of functional change. In this study, we used diffusion tensor imaging tractography to assess the impact of tumour location on the white matter structural network. To better understand how various lobe localized gliomas impact the topology underlying efficiency of information transfer between brain regions, we identified the major alterations in brain network connectivity patterns between the ipsilesional versus contralesional hemispheres in patients with gliomas localized to the frontal, parietal or temporal lobe. Results were indicative of altered network efficiency and the role of specific brain regions unique to different lobe localized gliomas. This work draws attention to connections and brain regions which have shared structural susceptibility in frontal, parietal and temporal lobe glioma cases. This study also provides a preliminary anatomical basis for understanding which affected white matter pathways may contribute to preoperative patient symptomology.

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Quantitative diffusion tensor imaging analysis does not distinguish pediatric canines with mucopolysaccharidosis I from control canines

The Neuroradiology Journal ◽

10.1177/1971400917718844 ◽

2017 ◽

Vol 30 (5) ◽

pp. 454-460

Author(s):

Dana M Middleton ◽

Jonathan Y Li ◽

Steven D Chen ◽

Leonard E White ◽

Patricia I Dickson ◽

...

Keyword(s):

Diffusion Tensor Imaging ◽

White Matter ◽

Fractional Anisotropy ◽

Imaging System ◽

Diffusion Tensor ◽

Brain Regions ◽

Magnetic Resonance Imaging System ◽

Radial Diffusivity ◽

Mucopolysaccharidosis I ◽

Diffusivity Measurements

Purpose We compared fractional anisotropy and radial diffusivity measurements between pediatric canines affected with mucopolysaccharidosis I and pediatric control canines. We hypothesized that lower fractional anisotropy and higher radial diffusivity values, consistent with dysmyelination, would be present in the mucopolysaccharidosis I cohort. Methods Six canine brains, three affected with mucopolysaccharidosis I and three unaffected, were euthanized at 7 weeks and imaged using a 7T small-animal magnetic resonance imaging system. Average fractional anisotropy and radial diffusivity values were calculated for four white-matter regions based on 100 regions of interest per region per specimen. A 95% confidence interval was calculated for each mean value. Results No difference was seen in fractional anisotropy or radial diffusivity values between mucopolysaccharidosis affected and unaffected brains in any region. In particular, the 95% confidence intervals for mucopolysaccharidosis affected and unaffected canines frequently overlapped for both fractional anisotropy and radial diffusivity measurements. In addition, in some brain regions a large range of fractional anisotropy and radial diffusivity values were seen within the same cohort. Conclusion The fractional anisotropy and radial diffusivity values of white matter did not differ between pediatric mucopolysaccharidosis affected canines and pediatric control canines. Possible explanations include: (a) a lack of white matter tissue differences between mucopolysaccharidosis affected and unaffected brains at early disease stages; (b) diffusion tensor imaging does not detect any existing differences; (c) inflammatory processes such as astrogliosis produce changes that offset the decreased fractional anisotropy values and increased radial diffusivity values that are expected in dysmyelination; and (d) our sample size was insufficient to detect differences. Further studies correlating diffusion tensor imaging findings to histology are warranted.

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Prediction of white matter integrity pattern in overweight and obese adults

Proceedings of The Nutrition Society ◽

10.1017/s0029665120001378 ◽

2020 ◽

Vol 79 (OCE2) ◽

Author(s):

Sussanne Reyes ◽

Patricio Peirano ◽

Betsy Lozoff ◽

Cecilia Algarin

Keyword(s):

White Matter ◽

Cognitive Flexibility ◽

Diffusion Tensor ◽

Brain Regions ◽

Normal Weight ◽

White Matter Integrity ◽

School Age ◽

Loss Avoidance ◽

Neurocognitive Tasks ◽

The Relationship

Abstract IntroductionObesity has been associated with lower white matter integrity (WMI) in limbic brain regions, including the fornix. Both early decrease of WMI in the fornix (WMIf) and midlife obesity have been related to dementia incidence with advancing age. No studies have explored early cognitive predictors of WMIf in overweight-obese (OO) adults. Aim of this study was to compare OO and normal-weight (NW) participants with respect to (a) WMIf in adulthood and (b) the relationship between cognitive performance at school-age and in adolescence with WMIf in adulthood.MethodsParticipants were part of a cohort followed since infancy who underwent magnetic resonance imaging studies in adulthood (22.3 ± 1.3 years). Diffusion tensor imaging was performed and Tract Based Spatial Statistics (TBSS) was used to obtain fractional anisotropy (FA) skeleton; increased FA relates to greater WMI. A mask for the fornix was created (JHU-ICBM DTI-81 Atlas) and then used to extract the average FA for each individual. Participants also performed neurocognitive tasks: (a) school-age (10.3 ± 1.0 years): the trail making test comprises two conditions and time difference between conditions reflects cognitive flexibility; (b) adolescence (15.6 ± 0.5 years): incentive task that test the effect of incentives (reward, loss avoidance or neutral) on inhibitory control performance (correct responses latency). In adulthood, BMI was categorized as NW (≥ 18.5 to < 25.0 kg/m2) and OO (≥ 25.0 kg/m2) groups. A t-test and univariate GLM were conducted. Analysis were adjusted by sex and age-specific BMI z-scores.ResultsParticipants were 27 NW (41% female) and 41 OO (49% female). Compared to NW, OO participants showed decreased FA in the fornix (0.585 vs. 0.618, p < 0.05), i.e. lower WMIf. Differences were apparent in the relationship between cognitive flexibility at school-age (F = 2.9, p = 0.06) and loss avoidance latency in adolescence (F = 3.5, p < 0.05) with FA in the fornix in adulthood. Increased cognitive flexibility at school-age (β = 0.335, p < 0.05) and decreased loss avoidance latency in adolescence (β = -0.581, p < 0.001) were related to higher FA in the fornix in OO adults. No relationship resulted significant in NW adults.DiscussionPerformance in neurocognitive tasks at earlier developmental stages were related with WMIf only in OO adults, group characterized by decreased WMIf. Our results provide evidence regarding specific neurocognitive tasks with predictive value for WMIf alterations. Further, they could contribute to the understanding of neural mechanisms underlying obesity and also provide insight relative to neurodegenerative risk with advancing age.SupportFondecyt 11160671 and NIH HD33487.

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

Neuropsychopharmacology ◽

10.1038/s41386-022-01272-x ◽

2022 ◽

Author(s):

Inês Carreira Figueiredo ◽

Faith Borgan ◽

Ofer Pasternak ◽

Federico E. Turkheimer ◽

Oliver D. Howes

Keyword(s):

White Matter ◽

Healthy Volunteers ◽

Diffusion Mri ◽

Clinical Symptoms ◽

Free Water ◽

Brain Regions ◽

Water Levels ◽

First Episode ◽

Whole Brain ◽

Illness Duration

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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In Vivo Characterization of Cortical and White Matter Microstructural Pathology in Growth Hormone-Secreting Pituitary Adenoma

Frontiers in Oncology ◽

10.3389/fonc.2021.641359 ◽

2021 ◽

Vol 11 ◽

Author(s):

Taoyang Yuan ◽

Jianyou Ying ◽

Chuzhong Li ◽

Lu Jin ◽

Jie Kang ◽

...

Keyword(s):

Growth Hormone ◽

Pituitary Adenoma ◽

White Matter ◽

Diffusion Tensor ◽

Critical Role ◽

Mean Diffusivity ◽

Occipital Cortex ◽

Test Surface ◽

Neuropsychological Dysfunction

BackgroundThe growth hormone (GH) and insulin-like-growth factor 1 (IGF-1) axis has long been recognized for its critical role in brain growth, development. This study was designed to investigate microstructural pathology in the cortex and white matter in growth hormone-secreting pituitary adenoma, which characterized by excessive secretion of GH and IGF-1.Methods29 patients with growth hormone-secreting pituitary adenoma (acromegaly) and 31 patients with non-functional pituitary adenoma as controls were recruited and assessed using neuropsychological test, surface-based morphometry, T1/T2-weighted myelin-sensitive magnetic resonance imaging, neurite orientation dispersion and density imaging, and diffusion tensor imaging.ResultsCompared to controls, we found 1) acromegaly had significantly increased cortical thickness throughout the bilateral cortex (pFDR < 0.05). 2) T1/T2-weighted ratio in the cortex were decreased in the bilateral occipital cortex and pre/postcentral central gyri but increased in the bilateral fusiform, insular, and superior temporal gyri in acromegaly (pFDR < 0.05). 3) T1/T2-weighted ratio were decreased in most bundles, and only a few areas showed increases in acromegaly (pFDR < 0.05). 4) Neurite density index (NDI) was significantly lower throughout the cortex and bundles in acromegaly (pTFCE < 0.05). 5) lower fractional anisotropy (FA) and higher mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in extensive bundles in acromegaly (pTFCE < 0.05). 6) microstructural pathology in the cortex and white matter were associated with neuropsychological dysfunction in acromegaly.ConclusionsOur findings suggested that long-term persistent and excess serum GH/IGF-1 levels alter the microstructure in the cortex and white matter in acromegaly, which may be responsible for neuropsychological dysfunction.

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Regions of white matter abnormalities in the arcuate fasciculus in veterans with anger and aggression problems

Brain Structure and Function ◽

10.1007/s00429-019-02016-2 ◽

2019 ◽

Vol 225 (4) ◽

pp. 1401-1411 ◽

Cited By ~ 1

Author(s):

Szabolcs David ◽

Lieke Heesink ◽

Elbert Geuze ◽

Thomas Gladwin ◽

Jack van Honk ◽

...

Keyword(s):

White Matter ◽

Diffusion Tensor ◽

Military Veterans ◽

Self Regulation ◽

Brain Regions ◽

Microstructural Properties ◽

Uncinate Fasciculus ◽

Arcuate Fasciculus ◽

White Matter Connectivity ◽

Diffusion Tensor Imaging Tractography

AbstractAggression after military deployment is a common occurrence in veterans. Neurobiological research has shown that aggression is associated with a dysfunction in a network connecting brain regions implicated in threat processing and emotion regulation. However, aggression may also be related to deficits in networks underlying communication and social cognition. The uncinate and arcuate fasciculi are integral to these networks, thus studying potential abnormalities in these white matter connections can further our understanding of anger and aggression problems in military veterans. Here, we use diffusion tensor imaging tractography to investigate white matter microstructural properties of the uncinate fasciculus and the arcuate fasciculus in veterans with and without anger and aggression problems. A control tract, the parahippocampal cingulum was also included in the analyses. More specifically, fractional anisotropy (FA) estimates are derived along the trajectory from all fiber pathways and compared between both groups. No between-group FA differences are observed for the uncinate fasciculus and the cingulum, however parts of the arcuate fasciculus show a significantly lower FA in the group of veterans with aggression and anger problems. Our data suggest that abnormalities in arcuate fasciculus white matter connectivity that are related to self-regulation may play an important role in the etiology of anger and aggression in military veterans.

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Large-Scale Evidence for an Association Between Peripheral Inflammation and White Matter Free Water in Schizophrenia and Healthy Individuals

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa134 ◽

2020 ◽

Author(s):

Maria A Di Biase ◽

Andrew Zalesky ◽

Suheyla Cetin-Karayumak ◽

Yogesh Rathi ◽

Jinglei Lv ◽

...

Keyword(s):

White Matter ◽

Large Scale ◽

Interleukin 2 ◽

Free Water ◽

Markers Of Inflammation ◽

Brain White Matter ◽

Inflammatory Processes ◽

Weighted Magnetic Resonance Imaging

Abstract Introduction Clarifying the role of neuroinflammation in schizophrenia is subject to its detection in the living brain. Free-water (FW) imaging is an in vivo diffusion-weighted magnetic resonance imaging (dMRI) technique that measures water molecules freely diffusing in the brain and is hypothesized to detect inflammatory processes. Here, we aimed to establish a link between peripheral markers of inflammation and FW in brain white matter. Methods All data were obtained from the Australian Schizophrenia Research Bank (ASRB) across 5 Australian states and territories. We first tested for the presence of peripheral cytokine deregulation in schizophrenia, using a large sample (N = 1143) comprising the ASRB. We next determined the extent to which individual variation in 8 circulating pro-/anti-inflammatory cytokines related to FW in brain white matter, imaged in a subset (n = 308) of patients and controls. Results Patients with schizophrenia showed reduced interleukin-2 (IL-2) (t = −3.56, P = .0004) and IL-12(p70) (t = −2.84, P = .005) and increased IL-6 (t = 3.56, P = .0004), IL-8 (t = 3.8, P = .0002), and TNFα (t = 4.30, P < .0001). Higher proinflammatory signaling of IL-6 (t = 3.4, P = .0007) and TNFα (t = 2.7, P = .0007) was associated with higher FW levels in white matter. The reciprocal increases in serum cytokines and FW were spatially widespread in patients encompassing most major fibers; conversely, in controls, the relationship was confined to the anterior corpus callosum and thalamic radiations. No relationships were observed with alternative dMRI measures, including the fractional anisotropy and tissue-related FA. Conclusions We report widespread deregulation of cytokines in schizophrenia and identify inflammation as a putative mechanism underlying increases in brain FW levels.

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Diffusion Tensor Imaging and Fiber Tractography

Handbook of Research on Advanced Techniques in Diagnostic Imaging and Biomedical Applications ◽

10.4018/978-1-60566-314-2.ch015 ◽

2009 ◽

pp. 229-246

Author(s):

Evanthia E. Tripoliti ◽

Dimitrios I. Fotiadis ◽

Konstantia Veliou

Keyword(s):

Diffusion Tensor Imaging ◽

White Matter ◽

Diffusion Tensor ◽

Brain Regions ◽

Cerebral White Matter ◽

Tissue Microstructure ◽

Diffusion Weighted Images ◽

Fiber Tracts ◽

Diffusion Weighted ◽

Magnetic Resonance Imaging Mri

Diffusion Tensor Imaging (DTI) is a magnetic resonance imaging (MRI) modality which can significantly improve our understanding of the brain structures and neural connectivity. DTI measures are thought to be representative of brain tissue microstructure and are particularly useful for examining organized brain regions, such as white matter tract areas. DTI measures the water diffusion tensor using diffusion weighted pulse sequences which are sensitive to microscopic random water motion. The resulting diffusion weighted images (DWI) display and allow quantification of how water diffuses along axes or diffusion encoding directions. This can help to measure and quantify the tissue’s orientation and structure, making it an ideal tool for examining cerebral white matter and neural fiber tracts. In this chapter the authors discuss the theoretical aspects of DTI, the information that can be extracted from DTI data, and the use of the extracted information for the reconstruction of fiber tracts and the diagnosis of a disease. In addition, a review of known fiber tracking algorithms is presented.

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Aberrant White Matter Networks Mediate Cognitive Impairment in Patients with Silent Lacunar Infarcts in Basal Ganglia Territory

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.67 ◽

2015 ◽

Vol 35 (9) ◽

pp. 1426-1434 ◽

Cited By ~ 9

Author(s):

Jinfu Tang ◽

Suyu Zhong ◽

Yaojing Chen ◽

Kewei Chen ◽

Junying Zhang ◽

...

Keyword(s):

White Matter ◽

Basal Ganglia ◽

Cognitive Deficits ◽

Large Scale ◽

Diffusion Tensor ◽

Brain Regions ◽

Lacunar Infarcts ◽

Healthy Elderly ◽

Brain White Matter ◽

Diffusion Tensor Imaging Tractography

Silent lacunar infarcts, which are present in over 20% of healthy elderly individuals, are associated with subtle deficits in cognitive functions. However, it remains largely unclear how these silent brain infarcts lead to cognitive deficits and even dementia. Here, we used diffusion tensor imaging tractography and graph theory to examine the topological organization of white matter networks in 27 patients with silent lacunar infarcts in the basal ganglia territory and 30 healthy controls. A whole-brain white matter network was constructed for each subject, where the graph nodes represented brain regions and the edges represented interregional white matter tracts. Compared with the controls, the patients exhibited a significant reduction in local efficiency and global efficiency. In addition, a total of eighteen brain regions showed significantly reduced nodal efficiency in patients. Intriguingly, nodal efficiency–behavior associations were significantly different between the two groups. The present findings provide new aspects into our understanding of silent infarcts that even small lesions in subcortical brain regions may affect large-scale cortical white matter network, as such may be the link between subcortical silent infarcts and the associated cognitive impairments. Our findings highlight the need for network-level neuroimaging assessment and more medical care for individuals with silent subcortical infarcts.

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