Superficial white matter microstructure affects processing speed in cerebral small vessel disease

Wang, Shuyue; Zhang, Fan; Huang, Peiyu; Hong, Hui; Jiaerken, Yeerfan; Yu, Xinfeng; Zhang, Ruiting; Zeng, Qingze; Zhang, Yao; Kikinis, Ron; Rathi, Yogesh; Makris, Nikos; Lou, Min; Pasternak, Ofer; Zhang, Minming; O’Donnell, Lauren J.

doi:10.1002/hbm.26004

Cited by 11 publications

(8 citation statements)

References 110 publications

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“…WMH is an important imaging sign of CSVD that shows highsignal intensity on T2 and fluid-attenuated inversion recovery (FLAIR) sequences. 58 WMH includes two main categories: deep subcortical and periventricular WMH. 59 The severity of white matter lesions is typically evaluated using the Fazekas grading scale.…”

Section: White Matter Hyperintensitymentioning

confidence: 99%

Cerebral Amyloid Angiopathy: An Undeniable Small Vessel Disease

Wang,

Liu,

Yue

et al. 2024

J Stroke

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Cerebral amyloid angiopathy (CAA) has been proven to be the most common pathological change in cerebral small vessel disease except arteriosclerosis. In recent years, with the discovery of imaging technology and new imaging markers, the diagnostic rate of CAA has greatly improved. CAA plays an important role in non-hypertensive cerebral hemorrhage and cognitive decline. This review comprehensively describes the etiology, epidemiology, pathophysiological mechanisms, clinical features, imaging manifestations, imaging markers, diagnostic criteria, and treatment of CAA to facilitate its diagnosis and treatment and reduce mortality.

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Section: White Matter Hyperintensitymentioning

confidence: 99%

Cerebral Amyloid Angiopathy: An Undeniable Small Vessel Disease

Wang,

Liu,

Yue

et al. 2024

J Stroke

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“…This activation is mediated by the expression of oxytocin and Nrf2, which are essential for promoting heme oxygenase and the production of Ang2-AT2 and VEGF-A. These factors are necessary for activating hematopoietic cell functions and anti-inflammatory growth via the NR4As pathway [63]. Dopamine receptors on hematopoietic stem cells (HSCs) and LSK cells can reflect the production of IL17, which, in turn, activates glucocorticoid-beta via the NR4As pathway.…”

Section: Methods and Resultsmentioning

confidence: 99%

“…Dopamine receptors on hematopoietic stem cells (HSCs) and LSK cells can reflect the production of IL17, which, in turn, activates glucocorticoid-beta via the NR4As pathway. This activation is followed by the activation of B-adrenergic and oxytocin receptors, which are necessary for Nrf2 production, promoting heme oxygenase and Ang2-AT2 and VEGF-A production, all of which are essential for hematopoietic reconstitution [63].…”

Section: Methods and Resultsmentioning

confidence: 99%

DPP4 Valorphin Activate NR4As Pathway and OPA1 That Protect from CoQ10 Deficiency, OPA1 Dysfunctions and WMH

El Tantawi

2023

Med Clin Sci

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Deficiencies in Threonine (Thr), Tryptophan hydroxylase (Tph), Glutamate (Glu), Glutamine (Gln), and Leucine can result from increased polarizability in mTORC1 and its subunits. These deficiencies may lead to disorders in OPA1 repair, which can be a primary cause of Coenzyme Q10 (CoQ10) deficiency disease. CoQ10 is crucial for maintaining the inner mitochondrial membrane and is necessary for the synthesis of the glucocorticoid receptor (GCR). Mitochondrial damage or dysfunction can lead to the accumulation of pro-inflammatory molecules, which may cause mutations in subunits and proteins. Reduced levels of Tryptophan, Glycine (Gly), and Arginine (Arg) can result in decreased Proline synthesis, subsequently reducing tRNA levels. This, in turn, can impair mitochondrial OPA1 repair and function due to decreased GTPase activity. The reduced function of GTPase can lead to decreased IL-17 synthesis and the accumulation of pro-inflammatory molecules, resulting in a reduction in serotonin production, as well as decreased production of GCbeta, oxytocin, and Nrf2. These changes can lead to a decrease in the proliferation of megakaryocytes and, consequently, reduced hematopoiesis, which is associated with white matter hyperintensity. Opioid receptors play a role in producing powerful analgesia, contributing to the function of immune cells, and modulating acquired immune responses, including the function of lymphocytes. Tryptophan, Leucine, and Tyrosine kinases are crucial for activating mitochondrial OPA1 repairs, which are essential for CoQ10 synthesis. Tryptophan (TGG) is necessary for activating Proline, which is essential for both OPA1 function and tRNA production. Additionally, it plays a role in IL17 synthesis and the activation of the NR4As pathway, which includes the activation of GCs-beta, oxytocin, and Nrf2 production, respectively. Cytotoxic edema can result from uncontrolled or uncompensated cation influx, primarily sodium (Na+). This edema occurs due to high levels of potassium (K) and sodium (Na) binding toxicity, leading to coagulation and reduced ATPase and GTPase activity. It starts with a decrease in CoQ10 synthesis and an increase in Plasma Glial Fibrillary Acidic Protein (GFAP), resulting in decreased mineralocorticoid. Increased sodium and potassium binding, associated with decreased anions binding in biological molecules, can be due to reduced GTPase and OPA1 function. This reduction in anions function is the result of a primary Coenzyme Q10 (CoQ10) deficiency, leading to elevated GFAP levels in cognitively normal older adults at risk of Alzheimer's disease. Primary Coenzyme Q10 (CoQ10) deficiency is typically associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypoxia, late-onset multiple-system atrophy-like symptoms, dystonia, spasticity, seizures, and intellectual disability. Autoimmune diseases and skin inflammatory disorders can start due to increased cation binding toxicity, which reduces ATPase and GTPase function, characterized by a deficiency in proper GTPase production, leading to a reduction in mitochondrial OPA1 function and a deficiency in GCs-beta synthesis via the NR4As pathway. GFAP is an important neuroinflammation biomarker, and an increase in its levels may indicate OPA1 dysfunction, a decrease in CoQ10, neuroinflammation, and a reduction in the NR4As pathway. The increase in GFAP during acute ischemic stroke can be initiated by increased cation binding to anions, leading to enhanced energy stability and decreased tRNA production, which is proline-dependent. This decrease in tRNAs and GTPase activity can result in a decrease in IL17 production, increased inflammation, decreased blood flow to the brain, and reduced oxygen supply to the brain, ultimately contributing to neuronal damage. A decrease in hemorphin (valorphin) reflects reduced lymphocyte function and a loss of cholinecontaining phospholipids (CCPLs). Valorphin contains Tyrosine, which is essential for kinases production, required for choline kinases synthesis, and crucial for activating tRNAs, serotonin, oxytocin, and Nrf2 via the NR4As pathway, all of which are essential for lymphocyte function and antiinflammatory growth. Nrf2 dysfunction, connected to NR4As and oxytocin dysfunction, plays a significant role in the pathogenesis of vascular cognitive impairment and dementia (VCID).

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“…We infer that the WMHs in the superficial layers would affect the microstructure of U-fibers. In the future, we will find out exactly how WMHs affect the microstructural properties of U-fibers and whether such association is affected by aging and other lesions ( 71 ).…”

Section: Discussionmentioning

confidence: 99%

U-fiber analysis: a toolbox for automated quantification of U-fibers and white matter hyperintensities

Zheng,

Fei,

et al. 2024

Quant Imaging Med Surg

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Background Whether white matter hyperintensities (WMHs) involve U-fibers is of great value in understanding the different etiologies of cerebral white matter (WM) lesions. However, clinical practice currently relies only on the naked eye to determine whether WMHs are in the vicinity of U-fibers, and there is a lack of good neuroimaging tools to quantify WMHs and U-fibers. Methods Here, we developed a multimodal neuroimaging toolbox named U-fiber analysis (UFA) that can automatically extract WMHs and quantitatively characterize the volume and number of WMHs in different brain regions. In addition, we proposed an anatomically constrained U-fiber tracking scheme and quantitatively characterized the microstructure diffusion properties, fiber length, and number of U-fibers in different brain regions to help clinicians to quantitatively determine whether WMHs in the proximal cortex disrupt the microstructure of U-fibers. To validate the utility of the UFA toolbox, we analyzed the neuroimaging data from 246 patients with cerebral small vessel disease (cSVD) enrolled at Zhongshan Hospital between March 2018 and November 2019 in a cross-sectional study. Results According to the manual judgment of the clinician, the patients with cSVD were divided into a WMHs involved U-fiber group (U-fiber-involved group, 51 cases) and WMHs not involved U-fiber group (U-fiber-spared group, 163 cases). There were no significant differences between the U-fiber-spared group and the U-fiber-involved group in terms of age (P=0.143), gender (P=0.462), education (P=0.151), Mini-Mental State Examination (MMSE) scores (P=0.151), and Montreal Cognitive Assessment (MoCA) scores (P=0.411). However, patients in the U-fiber-involved group had higher Fazekas scores (P<0.001) and significantly higher whole brain WMHs (P=0.046) and deep WMH volumes (P<0.001) compared to patients in the U-fiber-spared group. Moreover, the U-fiber-involved group had higher WMH volumes in the bilateral frontal [P(left) <0.001, P(right) <0.001] and parietal lobes [P(left) <0.001, P(right) <0.001]. On the other hand, patients in the U-fiber-involved group had higher mean diffusivity (MD) and axial diffusivity (AD) in the bilateral parietal [P(left, MD) =0.048, P(right, MD) =0.045, P(left, AD) =0.015, P(right, AD) =0.015] and right frontal-parietal regions [P(MD) =0.048, P(AD) =0.027], and had significantly reduced mean fiber length and number in the right parietal [P(length) =0.013, P(number) =0.028] and right frontal-parietal regions [P(length) =0.048] compared to patients in the U-fiber-spared group. Conclusions Our results suggest that WMHs in the proximal cortex may disrupt the microstructure of U-fibers. Our tool may provide new insights into the understanding of WM lesions of different etiologies in the brain.

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Superficial white matter microstructure affects processing speed in cerebral small vessel disease

Cited by 11 publications

References 110 publications

Cerebral Amyloid Angiopathy: An Undeniable Small Vessel Disease

Cerebral Amyloid Angiopathy: An Undeniable Small Vessel Disease

DPP4 Valorphin Activate NR4As Pathway and OPA1 That Protect from CoQ10 Deficiency, OPA1 Dysfunctions and WMH

U-fiber analysis: a toolbox for automated quantification of U-fibers and white matter hyperintensities

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