Oxygen Metabolic Stress and White Matter Injury in Patients With Cerebral Small Vessel Disease

Background and Purpose: Chronic hypoxia-ischemia is a putative mechanism underlying the development of white matter hyperintensities (WMH) and microstructural disruption in cerebral small vessel disease. WMH fall primarily within deep white matter (WM) watershed regions. We hypothesized that elevated oxygen extraction fraction (OEF), a signature of hypoxia-ischemia, would be detected in the watershed where WMH density is highest. We further hypothesized that OEF would be elevated in regions immediately surrounding WMH, at the leading edge of growth. Methods: In this cross-sectional study conducted from 2016 to 2019 at an academic medical center in St Louis, MO, participants (age >50) with a range of cerebrovascular risk factors underwent brain magnetic resonance imaging using pseudocontinuous arterial spin labeling, asymmetric spin echo, fluid-attenuated inversion recovery and diffusion tensor imaging to measure cerebral blood flow (CBF), OEF, WMH, and WM integrity, respectively. We defined the physiologic watershed as a region where CBF was below the 10th percentile of mean WM CBF in a young healthy cohort. We conducted linear regression to evaluate the relationship between CBF and OEF with structural and microstructural WM injury defined by fluid-attenuated inversion recovery WMH and diffusion tensor imaging, respectively. We conducted ANOVA to determine if OEF was increased in proximity to WMH lesions. Results: In a cohort of 42 participants (age 50–80), the physiologic watershed region spatially overlapped with regions of highest WMH lesion density. As CBF decreased and OEF increased, WMH density increased. Elevated watershed OEF was associated with greater WMH burden and microstructural disruption, after adjusting for vascular risk factors. In contrast, WM and watershed CBF were not associated with WMH burden or microstructural disruption. Moreover, OEF progressively increased while CBF decreased, in concentric contours approaching WMH lesions. Conclusions: Chronic hypoxia-ischemia in the watershed region may contribute to cerebral small vessel disease pathogenesis and development of WMH. Watershed OEF may hold promise as an imaging biomarker to identify individuals at risk for cerebral small vessel disease progression.

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Microstructural Predictors of Cognitive Impairment in Cerebral Small Vessel Disease and the Conditions of Their Formation

Diagnostics ◽

10.3390/diagnostics10090720 ◽

2020 ◽

Vol 10 (9) ◽

pp. 720

Author(s):

Larisa A. Dobrynina ◽

Zukhra Sh. Gadzhieva ◽

Kamila V. Shamtieva ◽

Elena I. Kremneva ◽

Bulat M. Akhmetzyanov ◽

...

Keyword(s):

Blood Flow ◽

Cognitive Impairment ◽

White Matter ◽

Diffusion Tensor ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Venous Blood Flow ◽

Csf Flow ◽

Vessel Disease

Introduction: Cerebral small vessel disease (CSVD) is the leading cause of vascular and mixed degenerative cognitive impairment (CI). The variability in the rate of progression of CSVD justifies the search for sensitive predictors of CI. Materials: A total of 74 patients (48 women, average age 60.6 ± 6.9 years) with CSVD and CI of varying severity were examined using 3T MRI. The results of diffusion tensor imaging with a region of interest (ROI) analysis were used to construct a predictive model of CI using binary logistic regression, while phase-contrast magnetic resonance imaging and voxel-based morphometry were used to clarify the conditions for the formation of CI predictors. Results: According to the constructed model, the predictors of CI are axial diffusivity (AD) of the posterior frontal periventricular normal-appearing white matter (pvNAWM), right middle cingulum bundle (CB), and mid-posterior corpus callosum (CC). These predictors showed a significant correlation with the volume of white matter hyperintensity; arterial and venous blood flow, pulsatility index, and aqueduct cerebrospinal fluid (CSF) flow; and surface area of the aqueduct, volume of the lateral ventricles and CSF, and gray matter volume. Conclusion: Disturbances in the AD of pvNAWM, CB, and CC, associated with axonal damage, are a predominant factor in the development of CI in CSVD. The relationship between AD predictors and both blood flow and CSF flow indicates a disturbance in their relationship, while their location near the floor of the lateral ventricle and their link with indicators of internal atrophy, CSF volume, and aqueduct CSF flow suggest the importance of transependymal CSF transudation when these regions are damaged.

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

Stroke ◽

10.1161/strokeaha.115.012065 ◽

2016 ◽

Vol 47 (6) ◽

pp. 1679-1684 ◽

Cited By ~ 23

Author(s):

Marco Pasi ◽

Inge W.M. van Uden ◽

Anil M. Tuladhar ◽

Frank-Erik de Leeuw ◽

Leonardo Pantoni

Keyword(s):

Diffusion Tensor Imaging ◽

White Matter ◽

Diffusion Tensor ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Vessel Disease ◽

Microstructural Damage

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Using DTI to assess white matter microstructure in cerebral small vessel disease (SVD) in multicentre studies

Clinical Science ◽

10.1042/cs20170146 ◽

2017 ◽

Vol 131 (12) ◽

pp. 1361-1373 ◽

Cited By ~ 32

Author(s):

Iain D. Croall ◽

Valerie Lohner ◽

Barry Moynihan ◽

Usman Khan ◽

Ahamad Hassan ◽

...

Keyword(s):

White Matter ◽

Diffusion Tensor ◽

Small Vessel Disease ◽

Mean Diffusivity ◽

Peak Height ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Single Centre ◽

Vessel Disease ◽

Multicentre Studies

Diffusion tensor imaging (DTI) metrics such as fractional anisotropy (FA) and mean diffusivity (MD) have been proposed as clinical trial markers of cerebral small vessel disease (SVD) due to their associations with outcomes such as cognition. However, studies investigating this have been predominantly single-centre. As clinical trials are likely to be multisite, further studies are required to determine whether associations with cognition of similar strengths can be detected in a multicentre setting. One hundred and nine patients (mean age =68 years) with symptomatic lacunar infarction and confluent white matter hyperintensities (WMH) on MRI was recruited across six sites as part of the PRESERVE DTI substudy. After handling missing data, 3T-MRI scanning was available from five sites on five scanner models (Siemens and Philips), alongside neuropsychological and quality of life (QoL) assessments. FA median and MD peak height were extracted from DTI histogram analysis. Multiple linear regressions were performed, including normalized brain volume, WMH lesion load, and n° lacunes as covariates, to investigate the association of FA and MD with cognition and QoL. DTI metrics from all white matter were significantly associated with global cognition (standardized β =0.268), mental flexibility (β =0.306), verbal fluency (β =0.376), and Montreal Cognitive Assessment (MoCA) (β =0.273). The magnitudes of these associations were comparable with those previously reported from single-centre studies found in a systematic literature review. In this multicentre study, we confirmed associations between DTI parameters and cognition, which were similar in strength to those found in previous single-centre studies. The present study supports the use of DTI metrics as biomarkers of disease progression in multicentre studies.

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Diffusion tensor tractography in cerebral small vessel disease: correlation with cognitive function

The Neuroradiology Journal ◽

10.1177/1971400916682753 ◽

2017 ◽

Vol 31 (1) ◽

pp. 83-89 ◽

Cited By ~ 7

Author(s):

Maria M D’Souza ◽

SP Gorthi ◽

Kunal Vadwala ◽

Richa Trivedi ◽

C Vijayakumar ◽

...

Keyword(s):

Cognitive Function ◽

White Matter ◽

Diffusion Tensor ◽

Small Vessel Disease ◽

Surrogate Marker ◽

Mean Diffusivity ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

White Matter Damage ◽

Vessel Disease

Background Patients with cerebral small vessel disease may suffer from varying levels of cognitive deficit and may progress on to vascular dementia. The extent of involvement, as seen on conventional magnetic resonance (MR) measures, correlates poorly with the level of cognitive decline. The purpose of this study was to investigate the utility of diffusion tensor imaging (DTI) as a marker for white matter damage in small vessel disease and to assess its correlation with cognitive function. Methods Thirty consecutive patients with cerebral small vessel disease underwent conventional MR imaging, DTI, and neuropsychological assessment. Results On tractographic analysis, fractional anisotropy was significantly reduced while mean diffusivity significantly increased in several white matter tracts. The alteration in DTI indices correlated well with cognitive function. No significant correlation was identified between T2 lesion load and cognitive performance. Conclusions Tractographic analysis of white matter integrity is a useful measure of disease severity and correlates well with cognitive function. It may have a significant potential in monitoring disease progression and may serve as a surrogate marker for treatment trials.

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Progression of MRI markers in cerebral small vessel disease: Sample size considerations for clinical trials

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.113 ◽

2015 ◽

Vol 36 (1) ◽

pp. 228-240 ◽

Cited By ~ 44

Author(s):

Philip Benjamin ◽

Eva Zeestraten ◽

Christian Lambert ◽

Irina Chis Ster ◽

Owen A Williams ◽

...

Keyword(s):

White Matter ◽

Sample Size ◽

Diffusion Tensor ◽

Small Vessel Disease ◽

Cognitive Change ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

White Matter Hyperintensity ◽

Vessel Disease ◽

Size Estimates

Detecting treatment efficacy using cognitive change in trials of cerebral small vessel disease (SVD) has been challenging, making the use of surrogate markers such as magnetic resonance imaging (MRI) attractive. We determined the sensitivity of MRI to change in SVD and used this information to calculate sample size estimates for a clinical trial. Data from the prospective SCANS (St George’s Cognition and Neuroimaging in Stroke) study of patients with symptomatic lacunar stroke and confluent leukoaraiosis was used ( n = 121). Ninety-nine subjects returned at one or more time points. Multimodal MRI and neuropsychologic testing was performed annually over 3 years. We evaluated the change in brain volume, T2 white matter hyperintensity (WMH) volume, lacunes, and white matter damage on diffusion tensor imaging (DTI). Over 3 years, change was detectable in all MRI markers but not in cognitive measures. WMH volume and DTI parameters were most sensitive to change and therefore had the smallest sample size estimates. MRI markers, particularly WMH volume and DTI parameters, are more sensitive to SVD progression over short time periods than cognition. These markers could significantly reduce the size of trials to screen treatments for efficacy in SVD, although further validation from longitudinal and intervention studies is required.

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T2 relaxation time of the normal-appearing white matter is related to the cognitive status in cerebral small vessel disease

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20972511 ◽

2020 ◽

pp. 0271678X2097251

Author(s):

Annemarie Brandhofe ◽

Christoph Stratmann ◽

Jan-Rüdiger Schüre ◽

Ulrich Pilatus ◽

Elke Hattingen ◽

...

Keyword(s):

Cognitive Impairment ◽

White Matter ◽

Diffusion Tensor ◽

Small Vessel Disease ◽

Cognitive Status ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Imaging Biomarker ◽

Vessel Disease ◽

Normal Appearing White Matter

Previous diffusion tensor imaging (DTI) studies indicate that impaired microstructural integrity of the normal-appearing white matter (NAWM) is related to cognitive impairment in cerebral small vessel disease (SVD). This study aimed to investigate whether quantitative T2 relaxometry is a suitable imaging biomarker for the assessment of tissue changes related to cognitive abnormalities in patients with SVD. 39 patients and 18 age-matched healthy control subjects underwent 3 T magnetic resonance imaging (MRI) with T2-weighted multiple spin echo sequences for T2 relaxometry and DTI sequences, as well as comprehensive cognitive assessment. Averaged quantitative T2, fractional anisotropy (FA) and mean diffusivity (MD) were determined in the NAWM and related to cognitive parameters controlling for age, normalized brain volume, white matter hyperintensity volume and other conventional SVD markers. In SVD patients, quantitative T2 values were significantly increased compared to controls (p = 0.002) and significantly negatively correlated with the global cognitive performance (r= –0.410, p = 0.014) and executive function (r= –0.399, p = 0.016). DTI parameters did not correlate with cognitive function. T2 relaxometry of the NAWM seems to be sensitive to microstructural tissue damage associated with cognitive impairment in SVD and might be a promising imaging biomarker for evaluation of disease progression and possible effects of therapeutic interventions.

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Early Segmental White Matter Fascicle Microstructural Damage Predicts the Corresponding Cognitive Domain Impairment in Cerebral Small Vessel Disease Patients by Automated Fiber Quantification

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2020.598242 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lili Huang ◽

Xin Chen ◽

Wenshan Sun ◽

Haifeng Chen ◽

Qing Ye ◽

...

Keyword(s):

Cognitive Function ◽

White Matter ◽

Diffusion Tensor ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Cognitive Domain ◽

Small Vessel ◽

Posterior Portion ◽

Vessel Disease ◽

The Right

Objective: To characterize earlier damage pattern of white matter (WM) microstructure in cerebral small vessel disease (CSVD) and its relationship with cognitive domain dysfunction.Methods: A total of 144 CSVD patients and 100 healthy controls who underwent neuropsychological measurements and diffusion tensor imaging (DTI) examination were recruited. Cognitive function, emotion, and gait were assessed in each participant. The automated fiber quantification (AFQ) technique was used to extract different fiber properties between groups, and partial correlation and general linear regression analyses were performed to assess the relationship between position-specific WM microstructure and cognitive function.Results: Specific segments in the association fibers, commissural WM regions of interest (ROIs), and projection fibers were damaged in the CSVD group [P < 0.05, family-wise error (FWE) correction], and these damaged segments showed interhemispheric symmetry. In addition, the damage to specific tract profiles [including the posteromedial component of the right cingulum cingulate (CC), the occipital lobe portion of the callosum forceps major, the posterior portion of the left superior longitudinal fasciculus (SLF), and the bilateral anterior thalamic radiation (ATR)] was related to the dysfunction in specific cognitive domains. Among these tracts, we found the ATR to be the key set of tracts whose profiles were most associated with cognitive dysfunction. The left ATR was a specific fiber bundle associated with episode memory and language function, whereas the fractional anisotropy (FA) values of the intermediate component of the right ATR were negatively correlated with executive function and gait evaluation. It should be noted that the abovementioned relationships could not survive the Bonferroni correction (p < 0.05/27), so we chose more liberal uncorrected statistical thresholds.Conclusions: Damage to the WM fiber bundles showed extensive interhemispheric symmetry and was limited to particular segments in CSVD patients. Disruption of strategically located fibers was associated with different cognitive deficits, especially the bilateral ATR.

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Alterations of White Matter Integrity in Cerebral Small Vessel Disease and Their Correlation with Cognitive Performance: A Trace-Based Spatial Statistics Study

10.21203/rs.3.rs-134624/v1 ◽

2021 ◽

Author(s):

Yifan Wang ◽

Tianyao Wang ◽

Zekuan Yu ◽

Bo Huang ◽

Biao Liu ◽

...

Keyword(s):

White Matter ◽

Spatial Statistics ◽

Diffusion Tensor ◽

Small Vessel Disease ◽

Internal Capsule ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Posterior Limb ◽

Vessel Disease ◽

Mri Scans

Abstract Background: This study aimed to understand the injury of white matter (WM) microstructure behind white matter hyperintensities (WMH) and identify the regions where injury was more pronounced with increasing WMH severity. Moreover, we analyzed whether this microstructural injury is related to cognition. Methods: 110 patients with WMH were recruited in this research. All subjects underwent 3.0T MRI scans and neuropsychological cognitive assessments. Simple mental state examination (MMSE) along with Montreal Cognitive Assessment (MoCA) were applied to assess the patient's overall cognitive ability. WMH of each subject was graded according to Fazekas grade scale and was divided into two groups: (A) WMH score of 1-2 points (n=64), (b) WMH score of 3-6 points (n=46). Trace-based spatial statistics (TBSS) was applied for the analysis of diffusion tensor imaging (DTI) data. All statistical analyses were performed in SPSS 26.0 statistical software. Results: The results indicate that patients with higher WMH scores showed extensively symmetrical areas of increased mean diffusion, axial diffusion and radial diffusion involving bilateral anterior limb, posterior limb and retrolenticular part of internal capsule, posterior corona radiata, external capsule, superior longitudinal fasciculus, and superior fronto-occipital fasciculus (P < 0.01). Conclusions: Finally, we come to the conclusion that cognition-related WM fiber tracts tend to be more vulnerable to be injured in patients of cerebral small vessel disease (CSVD). Moreover, changes in WM microstructure often predate changes of cognition. Early detection of microstructural changes and timely intervention can delay cognitive decline to some extent.

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Thalamic Fractional Anisotropy Predicts Accrual of Cerebral White Matter Damage in Older Subjects with Small-Vessel Disease

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.86 ◽

2014 ◽

Vol 34 (8) ◽

pp. 1321-1327 ◽

Cited By ~ 11

Author(s):

Michele Cavallari ◽

Nicola Moscufo ◽

Dominik Meier ◽

Pawel Skudlarski ◽

Godfrey D Pearlson ◽

...

Keyword(s):

White Matter ◽

Fractional Anisotropy ◽

Diffusion Tensor ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Community Dwelling ◽

Small Vessel ◽

Cerebral White Matter ◽

Mobility Impairment ◽

Vessel Disease

White matter hyperintensities (WMHs) and lacunes are magnetic resonance imaging hallmarks of cerebral small-vessel disease, which increase the risk of stroke, cognitive, and mobility impairment. Although most studies of cerebral small-vessel disease have focused on white matter abnormalities, the gray matter (GM) is also affected, as evidenced by frequently observed lacunes in subcortical GM. Diffusion tensor imaging (DTI) is sensitive to subtle neurodegenerative changes in deep GM structures. We explored the relationship between baseline DTI characteristics of the thalamus, caudate, and putamen, and the volume and subsequent accrual of WMHs over a 4-year period in 56 community-dwelling older (≤75 years) individuals. Baseline thalamic fractional anisotropy (FA) was an independent predictor of WMH accrual. WMH accrual also correlated with baseline lacune count and baseline WMH volume, the latter showing the strongest predictive power, explaining 27.3% of the variance. The addition of baseline thalamic FA in multivariate modeling increased this value by 70%, which explains 46.5% of the variance in WMH accrual rate. Thalamic FA might serve as a novel predictor of cerebral small-vessel disease progression in clinical settings and trials. Furthermore, our findings point to the possibility of a causal relationship between thalamic damage and the accrual of WMHs.

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