Gliovascular Mechanisms and White Matter Injury in Vascular Cognitive Impairment and Dementia

IntroductionCerebral small vessel disease (cSVD) accounts for 20%–25% of strokes and is the most common cause of vascular cognitive impairment (VCI). In an animal VCI model, inducing brief periods of limb ischaemia-reperfusion reduces subsequent ischaemic brain injury with remote and local protective effects, with hindlimb remote ischaemic conditioning (RIC) improving cerebral blood flow, decreasing white-matter injury and improving cognition. Small human trials suggest RIC is safe and may prevent recurrent strokes. It remains unclear what doses of chronic daily RIC are tolerable and safe, whether effects persist after treatment cessation, and what parameters are optimal for treatment response.Methods and analysisThis prospective, open-label, randomised controlled trial (RCT) with blinded end point assessment and run-in period, will recruit 24 participants, randomised to one of two RIC intensity groups: one arm treated once daily or one arm twice daily for 30 consecutive days. RIC will consistent of 4 cycles of blood pressure cuff inflation to 200 mm Hg for 5 min followed by 5 min deflation (total 35 min). Selection criteria include: age 60–85 years, evidence of cSVD on brain CT/MRI, Montreal Cognitive Assessment (MoCA) score 13–24 and preserved basic activities of living. Outcomes will be assessed at 30 days and 90 days (60 days after ceasing treatment). The primary outcome is adherence (completing ≥80% of sessions). Secondary safety/tolerability outcomes include the per cent of sessions completed and pain/discomfort scores from patient diaries. Efficacy outcomes include changes in cerebral blood flow (per arterial spin-label MRI), white-matter hyperintensity volume, diffusion tensor imaging, MoCA and Trail-Making tests.Ethics and disseminationResearch Ethics Board approval has been obtained. The results will provide information on feasibility, dose, adherence, tolerability and outcome measures that will help design a phase IIb RCT of RIC, with the potential to prevent VCI. Results will be disseminated through peer-reviewed publications, organisations and meetings.Trial registration numberNCT04109963.

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Abstract TP559: Sulforaphane Confers Neuroprotection Against Neuronal Loss, White Matter Injury and BBB Damage Following Experimental Vascular Cognitive Impairment

Stroke ◽

10.1161/str.50.suppl_1.tp559 ◽

2019 ◽

Vol 50 (Suppl_1) ◽

Author(s):

Leilei Mao ◽

Tuo Yang ◽

Cong Li ◽

Feng Zhang ◽

Baoliang Sun

Keyword(s):

Cognitive Impairment ◽

White Matter ◽

Neuronal Loss ◽

Vascular Cognitive Impairment ◽

White Matter Injury

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Abstract TP442: Periventricular Not Deep White Matter Hyperintensities Are Associated With Vascular Cognitive Impairment

Stroke ◽

10.1161/str.48.suppl_1.tp442 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Yan Chen ◽

Renyuan Liu ◽

Shuwei Qiu ◽

Yun Xu

Keyword(s):

Regression Analysis ◽

Cognitive Impairment ◽

White Matter ◽

Linear Regression ◽

Cognitive Performance ◽

White Matter Hyperintensities ◽

Rating Scale ◽

Linear Regression Analysis ◽

Vascular Cognitive Impairment ◽

Cerebral White Matter

Introduction: Cerebral White matter hyperintensities(WMH) are frequent findings on MRI scan. They are well known to correlate with vascular cognitive impairment(VCI). However, controversies still remain about the relationship between WMH locations and cognitive function across studies. Hypothesis: Periventricular WMHs(PWH) rather than deep WMHs(DWH) are associated with cognitive decline in VCI. Methods: Fifty-nine subjects with WMHs on MRI were divided into three groups, normal control(NC), mild cognitive impairment(MCI) and vascular dementia(VaD), according to clinical manifestation and neuropsychological performance. WMH volumes were evaluated by Fazekas rating scale and segmental volumetric. Correlations between cognitive performance and WMH volumes were determined in virtue of Spearman correlation analysis. Receiver operator characteristic (ROC) curves were generated to define the classification cut-off value of WMH volumes for distinguishing VCI versus normal controls. Multiple linear regression analysis was used to predict cognitive performance with WMH volumes and locations after adjusting for sex ,age and education level. Results: Cognitive capacities were gradually declined from NC through MCI to VaD patients while WMH volumes and Fazekas scores altered oppositely. Both PWH and DWH volumes and Fazekas scores were correlated with cognitive performance, and moreover, WMH volumes were correlated with Fazekas scores. ROC analysis showed a cut-off value of PWH rather than DWH to distinguish VCI from NC(AUC=0.745 and 0.635, p =0.001 and 0.076, respectively). Linear regression analysis demonstrated that only PWH volumes were associated with cognitive performance( p < 0.001). Conclusion: Our study demonstrate that PWHs are independent predictors for vascular contribution in white matter lesions and suggest clinicians that PWH should be emphasized on evaluating vascular cognitive impairment related with white matter load.

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Abstract WMP118: Involvement of MMP-9 in Inflammation-induced White Matter Injury in a Novel Rat Model of Vascular Cognitive Impairment

Stroke ◽

10.1161/str.44.suppl_1.awmp118 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Fakhreya Y Jalal ◽

Jeffrey Thompson ◽

Yi Yang ◽

Gary A Rosenberg

Keyword(s):

T Cells ◽

Cognitive Impairment ◽

White Matter ◽

Rat Model ◽

Hypoxia Inducible Factor ◽

Treated Group ◽

White Matter Injury ◽

Image Size ◽

Apparent Diffusion Coefficients ◽

Long Term Treatment

Objective: We have recently developed a rat model of white matter (WM) injury in stroke-prone spontaneously hypertensive rats (SHR-SP), which shows chronic oligodendrocyte death, blood-brain barrier (BBB) disruption, and cognitive impairment. In this study, we investigated the mechanisms of white matter damage secondary to chronic hypertensive disease. Methods: At 12 weeks of age, we subjected SHR-SP to permanent unilateral carotid artery occlusion (UCAO) followed by the Japanese permissive diet (JPD) and 1 % NaCl in drinking water. One group of UCAO/JPD rats received minocycline (50 mg/kg in DMSO, i.p. every other day for 9 weeks) and another had only UCAO/JPD with DMSO. WM lesions were characterized histologically, biochemically, and by MRI; cognitive impairment was tested by Morris water maze. Results: One to 3 weeks after UCAO/JPD, we found an increase in hypoxia inducible factor-1α (HIF-1α) in astrocytes, a fall in pyrol hydroxylase-2 (PHD-2), and an increase in matrix metalloproteinase-9 (MMP-9) expression. At week 1, there was infiltration of T-cells and MMP-9 co-localized with endothelial cells and neutrophils. By 3 weeks, we observed IgG leakage, indicating disruption of the BBB, with scattered hemorrhages. Long term treatment with minocycline prevented cognitive impairment along with reduction in T2-weighted image size, apparent diffusion coefficients, and fractional anisotropy compared to the vehicle-treated group. Relative cerebral blood flow was unaffected by minocycline treatment. Conclusion: Our results suggest that hypoxic hypoperfusion of the deep WM, which occurs secondary to hypertensive damage to blood vessels, initiates expression of MMP-9 and migration of T-cells, disrupting the BBB and damaging WM. The anti-inflammatory agent, minocycline, significantly protected the deep WM from injury.

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