脑小血管病的诊治现状及未来探索之路

doi:10.3969/j.issn.1673-5765.2024.04.001

摘要/Abstract

摘要： 脑小血管病（cerebral small vessel disease，CSVD）是一组临床、影像、病理综合征，主要累及颅内小血管，起病隐匿。CSVD与卒中、认知下降、情感障碍、步态异常及尿便失禁密切相关，给家庭和社会带来沉重的疾病负担和经济负担。但CSVD的致病机制仍不明确，临床诊断标准不统一，临床诊疗和试验研究面临重大挑战。本文旨在汇总当前CSVD的可能病因、发病机制和临床诊疗研究的进展及局限性，展望CSVD未来可能的临床研究方向。

关键词: 脑小血管病; 诊断; 分类; 病理; 影像学特征; 治疗

Abstract: Cerebral small vessel disease (CSVD) is a group of clinical, imaging and pathological syndromes mainly involving intracranial small vessels. The onset of CSVD is occult. It is closely related to stroke, cognitive decline, affective disorders, gait abnormalities and urinary and fecal incontinence. It brings heavy disease burden and economic burden to the family and society. However, the true pathogenesis of CSVD is still unclear, and the clinical diagnostic criteria are not uniform, which makes clinical diagnosis and treatment and experimental research face major challenges. The purpose of this paper is to discuss the progress and limitations of the etiology, pathogenesis, clinical diagnosis and treatment of CSVD, and to look forward to the possible clinical research direction of CSVD in the future.

Key words: Cerebral small vessel disease; Diagnosis; Classification; Pathology; Imaging characteristic; Treatment

中图分类号:

王伊龙. 脑小血管病的诊治现状及未来探索之路[J]. 中国卒中杂志, 2024, 19(4): 363-374.

WANG Yilong. Diagnosis and Treatment of Cerebral Small Vessel Disease and the Way of Future Exploration[J]. Chinese Journal of Stroke, 2024, 19(4): 363-374.

参考文献

[1] BERROCAL-IZQUIERDO N，BIOQUE M，BERNARDO M. Is cerebrovascular disease a silent condition in patients with chronic schizophrenia-related disorders？[J]. Int Clin Psychopharmacol，2017，32（2）：80-86.
[2] VAN AGTMAAL M J M，HOUBEN A J H M，POUWER F，et al. Association of microvascular dysfunction with late-life depression：a systematic review and meta-analysis[J]. JAMA Psychiatry，2017，74（7）：729-739.
[3] LI Q，YANG Y，REIS C，et al. Cerebral small vessel disease[J]. Cell Transplant，2018，27（12）：1711-1722.
[4] DEY A K，STAMENOVA V，TURNER G，et al. Pathoconnectomics of cognitive impairment in small vessel disease：a systematic review[J]. Alzheimers Dement，2016，12（7）：831-845.
[5] PANTONI L. Cerebral small vessel disease：from pathogenesis and clinical characteristics to therapeutic challenges[J]. Lancet Neurol，2010，9（7）：689-701.
[6] WARDLAW J M，SMITH C，DICHGANS M. Mechanisms of sporadic cerebral small vessel disease：insights from neuroimaging[J]. Lancet Neurol，2013，12（5）：483-497.
[7] LITAK J，MAZUREK M，KULESZA B，et al. Cerebral small vessel disease[J/OL]. Int J Mol Sci，2020，21（24）：9729[2024-01-01]. https://doi.org/10.3390/ijms21249729.
[8] RINCON F，WRIGHT C B. Current pathophysiological concepts in cerebral small vessel disease[J/OL]. Front Aging Neurosci，2014，6：24[2024-01-01]. https://doi.org/10.3389/fnagi.2014.00024.
[9] WONG S M，JANSEN J F A，ZHANG C E，et al. Blood-brain barrier impairment and hypoperfusion are linked in cerebral small vessel disease[J/OL]. Neurology，2019，92（15）：e1669-e1677[2024-01-01]. https://doi.org/10.1212/WNL.0000000000007263.
[10] ZHANG C E，WONG S M，VAN DE HAAR H J，et al. Blood-brain barrier leakage is more widespread in patients with cerebral small vessel disease[J]. Neurology，2017，88（5）：426-432.
[11] NEZU T，HOSOMI N，AOKI S，et al. Endothelial dysfunction is associated with the severity of cerebral small vessel disease[J]. Hypertens Res，2015，38（4）：291-297.
[12] ILIFF J J，WANG M H，LIAO Y H，et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes，including amyloid β [J/OL]. Sci Transl Med，2012，4（147）：147ra111[2024-01-01]. https://doi.org/10.1126/scitranslmed.3003748.
[13] ASPELUND A，ANTILA S，PROULX S T，et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules[J]. J Exp Med，2015，212（7）：991-999.
[14] BENVENISTE H，ELKIN R，HEERDT P M，et al. The glymphatic system and its role in cerebral homeostasis[J]. J Appl Physiol（1985），2020，129（6）：1330-1340.
[15] GOUVEIA-FREITAS K，BASTOS-LEITE A J. Perivascular spaces and brain waste clearance systems：relevance for neurodegenerative and cerebrovascular pathology[J]. Neuroradiology，2021，63（10）：1581-1597.
[16] MENTIS A A，DARDIOTIS E，CHROUSOS G P. Apolipoprotein E4 and meningeal lymphatics in Alzheimer disease：a conceptual framework[J]. Mol Psychiatry，2021，26（4）：1075-1097.
[17] XUE Y，LIU N，ZHANG M Y，et al. Concomitant enlargement of perivascular spaces and decrease in glymphatic transport in an animal model of cerebral small vessel disease[J/OL]. Brain Res Bull，2020，161：78-83[2024-01-01]. https://doi.org/10.1016/j.brainresbull.2020.04.008.
[18] WOLF S A，BODDEKE H W G M，KETTENMANN H. Microglia in physiology and disease[J/OL]. Annu Rev Physiol，2017，79：619-643[2024-01-01]. https://doi.org/10.1146/annurev-physiol-022516-034406.
[19] 赵洋，束宁德，王美玲，等. 神经血管单元在脑小血管病中的作用[J]. 国际脑血管病杂志，2022，30（2）：146-150.
ZHAO Y，SHU N D，WANG M L，et al. Role of neurovascular units in cerebral small vessel disease[J]. Int J Cerebrovasc Dis，2022，30（2）：146-150.
[20] 王丽莎，徐艳. 炎症与脑小血管病[J]. 国际脑血管病杂志，2017，25（8）：729-733.
WANG L S，XU Y. Inflammation and cerebral small vessel disease[J]. Int J Cerebrovasc Dis，2017，25（8）：729-733.
[21] WALKER K A，POWER M C，HOOGEVEEN R C，et al. Midlife systemic inflammation，late-life white matter integrity，and cerebral small vessel disease：the atherosclerosis risk in communities study[J]. Stroke，2017，48（12）：3196-3202.
[22] DE GUIO F，VIGNAUD A，ROPELE S，et al. Loss of venous integrity in cerebral small vessel disease：a 7-T MRI study in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy（CADASIL）[J]. Stroke，2014，45（7）：2124-2126.
[23] CHARIDIMOU A，PANTONI L，LOVE S. The concept of sporadic cerebral small vessel disease：a road map on key definitions and current concepts[J]. Int J Stroke，2016，11（1）：6-18.
[24] CAPLAN L R. Lacunar infarction and small vessel disease：pathology and pathophysiology[J]. J Stroke，2015，17（1）：2-6.
[25] BERNBAUM M，MENON B K，FICK G，et al. Reduced blood flow in normal white matter predicts development of leukoaraiosis[J]. J Cereb Blood Flow Metab，2015，35（10）：1610-1615.
[26] VAN DER VEEN P H，MULLER M，VINCKEN K L，et al. Longitudinal relationship between cerebral small-vessel disease and cerebral blood flow：the second manifestations of arterial disease-magnetic resonance study[J]. Stroke，2015，46（5）：1233-1238.
[27] JIMÉNEZ I，AGULLA J，POUSO M，et al. Cognitive impairment associated to leukoaraiosis：its pathophysiology，clinical manifestations and treatment[J]. Rev Neurol，2008，47（10）：536-544.
[28] PAPMA J M，DE GROOT M，DE KONING I，et al. Cerebral small vessel disease affects white matter microstructure in mild cognitive impairment[J]. Hum Brain Mapp，2014，35（6）：2836-2851.
[29] DUERING M，CSANADI E，GESIERICH B，et al. Incident lacunes preferentially localize to the edge of white matter hyperintensities：insights into the pathophysiology of cerebral small vessel disease[J/OL]. Brain，2013，136（Pt 9）：2717-2726[2024-01-01]. https://doi.org/10.1093/brain/awt184.
[30] DE GROOT M，VERHAAREN B F J，DE BOER R，et al. Changes in normal-appearing white matter precede development of white matter lesions[J]. Stroke，2013，44（4）：1037-1042.
[31] MUNOZ D G. Leukoaraiosis and ischemia：beyond the myth[J]. Stroke，2006，37（6）：1348-1349.
[32] HAINSWORTH A H，MARKUS H S. Do in vivo experimental models reflect human cerebral small vessel disease？A systematic review[J]. J Cereb Blood Flow Metab，2008，28（12）：1877-1891.
[33] AURIEL E，CSIBA L，BERENYI E，et al. Leukoaraiosis is associated with arterial wall thickness：a quantitative analysis[J]. Neuropathology，2012，32（3）：227-233.
[34] HASSAN A，HUNT B J，O’SULLIVAN M，et al. Homocysteine is a risk factor for cerebral small vessel disease，acting via endothelial dysfunction[J/OL]. Brain，2004，127（Pt 1）：212-219[2024-01-01]. https://doi.org/10.1093/brain/awh023.
[35] HAINSWORTH A H，OOMMEN A T，BRIDGES L R. Endothelial cells and human cerebral small vessel disease[J]. Brain Pathol，2015，25（1）：44-50.
[36] ZHOU H Y，GAO F，YANG X L，et al. Endothelial BACE1 impairs cerebral small vessels via tight junctions and eNOS[J]. Circ Res，2022，130（9）：1321-1341.
[37] HAINSWORTH A H，FISHER M J. A dysfunctional blood-brain barrier and cerebral small vessel disease[J]. Neurology，2017，88（5）：420-421.
[38] WISEMAN S J，DOUBAL F N，CHAPPELL F M，et al. Plasma biomarkers of inflammation，endothelial function and hemostasis in cerebral small vessel disease[J]. Cerebrovasc Dis，2015，40（3/4）：157-164.
[39] ARIBISALA B S，WISEMAN S，MORRIS Z，et al. Circulating inflammatory markers are associated with magnetic resonance imaging-visible perivascular spaces but not directly with white matter hyperintensities[J]. Stroke，2014，45（2）：605-607.
[40] CHOI J C. Genetics of cerebral small vessel disease[J]. J Stroke，2015，17（1）：7-16.
[41] 张昊晗，秦晓明，吴颖颖，等. 携带非半胱氨酸NOTCH3基因突变的伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病患者五例临床及影像学特征分析[J]. 中华神经科杂志，2020，53（3）：184-191.
ZHANG H H，QIN X M，WU Y Y，et al. Analysis of clinical and imaging features of cysteine-sparing NOTCH3 gene missense mutations in five cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy patients[J]. Chin J Neurol，2020，53（3）：184-191.
[42] TAN R，TRAYLOR M，RUTTEN-JACOBS L，et al. New insights into mechanisms of small vessel disease stroke from genetics[J]. Clin Sci（Lond），2017，131（7）：515-531.
[43] WARDLAW J M，SMITH E E，BIESSELS G J，et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration[J]. Lancet Neurol，2013，12（8）：822-838.
[44] 叶瑾怡，王赞，龚宇田，等. 脑小血管病研究的神经影像学标准STRIVE-2——自2013年以来的新进展[J]. 中国卒中杂志，2023，18（10）：1160-1174.
YE J Y，WANG Z，GONG Y T，et al. Neuroimaging standards for research into cerebral small vessel disease（STRIVE-2）—advances since 2013[J]. Chin J Stroke，2023，18（10）：1160-1174.
[45] SHI Y L，WARDLAW J M. Update on cerebral small vessel disease：a dynamic whole-brain disease[J]. Stroke Vasc Neurol，2016，1（3）：83-92.
[46] WARDLAW J M，CHAPPELL F M，VALDÉS HERNÁNDEZ M D C，et al. White matter hyperintensity reduction and outcomes after minor stroke[J]. Neurology，2017，89（10）：1003-1010.
[47] WARDLAW J M，DEBETTE S，JOKINEN H，et al. ESO guideline on covert cerebral small vessel disease[J/OL]. Eur Stroke J，2021，6（2）：CXI-CLXII[2024-01-01]. https://doi.org/10.1177/23969873211012132.
[48] KWOK C S，SHOAMANESH A，COPLEY H C，et al. Efficacy of antiplatelet therapy in secondary prevention following lacunar stroke：pooled analysis of randomized trials[J]. Stroke，2015，46（4）：1014-1023.
[49] BLAIR G W，APPLETON J P，FLAHERTY K，et al. Tolerability，safety and intermediary pharmacological effects of cilostazol and isosorbide mononitrate，alone and combined，in patients with lacunar ischaemic stroke：the lacunar intervention-1（LACI-1）trial，a randomised clinical trial[J/OL]. EClinicalMedicine，2019，11：34-43[2024-01-01]. https://doi.org/10.1016/j.eclinm.2019.04.001.
[50] KIM B J，KWON S U，PARK J H，et al. Cilostazol versus aspirin in ischemic stroke patients with high-risk cerebral hemorrhage：subgroup analysis of the PICASSO trial[J]. Stroke，2020，51（3）：931-937.
[51] SPS3 INVESTIGATORS，BENAVENTE OR，HART RG，et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke[J]. N Engl J Med，2012，367（9）：817-825.
[52] CÔTÉ R，ZHANG Y，HART R G，et al. ASA failure：does the combination ASA/clopidogrel confer better long-term vascular protection？[J]. Neurology，2014，82（5）：382-389.
[53] XIE X W，JING J，MENG X，et al. Dual antiplatelet therapies and causes in minor stroke or transient ischemic attack：a prespecified analysis in the CHANCE-2 trial[J]. Stroke，2023，54（9）：2241-2250.
[54] NISHIYAMA Y，KIMURA K，OTSUKA T，et al. Dual antiplatelet therapy with cilostazol for secondary prevention in lacunar stroke：subanalysis of the CSPS.com trial[J]. Stroke，2023，54（3）：697-705.
[55] PERGOLA P E，WHITE C L，SZYCHOWSKI J M，et al. Achieved blood pressures in the secondary prevention of small subcortical strokes（SPS3）study：challenges and lessons learned[J]. Am J Hypertens，2014，27（8）：1052-1060.
[56] LAU K K，LI L，SIMONI M，et al. Long-term premorbid blood pressure and cerebral small vessel disease burden on imaging in transient ischemic attack and ischemic stroke[J]. Stroke，2018，49（9）：2053-2060.
[57] SPS3 STUDY GROUP，BENAVENTE O R，COFFEY C S，et al. Blood-pressure targets in patients with recent lacunar stroke：the SPS3 randomised trial[J]. Lancet，2013，382（9891）：507-515.
[58] CROALL I D，TOZER D J，MOYNIHAN B，et al. Effect of standard vs. intensive blood pressure control on cerebral blood flow in small vessel disease：the PRESERVE randomized clinical trial[J]. JAMA Neurol，2018，75（6）：720-727.
[59] DOLUI S，DETRE J A，GAUSSOIN S A，et al. Association of intensive vs. standard blood pressure control with cerebral blood flow：secondary analysis of the SPRINT MIND randomized clinical trial[J]. JAMA Neurol，2022，79（4）：380-389.
[60] RASHID T，LI K，TOLEDO J B，et al. Association of intensive vs. standard blood pressure control with regional changes in cerebral small vessel disease biomarkers：post hoc secondary analysis of the SPRINT MIND randomized clinical trial[J/OL]. JAMA Netw Open，2023，6（3）：e231055[2024-01-01]. https://doi.org/10.1001/jamanetworkopen. 2023.1055.
[61] GOLDSTEIN E D，WOLCOTT Z，GARG G，et al. Effect of antihypertensives by class on cerebral small vessel disease：a post hoc analysis of SPRINT-MIND[J]. Stroke，2022，53（8）：2435-2440.
[62] MARKUS H S，DE LEEUW F E. Cerebral small vessel disease：recent advances and future directions[J]. Int J Stroke，2023，18（1）：4-14.
[63] PFLANZ C P，EGLE M S，O’BRIEN J T，et al. Association of blood pressure lowering intensity with white matter network integrity in patients with cerebral small vessel disease[J/OL]. Neurology，2022，99（17）：e1945-e1953[2024-01-01]. https://doi.org/10.1212/WNL.0000000000201018.
[64] Stroke Prevetion by Aggressive Reduction in Cholestrol Levels Investigators，KARAM J G，LONEY-HUTCHINSON L，et al. High-dose atorvastatin after stroke or transient ischemic attack：the stroke prevention by aggressive reduction in cholesterol levels（SPARCL）investigators[J]. J Cardiometab Syndr，2008，3（1）：68-69.
[65] ZHANG H，CUI Y，ZHAO Y X，et al. Effects of sartans and low-dose statins on cerebral white matter hyperintensities and cognitive function in older patients with hypertension：a randomized，double-blind and placebo-controlled clinical trial[J]. Hypertens Res，2019，42（5）：717-729.
[66] GEORGAKIS M K，MALIK R，ANDERSON C D，et al. Genetic determinants of blood lipids and cerebral small vessel disease：role of high-density lipoprotein cholesterol[J]. Brain，2020，143（2）：597-610.
[67] TEN DAM V H，VAN DEN HEUVEL D M，VAN BUCHEM M A，et al. Effect of pravastatin on cerebral infarcts and white matter lesions[J]. Neurology，2005，64（10）：1807-1809.
[68] BALINT B，JEPCHUMBA V K，GUEANT J L，et al. Mechanisms of homocysteine-induced damage to the endothelial，medial and adventitial layers of the arterial wall[J/OL]. Biochimie，2020，173：100-106[2024-01-01]. https://doi.org/10.1016/j.biochi.
2020.02.012.
[69] NAM K W，KWON H M，JEONG H Y，et al. Serum homocysteine level is related to cerebral small vessel disease in a healthy population[J/OL]. Neurology，2019，92（4）：e317-e325[2024-01-01]. https://doi.org/10.1212/WNL.0000000000006816.
[70] CAO Y Z，SU N，ZHANG D D，et al. Correlation between total homocysteine and cerebral small vessel disease：a mendelian randomization study[J]. Eur J Neurol，2021，28（6）：1931-1938.
[71] WONG A，MOK V，FAN Y H，et al. Hyperhomocysteinemia is associated with volumetric white matter change in patients with small vessel disease[J]. J Neurol，2006，253（4）：441-447.
[72] VITATOPS Trial Study Group. B vitamins in patients with recent transient ischaemic attack or stroke in the vitamins to prevent stroke（VITATOPS）trial：a randomised，double-blind，parallel，placebo-controlled trial[J]. Lancet Neurol，2010，9（9）：855-865.
[73] CAVALIERI M，SCHMIDT R，CHEN C，et al. B vitamins and magnetic resonance imaging-detected ischemic brain lesions in patients with recent transient ischemic attack or stroke：the vitamins to prevent stroke（VITATOPS）MRI-substudy[J]. Stroke，2012，43（12）：3266-3270.
[74] MI T M，YU F，JI X M，et al. The interventional effect of remote ischemic preconditioning on cerebral small vessel disease：a pilot randomized clinical trial[J]. Eur Neurol，2016，76（1/2）：28-34.
[75] TEICH A F，SAKURAI M，PATEL M，et al. PDE5 exists in human neurons and is a viable therapeutic target for neurologic disease[J]. J Alzheimers Dis，2016，52（1）：295-302.
[76] VASITA E，YASMEEN S，ANDOH J，et al. The cGMP-degrading enzyme phosphodiesterase-5（PDE5）in cerebral small arteries of older people[J]. J Neuropathol Exp Neurol，2019，78（2）：191-194.
[77] FORGUE S T，PATTERSON B E，BEDDING A W，et al. Tadalafil pharmacokinetics in healthy subjects[J]. Br J Clin Pharmacol，2006，61（3）：280-288.
[78] GARCÍA-OSTA A，CUADRADO-TEJEDOR M，GARCÍA-BARROSO C，et al. Phosphodiesterases as therapeutic targets for Alzheimer’s disease[J]. ACS Chem Neurosci，2012，3（11）：832-844.
[79] PAULS M M H，BINNIE L R，BENJAMIN P，et al. The PASTIS trial：testing tadalafil for possible use in vascular cognitive impairment[J]. Alzheimers Dement，2022，18（12）：2393-2402.
[80] WISEMAN S，MARLBOROUGH F，DOUBAL F，et al. Blood markers of coagulation，fibrinolysis，endothelial dysfunction and inflammation in lacunar stroke versus non-lacunar stroke and non-stroke：systematic review and meta-analysis[J]. Cerebrovasc Dis，2014，37（1）：64-75.
[81] KLOPPENBORG R P，GEERLINGS M I，VISSEREN F L，et al. Homocysteine and progression of generalized small-vessel disease：the SMART-MR study[J]. Neurology，2014，82（9）：777-783.
[82] VILLASEÑOR R，KUENNECKE B，OZMEN L，et al. Region-specific permeability of the blood-brain barrier upon pericyte loss[J]. J Cereb Blood Flow Metab，2017，37（12）：3683-3694.
[83] MIWA K，OKAZAKI S，SAKAGUCHI M，et al. Interleukin-6，interleukin-6 receptor gene variant，small-vessel disease and incident dementia[J]. Eur J Neurol，2016，23（3）：656-663.
[84] LAVALLÉE P C，LABREUCHE J，FAILLE D，et al. Circulating markers of endothelial dysfunction and platelet activation in patients with severe symptomatic cerebral small vessel disease[J]. Cerebrovasc Dis，2013，36（2）：131-138.
[85] GAO Q，FAN Y，MU L Y，et al. S100B and ADMA in cerebral small vessel disease and cognitive dysfunction[J]. J Neurol Sci，2015，354（1/2）：27-32.
[86] NEZU T，HOSOMI N，AOKI S，et al. Alpha2-macroglobulin as a promising biomarker for cerebral small vessel disease in acute ischemic stroke patients[J]. J Neurol，2013，260（10）：2642-2649.
[87] 聂海宏，陈晓雪，张忠玲. 周细胞在脑小血管病发病机制中的作用[J]. 国际脑血管病杂志，2021，29（6）：463-466.
NEI H H，CHEN X X，ZHANG Z L. Role of pericytes in the pathogenesis of cerebral small vessel disease[J]. Int J Cerebrovasc Dis，2021，29（6）：463-466.
[88] MÄE M A，HE L，NORDLING S，et al. Single-cell analysis of blood-brain barrier response to pericyte loss
[J/OL]. Circ Res，2021，128（11）：e46-e62[2024-01-01]. https://doi.org/10.1161/CIRCRESAHA.120.317473.
[89] HUANG J，LI J W，FENG C，et al. Blood-brain barrier damage as the starting point of leukoaraiosis caused by cerebral chronic hypoperfusion and its involved mechanisms：effect of agrin and aquaporin-4[J/OL]. Biomed Res Int，2018，2018：2321797[2024-01-01]. https://doi.org/10.1155/2018/2321797.
[90] ARBA F，MAIR G，CARPENTER T，et al. Cerebral white matter hypoperfusion increases with small-vessel disease burden. data from the third international stroke trial[J]. J Stroke Cerebrovasc Dis，2017，26（7）：1506-1513.
[91] KATO T，MANABE R I，IGARASHI H，et al. Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model[J/OL]. J Clin Invest，2021，131（22）：e140555[2024-01-01]. https://doi.org/10.1172/JCI140555.
[92] MISHRA A，DUPLAÀ C，VOJINOVIC D，et al. Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate[J]. Brain，2022，145（6）：1992-2007.
[93] HARSHFIELD E L，SANDS C J，TULADHAR A M，et al. Metabolomic profiling in small vessel disease identifies multiple associations with disease severity[J]. Brain，2022，145（7）：2461-2471.
[94] SILASI G，SHE J，BOYD J D，et al. A mouse model of small-vessel disease that produces brain-wide-identified microocclusions and regionally selective neuronal injury[J]. J Cereb Blood Flow Metab，2015，35（5）：734-738.