Brain︱ new method!

Written by Liu Xinlang, edited by Liu Xinlang, Wang Sizhen Small vessel disease (SVD) is a disease characterized by lesions of the superficial and deep penetrating arteries and arterioles of the brain, and it is also a disorder of gait, cognitive disorder, mood disorder and stroke The main reason [1]
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Cerebral amyloid angiopathy (CAA) and hypertension SVD are the most common types of sporadic SVD
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Conventional magnetic resonance imaging (MRI) can reflect the typical radiological characteristics of SVD parenchymal damage, including cerebral microbleeds (CMBs), white matter hyperintensities (WMH), lacuna and vascular space expansion [2]
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Using amyloid positron emission scanning (PET) to measure cerebral vascular amyloid can assess the severity of CAA in vivo [3, 4]
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 Recently, in studies exploring the relationship between inflammation biomarkers and SVD neuroimaging markers, inflammation related to cerebrovascular pathology has been increasingly recognized [5, 6]
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Targeted inflammation has been used as a new treatment for SVD
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The results of preclinical studies have shown that the use of drug intervention to inhibit the activation of microglia induced by cerebrovascular amyloid can alleviate the progression of CAA
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However, the difference between CAA and hypertensive SVD in response to inflammation is largely unclear
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 Triggering receptor expressed on myeloid cells 2 (TREM2), an innate immune receptor of the immunoglobulin superfamily, affects various functions of cells, including activation, inflammation, phagocytosis, Proliferate and survive
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In the brain, TREM2 is mainly expressed in microglia and is believed to regulate the activation of pro-inflammatory and anti-inflammatory microglia under conditions related to Alzheimer's disease (AD) [7]
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Soluble sTREM2 (sTREM2) in cerebrospinal fluid has been considered as a surrogate biomarker for microglia activation in many neurodegenerative diseases [8, 9]
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STREM2 can also be detected in the blood.
The level of sTREM2 in peripheral blood is closely related to the level of sTREM2 in cerebrospinal fluid [10, 11], which suggests that peripheral sTREM2 may play a role in the pathology of the central nervous system
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However, it is not clear whether the peripheral level of sTREM2 reflects the degree of parenchymal damage in SVD patients, and whether it is related to brain pathology
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 On September 13, 2021, the Che-Feng Chang research group of the National Taiwan University School of Medicine published a research paper on Brain entitled "Plasma soluble TREM2 is associated with white matter lesions independent of amyloid and tau", and proposed plasma solubility TREM2 is related to white matter hyperintensity, but has nothing to do with amyloid pathology and tau pathology
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These findings emphasize the potential utility of plasma soluble TREM2 as a strong predictor of white matter damage associated with small vessel diseases (including SVD), and suggest that the innate immune response may be a potential target for effective treatment of such diseases
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 The study included 76 subjects: 10 AD patients and 66 spontaneous intracerebral hemorrhage survivors, including 20 cases of cerebral amyloid vascular small vascular disease (SVD-CAA) and hypertensive small vascular disease ( SVD-HTN) 46 cases (Table 1)
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MRI and 11C-PiB PET were performed on the brains of all subjects to assess the markers of radioactive small vessel disease and cerebral amyloid load.
The AD group and SVD-CAA group were tested by 18F-T807 PET to assess the pathology of cortical tau protein
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Compare its plasma sTREM2 level and its relationship with neuroimaging markers and brain amyloid load (Figure 1)
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Table 1: Sample details (picture quoted from: Tsai et al.
, Brain 2021; awab332) Figure 1 Flow chart of patient registration and imaging (picture quoted from: Tsai et al.
, Brain 2021; awab332) Researcher, first, compare The plasma sTREM2 levels of SVD patients and clinical AD patients are analyzed
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Compared with the AD group: 1) SVD patients carrying ApoE4 alleles are significantly fewer, and their Mini Mental State Scale (MMSE) results are better (Supplement: MMSE is one of the most influential standardized mental state examination tools , It can be used for AD screening as a method of cognitive impairment, simple and easy); 2) SVD group is related to neuroimaging SVD markers, including higher microbleeding number and larger WMH volume; 3 ) In PiB PET scan, the amyloid load of SVD patients was lower; 4) There was no significant difference in plasma sTREM2 levels between SVD patients and AD patients (p = 0.
690), plasma levels between SVD-CAA and SVD-HTN subgroups The level of sTREM2 was comparable (p = 0.
829) (Figure 2)
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Then, the correlation between plasma sTREM2 levels and other plasma biomarkers (including total tau protein, Aβ40, Aβ42, and the ratio of Aβ40 to Aβ42) in the AD, SVD-CAA and SVD-HTN groups was evaluated and found: 1) Plasma sTREM2 It is not correlated with other plasma biomarkers in AD; 2) However, in the SVD-CAA group, plasma sTREM2 levels were positively correlated with plasma Aβ40 levels (p=0.
033), and also showed a strong correlation trend with plasma Aβ42 levels ( p=0.
055); 3) In the SVD-HTN group, plasma sTREM2 was positively correlated with the total tau protein level (p=0.
028)
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These results indicate that the plasma sTREM2 of AD and SVD are comparable to a certain extent
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Figure 2 Box diagram of plasma sTREM2 in patients with AD, SVD-CAA and SVD-HTN (picture quoted from: Tsai et al.
, Brain 2021; awab332) Next, in order to determine whether any related SVD damage is related to plasma sTREM2, The authors assessed the association between sTREM2 and radiological biomarkers
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It was found that plasma sTREM2 was positively correlated with WMH volume (p<0.
001) (Figure 3A), and was related to the total number of cerebral microbleeds (p=0.
495) (Figure 3B) or cerebral amyloid load (p=0.
57) (Figure 3C) ) No correlation
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Figure 3 The correlation between plasma sTREM2 and neuroimaging markers (picture quoted from: Tsai et al.
, Brain 2021; awab332) In order to further study the effect of small vessel disease on plasma sTREM2 levels in the presence of amyloid and tau protein lesions Impact
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The researchers performed a PET scan of tau protein in Aβ-positive SVD-CAA and AD patients to measure tau protein deposition in the cortex of the patients
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It was found that out of a total of 25 patients, 12 (48%) patients were tau PET positive, and their plasma sTREM2 was higher than that of tau PET negative patients (p = 0.
002) (Figure 4)
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After multiple linear regression analysis of plasma sTREM2, tau positive rate, WMH volume and amyloid load, it was found that plasma sTREM2 was still correlated with tau positive (p=0.
001) and WMH volume increase (p=0.
013), but It has nothing to do with amyloid load (p=0.
221)
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Figure 4 Box diagram of plasma sTREM2 in patients with tau PET-negative and tau PET-positive scans (picture quoted from: Tsai et al.
, Brain 2021; awab332) Explore whether plasma sTREM2 is related to cognitive status.
Discovery: in AD and SVD patients There was no significant correlation between MMSE score and plasma sTREM2 level (p=0.
160)
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But interestingly, in these two groups of patients, the MMSE score of tau PET-positive patients was only positively correlated with plasma sTREM2 (p=0.
023), but there was no correlation in tau PET-negative patients (p=0.
716) (Figure 5A)
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After adjusting for age and education years, the MMSE score of tau PET-positive patients and the plasma sTREM2 level were still significant (p=0.
049)
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 The researchers further used the WMH severity scale to assess the correlation between plasma sTREM2 and MMSE scores in patients with SVD (SVD-CAA and SVD-HTN)
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It was found that there was no significant correlation between the MMSE score and plasma sTREM2 in subjects with high or low WMH (Figure 5B), suggesting that there was no correlation between plasma sTREM2 and cognitive performance regardless of the SVD stage
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 Figure 5 The correlation between plasma sTREM2 and cognitive scores (picture quoted from: Tsai et al.
, Brain 2021; awab332) Conclusion and discussion of the article, enlightenment and prospects for cerebral small vessel disease (SVD) is the superficial and deep arterioles of the brain Lesions
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White matter hyperintensity (WMH) is a sign of the severity of SVD and white matter damage
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Although the main function of sTREM2-dependent inflammation in SVD is unclear, peripheral sTREM2 is an important immune response related to SVD neurovascular injury
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At present, only a few studies have investigated plasma or serum sTREM2, and its role in the pathology of the central nervous system is still controversial [12]
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In fact, many studies have reported a strong correlation between peripheral sTREM2 and cerebrospinal fluid sTREM2 levels [10, 11], indicating the potential role of peripheral sTREM2 in CNS pathology
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Therefore, studying the relationship between plasma sTREM2 levels and white matter lesions in the brain and tau pathology will help to further support these conclusions
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 First of all, this study found that plasma sTREM2 levels are comparable between SVD patients and AD patients
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Secondly, plasma sTREM2 in SVD patients is positively correlated with WMH volume and has nothing to do with Aβ load, suggesting that the increase in bone marrow cell-related inflammation and the appearance of TREM2 signals in the progression of SVD have nothing to do with brain Aβ deposition, and may be related to white matter lesions in SVD
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Finally, higher plasma sTREM2 and higher WMH volume are respectively associated with positive cortical tau pathology, but have nothing to do with amyloid deposits in Aβ diseases, suggesting that high levels of sTREM2 in tau-mediated neurological diseases It may be a potential prognostic marker in AD or CAA
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However, no correlation between plasma sTREM2 and cognitive score was found in early or late SVD
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 One of the highlights of the study is the inclusion of SVD-CAA in the research content, which allows researchers to discover the separate effects of SVD, Aβ, and tau pathology on the elevation of plasma sTREM2, because CAA and AD often overlap in clinical manifestations and pathology.
【13】
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Another important highlight is the use of in vivo molecular imaging to measure the pathology of brain Aβ and tau protein, which allows researchers to study their relationship with plasma sTREM2 in real time
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 This study also has limitations
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First, the study only measured plasma sTREM2, not the level in cerebrospinal fluid
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Plasma sTREM2 may come from peripheral blood and is affected by other systemic diseases [14]
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Second, SVD patients come from survivors of spontaneous intracerebral hemorrhage, rather than patients with other clinical manifestations
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However, the authors cannot completely rule out the possibility that the observed sTREM2 level reflects the inflammation caused by undissolved hematoma, but in order to minimize the influence of this factor, the study only included at least 6 months after the cerebral hemorrhage event Of patients
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Finally, there is a lack of sTREM2 data from normal healthy controls
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 Overall, the study showed that SVD-related WMH is associated with plasma sTREM2, and has nothing to do with brain Aβ and tau deposition
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Research also suggests the importance of revealing the complex relationship between TREM2 and related inflammation, neurovascular unit damage, and ultimately neurodegeneration in the future, because small blood vessel pathology plays a major role in stroke and other neurodegenerative diseases
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The study also shows that the innate immune response may be a potential target for effective treatment of cerebral small vessel diseases
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Original link: https://doi.
org/10.
1093/brain/awab332 Selected articles from previous issues [1] JAMA Neurol︱ Attention! Young people are more likely to suffer from "Alzheimer's disease"? [2] Loss of EMBO J︱ neuron Miro1 protein destroys mitochondrial autophagy and over-activates the integrated stress response [3] Interpretation of Science Frontier Review︱Regulatory mechanism of nicotinic acetylcholine receptor accessory molecules and application prospects of disease treatment and transformation [4] Cereb Cortex︱ oxytocin can regulate the individualized processing of facial identities in the early brain areas and the classification and processing of facial ethnicity [5] Nat Commun | Mechanism [6] Cereb Cortex︱ Ku Yixuan team reveals the ipsilateral sensory cortex representation pattern of working memory [7] Neurosci Bull︱ synapse-associated protein Dlg1 improves depression-like behavior in mice by inhibiting microglia activation [8] Brain | first! PAX6 may be a key factor in the pathogenesis of Alzheimer's disease and a new therapeutic target [9] Sci Adv︱ blockbuster! DNA methylation protein DNMT1 mutation can induce neurodegenerative diseases [10] Cell︱ new discovery! New enlightenment of midbrain-regulated movement phenomenon for the treatment of Parkinson’s disease [11] Cereb Cortex︱MET tyrosine kinase signal transduction timing abnormality is a key mechanism affecting the development and behavior of normal cortical neural circuits in mice [12] Nat Biomed Eng︱ The team of academician Ye Yuru develops a new strategy for whole-brain gene editing-mediated treatment of Alzheimer’s disease [13] Luo Liqun Science's heavy review System interpretation ︱ Neural circuit structure-a system that makes the brain "computer" run at high speed [14] Sci Adv ︱Important discovery! The calcium homeostasis regulatory protein Calhm2 regulates the activation of microglia and participates in the process of Alzheimer's disease [15] EMBO J︱ new discovery! AGHGAP11B promotes the expansion of the neocortex into adulthood and improves cognitive ability.
References (slide up and down to view) [1] Wardlaw JM, Smith C, Dichgans M.
Small vessel disease: mechanisms and clinical implications.
Lancet Neurol.
Jul 2019;18(7 ):