Clinical relevance of acute cerebral microinfarcts in vascular cognitive impairment

Ferro, Doeschka A.; Brink, Hilde van den; Exalto, Lieza G.; Boomsma, Jooske M.F.; Barkhof, Frederik; Prins, Niels D.; Flier, Wiesje M. van der; Biessels, Geert Jan

doi:10.1212/wnl.0000000000007250

Cited by 23 publications

(24 citation statements)

References 34 publications

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“…A possible limitation of the study is that we obtained a measure of overall CBF at the level of the large extracranial arteries using two-dimensional phase-contrast MRI and did not measure CBF at the tissue level. Yet, the observed mean CBF values in our study are comparable to other studies that did use measures at the tissue level [1][2][3][4][5][6][7][8][9][10][11][12][13]. This does not exclude that there can be regional areas of abnormal perfusion at the site where lesions develop or have developed.…”

Section: Discussionsupporting

confidence: 83%

“…We found no relationship between CBF and MBs or lacunes after correction for age and sex in our primary or secondary analyses. A limited number of studies, both cross-sectional and longitudinal, have assessed the association between CBF and these features of SVD [5][6][7][8][9][10][11][12][13]. A single study on MBs, in a rather small and selected population of patients with symptomatic SVD, did show a relationship between multiple MBs (5 or more) and lower CBF in one of several brain regions tested [16].…”

Section: Discussionmentioning

confidence: 99%

“…Enlarged PVS were rated based on the method used by Staals et al [4]. Medial temporal lobe atrophy was assessed according to the Scheltens scale (scores for both hemispheres were averaged) [7].…”

Section: Methodsmentioning

confidence: 99%

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Cerebral Perfusion and the Burden of Small Vessel Disease in Patients Referred to a Memory Clinic

et al. 2020

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Background: Cerebral small vessel disease (SVD) lesions on MRI are common in patients with cognitive impairment. It has been suggested that cerebral hypoperfusion is involved in the etiology of these lesions. Objective: The aim of the study was to determine the relationship between cerebral blood flow (CBF) and SVD burden in patients referred to a memory clinic with SVD on MRI. Method: We included 132 memory clinic patients (mean age 73 ± 10, 56% male) with SVD on MRI. We excluded patients with large non-lacunar cortical infarcts. Global CBF (mL/min per 100 mL of brain tissue) was derived from 2-dimensional phase-contrast MRI focused on the internal carotid arteries and the basilar artery. SVD burden was defined as the sum of (each 1 point): white matter hyperintensities (WMHs) Fazekas 1 or more, lacunes, microbleeds (MBs), or enlarged perivascular spaces (PVS) presence, and each SVD feature separately. Linear regression analyses were performed to study the association between CBF and SVD burden, age- and sex-adjusted. Results: Median SVD burden score was 2, 36.4% of patients had MBs, 35.6% lacunar infarcts, 48.4% intermediate to severe enlarged PVS, and 57.6% a WMH Fazekas score 2 or more. Median WMH volume was 21.4 mL (25% quartile: 9.6 mL, 75% quartile: 32.5 mL). Mean CBF ± SD was 44.0 ± 11.9 mL/min per 100 mL brain. There was no relation between CBF and overall SVD burden (CBF difference per burden score point [95% CI]: −0.5 [−2.4; 1.4] mL/min/100 mL brain, p = 0.9). CBF did also not differ according to presence or absence or an high burden of any of the individual SVD features. Moreover, there was no significant relation between WMH volume and CBF (CBF difference per ml increase in WMH [95% CI] −0.6 [−1.5; 0.3] mL/min/100 mL brain p = 0.2). Conclusion: Global CBF was not related to overall SVD burden or with individual SVD features in this memory clinic cohort, indicating that in this setting these lesions were not primarily due to cerebral hypoperfusion.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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Cerebral Perfusion and the Burden of Small Vessel Disease in Patients Referred to a Memory Clinic

et al. 2020

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“…However, recurrent stroke risk is difficult to predict, as most CMIs cannot be detected via magnetic resonance imaging. Recently, it has been reported that diffusion-weighted imaging can detect and monitor acute CMIs for a month, which may provide a better intervention window (Auriel, Westover et al, 2015, Ferro, van den Brink et al, 2019. In this study, we found that a single CMI could induce epigenetic alterations (H3K4me1 and H3K4me3) in the contralateral side, suggesting that a single CMI may have a big impact on the brain at the epigenetic level.…”

Section: Discussionsupporting

confidence: 49%

Cortical microinfarcts potentiate recurrent ischemic injury through NLRP3-dependent trained immunity

Feng

et al. 2020

Preprint

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Microinfarcts are common among the elderly, and patients with microinfarcts are more vulnerable to another stroke. However, the potential effect of microinfarct on recurrent stroke remains elusive. In this study, we investigated the detrimental effect of microinfarct on recurrent stroke in mice. Microinfarct was induced using two-photon laser and photothrombotic stroke was induced in the cortex contralateral to microinfarct four weeks later. We found that CMI could trigger the formation of innate immune memory, which exacerbated the pro-inflammatory response and ischemic injury in second photothrombotic stroke. Furthermore, we clarified the role of NLRP3 inflammasome in the nuclei of microglia, which interacts with the MLL1 complex and thereby increases H3K4 methylation, suggesting that NLRP3 is critical in microinfarct-induced innate immune memory. Additionally, NLRP3 knockout in microglia attenuated microinfarct-induced detrimental effects on recurrent stroke. Our study highlights the detrimental effect of trained immunity on the recurrent stroke and reveals the important role of NLRP3 in mediating the formation of this memory, which may be a therapeutic target to mitigate recurrent strokes.

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“…These symptoms have a negative impact on the daily life of patients with VCI. 4 With the gradual increase in VCI patients, effective treatments are more and more urgent. Many studies have been devoted to the neuroinflammation and oxidative stress owing to chronic inflammation and long-term cerebrovascular dysfunction deficiency in cognitive altered process; these studies focused on endothelium and neuronal disruption acting as a promoter of neurodegenerative events.…”

Section: Introductionmentioning

confidence: 99%

The Neuroprotective Effects of Danggui-Shaoyao San on Vascular Cognitive Impairment: Involvement of the Role of the Low-Density Lipoprotein Receptor-Related Protein

Cai

Zheng

et al. 2020

Rejuvenation Research

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Effective drugs for treating dementia are still rare. Danggui-Shaoyao San (DSS), a traditional Chinese medicine, has been widely used in oriental countries for the treatment of various gynecological diseases. Many studies reported that DSS could ameliorate cognitive impairment. In this study, we aimed to investigate the underlying mechanism of DSS on vascular cognitive impairment (VCI) rats. Chronic cerebral hypoperfusion (CCH) is one of the main causes of VCI. CCH resulted in a chain of pathological process, including neuroinflammation, neuronal apoptosis, and oxidative stress. The most widely used animal model of VCI is permanent bilateral common carotid artery occlusion in rats. In this research, we determined whether DSS attenuated cognitive impairment by targeting I kappa B kinase (IKK)/nuclear factor of kappa B (NF-jB) signal pathway in VCI rats. Morris water maze and fear conditioning tests results indicated that DSS [7.2 g/(kg$d)] could improve learning and memory ability in VCI rats. We also found DSS significantly elevated the levels of low-density lipoprotein receptor-related protein 1 (LRP1) in the brain of VCI rats and this might indirectly target the IKK/NF-jB signal pathway to exert inhibitory effect on neuroinflammation, neuronal apoptosis, and oxidative stress in VCI rats. The present researches indicated that DSS might attenuate cognitive impairment by targeting IKK/NF-jB signal pathway in VCI rats and DSS might be a promising agent on VCI.

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Clinical relevance of acute cerebral microinfarcts in vascular cognitive impairment

Cited by 23 publications

References 34 publications

Cerebral Perfusion and the Burden of Small Vessel Disease in Patients Referred to a Memory Clinic

Cerebral Perfusion and the Burden of Small Vessel Disease in Patients Referred to a Memory Clinic

Cortical microinfarcts potentiate recurrent ischemic injury through NLRP3-dependent trained immunity

The Neuroprotective Effects of Danggui-Shaoyao San on Vascular Cognitive Impairment: Involvement of the Role of the Low-Density Lipoprotein Receptor-Related Protein

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