Pathogenesis Of White Matter Hyperintensities Research Articles

Heme Oxygenase-1 Gene (GT)n Polymorphism Linked to Deep White Matter Hyperintensities, Not Periventricular Hyperintensities.

Oxidative stress plays a principal role in the pathogenesis of white matter hyperintensities (WMHs). The induction of heme oxygenase-1 (HO-1) gene in the brain represents 1 of the pivotal mechanisms to counteract the noxious effects of reactive oxygen species, and the transcriptional modulation of HO-1 induction depends on the length of a GT-repeat (GT)n in the promoter region. We investigated whether the HO-1 gene (GT)n polymorphism is associated with the risk of WMHs. A total of 849 subjects from the memory clinic were consecutively enrolled, and the HO-1 (GT)n genotype was determined. WMHs were assessed with the Fazekas scale and further divided into periventricular WMHs and deep WMHs (DWMHs). Allelic HO-1 (GT)n polymorphisms were classified as short (≤24 (GT)n), median (25≤[GT]n<31), or long (31≤[GT]n). Multivariate logistic regression analysis was used to evaluate the effect of the HO-1 (GT)n variants on WMHs. The number of repetitions of the HO-1 gene (GT)n ranged from 15 to 39 with a bimodal distribution at lengths 23 and 30. The proportion of S/S genotypes was higher for moderate/severe DWMHs than none/mild DWMHs (22.22% versus 12.44%; P=0.001), but the association for periventricular WMHs was not statistically significant. Logistic regression suggested that the S/S genotype was significantly associated with moderate/severe DWMHs (S/S versus non-S/S: odds ratio, 2.001 [95% CI, 1.323-3.027]; P<0.001). The HO-1 gene (GT)n S/S genotype and aging synergistically contributed to the progression of DWMHs (relative excess risk attributable to interaction, 6.032 [95% CI, 0.149-11.915]). Short (GT)n variants in the HO-1 gene may confer susceptibility to rather than protection from DWMHs, but not periventricular WMHs. URL: https://www.chictr.org.cn; Unique identifier: ChiCTR2100045869.

Ring finger protein 216 loss-of-function induces white matter hyperintensities by inhibiting oligodendroglia proliferation.

White matter hyperintensities(WMHs) refer to a group of diseases with numerous etiologies while oligodendrocytes remain the centerpiece in the pathogenesis of WMHs. Ring Finger Protein 216 (RNF216) encodes a ubiquitin ligase, and its mutation begets WMHs, ataxia, and cognitive decline in patients. Yet no study has revealed the function of RNF216 in oligodendroglia and WHIs before. In this study, we summarized the phenotypes of RNF216-mutation cases and explored the normal distribution of RNF216 in distinct brain regions and neuronal cells by bioinformatic analysis. Furthermore, MO3.13, a human oligodendrocyte cell line, was applied to study the function alteration after RNF216 knockdown. As a result, WMHs were the most common symptom in RNF216-mutated diseases, and RNF216 was indeed relatively enriched in corpus callosum and oligodendroglia in humans. The downregulation of RNF216 in oligodendroglia remarkably hampered cell proliferation by inhibiting the Akt pathway while having no significant effect on cell injury and oligodendrocyte maturation. Combining clinical, bioinformatical, and experimental evidence, our study implied the pivotal role of RNF216 in WMHs which might serve as a potent target in the therapy of WMHs.

HLA-C*07:01 and HLA-DQB1*02:01 protect against white matter hyperintensities and deterioration of cognitive function: A population-based cohort study

BackgroundNeuroinflammation and aberrant immune regulation are increasingly implicated in the pathophysiology of white matter hyperintensities (WMH), an imaging marker of cerebrovascular pathologies and predictor of cognitive impairment. The role of human leukocyte antigen (HLA) genes, critical in immunoregulation and associated with susceptibility to neurodegenerative diseases, in WMH pathophysiology remains unexplored. MethodsWe performed association analyses between classical HLA alleles and WMH volume, derived from MRI scans of 38 302 participants in the UK Biobank. To identify independent functional alleles driving these associations, we conducted conditional forward stepwise regression and lasso regression. We further investigated whether these functional alleles showed consistent associations with WMH across subgroups characterized by varying levels of clinical determinants. Additionally, we validated the clinical relevance of the identified alleles by examining their association with cognitive function (n = 147 549) and dementia (n = 460 029) in a larger cohort. FindingsFour HLA alleles (DQB1*02:01, DRB1*03:01, C*07:01, and B*08:01) showed an association with reduced WMH volume after Bonferroni correction for multiple comparisons. Among these alleles, DQB1*02:01 exhibited the most significant association (β = −0.041, 95 % CI: −0.060 to −0.023, p = 1.04 × 10−5). Forward selection and lasso regression analyses indicated that DQB1*02:01 and C*07:01 primarily drove this association. The protective effect against WMH conferred by DQB1*02:01 and C*07:01 persisted in clinically relevant subgroups, with a stronger effect observed in older participants. Carrying DQB1*02:01 and C*07:01 was associated with higher cognitive function, but no association with dementia was found. InterpretationOur population-based findings support the involvement of immune-associated mechanisms, particularly both HLA class I and class II genes, in the pathogenesis of WMH and subsequent consequence of cognitive functions.

Contribution of Inflammation and Hypoperfusion to White Matter Hyperintensities-Related Cognitive Impairment.

White matter hyperintensities (WMHs) of presumed vascular origin are one of the most important neuroimaging markers of cerebral small vessel disease (CSVD), which are closely associated with cognitive impairment. The aim of this study was to elucidate the pathogenesis of WMHs from the perspective of inflammation and hypoperfusion mechanisms. A total of 65 patients with WMHs and 65 healthy controls were enrolled in this study. Inflammatory markers measurements [hypersensitive C-reactive protein (hsCRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2)], cognitive evaluation, and pseudocontinuous arterial spin labeling (PCASL) MRI scanning were performed in all the subjects. The multivariate logistic regression analysis showed that Lp-PLA2 was an independent risk factor for WMHs. Cerebral blood flow (CBF) in the whole brain, gray matter (GM), white matter (WM), left orbital medial frontal gyrus [MFG.L (orbital part)], left middle temporal gyrus (MTG.L), and right thalamus (Tha.R) in the patients was lower than those in the controls and CBF in the left triangular inferior frontal gyrus [IFG.L (triangular part)] was higher in the patients than in the controls. There was a significant correlation between Lp-PLA2 levels and CBF in the whole brain (R = −0.417, p < 0.001) and GM (R = −0.278, p = 0.025), but not in the WM in the patients. Moreover, CBF in the MFG.L (orbital part) and the Tha.R was, respectively, negatively associated with the trail making test (TMT) and the Stroop color word test (SCWT), suggesting the higher CBF, the better executive function. The CBF in the IFG.L (triangular part) was negatively correlated with attention scores in the Cambridge Cognitive Examination-Chinese Version (CAMCOG-C) subitems (R = −0.288, p = 0.020). Our results revealed the vascular inflammation roles in WMHs, which may through the regulation of CBF in the whole brain and GM. Additionally, CBF changes in different brain regions may imply a potential role in the modulation of cognitive function in different domains.

White matter hyperintensities and patterns of atrophy in early onset Alzheimer’s disease with causative gene mutations

ObjectiveWhite matter hyperintensities could be found in many degenerative dementias including Alzheimer’s disease (AD). Pathogenesis of white matter hyperintensities in AD is complicated. We aim to identify the features of white matter hyperintensities and the atrophy pattern in early onset Alzheimer’s disease with causative gene mutations. Methods7 AD dementia patients with causative mutations were included and the clinical history, neuropsychology, neuroimaging,APOE genotype and whole-genome sequencing (WGS) were analyzed. Axial T1-weighted images and Fluid attenuated inversion recovery (FLAIR) were analyzed with visual rating scale to examine cortical atrophy and white matter hyperintensities. Results5 female and 2 male patients with 4PSEN1, 2PSEN2 and 1APP mutation were included. The average age of onset was 46.7y/o (44–52) and the duration of disease was 28.6 months (8−60). Clinical phenotype included memory loss (100 %), visual/spatial disorder (100 %), executive dysfunction (100 %), calculation disorder (85.7 %), disorientation (85.7 %), language problem (57.1 %), personality change (28.6 %) and movement disorder (14.3 %). The grading of posterior cortex atrophy was higher than medial temporal lobe atrophy. Periventricular hyperintensities surrounding occipital and frontal horn of ventricle and sub-ventricular bands were most common, while small foci of lesions were also detected in deep white matter, sub-cortical and juxta-cortical area. Mutations carriers in the APP gene or PSEN1 gene postcodon 200 had more severe white matter hyperintensities than other mutations. ConclusionWhite matter hyperintensities were found in early onset AD with causative mutations. The severity was related to genotypes and spatial distributions. Axon degeneration following neuronal loss and ischemic injury might be the pathogenesis of white matter damage. Severer atrophy in the posterior cortex than medial temporal lobe can present in early onset AD.

Reader response: WMH and long-term outcomes in ischemic stroke: A systematic review and meta-analysis.

I read with interest the article on white matter hyperintensities (WMH) by Georgakis et al.1 suggesting that WMH are linked to long-term outcomes in ischemic stroke. Pathogenesis of WMH is uncertain, and generalization is difficult.2 WMH are also found bilaterally in migraine patients, with no definitive long-term deterioration in functional or cognitive abilities despite the continuation of age-related accelerated atherosclerosis.2,3

White matter hyperintensities in migraine: Clinical significance and central pulsatile hemodynamic correlates.

Background The role of central pulsatile hemodynamics in the pathogenesis of white matter hyperintensities in migraine patients has not been clarified. Methods Sixty patients with migraine (20-50 years old; women, 68%) without overt vascular risk factors and 30 demographically-matched healthy controls were recruited prospectively. Cerebral white matter hyperintensities volume was determined by T1-weighted magnetic resonance imaging with CUBE-fluid-attenuated-inversion-recovery sequences. Central systolic blood pressure, carotid-femoral pulse wave velocity, and carotid augmentation index were measured by applanation tonometry. Carotid pulsatility index was derived from Doppler ultrasound carotid artery flow analysis. Results Compared to the controls, the migraine patients had higher white matter hyperintensities frequency (odds ratio, 2.75; p = 0.04) and greater mean white matter hyperintensities volume (0.174 vs. 0.049, cm3, p = 0.04). Multivariable regression analysis showed that white matter hyperintensities volume in migraine patients was positively associated with central systolic blood pressure ( p = 0.04) and carotid-femoral pulse wave velocity ( p < 0.001), but negatively associated with carotid pulsatility index ( p = 0.04) after controlling for potential confounding factors. The interaction effects observed indicated that the influence of carotid-femoral pulse wave velocity ( p = 0.004) and central systolic blood pressure ( p = 0.03) on white matter hyperintensities formation was greater for the lower-carotid pulsatility index subgroup of migraine patients. White matter hyperintensities volume in migraine patients increased with decreasing carotid pulsatility index and with increasing central systolic blood pressure or carotid-femoral pulse wave velocity. Conclusions White matter hyperintensities are more common in patients with migraine than in healthy controls. Increased aortic stiffness or central systolic blood pressure in the presence of low intracranial artery resistance may predispose patients with migraine to white matter hyperintensities formation.

A Brain Region-Based Deep Medullary Veins Visual Score on Susceptibility Weighted Imaging.

Cerebral venous collagenosis played a role in the pathogenesis of white matter hyperintensities (WMHs) through venous ischemia. Since pathological changes of veins from intramural stenosis to luminal occlusion is a dynamic process, we aimed to create a deep medullary veins (DMVs) visual grade on susceptibility-weighted images (SWI) and explore the relationship of DMVs and WMHs based on venous drainage regions. We reviewed clinical, laboratory and imaging data from 268 consecutive WMHs patients and 20 controls. SWI images were used to observe characteristics of DMVs and a brain region-based DMVs visual score was given by two experienced neuroradiologists. Fluid attenuated inversion recovery (FLAIR) images were used to calculate WMHs volume. Logistic-regression analysis and partial Pearson’s correlation analysis were used to examine the association between the DMVs score and WMHs volume. We found that the DMVs score was significantly higher in WMHs patients than in controls (p < 0.001). Increased DMVs score was independently associated with higher WMHs volume after adjusting for total cholesterol level and number of lacunes (p < 0.001). Particularly, DMVs scores were correlated with regional PVHs volumes in the same brain region most. The newly proposed DMVs grading method allows the clinician to monitor the course of DMVs disruption. Our findings of cerebral venous insufficiency in WMHs patients may help to elucidate the pathogenic mechanisms and progression of WMHs.

Higher blood-brain barrier permeability is associated with higher white matter hyperintensities burden.

The pathogenesis of white matter hyperintensities (WMH) is incompletely understood but blood-brain barrier (BBB) dysfunction may play a key role. This study aimed to investigate the relationship between BBB permeability and the severity of WMH burden. Consecutive participants without symptomatic stroke history presented for physical examination were recruited in this cross-sectional study and divided into three WMH burden groups according to total Fazekas scores. They received dynamic contrast-enhanced-magnetic resonance imaging to measure BBB permeability, and received Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). A total of 102 participants aged 49-90years (mean age of 69.82years) were enrolled (36 with low WMH burden, 35 with medium WMH burden, and 31 with high WMH burden). Multivariable linear regression analyses revealed that participants with higher WMH burden had significantly higher BBB leakage rate and area under the leakage curve in normal-appearing white matter, WMH, cortical gray matter, and deep gray matter (DGM) after adjustment for age, sex, and vascular risk factors. Scores on MMSE and MoCA decreased with increasing leakage rate in WMH and DGM after adjustment for age, sex, WMH burden, and education years. We found that higher BBB permeability is associated with higher WMH burden and cognitive decline. The compromised BBB integrity may be a critical contributor to the pathogenesis of WMH and part of a series of pathological processes that finally lead to cognitive impairment.

High sensitivity C-reactive protein and cerebral white matter hyperintensities on magnetic resonance imaging in migraine patients

BackgroundMigraine is a common headache disorder that may be associated with vascular disease and cerebral white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) scan. High sensitivity C-reactive protein (hs-CRP) is a marker of inflammation that may predict subclinical atherosclerosis. However, the relation between migraine, vascular risks, and WMHs is unknown. We evaluated hs-CRP levels and the relation between hs-CRP level and WMHs in adult migraine patients.MethodsThis case–control study included 432 subjects (216 migraine patients [without aura, 143 patients; with aura, 73 patients]; 216 healthy control subjects without migraine; age range 18–50 y). Migraine diagnosis was determined according to the International Classification of Headache Disorders II diagnostic criteria. The migraine patients and control subjects had no known vascular risk factors, inflammatory disease, or comorbid disease. The presence and number of WMHs on MRI scans were determined, and serum hs-CRP levels were measured by latex-enhanced immunoturbidimetry.ResultsMean hs-CRP level was significantly greater in migraine patients (1.94 ± 2.03 mg/L) than control subjects (0.82 ± 0.58 mg/L; P ≤ .0001). The mean number of WMHs per subject and the presence of WMHs was significantly greater in migraine patients (69 patients [31.9%]; 1.68 ± 3.12 mg/dL) than control subjects (21 subjects [9.7%]; 0.3 ± 1.3; P ≤ .001). However, there was no correlation between hs-CRP level and WMHs in migraine patients (r = 0.024; not significant). The presence of WMHs was increased 4.35-fold in migraine patients (odds ratio 4.35, P ≤ .001).ConclusionsHigh hs-CRP level may be a marker of the proinflammatory state in migraine patients. However, the absence of correlation between hs-CRP level and WMHs suggests that hs-CRP is not causally involved in the pathogenesis of WMHs in migraine patients. The WMHs were located mostly in the frontal lobe and subcortical area.

Increased visibility of deep medullary veins in leukoaraiosis: a 3-T MRI study.

Cerebral venous collagenosis has been implicated in leading to white matter hyperintensities (WMHs) via venous ischemia. We sought to determine whether cerebral venous dilation or ischemia correlate with the severity of WMHs by quantitative in vivo imaging techniques. This was an investigator-initiated prospective single-center study. We reviewed clinical, laboratory data from 158 consecutive WMHs patients and 50 controls, and measured the number of voxels of deep medullary veins (DMVs) on susceptibility-weighted image and assessed the WMH volume (as a marker of the severity of WMHs) on a 3-T magnetic resonance system. We then performed the logistic-regression analysis and partial Pearson’s correlation analysis to examine the association between the venous voxel count and WMH volume. The number of voxels of DMVs was significantly higher in WMHs than in controls. Increased number of voxels of DMVs was independently associated with both WMH volume of the whole brain and coregistered regional WMH volume after adjusting for age and number of lacunes. Our study indicates that cerebral deep venous insufficiency or ischemia play a role in the pathogenesis of WMHs, which may provide prognostic information on patients with WMHs and may have implications for therapeutic interventions.

Abstract TP181: Serum Eiocosapentaenoic Acids Is Protective Against White Matter Lesions

[Introduction] White matter hyperintensities (WMH) are considered manifestation of arteriosclerotic small vessel disease and WMH burden increases risk of ischemic stroke and cognitive decline. There are only a few evidences concerning the relationship between polyunsaturated fatty acids (PUFA) and WMH. The present study was designed to elucidate the association between WMH and PUFA profile including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) in patients with Alzheimer’s disease (AD). [Methods] The present study was based on 119 patients who were diagnosed as having a probable AD according to the NINCDS-ADRDA criteria. Their mean age was 78.3 years old. All subjects underwent neuropsychological evaluation including mini mental state exam (MMSE) and 1.5-Tesla MRI. Fasting blood samples were also collected for the PUFA measurements. We measured the ratio of serum EPA, DHA and AA concentration to the total PUFA concentration. The WMH were evaluated on T2-weight images and classified into periventricular hyperintensity (PVH) and deep white matter hyperintensity (DWMH). The severity of WMH was graded 5 categories. We investigated the relationship between WMH and PUFA profiles. [Results] The EPA ratio correlated negatively with both PVH (rs=-0.2036, p=0.0264) and DWMH grade (rs=-0.3155, p=0.0005). It remained still significant after adjustment for age, sex, statins use, antithrombotics use, mean blood pressure and presence of hypertension (standardized partial regression coefficient(β)=-0.2516, p=0.0122 for PVH, β=-0.3598, p=0.0001 for DWMH). Neither DHA nor AA ratio correlated with DWMH or PVH grade. The EPA ratio but not DHA or AA ratio correlated positively with total MMSE score (rs=0.2310, p=0.0115). [Conclusions] Our data revealed that the serum EPA was protective against WMH as well as cognitive decline in AD patients. Pathophysiology underlying WMH is complex and the possible mechanisms involved in the pathogenesis of WMH encompass incomplete brain ischemia, increased permeability of blood-brain barrier, and inflammation responses. The relationship between serum EPA and WMH can be partly explained by those anti-ischemic and anti-arteriosclerotic effects of EPA.

Brain iron deposition in white matter hyperintensities: a 3-T MRI study

Iron accumulation has been implicated in the pathogenesis of demyelinating diseases. Therefore, we hypothesized that abnormal high cerebral iron deposition may be involved in the development of white matter hyperintensities (WMHs). We used R2* relaxometry to assess whether iron levels in different brain regions correlate with the severity of WMHs. This technique has been recently validated in a postmortem study to demonstrate in vivo brain iron accumulation in a quantitative manner. Fifty-two consecutive WMH patients and 30 healthy controls with 3-T magnetic resonance imaging (MRI) were reviewed in this study. We measured WMH volume (as a marker of the severity of WMHs) on MRI, and the transverse relaxation rate R2*, as an estimate of iron content in seven brain regions. We found that R2* in globus pallidus was associated with WMH volume after adjusting for sociodemographic variables (partial correlation coefficient = 0.521, P < 0.001) and in a multivariate analysis adjusted for common vascular risk factors (partial correlation coefficient = 0.572, P = 0.033). Regional R2* in globus pallidus was also significantly higher in WMHs than in controls (P = 0.042). Iron content in globus pallidus, as assessed by R2* relaxometry, is independently linked to the severity of WMHs in our cohort of patients, suggesting that iron deposition in the brain may play a role in the pathogenesis of WMHs. This may provide prognostic information on patients with WMHs and may have implications for therapeutic interventions in WMHs.

Chronic Kidney Disease Is Associated With White Matter Hyperintensity Volume

White matter hyperintensities have been associated with increased risk of stroke, cognitive decline, and dementia. Chronic kidney disease is a risk factor for vascular disease and has been associated with inflammation and endothelial dysfunction, which have been implicated in the pathogenesis of white matter hyperintensities. Few studies have explored the relationship between chronic kidney disease and white matter hyperintensities. The Northern Manhattan Study is a prospective, community-based cohort of which a subset of stroke-free participants underwent MRIs. MRIs were analyzed quantitatively for white matter hyperintensities volume, which was log-transformed to yield a normal distribution (log-white matter hyperintensity volume). Kidney function was modeled using serum creatinine, the Cockcroft-Gault formula for creatinine clearance, and the Modification of Diet in Renal Disease formula for estimated glomerular filtration rate. Creatinine clearance and estimated glomerular filtration rate were trichotomized to 15 to 60 mL/min, 60 to 90 mL/min, and >90 mL/min (reference). Linear regression was used to measure the association between kidney function and log-white matter hyperintensity volume adjusting for age, gender, race-ethnicity, education, cardiac disease, diabetes, homocysteine, and hypertension. Baseline data were available on 615 subjects (mean age 70 years, 60% women, 18% whites, 21% blacks, 62% Hispanics). In multivariate analysis, creatinine clearance 15 to 60 mL/min was associated with increased log-white matter hyperintensity volume (beta 0.322; 95% CI, 0.095 to 0.550) as was estimated glomerular filtration rate 15 to 60 mL/min (beta 0.322; 95% CI, 0.080 to 0.564). Serum creatinine, per 1-mg/dL increase, was also positively associated with log-white matter hyperintensity volume (beta 1.479; 95% CI, 1.067 to 2.050). The association between moderate-severe chronic kidney disease and white matter hyperintensity volume highlights the growing importance of kidney disease as a possible determinant of cerebrovascular disease and/or as a marker of microangiopathy.