Correlation between neutrophil gelatinase phase lipocalin and cerebral small vessel disease

Cerebral small vessel disease (CSVD) is common in the elderly population. Neutrophil gelatinase-associated lipocalin (NGAL) is closely related to cardiovascular and cerebrovascular diseases. NGAL causes pathological changes, such as damage to the vascular endothelium, by causing inflammation, which results in other related diseases. The purpose of this study was to investigate whether serum NGAL levels could predict disease severity in patients with CSVD.The patients with CSVD who visited the Department of Neurology at the First Affiliated Hospital of Zhengzhou University between January 2018 and June 2022 were prospectively included. The total CSVD burden score was calculated using whole-brain magnetic resonance imaging (MRI), and the patients were divided into a mild group (total CSVD burden score < 2 points) and a severe group (total CSVD burden score ≥ 2 points). Age, sex, height, smoking and alcohol consumption history, medical history, and serological results of patients were collected to perform the univariate analysis. Multivariate logistic regression was used to analyze the risk factors that affect CSVD severity. The multiple linear regression method was used to analyze which individual CSVD markers (periventricular white matter hyperintensities, deep white matter hyperintensities, lacune, and cerebral microbleed) play a role in the association between total CSVD burden score and NGAL.A total of 427 patients with CSVD (140 in the mild group and 287 in the severe group) were included in the study. A multivariate logistic regression analysis showed that the following factors were significantly associated with CSVD severity: male sex [odds ratio(OR), 1.912; 95% confidence interval (CI), 1.150–3.179], age (OR, 1.046; 95% CI, 1.022–1.070), history of cerebrovascular disease (OR, 3.050; 95% CI, 1.764–5.274), serum NGAL level (OR, 1.005; 95% CI, 1.002–1.008), and diabetes (OR, 2.593; 95% CI, 1.424–4.722). A multivariate linear regression shows that periventricular white matter hyperintensities and cerebral microbleed are associated with serum NGAL concentrations (P < 0.05).Serum NGAL level is closely related to CSVD severity and is a risk factor for the burden of CSVD brain damage. Serum NGAL has high specificity in reflecting the severity of CSVD.

[1]  Haiqing Song,et al.  Plasma inflammatory biomarkers in cerebral small vessel disease: A review , 2022, CNS neuroscience & therapeutics.

[2]  Ruijun Liu,et al.  Research progress on risk factors related to intracranial artery, carotid artery, and coronary artery stenosis , 2022, Frontiers in Cardiovascular Medicine.

[3]  H. Pawluk,et al.  Selected Mediators of Inflammation in Patients with Acute Ischemic Stroke , 2022, International journal of molecular sciences.

[4]  Danxi Li,et al.  Cerebral Small Vessel Disease: Neuroimaging Features, Biochemical Markers, Influencing Factors, Pathological Mechanism and Treatment , 2022, Frontiers in Neurology.

[5]  F. López-Espuela,et al.  Role of Inflammatory Cytokines in the Conversion of Mild Cognitive Im- pairment to Dementia: A Prospective Study. , 2022, Current Alzheimer research.

[6]  Jun Lu,et al.  Inflammatory Cytokines and Risk of Ischemic Stroke: A Mendelian Randomization Study , 2022, Frontiers in Pharmacology.

[7]  Wei Sun,et al.  Neutrophil Gelatinase-Associated Lipocalin 2 Accelerates Hypoxia-Induced Endothelial Cell Injury via eNOS/NRF2 Signalling , 2021, Cell journal.

[8]  C. Beyer,et al.  Lipocalin 2 as a Putative Modulator of Local Inflammatory Processes in the Spinal Cord and Component of Organ Cross talk After Spinal Cord Injury , 2021, Molecular Neurobiology.

[9]  A. Wu,et al.  Age-related cerebral small vessel disease and inflammaging , 2020, Cell Death & Disease.

[10]  M. Nagarkatti,et al.  Lipocalin 2 induces neuroinflammation and blood-brain barrier dysfunction through liver-brain axis in murine model of nonalcoholic steatohepatitis , 2020, Journal of Neuroinflammation.

[11]  J. O'Brien,et al.  Inflammation and cerebral small vessel disease: A systematic review , 2019, Ageing Research Reviews.

[12]  J. Jansen,et al.  Blood-brain barrier impairment and hypoperfusion are linked in cerebral small vessel disease , 2019, Neurology.

[13]  A. Brickman,et al.  Circulating inflammatory biomarkers are related to cerebrovascular disease in older adults , 2018, Neurology: Neuroimmunology & Neuroinflammation.

[14]  zhao yang,et al.  Interleukin 17A exacerbates ER‐stress‐mediated inflammation of macrophages following ICH , 2018, Molecular immunology.

[15]  H. Markus,et al.  Causal Impact of Type 2 Diabetes Mellitus on Cerebral Small Vessel Disease , 2018, Stroke.

[16]  N. Sousa,et al.  Lipocalin-2 regulates adult neurogenesis and contextual discriminative behaviours , 2018, Molecular Psychiatry.

[17]  Jinglei Lv,et al.  Effects of cerebral small vessel disease on the outcome of patients with ischemic stroke caused by large artery atherosclerosis , 2018, Neurological research.

[18]  P. Mulder,et al.  Aldosterone Target NGAL (Neutrophil Gelatinase–Associated Lipocalin) Is Involved in Cardiac Remodeling After Myocardial Infarction Through NF&kgr;B Pathway , 2017, Hypertension.

[19]  C. Iadecola.  The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease , 2017, Neuron.

[20]  V. Mok,et al.  Prevalence, risk factors and consequences of cerebral small vessel diseases: data from three Asian countries , 2017, Journal of Neurology, Neurosurgery, and Psychiatry.

[21]  P. Hofman,et al.  Blood–brain barrier leakage is more widespread in patients with cerebral small vessel disease , 2017, Neurology.

[22]  Joanna M Wardlaw,et al.  Update on cerebral small vessel disease: a dynamic whole-brain disease , 2016, Stroke and Vascular Neurology.

[23]  J. Wojta,et al.  Neutrophil Gelatinase-Associated Lipocalin (NGAL) is Associated with Symptomatic Carotid Atherosclerosis and Drives Pro-inflammatory State In Vitro. , 2016, European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery.

[24]  A. Papavassiliou,et al.  Novel biomarkers assessing renal function in heart failure: relation to inflammatory status and cardiac remodelling. , 2014, Current medicinal chemistry.

[25]  Joanna M. Wardlaw,et al.  Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden , 2014, Neurology.

[26]  G. Aksan,et al.  Serum neutrophil gelatinase-associated lipocalin levels are correlated with the complexity and the severity of atherosclerosis in acute coronary syndrome , 2014, Anatolian journal of cardiology.

[27]  Nick C Fox,et al.  Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration , 2013, The Lancet Neurology.

[28]  E. Vicaut,et al.  Cerebral and Extracerebral Vasoreactivity in Symptomatic Lacunar Stroke Patients: A Case-Control Study , 2013, International journal of stroke : official journal of the International Stroke Society.

[29]  M. Dichgans,et al.  Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging , 2013, The Lancet Neurology.

[30]  A. Friedman,et al.  Pathophysiology of the Neurovascular Unit: Disease Cause or Consequence? , 2012, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[31]  F. Málek.  [The importance of NGAL and cystatin C biomarkers in cardiovascular diseases-editorial]. , 2012, Vnitrni lekarstvi.

[32]  J. Morris,et al.  The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[33]  L. Pantoni.  Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges , 2010, The Lancet Neurology.

[34]  Karen J. Ferguson,et al.  Enlarged Perivascular Spaces on MRI Are a Feature of Cerebral Small Vessel Disease , 2010, Stroke.

[35]  G. Lip,et al.  Glycemic Status Underlies Increased Arterial Stiffness and Impaired Endothelial Function in Migrant South Asian Stroke Survivors Compared to European Caucasians: Pathophysiological Insights From the West Birmingham Stroke Project , 2009, Stroke.

[36]  Joanna M. Wardlaw,et al.  Blood–brain barrier: Ageing and microvascular disease – systematic review and meta-analysis , 2009, Neurobiology of Aging.

[37]  E. Tolosa,et al.  Clinical diagnostic criteria for dementia associated with Parkinson's disease , 2007, Movement disorders : official journal of the Movement Disorder Society.

[38]  J. Reckelhoff.  Cardiovascular disease, estrogen deficiency, and inflammatory cytokines. , 2006, Hypertension.

[39]  G. Rosenberg,et al.  Blood–brain barrier disruption by stromelysin-1 facilitates neutrophil infiltration in neuroinflammation , 2006, Neurobiology of Disease.

[40]  J. Sundberg,et al.  Role of COL4A1 in small-vessel disease and hemorrhagic stroke. , 2006, The New England journal of medicine.

[41]  A. Gabrielsen,et al.  Expression of Neutrophil Gelatinase–Associated Lipocalin in Atherosclerosis and Myocardial Infarction , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[42]  C. Betsholtz,et al.  Endothelial/Pericyte Interactions , 2005, Circulation research.

[43]  D. Corbett,et al.  Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases , 2003, Annals of neurology.

[44]  P. Sandercock,et al.  Is Breakdown of the Blood-Brain Barrier Responsible for Lacunar Stroke, Leukoaraiosis, and Dementia? , 2003, Stroke.

[45]  A. Hofman,et al.  1H chemical shift imaging of the human brain at age 60–90 years reveals metabolic differences between women and men , 1999, Magnetic resonance in medicine.

[46]  H. Kessler,et al.  The solution structure and dynamics of human neutrophil gelatinase-associated lipocalin. , 1999, Journal of molecular biology.

[47]  D. Harrison,et al.  Cellular and molecular mechanisms of endothelial cell dysfunction. , 1997, The Journal of clinical investigation.

[48]  H. Sengeløv,et al.  Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. , 1993, The Journal of biological chemistry.

[49]  A. Alavi,et al.  MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. , 1987, AJR. American journal of roentgenology.