White Matter Hyperintensities Penumbra Research Articles

Imaging of Angiogenesis in White Matter Hyperintensities.

Background White matter hyperintensities (WMHs) are areas of increased signal intensity on T2-weighted magnetic resonance imaging (MRI). WMH penumbra may be a potential target for early intervention in WMHs. We explored the relationship between angiogenesis and WMH penumbra in patients with WMHs. Methods and Results Twenty-one patients with confluent WMHs of Fazekas grade ≥2 were included. All the participants underwent 68Ga-NOTA-PRGD2 positron emission tomography/magnetic resonance imaging. WMH penumbra was analyzed with masks created for the WMH and 7 normal-appearing white matter layers; each layer was dilated away from the WMH by 2 mm. Angiogenesis array and ELISA were used to detect the serum levels of angiogenic factors, inflammatory factors, HIF-1 alpha, and S100B. Fourteen patients with increased 68Ga-NOTA-PRGD2 maximum standardized uptake (>0.17) were classified into group 2. Seven patients with maximum standardized uptake ≤0.17 were classified as group 1. WMH volume and serum levels of integrin αvβ3, vascular endothelial growth factor receptor 22, and interleukin-1β tended to be higher in group 2 than in group 1. In group 2, 68Ga-NOTA-PRGD2 uptake was significantly increased at the border between the WMH and normal-appearing white matter than in WMHs (P=0.004). The structure penumbra, defined by fractional anisotropy, was wider in group 2 (8 mm) than in group 1 (2 mm). The cerebral blood flow penumbra was 12 mm in both groups. Angiogenesis showed a correlation with reduced cerebral blood flow and microstructure integrity. Conclusions Our study provides evidence that angiogenesis occurs in the WMH penumbra. Further studies are warranted to verify the effect of angiogenesis on WMH growth.

Diffusion tensor free water MRI predicts progression of FLAIR white matter hyperintensities after ischemic stroke.

The progression of FLAIR white matter hyperintensities (WMHs) on MRI heralds vascular-mediated cognitive decline. Even before FLAIR WMH progression, adjacent normal appearing white matter (NAWM) already demonstrates microstructural deterioration on diffusion tensor imaging (DTI). We hypothesized that elevated DTI free water (FW) would precede FLAIR WMH progression, implicating interstitial fluid accumulation as a key pathological step in the progression of cerebral small vessel disease. Participants at least 3 months after an ischemic stroke or TIA with WMH on MRI underwent serial brain MRIs every 3 months over the subsequent year. For each participant, the WMHs were automatically segmented, serial MRIs were aligned, and a region of WMH penumbra tissue at risk was defined by dilating lesions at any time point and subtracting baseline lesions. Penumbra voxels were classified as either stable or progressing to WMH if they were segmented as new lesions and demonstrated increasing FLAIR intensity over time. Aligned DTI images included FW and FW-corrected fractional anisotropy (FATissue) and mean diffusivity (MDTissue). Logistic regression and area under the receiver-operator characteristic curve (AUC) were used to test whether baseline DTI predicted voxel-wise classification of stable penumbra or progression to WMH while covarying for clinical risk factors. In the included participants (n = 26, mean age 71 ± 9 years, 31% female), we detected a median annual voxel-wise WMH growth of 2.9 ± 2.6 ml. Each baseline DTI metric was associated with lesion progression in the penumbra, but FW had the greatest AUC of 0.732 (0.730 - 0.733) for predicting voxel-wise WMH progression pooled across participants. Baseline increased interstitial fluid, estimated as FW on DTI, predicted the progression of NAWM to WMH over the following year. These results implicate the presence of FW in the pathogenesis of cerebral small vessel disease progression.

Characterizing the penumbras of white matter hyperintensities in patients with cerebral small vessel disease

PurposeThe white matter hyperintensity penumbra (WMH-P) is the subtly changed normal-appearing white matter (NAWM) that surrounds white matter hyperintensities (WMHs). The goal of this study was to define WMH-P in cerebral small vessel disease (CSVD) by arterial spin labeling (ASL) and diffusion tensor imaging (DTI)/diffusion kurtosis imaging (DKI).Materials and methodsWe prospectively analyzed 42 patients with CSVD. To determine the range of cerebral blood flow (CBF) and DTI/DKI penumbras around white matter hyperintensities, we generated NAWM layer masks from periventricular WMHs (PVWMHs) and deep WMHs (DWMHs). Mean values of CBF, fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity, mean kurtosis, axial kurtosis, and radial kurtosis within the WMHs and their corresponding NAWM layer masks were analyzed. Paired sample t tests were used for analysis, and differences were considered statistically significant if the associated p value was ≤ 0.05.ResultsFor DWMHs, the CBF penumbras were 13 mm, and the DTI/DKI penumbras were 8 mm. For PVWMHs, the CBF penumbras were 14 mm, and the DTI/DKI penumbras were 14 mm.ConclusionsOur findings revealed that DTI/DKI and ASL can show structural and blood flow changes in brain tissue surrounding WMHs. In DWMHs, the blood flow penumbra was larger than the structural penumbra, while in PVWMHs, the blood flow penumbra was almost the same as the structural penumbra.

Pathological features of the 7T post-mortem MRI white matter hyperintensity penumbra.

T2-weighted white matter hyperintensities (WMH) are ubiquitous with age, and associated mild cognitive impairment and dementia. Recent studies have demonstrated altered microstructural integrity and perfusion within the normal appearing white matter (NAWM) surrounding WMHs, the "WMH penumbra", indicating more widespread WM tissue damage than is commonly observed on routine MRI. While common pathological features associated with in vivo WMH burden have been described, histochemical (HC) features obtained by directly targeting the WMH core and surrounding NAWM remain largely uncharacterized. Post mortem (PM) 7T MRI was obtained on 6 brain hemispheres from Oregon Alzheimer's Disease Research Center subjects (Table 1). Fifty-three WMH and NAWM penumbra regions of interest (ROI) were identified from 11 brain regions and targeted for HC analysis (Table 2). Tissue samples were stained with hematoxylin & eosin-luxol fast blue (HELFB), aquaporin-1 (AQP1), and vimentin and scanned for quantitative ROI analysis. WMHs were segmented on T2-weighted images, and WMH masks were dilated by 1mm increments to define a 5 mm NAWM penumbra and coregistered to IHC images (Figure 1). Digitalized IHC mages were assessed quantitatively using mean pixel saturation (AQP1,Vimentin) or thresholded area coverage (HELFB). Mixed effects models were used to examine mean differences in IHC staining between WMH and the NAWM penumbra and change in HC staining within the NAWM with distance from WMHs. Analyses were adjusted for global WMH burden, and individual slide effects to account for potential differences in staining. WMHs demonstrated increased vimentin, and decreased AQP1 and HELFB staining, compared with the NAWM penumbra. Within the NAWM penumbra, there was an increase in vimentin and a decrease in AQP1 and myelin content with closer proximity to WMHs (Figure 2). The MRI-identified NAWM region surrounding WMHs show a gradient of demyelination and astrocytopathy with distance from WMHs. Findings confirm the presence of the WMH penumbra consisting of damaged tissue that is likely vulnerable to further injury over time that could be a target for intervention in life. Results suggest that MRI visible WMHs are a state marker of more widespread tissue degeneration that may contribute to cognitive decline in older individuals.

Comparing the Performance of Two Radiomic Models to Predict Progression and Progression Speed of White Matter Hyperintensities.

Purpose: The aim of this study was to compare two radiomic models in predicting the progression of white matter hyperintensity (WMH) and the speed of progression from conventional magnetic resonance images.Methods: In this study, 232 people were retrospectively analyzed at Medical Center A (training and testing groups) and Medical Center B (external validation group). A visual rating scale was used to divide all patients into WMH progression and non-progression groups. Two regions of interest (ROIs)—ROI whole-brain white matter (WBWM) and ROI WMH penumbra (WMHp)—were segmented from the baseline image. For predicting WMH progression, logistic regression was applied to create radiomic models in the two ROIs. Then, age, sex, clinical course, vascular risk factors, and imaging factors were incorporated into a stepwise regression analysis to construct the combined diagnosis model. Finally, the presence of a correlation between radiomic findings and the speed of progression was analyzed.Results: The area under the curve (AUC) was higher for the WMHp-based radiomic model than the WBWM-based radiomic model in training, testing, and validation groups (0.791, 0.768, and 0.767 vs. 0.725, 0.693, and 0.691, respectively). The WBWM-based combined model was established by combining age, hypertension, and rad-score of the ROI WBWM. Also, the WMHp-based combined model is built by combining the age and rad-score of the ROI WMHp. Compared with the WBWM-based model (AUC = 0.779, 0.716, 0.673 in training, testing, and validation groups, respectively), the WMHp-based combined model has higher diagnostic efficiency and better generalization ability (AUC = 0.793, 0.774, 0.777 in training, testing, and validation groups, respectively). The speed of WMH progression was related to the rad-score from ROI WMHp (r = 0.49) but not from ROI WBWM.Conclusion: The heterogeneity of the penumbra could help identify the individuals at high risk of WMH progression and the rad-score of it was correlated with the speed of progression.

Loss of Integrity of Corpus Callosum White Matter Hyperintensity Penumbra Predicts Cognitive Decline in Patients With Subcortical Vascular Mild Cognitive Impairment.

Loss of white matter (WM) integrity contributes to subcortical vascular mild cognitive impairment (svMCI). Diffusion tensor imaging (DTI) has revealed damage beyond the area of WM hyperintensity (WMH) including in normal-appearing WM (NAWM); however, the functional significance of this observation is unclear. To answer this question, in this study we investigated the relationship between microstructural changes in the WMH penumbra (WMH-P) and cognitive function in patients with svMCI by regional tract-based analysis. A total of 111 patients with svMCI and 72 patients with subcortical ischemic vascular disease (SIVD) without cognitive impairment (controls) underwent DTI and neuropsychological assessment. WMH burden was determined before computing mean values of fractional anisotropy (FA) and mean diffusivity (MD) within WMHs and WMH-Ps. Pearson’s partial correlations were used to assess the relationship between measurements showing significant intergroup differences and composite Z-scores representing global cognitive function. Multiple linear regression analysis was carried out to determine the best model for predicting composite Z-scores. We found that WMH burden in the genu, body, and splenium of the corpus callosum (GCC, BCC, and SCC respectively); bilateral anterior, superior, and posterior corona radiata; left sagittal stratum was significantly higher in the svMCI group than in the control group (p < 0.05). The WMH burden of the GCC, BCC, SCC, and bilateral anterior corona radiata was negatively correlated with composite Z-scores. Among diffusion parameters showing significant differences across the 10 WM regions, mean FA values of WMH and WMH-P of the BCC were correlated with composite Z-scores in svMCI patients. The results of the multiple linear regression analysis showed that the FA of WMH-P of the BCC and WMH burden of the SCC and GCC were independent predictors of composite Z-score, with the FA of WMH-P of the BCC making the largest contribution. These findings indicate that disruption of the CC microstructure—especially the WMH-P of the BCC—may contribute to the cognitive deficits associated with SIVD.

White matter hyperintensities induce distal deficits in the connected fibers.

White matter hyperintensities (WMH) are common in elderly individuals and cause brain network deficits. However, it is still unclear how the global brain network is affected by the focal WMH. We aimed to investigate the diffusion of WMH‐related deficits along the connecting white matters (WM). Brain magnetic resonance imaging data and neuropsychological evaluations of 174 participants (aged 74 ± 5 years) were collected and analyzed. For each participant, WMH lesions were segmented using a deep learning method, and 18 major WM tracts were reconstructed using automated quantitative tractography. The diffusion characteristics of distal WM tracts (with the WMH penumbra excluded) were calculated. Multivariable linear regression analysis was performed. We found that a high burden of tract‐specific WMH was related to worse diffusion characteristics of distal WM tracts in a wide range of WM tracts, including the forceps major (FMA), forceps minor (FMI), anterior thalamic radiation (ATR), cingulum cingulate gyrus (CCG), corticospinal tract (CST), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus‐parietal (SLFP), superior longitudinal fasciculus‐temporal (SLFT), and uncinate fasciculus (UNC). Furthermore, a higher mean diffusivity (MD) of distal tracts was linked to worse attention and executive function in the FMI, right CCG, left ILF, SLFP, SLFT, and UNC. The effect of WMH on the microstructural integrity of WM tracts may propagate along tracts to distal regions beyond the penumbra and might eventually affect attention and executive function.

Comparison Between Blood-Brain Barrier Water Exchange Rate and Permeability to Gadolinium-Based Contrast Agent in an Elderly Cohort.

Background: Dynamic contrast-enhanced (DCE) MRI using intravenous injection of gadolinium-based contrast agents (GBCAs) is commonly used for imaging blood-brain barrier (BBB) permeability. Water is an alternative endogenous tracer with limited exchange rate across the BBB. A direct comparison between BBB water exchange rate and BBB permeability to GBCA is missing. The purpose of this study was to directly compare BBB permeability to GBCA (Ktrans and kGad = Ktrans/Vp) and water exchange rate (kw) in a cohort of elderly subjects at risk of cerebral small vessel disease (cSVD).Methods: Ktrans/kGad and kw were measured by DCE-MRI and diffusion prepared pseudo-continuous arterial spin labeling (DP-pCASL), respectively, at 3 Tesla in 16 elderly subjects (3 male, age = 67.9 ± 3.0 yrs) at risk of cSVD. The test-retest reproducibility of kw measurements was evaluated with repeated scans ~6 weeks apart. Mixed effects linear regression was performed in the whole brain, gray matter (GM), white matter (WM), and 6 subcortical brain regions to investigate associations between Ktrans/kGad and test-retest kw. In addition, kw and Ktrans/kGad were compared in normal appearing white matter (NAWM), white matter hyperintensity (WMH) lesions and penumbra.Results: Significant correlation was found between kw and Ktrans only in WM (β = 6.7 × 104, P = 0.036), caudate (β = 8.6 × 104, P = 0.029), and middle cerebral artery (MCA) perforator territory (β = 6.9 × 104, P = 0.009), but not in the whole brain, GM or rest 5 brain regions. Significant correlation was found between kw and kGad in MCA perforator territory (β = 1.5 × 103, P = 0.049), medial-temporal lobe (β = 3.5 × 103, P = 0.032), and hippocampus (β = 3.4 × 103, P = 0.038), but not in the rest brain regions. Good reproducibility of kw measurements (ICC=0.75) was achieved. Ktrans was significantly lower inside WMH than WMH penumbra (16.2%, P = 0.026), and kGad was significantly lower in NAWM than in the WMH penumbra (20.8%, P < 0.001).Conclusion: kw provides a measure of water exchange rate across the BBB with good test-retest reproducibility. The BBB mechanism underlying kw and Ktrans/kGad is likely to be different, as manifested by correlations in only three brain regions for each pair of comparison between kw and Ktrans or kGad.

Characterizing the Penumbras of White Matter Hyperintensities and Their Associations With Cognitive Function in Patients With Subcortical Vascular Mild Cognitive Impairment.

Normal-appearing white matter (NAWM) surrounding white matter hyperintensities (WMHs), frequently known as the WMH penumbra, is associated with subtle white matter injury and has a high risk for future conversion to WMHs. The goal of this study was to define WMH penumbras and to further explore whether the diffusion and perfusion parameters of these penumbras could better reflect cognitive function alterations than WMHs in subjects with subcortical vascular mild cognitive impairment (svMCI). Seventy-three svMCI subjects underwent neuropsychological assessments and 3T MRI scans, including diffusion tensor imaging (DTI) and arterial spin labeling (ASL). To determine the extent of cerebral blood flow (CBF) and DTI penumbras. A NAWM layer mask was generated for periventricular WMHs (PVWMHs) and deep WMHs (DWMHs) separately. Mean values of CBF, fractional anisotropy (FA), mean diffusivity (MD) within the WMHs and their corresponding NAWM layer masks were computed and compared using paired t-tests. Pearson's partial correlations were used to assess the relations of the mean CBF, FA, and MD values within the corresponding penumbras with composite z-scores of global cognition and four cognitive domains controlling for age, sex, and education. For both PVWMHs and DWMHs, the CBF penumbras were wider than the DTI penumbras. Only the mean FA value of the PVWMH-FA penumbra was correlated with the composite z-scores of global cognition before correction (r = 0.268, p = 0.024), but that correlation did not survive after correcting the p-value for multiple comparisons. Our findings showed extensive white matter perfusion disturbances including white matter tissue, both with and without microstructural alterations. The imaging parameters investigated, however, did not correlate to cognition.

Baseline NAWM structural integrity and CBF predict periventricular WMH expansion over time.

We aimed to describe and compare baseline cerebral blood flow (CBF) and microstructural characteristics of normal-appearing white matter (NAWM) within the vulnerable periventricular white matter hyperintensity (PVWMH) penumbra region in predicting white matter hyperintensity (WMH) growth over time. Fifty-two patients, aged 82.8 years, underwent serial brain MRI, including pulsed arterial spin labeling and diffusion tensor imaging (DTI). New WMH and persistent NAWM voxels in relation to WMH penumbra at follow-up were identified. Mean baseline CBF and DTI variables of the new WMH and persistent NAWM voxels were computed. Univariate analyses with paired t tests were performed. Generalized estimating equation analyses were used to compare the relationships of baseline CBF, and structural penumbras with WMH growth, controlling for confounders. Low baseline CBF and fractional anisotropy, and high mean diffusivity (MD), were independently associated with new PVWMH voxels, with MD being the best predictor of WMH growth. A separate model demonstrated that radial diffusivity had the strongest relationship with WMH growth compared with CBF and axial diffusivity. CBF and DTI measures independently predict WMH growth over time. DTI is a more sensitive predictor of WMH growth than CBF, with WMH progression likely due to demyelinating injury secondary to low perfusion. Findings support the use of MD as a sensitive marker of NAWM vulnerability in future trials aimed at preserving WM integrity.

White Matter Microstructural Damage on Diffusion Tensor Imaging in Cerebral Small Vessel Disease

Cerebral small vessel disease (SVD) is a major health problem for its contribution to ≈45% of dementias, and about a fifth of all strokes worldwide, representing one of the most important causes of disabilities.1 The term SVD refers to a group of pathological processes with various etiologies that affect the small arteries, arterioles, venules, and capillaries of the brain. The most common forms are age- and hypertension-related SVD and cerebral amyloid angiopathy (CAA).2 Vessel wall changes may lead to both ischemic and hemorrhagic consequences: (1) a state of chronic hypoperfusion or vascular dysfunction responsible for incomplete infarction,3,4 (2) acute focal necrosis (lacunar infarct), or (3) vessel rupture manifesting as hemorrhagic SVD. The clinical consequences of SVD are various and mainly consist of cognitive, mood, and motor dysfunctions leading to functional disability in the late stages of the disease. Magnetic resonance imaging (MRI) has become crucial in the diagnosis of SVD enabling the evaluation of the disease progression both in the clinical and research settings. However, correlations between clinical features of SVD and conventional MRI measures have been partially discordant. Some authors suggested that the cumulative effect of SVD lesions, rather than the individual lesions themselves determines the clinical impact,5 whereas others suggested that the presence and severity of alterations nonvisible on conventional MRI might also be an explanation.6 In the past decade, diffusion tensor imaging (DTI) has been increasingly used for the evaluation of SVD patients because it is sensitive to tissue damage and can show abnormalities in both areas of white matter hyperintensities (WMH) and in normal appearing WM (NAWM). Despite the high sensitivity in detecting cerebral damage, DTI has a low specificity in detecting the underlying cause. In fact, we can only infer that DTI changes reflect a loss of WM …

Relationship Between White Matter Hyperintensities Penumbra and Cavity Formation.

BackgroundPenumbra has been detected on the edge of white matter hyperintensities (WMH). The aim of our study was to investigate whether cavity formation is different between acute infarcts on the edge of WMH and those away from the edge.Material/MethodsNinety-six subjects with acute lacunar infarct ≤25 mm in diameter were recruited. Subjects with infarct contacting or overlapping with WMH (on axial T2 or coronal FLAIR) were defined as the Edge Group (on the edge of the WMH). Those outside the edge of the WMH were the Non-edge Group. Vascular risk factors, clinical data, baseline infarct size, infarct sites, and severity of WMH (by Fazekas scale) were recorded. Cavity formation was identified by MR follow-up imaging. Risk factors for cavity formation were also investigated.ResultsThere were 37 (38.5%) subjects in the Edge Group and 59 (61.5%) in the Non-edge Group; 55 (57.3%) subjects had cavity formation in follow-up imaging. Subjects in the Edge Group had higher risk of developing cavities than those in the Non-edge Group (78.4% vs. 44.1%, p<0.05). In univariate analysis, subjects with cavity formation had larger infarct size and their infarcts were more often located in subcortical white matter. Vascular risk factors, clinical data, and WMH did not differ between subjects with cavity formation and those without. In logistic regression analysis, DWI infarct size and being in the Edge Group were independent risk factors for cavity formation.ConclusionsLacunar infarcts on the edge of WMH are more likely to develop cavities, suggesting that WMH penumbra affects cavity formation.

Characterizing the white matter hyperintensity penumbra with cerebral blood flow measures.

ObjectiveWhite matter hyperintensities (WMHs) are common with age, grow over time, and are associated with cognitive and motor impairments. Mechanisms underlying WMH growth are unclear. We aimed to determine the presence and extent of decreased normal appearing white matter (NAWM) cerebral blood flow (CBF) surrounding WMHs to identify ‘WM at risk’, or the WMH CBF penumbra. We aimed to further validate cross-sectional finding by determining whether the baseline WMH penumbra CBF predicts the development of new WMHs at follow-up.MethodsSixty-one cognitively intact elderly subjects received 3 T MPRAGE, FLAIR, and pulsed arterial spin labeling (PASL). Twenty-four subjects returned for follow-up MRI. The inter-scan interval was 18 months. A NAWM layer mask, comprised of fifteen layers, 1 mm thick each surrounding WMHs, was generated for periventricular (PVWMH) and deep (DWMH) WMHs. Mean CBF for each layer was computed. New WMH and persistent NAWM voxels for each penumbra layer were defined from follow-up MRI.ResultsCBF in the area surrounding WMHs was significantly lower than the total brain NAWM, extending approximately 12 mm from both the established PVWMH and DWMH. Voxels with new WMH at follow-up had significantly lower baseline CBF than voxels that maintained NAWM, suggesting that baseline CBF can predict the development of new WMHs over time.ConclusionsA CBF penumbra exists surrounding WMHs, which is associated with future WMH expansion. ASL MRI can be used to monitor interventions to increase white matter blood flow for the prevention of further WM damage and its cognitive and motor consequences.

The Power of Hybrid/Fusion Imaging Metrics in Future PACS Systems: A Case Study into the White Matter Hyperintensity Prenumbra using FLAIR and Diffusion MR.

Most white matter related neurological disease exhibit a large number of White Matter Hyperintensities (WMHs) on FLAIR MRI images. However, these lesions are not well understood. At the same time, Diffusion MRI has been gaining popularity as a powerful method of characterizing White Matter (WM) integrity. This work aims to study the behavior of the diffusion signal within the WMH voxels. The goal is to develop hybrid MR metrics that leverage information from multiple MR acquisitions to solve clinical problems. In our case, we are trying to address the WMH penumbra (as defined by Maillard et al 20112) where WMH delineates a foci that is more widespread than than the actual damage area presumably due to acute inflammation. Our results show that diffusion MR metrics may be able to better delineate tissue that is inflamed versus scar tissue but may be less specific to lesions than FLAIR. Therefore, a hybrid metric that encodes information from both FLAIR and Diffusion MR may yield new and novel imaging information about the progression of white matter disease progression. We hope that this work also demonstrates how future PACS systems could have image fusion capabilities that would be able to leverage information from multiple imaging series to yield new and novel imaging contrast.

White matter hyperintensity penumbra is differentially vulnerable to further degeneration in the elderly

White matter hyperintensity penumbra is differentially vulnerable to further degeneration in the elderly