Mol Neurodegener

. 2023 Jul 11;18(1):46. doi: 10.1186/s13024-023-00640-5.

Pathophysiology and probable etiology of cerebral small vessel disease in vascular dementia and Alzheimer's disease

Yasuteru Inoue 1, Francis Shue 1, Guojun Bu 2, Takahisa Kanekiyo 3

Affiliations expand

• PMID: 37434208

•  PMCID: PMC10334598

•  DOI: 10.1186/s13024-023-00640-5

Free PMC article

Abstract

Vascular cognitive impairment and dementia (VCID) is commonly caused by vascular injuries in cerebral large and small vessels and is a key driver of age-related cognitive decline. Severe VCID includes post-stroke dementia, subcortical ischemic vascular dementia, multi-infarct dementia, and mixed dementia. While VCID is acknowledged as the second most common form of dementia after Alzheimer's disease (AD) accounting for 20% of dementia cases, VCID and AD frequently coexist. In VCID, cerebral small vessel disease (cSVD) often affects arterioles, capillaries, and venules, where arteriolosclerosis and cerebral amyloid angiopathy (CAA) are major pathologies. White matter hyperintensities, recent small subcortical infarcts, lacunes of presumed vascular origin, enlarged perivascular space, microbleeds, and brain atrophy are neuroimaging hallmarks of cSVD. The current primary approach to cSVD treatment is to control vascular risk factors such as hypertension, dyslipidemia, diabetes, and smoking. However, causal therapeutic strategies have not been established partly due to the heterogeneous pathogenesis of cSVD. In this review, we summarize the pathophysiology of cSVD and discuss the probable etiological pathways by focusing on hypoperfusion/hypoxia, blood-brain barriers (BBB) dysregulation, brain fluid drainage disturbances, and vascular inflammation to define potential diagnostic and therapeutic targets for cSVD.

Keywords: Arteriolosclerosis; Blood–brain barriers (BBB); Cerebral amyloid angiopathy (CAA); Cerebral small vessel disease (cSVD); Glymphatic drainage; Hypoperfusion/Hypoxia; Intramural periarterial drainage (IPAD); Vascular cognitive impairment and dementia (VCID); Vascular inflammation.

Transl Stroke Res

. 2023 Nov 28. doi: 10.1007/s12975-023-01218-5. Online ahead of print.

Inflammation, Anti-inflammatory Interventions, and Post-stroke Cognitive Impairment: a Systematic Review and Meta-analysis of Human and Animal Studies

Reinier W P Tack 1, Claudia Amboni 2, Danny van Nuijs 2, Marcela Pekna 3, Mervyn D I Vergouwen 4, Gabriel J E Rinkel 4, Elly M Hol 5

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• PMID: 38012509

•  DOI: 10.1007/s12975-023-01218-5

Abstract

The pathophysiology and treatment of post-stroke cognitive impairment (PSCI) are not clear. Stroke triggers an inflammatory response, which might affect synapse function and cognitive status. We performed a systematic review and meta-analysis to assess whether patients with PSCI have increased levels of inflammatory markers and whether anti-inflammatory interventions in animals decrease PSCI. We systematically searched PubMed, EMBASE, and PsychInfo for studies on stroke. For human studies, we determined the standardized mean difference (SMD) on the association between PSCI and markers of inflammation. For animal studies, we determined the SMD of post-stroke cognitive outcome after an anti-inflammatory intervention. Interventions were grouped based on proposed mechanism of action. In patients, the SMD of inflammatory markers for those with versus those without PSCI was 0.46 (95% CI 0.18; 0.76; I2 = 92%), and the correlation coefficient between level of inflammation and cognitive scores was - 0.25 (95% CI - 0.34; - 0.16; I2 = 75%). In animals, the SMD of cognition for those treated with versus those without anti-inflammatory interventions was 1.43 (95% CI 1.12; 1.74; I2 = 83%). The largest effect sizes in treated animals were for complement inhibition (SMD = 1.94 (95% CI 1.50; 2.37), I2 = 51%) and fingolimod (SMD = 2.1 (95% CI 0.75; 3.47), I2 = 81%). Inflammation is increased in stroke survivors with cognitive impairment and is negatively correlated with cognitive functioning. Anti-inflammatory interventions seem to improve cognitive functioning in animals. Complement inhibition and fingolimod are promising therapies on reducing PSCI.

Keywords: Cognitive impairment; Complement; Inflammation; Microglia; Stroke.

Cells

. 2023 Apr 13;12(8):1153. doi: 10.3390/cells12081153.

Spatiotemporal Cofilin Signaling, Microglial Activation, Neuroinflammation, and Cognitive Impairment Following Hemorrhagic Brain Injury

Daniyah A Almarghalani 1, Xiaojin Sha 2, Robert E Mrak 3, Zahoor A Shah 4

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• PMID: 37190062

•  PMCID: PMC10137307

•  DOI: 10.3390/cells12081153

Free PMC article

Abstract

Intracerebral hemorrhage (ICH) is a significant health concern associated with high mortality. Cofilin plays a crucial role in stress conditions, but its signaling following ICH in a longitudinal study is yet to be ascertained. In the present study, we examined the cofilin expression in human ICH autopsy brains. Then, the spatiotemporal cofilin signaling, microglia activation, and neurobehavioral outcomes were investigated in a mouse model of ICH. Human autopsy brain sections from ICH patients showed increased intracellular cofilin localization within microglia in the perihematomal area, possibly associated with microglial activation and morphological changes. Various cohorts of mice were subjected to intrastriatal collagenase injection and sacrificed at time points of 1, 3, 7, 14, 21, and 28 days. Mice suffered from severe neurobehavioral deficits after ICH, lasting for 7 days, followed by a gradual improvement. Mice suffered post-stroke cognitive impairment (PSCI) both acutely and in the chronic phase. Hematoma volume increased from day 1 to 3, whereas ventricle size increased from day 21 to 28. Cofilin protein expression increased in the ipsilateral striatum on days 1 and 3 and then decreased from days 7 to 28. An increase in activated microglia was observed around the hematoma on days 1 to 7, followed by a gradual reduction up to day 28. Around the hematoma, activated microglia showed morphological changes from ramified to amoeboid. mRNA levels of inflammatory [tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and interleukin-6 (IL-6) and anti-inflammatory markers [interleukin-10 (IL-10), transforming growth factor-β TGF-β, and arginase I (Arg1)] increased during the acute phase and decreased in the chronic phase. Blood cofilin levels increased on day 3 and matched the increase in chemokine levels. slingshot protein phosphatase 1 (SSH1) protein, which activates cofilin, was increased from day 1 to 7. These results suggest that microglial activation might be the sequel of cofilin overactivation following ICH, leading to widespread neuroinflammation and consequent PSCI.

Keywords: ICH; cofilin; cofilin rods/aggregates; microglial activation; neuroinflammation; post-stroke cognitive impairment.

Behav Brain Res

. 2023 Mar 28:442:114301. doi: 10.1016/j.bbr.2023.114301. Epub 2023 Jan 26.

Baicalin facilitates remyelination and suppresses neuroinflammation in rats with chronic cerebral hypoperfusion by activating Wnt/β-catenin and inhibiting NF-κB signaling

Yining Xiao 1, Tianyuan Guan 2, Xiaofeng Yang 3, Jing Xu 4, Jiawei Zhang 5, Qianqian Qi 2, Zhenjie Teng 1, Yanhong Dong 4, Yaran Gao 6, Meixi Li 6, Nan Meng 6, Peiyuan Lv 7

Affiliations expand

• PMID: 36707260

•  DOI: 10.1016/j.bbr.2023.114301

Abstract

One main factor contributing to the cognitive loss in vascular dementia (VD) is white matter lesions (WMLs) carried on by chronic cerebral hypoperfusion (CCH). A secondary neuroinflammatory response to CCH accelerates the loss and limits the regeneration of oligodendrocytes, leading to progressive demyelination and insufficient remyelination in the white matter. Thus, promoting remyelination and inhibiting neuroinflammation may be an ideal therapeutic strategy. Baicalin (BAI) is known to exhibit protective effects against various inflammatory and demyelinating diseases. However, whether BAI has neuroprotective effects against CCH has not been investigated. To determine whether BAI inhibits CCH-induced demyelination and neuroinflammation, we established a model of CCH in rats by occluding the two common carotid arteries bilaterally. Our results revealed that BAI could remarkably ameliorate cognitive impairment and mitigate CA1 pyramidal neuron damage and myelin loss. BAI exhibited enhancement of remyelination by increasing the expression of myelin basic protein (MBP) and oligodendrocyte transcription factor 2 (Olig2), inhibiting the loss of oligodendrocytes and promoting oligodendrocyte regeneration in the corpus callosum of CCH rats. Furthermore, BAI modified microglia polarization to the anti-inflammatory phenotype and inhibited the release of pro-inflammatory cytokines. Mechanistically, BAI treatment significantly induced phosphorylation of glycogen synthase kinase 3β (GSK3β), enhanced the expression of β-catenin and its nuclear translocation. Simultaneously, BAI reduced the expression of nuclear NF-κB. Collectively, our results suggest that BAI ameliorates cognitive impairment in CCH-induced VD rats through its pro-remyelination and anti-inflammatory capacities, possibly by activating the Wnt/β-catenin and suppressing the NF-κB signaling.

Keywords: Baicalin; Chronic cerebral hypoperfusion; NF-κB; Neuroinflammation; Remyelination; Wnt/β-catenin.