Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Molecular biomarkers for vascular cognitive impairment and dementia

Nature Reviews Neurology volume 19, pages 737–753 (2023)Cite this article

Subjects

Abstract

As disease-specific interventions for dementia are being developed, the ability to identify the underlying pathology and dementia subtypes is increasingly important. Vascular cognitive impairment and dementia (VCID) is the second most common cause of dementia after Alzheimer disease, but progress in identifying molecular biomarkers for accurate diagnosis of VCID has been relatively limited. In this Review, we examine the roles of large and small vessel disease in VCID, considering the underlying pathophysiological processes that lead to vascular brain injury, including atherosclerosis, arteriolosclerosis, ischaemic injury, haemorrhage, hypoperfusion, endothelial dysfunction, blood–brain barrier breakdown, inflammation, oxidative stress, hypoxia, and neuronal and glial degeneration. We consider the key molecules in these processes, including proteins and peptides, metabolites, lipids and circulating RNA, and consider their potential as molecular biomarkers alone and in combination. We also discuss the challenges in translating the promise of these biomarkers into clinical application.

Key points

  • VCID has multiple underlying pathologies that can contribute to cognitive impairment.

  • Identification of molecular biomarkers that can differentiate VCID from healthy ageing and Alzheimer disease remains challenging.

  • Multiple molecular biomarkers have been associated with VCID, but none has yet been translated into clinical application.

  • The heterogeneity and complexity of VCID means that use of multiple biomarkers in combination tends to be necessary.

  • Promising biomarkers related to various pathophysiological pathways could be combined into panels to optimize sensitivity and specificity; machine learning could be useful for constructing these panels.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Pathophysiological processes of vascular cognitive impairment and dementia, their interactions and potential biomarkers.

Similar content being viewed by others

References

  1. Gorelick, P. B. et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42, 2672–2713 (2011). An overall guide for practitioners to gain a better understanding of VCID.

    PubMed  PubMed Central  Google Scholar 

  2. Kalaria, R. N. & Ballard, C. Overlap between pathology of Alzheimer disease and vascular dementia. Alzheimer Dis. Assoc. Disord. 13, S115–S123 (1999).

    PubMed  Google Scholar 

  3. Iadecola, C. et al. Vascular cognitive impairment and dementia: JACC Scientific Expert Panel. J. Am. Coll. Cardiol. 73, 3326–3344 (2019). A critical appraisal of the epidemiology, pathobiology, neuropathology and neuroimaging of VCID.

    PubMed  PubMed Central  Google Scholar 

  4. Simrén, J. et al. The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer’s disease. Alzheimers Dement. 17, 1145–1156 (2021).

    PubMed  PubMed Central  Google Scholar 

  5. Jack, C. R. Jr. et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 14, 535–562 (2018).

    PubMed  PubMed Central  Google Scholar 

  6. Iadecola, C. The pathobiology of vascular dementia. Neuron 80, 844–866 (2013). A review of the pathophysiology of VCID.

    CAS  PubMed  Google Scholar 

  7. van der Flier, W. M. et al. Vascular cognitive impairment. Nat. Rev. Dis. Prim. 4, 18003 (2018). A comprehensive review of VCID.

    PubMed  Google Scholar 

  8. Zhou, X. J., Vaziri, N. D., Wang, X. Q., Silva, F. G. & Laszik, Z. Nitric oxide synthase expression in hypertension induced by inhibition of glutathione synthase. J. Pharmacol. Exp. Ther. 300, 762–767 (2002).

    CAS  PubMed  Google Scholar 

  9. Dowsett, L. et al. ADMA: a key player in the relationship between vascular dysfunction and inflammation in atherosclerosis. J. Clin. Med. 9, 3026 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Iadecola, C. & Gottesman, R. F. Neurovascular and cognitive dysfunction in hypertension. Circ. Res. 124, 1025–1044 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Iadecola, C. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96, 17–42 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Kernagis, D. N. & Laskowitz, D. T. Evolving role of biomarkers in acute cerebrovascular disease. Ann. Neurol. 71, 289–303 (2012).

    CAS  PubMed  Google Scholar 

  13. Faraco, G. et al. Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response. Nat. Neurosci. 21, 240–249 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Faraco, G. et al. Dietary salt promotes cognitive impairment through tau phosphorylation. Nature 574, 686–690 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Shimokawa, H. & Godo, S. Nitric oxide and endothelium-dependent hyperpolarization mediated by hydrogen peroxide in health and disease. Basic Clin. Pharmacol. Toxicol. 127, 92–101 (2020).

    CAS  PubMed  Google Scholar 

  16. Zlokovic, B. V. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat. Rev. Neurosci. 12, 723–738 (2011). A review of pathophysiology of the neurovascular unit.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Sweeney, M. D., Sagare, A. P. & Zlokovic, B. V. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol. 14, 133–150 (2018). A review of the blood–brain barrier in Alzheimer disease and other neurodegenerative disorders.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Nation, D. A. et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat. Med. 25, 270–276 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Sweeney, M. D. et al. A novel sensitive assay for detection of a biomarker of pericyte injury in cerebrospinal fluid. Alzheimers Dement. 16, 821–830 (2020).

    PubMed  PubMed Central  Google Scholar 

  20. Rosenberg, G. A. Willis lecture: biomarkers for inflammatory white matter injury in Binswanger disease provide pathways to precision medicine. Stroke 53, 3514–3523 (2022).

    PubMed  PubMed Central  Google Scholar 

  21. Nikolakopoulou, A. M. et al. Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss. Nat. Neurosci. 22, 1089–1098 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Procter, T. V., Williams, A. & Montagne, A. Interplay between brain pericytes and endothelial cells in dementia. Am. J. Pathol. 191, 1917–1931 (2021).

    CAS  PubMed  Google Scholar 

  23. Armulik, A. et al. Pericytes regulate the blood-brain barrier. Nature 468, 557–561 (2010).

    CAS  PubMed  Google Scholar 

  24. Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C. & Gage, F. H. Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918–934 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Touyz, R. M. & Briones, A. M. Reactive oxygen species and vascular biology: implications in human hypertension. Hypertens. Res. 34, 5–14 (2011).

    CAS  PubMed  Google Scholar 

  26. Mayhan, W. G., Arrick, D. M., Sharpe, G. M. & Sun, H. Age-related alterations in reactivity of cerebral arterioles: role of oxidative stress. Microcirculation 15, 225–236 (2008).

    CAS  PubMed  Google Scholar 

  27. Dong, Y. F. et al. Attenuation of brain damage and cognitive impairment by direct renin inhibition in mice with chronic cerebral hypoperfusion. Hypertension 58, 635–642 (2011).

    CAS  PubMed  Google Scholar 

  28. Santhanam, A. V., d’Uscio, L. V. & Katusic, Z. S. Erythropoietin increases bioavailability of tetrahydrobiopterin and protects cerebral microvasculature against oxidative stress induced by eNOS uncoupling. J. Neurochem. 131, 521–529 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Prasad, K. AGE-RAGE stress: a changing landscape in pathology and treatment of Alzheimer’s disease. Mol. Cell Biochem. 459, 95–112 (2019).

    CAS  PubMed  Google Scholar 

  30. Tang, Y. & Le, W. Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol. Neurobiol. 53, 1181–1194 (2016).

    CAS  PubMed  Google Scholar 

  31. Guo, S., Wang, H. & Yin, Y. Microglia polarization from M1 to M2 in neurodegenerative diseases. Front. Aging Neurosci. 14, 815347 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Kim, E., Otgontenger, U., Jamsranjav, A. & Kim, S. S. Deleterious alteration of glia in the brain of Alzheimer’s disease. Int. J. Mol. Sci. 21, 6676 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Chen, B., Cheng, Q., Yang, K. & Lyden, P. D. Thrombin mediates severe neurovascular injury during ischemia. Stroke 41, 2348–2352 (2010).

    CAS  PubMed  Google Scholar 

  34. Zoia, A., Drigo, M., Caldin, M., Simioni, P. & Piek, C. J. Fibrinolysis in dogs with intracavitary effusion: a review. Animals 12, 2487 (2022).

    PubMed  PubMed Central  Google Scholar 

  35. Chen, Z. L. & Strickland, S. Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell 91, 917–925 (1997).

    CAS  PubMed  Google Scholar 

  36. Ihara, M. et al. Chronic cerebral hypoperfusion induces MMP-2 but not MMP-9 expression in the microglia and vascular endothelium of white matter. J. Cereb. Blood Flow Metab. 21, 828–834 (2001).

    CAS  PubMed  Google Scholar 

  37. Arai, K. & Lo, E. H. An oligovascular niche: cerebral endothelial cells promote the survival and proliferation of oligodendrocyte precursor cells. J. Neurosci. 29, 4351–4355 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Ihara, M. & Tomimoto, H. Lessons from a mouse model characterizing features of vascular cognitive impairment with white matter changes. J. Aging Res. 2011, 978761 (2011).

    PubMed  PubMed Central  Google Scholar 

  39. Rosenberg, G. A. Binswanger’s disease: biomarkers in the inflammatory form of vascular cognitive impairment and dementia. J. Neurochem. 144, 634–643 (2018).

    CAS  PubMed  Google Scholar 

  40. Wardlaw, J. M. et al. Vascular risk factors, large-artery atheroma, and brain white matter hyperintensities. Neurology 82, 1331–1338 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Saadoun, D., Vautier, M. & Cacoub, P. Medium- and large-vessel vasculitis. Circulation 143, 267–282 (2021).

    CAS  PubMed  Google Scholar 

  42. Sun, Z. Aging, arterial stiffness, and hypertension. Hypertension 65, 252–256 (2015).

    CAS  PubMed  Google Scholar 

  43. Gaengel, K., Genové, G., Armulik, A. & Betsholtz, C. Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler. Thromb. Vasc. Biol. 29, 630–638 (2009).

    CAS  PubMed  Google Scholar 

  44. Silva, I. T., Mello, A. P. & Damasceno, N. R. Antioxidant and inflammatory aspects of lipoprotein-associated phospholipase A2 (Lp-PLA2): a review. Lipids Health Dis. 10, 170 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Huang, Y. T., Hong, F. F. & Yang, S. L. Atherosclerosis: the culprit and co-victim of vascular dementia. Front. Neurosci. 15, 673440 (2021).

    PubMed  PubMed Central  Google Scholar 

  46. Velican, C. Studies on the age-related changes occurring in human cerebral arteries. Atherosclerosis 11, 509–529 (1970).

    CAS  PubMed  Google Scholar 

  47. Ritz, K., Denswil, N. P., Stam, O. C., van Lieshout, J. J. & Daemen, M. J. Cause and mechanisms of intracranial atherosclerosis. Circulation 130, 1407–1414 (2014). A review of the pathophysiology of intracranial atherosclerosis.

    PubMed  Google Scholar 

  48. Resch, J. A. & Baker, A. B. Etiologic mechanisms in cerebral atherosclerosis. Preliminary study of 3,839 cases. Arch. Neurol. 10, 617–628 (1964).

    CAS  PubMed  Google Scholar 

  49. D’Armiento, F. P. et al. Age-related effects on atherogenesis and scavenger enzymes of intracranial and extracranial arteries in men without classic risk factors for atherosclerosis. Stroke 32, 2472–2479 (2001).

    PubMed  Google Scholar 

  50. Fatkin, D., Kelly, R. P. & Feneley, M. P. Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. J. Am. Coll. Cardiol. 23, 961–969 (1994).

    CAS  PubMed  Google Scholar 

  51. Blann, A. D., Nadar, S. K. & Lip, G. Y. The adhesion molecule P-selectin and cardiovascular disease. Eur. Heart J. 24, 2166–2179 (2003).

    CAS  PubMed  Google Scholar 

  52. Kamel, H., Okin, P. M., Elkind, M. S. & Iadecola, C. Atrial fibrillation and mechanisms of stroke: time for a new model. Stroke 47, 895–900 (2016).

    PubMed  PubMed Central  Google Scholar 

  53. Magid-Bernstein, J. et al. Cerebral hemorrhage: pathophysiology, treatment, and future directions. Circ. Res. 130, 1204–1229 (2022). A review of the pathophysiology of cerebral haemorrhage.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Jolink, W. M. T. et al. Location-specific risk factors for intracerebral hemorrhage: systematic review and meta-analysis. Neurology 95, e1807–e1818 (2020).

    CAS  PubMed  Google Scholar 

  55. Kremer, P. H., Jolink, W. M., Kappelle, L. J., Algra, A. & Klijn, C. J. Risk factors for lobar and non-lobar intracerebral hemorrhage in patients with vascular disease. PLoS ONE 10, e0142338 (2015).

    PubMed  PubMed Central  Google Scholar 

  56. Magaki, S. et al. Charcot-Bouchard aneurysms revisited: clinicopathologic correlations. Mod. Pathol. 34, 2109–2121 (2021).

    PubMed  PubMed Central  Google Scholar 

  57. Jin, J. et al. Inflammation and immune cell abnormalities in intracranial aneurysm subarachnoid hemorrhage (SAH): relevant signaling pathways and therapeutic strategies. Front. Immunol. 13, 1027756 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Aoki, T. & Nishimura, M. Targeting chronic inflammation in cerebral aneurysms: focusing on NF-kappaB as a putative target of medical therapy. Expert Opin. Ther. Targets 14, 265–273 (2010).

    CAS  PubMed  Google Scholar 

  59. Aoki, T. & Narumiya, S. Prostaglandins and chronic inflammation. Trends Pharmacol. Sci. 33, 304–311 (2012).

    CAS  PubMed  Google Scholar 

  60. Zhang, Z. et al. New mechanisms and targets of subarachnoid hemorrhage: a focus on mitochondria. Curr. Neuropharmacol. 20, 1278–1296 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Budohoski, K. P. et al. The pathophysiology and treatment of delayed cerebral ischaemia following subarachnoid haemorrhage. J. Neurol. Neurosurg. Psychiatry 85, 1343–1353 (2014). A review of the pathophysiology of subarachnoid haemorrhage.

    PubMed  Google Scholar 

  62. National Center for Advancing Translational Sciences (NCATS). Toolkit for patient-focused therapy development. https://toolkit.ncats.nih.gov/module/discovery/developing-translational-research-tools/biomarkers/ (accessed 19 October 2023).

  63. Shoamanesh, A. et al. Inflammatory biomarkers, cerebral microbleeds, and small vessel disease: Framingham Heart Study. Neurology 84, 825–832 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Zuliani, G. et al. Markers of endothelial dysfunction in older subjects with late onset Alzheimer’s disease or vascular dementia. J. Neurol. Sci. 272, 164–170 (2008).

    CAS  PubMed  Google Scholar 

  65. El Husseini, N. et al. Vascular cellular adhesion molecule-1 (VCAM-1) and memory impairment in African-Americans after small vessel-type stroke. J. Stroke Cerebrovasc. Dis. 29, 104646 (2020).

    PubMed  Google Scholar 

  66. Engelhart, M. J. et al. Inflammatory proteins in plasma and the risk of dementia: the Rotterdam Study. Arch. Neurol. 61, 668–672 (2004).

    PubMed  Google Scholar 

  67. Lavallee, P. C. et al. Circulating markers of endothelial dysfunction and platelet activation in patients with severe symptomatic cerebral small vessel disease. Cerebrovasc. Dis. 36, 131–138 (2013).

    CAS  PubMed  Google Scholar 

  68. Janes, F. et al. ADMA as a possible marker of endothelial damage. A study in young asymptomatic patients with cerebral small vessel disease. Sci. Rep. 9, 14207 (2019).

    PubMed  PubMed Central  Google Scholar 

  69. Pikula, A. et al. Association of plasma ADMA levels with MRI markers of vascular brain injury: Framingham Offspring Study. Stroke 40, 2959–2964 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Gao, Q. et al. S100B and ADMA in cerebral small vessel disease and cognitive dysfunction. J. Neurol. Sci. 354, 27–32 (2015).

    CAS  PubMed  Google Scholar 

  71. Notsu, Y. et al. Evaluation of asymmetric dimethylarginine and homocysteine in microangiopathy-related cerebral damage. Am. J. Hypertens. 22, 257–262 (2009).

    CAS  PubMed  Google Scholar 

  72. Ihara, M., Washida, K., Yoshimoto, T. & Saito, S. Adrenomedullin: a vasoactive agent for sporadic and hereditary vascular cognitive impairment. Cereb. Circ. Cogn. Behav. 2, 100007 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Kis, B. et al. Cerebral endothelial cells are a major source of adrenomedullin. J. Neuroendocrinol. 14, 283–293 (2002).

    CAS  PubMed  Google Scholar 

  74. Kuriyama, N. et al. Association between mid-regional proadrenomedullin levels and progression of deep white matter lesions in the brain accompanying cognitive decline. J. Alzheimers Dis. 56, 1253–1262 (2017).

    CAS  PubMed  Google Scholar 

  75. Carmeliet, P. et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat. Med. 7, 575–583 (2001).

    CAS  PubMed  Google Scholar 

  76. Hinman, J. D. et al. Placental growth factor as a sensitive biomarker for vascular cognitive impairment. Alzheimers Dement. 19, 3519–3527 (2023).

    CAS  PubMed  Google Scholar 

  77. Luna, R. L. et al. Placental growth factor deficiency is associated with impaired cerebral vascular development in mice. Mol. Hum. Reprod. 22, 130–142 (2016).

    CAS  PubMed  Google Scholar 

  78. Erhardt, E. B. et al. Inflammatory biomarkers aid in diagnosis of dementia. Front. Aging Neurosci. 13, 717344 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang, J. et al. Dynamic changes of CSF sPDGFRβ during ageing and AD progression and associations with CSF ATN biomarkers. Mol. Neurodegener. 17, 9 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Sagare, A. P., Sweeney, M. D., Makshanoff, J. & Zlokovic, B. V. Shedding of soluble platelet-derived growth factor receptor-β from human brain pericytes. Neurosci. Lett. 607, 97–101 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Montagne, A. et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85, 296–302 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Miners, J. S., Kehoe, P. G., Love, S., Zetterberg, H. & Blennow, K. CSF evidence of pericyte damage in Alzheimer’s disease is associated with markers of blood-brain barrier dysfunction and disease pathology. Alzheimers Res. Ther. 11, 81 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Lv, X. et al. Changes in CSF sPDGFRβ level and their association with blood-brain barrier breakdown in Alzheimer’s disease with or without small cerebrovascular lesions. Alzheimers Res. Ther. 15, 51 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Bjerke, M. et al. Cerebrospinal fluid matrix metalloproteinases and tissue inhibitor of metalloproteinases in combination with subcortical and cortical biomarkers in vascular dementia and Alzheimer’s disease. J. Alzheimers Dis. 27, 665–676 (2011).

    CAS  PubMed  Google Scholar 

  85. Adair, J. C. et al. Measurement of gelatinase B (MMP-9) in the cerebrospinal fluid of patients with vascular dementia and Alzheimer disease. Stroke 35, e159–e162 (2004).

    CAS  PubMed  Google Scholar 

  86. Candelario-Jalil, E. et al. Matrix metalloproteinases are associated with increased blood-brain barrier opening in vascular cognitive impairment. Stroke 42, 1345–1350 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Erhardt, E. B. et al. Biomarkers identify the Binswanger type of vascular cognitive impairment. J. Cereb. Blood Flow Metab. 39, 1602–1612 (2019).

    Google Scholar 

  88. Gong, M. & Jia, J. Contribution of blood-brain barrier-related blood-borne factors for Alzheimer’s disease vs. vascular dementia diagnosis: a pilot study. Front. Neurosci. 16, 949129 (2022).

    PubMed  PubMed Central  Google Scholar 

  89. Wallin, A. et al. Biochemical markers in vascular cognitive impairment associated with subcortical small vessel disease — a consensus report. BMC Neurol. 17, 102 (2017). A review of biomarkers associated with VCID.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Skillback, T. et al. CSF/serum albumin ratio in dementias: a cross-sectional study on 1861 patients. Neurobiol. Aging 59, 1–9 (2017).

    PubMed  Google Scholar 

  91. Kettunen, P. et al. Blood-brain barrier dysfunction and reduced cerebrospinal fluid levels of soluble amyloid precursor protein-β in patients with subcortical small-vessel disease. Alzheimers Dement. 14, e12296 (2022).

    Google Scholar 

  92. Li, L. et al. Oxidative LDL modification is increased in vascular dementia and is inversely associated with cognitive performance. Free Radic. Res. 44, 241–248 (2010).

    CAS  PubMed  Google Scholar 

  93. Murr, J., Carmichael, P. H., Julien, P. & Laurin, D. Plasma oxidized low-density lipoprotein levels and risk of Alzheimer’s disease. Neurobiol. Aging 35, 1833–1838 (2014).

    CAS  PubMed  Google Scholar 

  94. Fitzpatrick, A. L. et al. Lipoprotein-associated phospholipase A2 and risk of dementia in the Cardiovascular Health Study. Atherosclerosis 235, 384–391 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Wright, C. B. et al. Inflammatory biomarkers of vascular risk as correlates of leukoariosis. Stroke 40, 3466–3471 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Esterbauer, H., Schaur, R. J. & Zollner, H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic. Biol. Med. 11, 81–128 (1991).

    CAS  PubMed  Google Scholar 

  97. Gustaw-Rothenberg, K., Kowalczuk, K. & Stryjecka-Zimmer, M. Lipids’ peroxidation markers in Alzheimer’s disease and vascular dementia. Geriatr. Gerontol. Int. 10, 161–166 (2010).

    PubMed  Google Scholar 

  98. Polidori, M. C. et al. Plasma antioxidant status, immunoglobulin g oxidation and lipid peroxidation in demented patients: relevance to Alzheimer disease and vascular dementia. Dement. Geriatr. Cogn. Disord. 18, 265–270 (2004).

    CAS  PubMed  Google Scholar 

  99. Helmy, A. A., Naseer, M. M., Shafie, S. E. & Nada, M. A. Role of interleukin 6 and alpha-globulins in differentiating Alzheimer and vascular dementias. Neurodegener. Dis. 9, 81–86 (2012).

    CAS  PubMed  Google Scholar 

  100. Wada-Isoe, K., Wakutani, Y., Urakami, K. & Nakashima, K. Elevated interleukin-6 levels in cerebrospinal fluid of vascular dementia patients. Acta Neurol. Scand. 110, 124–127 (2004).

    CAS  PubMed  Google Scholar 

  101. Nagai, K., Kozaki, K., Sonohara, K., Akishita, M. & Toba, K. Relationship between interleukin-6 and cerebral deep white matter and periventricular hyperintensity in elderly women. Geriatr. Gerontol. Int. 11, 328–332 (2011).

    PubMed  Google Scholar 

  102. Hoshi, T. et al. Serum inflammatory proteins and frontal lobe dysfunction in patients with cardiovascular risk factors. Eur. J. Neurol. 17, 1134–1140 (2010).

    CAS  PubMed  Google Scholar 

  103. Aribisala, B. S. et al. Circulating inflammatory markers are associated with magnetic resonance imaging-visible perivascular spaces but not directly with white matter hyperintensities. Stroke 45, 605–607 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. De Luigi, A. et al. Peripheral inflammatory response in Alzheimer’s disease and multiinfarct dementia. Neurobiol. Dis. 11, 308–314 (2002).

    PubMed  Google Scholar 

  105. Tarkowski, E., Blennow, K., Wallin, A. & Tarkowski, A. Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J. Clin. Immunol. 19, 223–230 (1999).

    CAS  PubMed  Google Scholar 

  106. Sproston, N. R. & Ashworth, J. J. Role of C-reactive protein at sites of inflammation and infection. Front. Immunol. 9, 754 (2018).

    PubMed  PubMed Central  Google Scholar 

  107. Shang, J. et al. Different associations of plasma biomarkers in Alzheimer’s disease, mild cognitive impairment, vascular dementia, and ischemic stroke. J. Clin. Neurol. 14, 29–34 (2018).

    PubMed  Google Scholar 

  108. Vishnu, V. Y. et al. Role of inflammatory and hemostatic biomarkers in Alzheimer’s and vascular dementia — a pilot study from a tertiary center in Northern India. Asian J. Psychiatry 29, 59–62 (2017).

    CAS  Google Scholar 

  109. Ke, X. J. & Zhang, J. J. Changes in HIF-1alpha, VEGF, NGF and BDNF levels in cerebrospinal fluid and their relationship with cognitive impairment in patients with cerebral infarction. J. Huazhong Univ. Sci. Technol. Med. Sci. 33, 433–437 (2013).

    CAS  Google Scholar 

  110. Satizabal, C. L., Zhu, Y. C., Mazoyer, B., Dufouil, C. & Tzourio, C. Circulating IL-6 and CRP are associated with MRI findings in the elderly: the 3C-Dijon Study. Neurology 78, 720–727 (2012).

    CAS  PubMed  Google Scholar 

  111. van Dijk, E. J. et al. C-reactive protein and cerebral small-vessel disease: the Rotterdam Scan Study. Circulation 112, 900–905 (2005).

    PubMed  Google Scholar 

  112. Mitaki, S., Nagai, A., Oguro, H. & Yamaguchi, S. C-reactive protein levels are associated with cerebral small vessel-related lesions. Acta Neurol. Scand. 133, 68–74 (2016).

    CAS  PubMed  Google Scholar 

  113. Wada, M. et al. Cerebral small vessel disease and C-reactive protein: results of a cross-sectional study in community-based Japanese elderly. J. Neurol. Sci. 264, 43–49 (2008).

    CAS  PubMed  Google Scholar 

  114. Miralbell, J. et al. Cognitive patterns in relation to biomarkers of cerebrovascular disease and vascular risk factors. Cerebrovasc. Dis. 36, 98–105 (2013).

    CAS  PubMed  Google Scholar 

  115. Masumura, M., Hata, R., Nagai, Y. & Sawada, T. Oligodendroglial cell death with DNA fragmentation in the white matter under chronic cerebral hypoperfusion: comparison between normotensive and spontaneously hypertensive rats. Neurosci. Res. 39, 401–412 (2001).

    CAS  PubMed  Google Scholar 

  116. De Luigi, A. et al. Inflammatory markers in Alzheimer’s disease and multi-infarct dementia. Mech. Ageing Dev. 122, 1985–1995 (2001).

    PubMed  Google Scholar 

  117. Ali, M. & Bracko, O. VEGF paradoxically reduces cerebral blood flow in Alzheimer’s disease mice. Neurosci. Insights 17, 26331055221109254 (2022).

    PubMed  PubMed Central  Google Scholar 

  118. Tarkowski, E. et al. Increased intrathecal levels of the angiogenic factors VEGF and TGF-beta in Alzheimer’s disease and vascular dementia. Neurobiol. Aging 23, 237–243 (2002).

    CAS  PubMed  Google Scholar 

  119. Chakraborty, A. et al. Vascular endothelial growth factor remains unchanged in cerebrospinal fluid of patients with Alzheimer’s disease and vascular dementia. Alzheimers Res. Ther. 10, 58 (2018).

    PubMed  PubMed Central  Google Scholar 

  120. Rapisarda, A. & Melillo, G. Role of the VEGF/VEGFR axis in cancer biology and therapy. Adv. Cancer Res. 114, 237–267 (2012).

    CAS  PubMed  Google Scholar 

  121. Trares, K. et al. Association of the inflammation-related proteome with dementia development at older age: results from a large, prospective, population-based cohort study. Alzheimers Res. Ther. 14, 128 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Lazarovici, P., Marcinkiewicz, C. & Lelkes, P. I. Cross talk between the cardiovascular and nervous systems: neurotrophic effects of vascular endothelial growth factor (VEGF) and angiogenic effects of nerve growth factor (NGF) — implications in drug development. Curr. Pharm. Des. 12, 2609–2622 (2006).

    CAS  PubMed  Google Scholar 

  123. Kandasamy, M. et al. TGF-β signaling: a therapeutic target to reinstate regenerative plasticity in vascular dementia? Aging Dis. 11, 828–850 (2020).

    PubMed  PubMed Central  Google Scholar 

  124. Malaguarnera, L., Motta, M., Di Rosa, M., Anzaldi, M. & Malaguarnera, M. Interleukin-18 and transforming growth factor-beta 1 plasma levels in Alzheimer’s disease and vascular dementia. Neuropathology 26, 307–312 (2006).

    PubMed  Google Scholar 

  125. Dong, H., Zhang, Y., Huang, Y. & Deng, H. Pathophysiology of RAGE in inflammatory diseases. Front. Immunol. 13, 931473 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Tang, S. C. et al. Elevated plasma level of soluble form of RAGE in ischemic stroke patients with dementia. Neuromol. Med. 19, 579–583 (2017).

    CAS  Google Scholar 

  127. Qian, L. et al. Early biomarkers for post-stroke cognitive impairment. J. Neurol. 259, 2111–2118 (2012).

    CAS  PubMed  Google Scholar 

  128. Kim, O. Y. & Song, J. The importance of BDNF and RAGE in diabetes-induced dementia. Pharmacol. Res. 160, 105083 (2020).

    CAS  PubMed  Google Scholar 

  129. Huang, L. K. et al. Plasma phosphorylated-tau181 is a predictor of post-stroke cognitive impairment: a longitudinal study. Front. Aging Neurosci. 14, 889101 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Pinto-Benito, D., Paradela-Leal, C., Ganchala, D., de Castro-Molina, P. & Arevalo, M. A. IGF-1 regulates astrocytic phagocytosis and inflammation through the p110α isoform of PI3K in a sex-specific manner. Glia 70, 1153–1169 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Toth, P. et al. IGF-1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice. J. Cereb. Blood Flow Metab. 34, 1887–1897 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Quinlan, P., Horvath, A., Nordlund, A., Wallin, A. & Svensson, J. Low serum insulin-like growth factor-I (IGF-I) level is associated with increased risk of vascular dementia. Psychoneuroendocrinology 86, 169–175 (2017).

    CAS  PubMed  Google Scholar 

  133. Ban, Y. et al. Impact of increased plasma serotonin levels and carotid atherosclerosis on vascular dementia. Atherosclerosis 195, 153–159 (2007).

    CAS  PubMed  Google Scholar 

  134. Kang, J. et al. Positive association between serum insulin-like growth factor-1 and cognition in patients with cerebral small vessel disease. J. Stroke Cerebrovasc. Dis. 30, 105790 (2021).

    PubMed  Google Scholar 

  135. Suk, K. Lipocalin-2 as a therapeutic target for brain injury: an astrocentric perspective. Prog. Neurobiol. 144, 158–172 (2016).

    CAS  PubMed  Google Scholar 

  136. Llorens, F. et al. Cerebrospinal fluid lipocalin 2 as a novel biomarker for the differential diagnosis of vascular dementia. Nat. Commun. 11, 619 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Ojala, J. O., Sutinen, E. M., Salminen, A. & Pirttilä, T. Interleukin-18 increases expression of kinases involved in tau phosphorylation in SH-SY5Y neuroblastoma cells. J. Neuroimmunol. 205, 86–93 (2008).

    CAS  PubMed  Google Scholar 

  138. Altendahl, M. et al. An IL-18-centered inflammatory network as a biomarker for cerebral white matter injury. PLoS ONE 15, e0227835 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Mossanen Parsi, M., Duval, C. & Ariëns, R. A. S. Vascular dementia and crosstalk between the complement and coagulation systems. Front. Cardiovasc. Med. 8, 803169 (2021).

    PubMed  PubMed Central  Google Scholar 

  140. Pyun, J. M., Ryoo, N., Park, Y. H. & Kim, S. Fibrinogen levels and cognitive profile differences in patients with mild cognitive impairment. Dement. Geriatr. Cogn. Disord. 49, 489–496 (2020).

    CAS  PubMed  Google Scholar 

  141. Gallacher, J. et al. Is sticky blood bad for the brain?: hemostatic and inflammatory systems and dementia in the Caerphilly Prospective Study. Arterioscler. Thromb. Vasc. Biol. 30, 599–604 (2010).

    CAS  PubMed  Google Scholar 

  142. Carcaillon, L. et al. Elevated plasma fibrin D-dimer as a risk factor for vascular dementia: the Three-City cohort study. J. Thromb. Haemost. 7, 1972–1978 (2009).

    CAS  PubMed  Google Scholar 

  143. Staszewski, J., Piusinska-Macoch, R., Brodacki, B., Skrobowska, E. & Stepien, A. Association between hemostatic markers, serum lipid fractions and progression of cerebral small vessel disease: a 2-year follow-up study. Neurol. Neurochir. Pol. 52, 54–63 (2018).

    PubMed  Google Scholar 

  144. Wang, X. et al. Endothelial function, inflammation, thrombosis, and basal ganglia perivascular spaces in patients with stroke. J. Stroke Cerebrovasc. Dis. 25, 2925–2931 (2016).

    PubMed  PubMed Central  Google Scholar 

  145. van Oijen, M., Witteman, J. C., Hofman, A., Koudstaal, P. J. & Breteler, M. M. Fibrinogen is associated with an increased risk of Alzheimer disease and vascular dementia. Stroke 36, 2637–2641 (2005).

    PubMed  Google Scholar 

  146. Mari, D. et al. Hemostasis abnormalities in patients with vascular dementia and Alzheimer’s disease. Thromb. Haemost. 75, 216–218 (1996).

    CAS  PubMed  Google Scholar 

  147. Tomimoto, H. et al. Coagulation activation in patients with Binswanger disease. Arch. Neurol. 56, 1104–1108 (1999).

    CAS  PubMed  Google Scholar 

  148. Tomimoto, H. et al. The coagulation-fibrinolysis system in patients with leukoaraiosis and Binswanger disease. Arch. Neurol. 58, 1620–1625 (2001).

    CAS  PubMed  Google Scholar 

  149. Nagai, M., Hoshide, S. & Kario, K. Association of prothrombotic status with markers of cerebral small vessel disease in elderly hypertensive patients. Am. J. Hypertens. 25, 1088–1094 (2012).

    CAS  PubMed  Google Scholar 

  150. Tran, N. D., Wong, V. L., Schreiber, S. S., Bready, J. V. & Fisher, M. Regulation of brain capillary endothelial thrombomodulin mRNA expression. Stroke 27, 2304–2310 (1996).

    CAS  PubMed  Google Scholar 

  151. Giwa, M. O. et al. Neuropathologic evidence of endothelial changes in cerebral small vessel disease. Neurology 78, 167–174 (2012).

    CAS  PubMed  Google Scholar 

  152. Cesari, M., Pahor, M. & Incalzi, R. A. Plasminogen activator inhibitor-1 (PAI-1): a key factor linking fibrinolysis and age-related subclinical and clinical conditions. Cardiovasc. Ther. 28, e72–e91 (2010).

    CAS  PubMed  Google Scholar 

  153. Gaffney, P. J. Fibrin(-ogen) interactions with plasmin. Haemostasis 6, 2–25 (1977).

    CAS  PubMed  Google Scholar 

  154. Ban, Y. et al. Increased plasma urotensin-II and carotid atherosclerosis are associated with vascular dementia. J. Atheroscler. Thromb. 16, 179–187 (2009).

    CAS  PubMed  Google Scholar 

  155. Norgren, N., Rosengren, L. & Stigbrand, T. Elevated neurofilament levels in neurological diseases. Brain Res. 987, 25–31 (2003).

    CAS  PubMed  Google Scholar 

  156. Ma, W. et al. Elevated levels of serum neurofilament light chain associated with cognitive impairment in vascular dementia. Dis. Markers 2020, 6612871 (2020).

    PubMed  PubMed Central  Google Scholar 

  157. Peters, N. et al. Serum neurofilament light chain is associated with incident lacunes in progressive cerebral small vessel disease. J. Stroke 22, 369–376 (2020).

    PubMed  PubMed Central  Google Scholar 

  158. Marchegiani, F. et al. Diagnostic performance of new and classic CSF biomarkers in age-related dementias. Aging 11, 2420–2429 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Sjögren, M. et al. Neurofilament protein in cerebrospinal fluid: a marker of white matter changes. J. Neurosci. Res. 66, 510–516 (2001).

    PubMed  Google Scholar 

  160. Jonsson, M. et al. Cerebrospinal fluid biomarkers of white matter lesions — cross-sectional results from the LADIS study. Eur. J. Neurol. 17, 377–382 (2010).

    CAS  PubMed  Google Scholar 

  161. Huss, A. et al. Association of serum GFAP with functional and neurocognitive outcome in sporadic small vessel disease. Biomedicines 10, 1869 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Duering, M. et al. Serum neurofilament light chain levels are related to small vessel disease burden. J. Stroke 20, 228–238 (2018).

    PubMed  PubMed Central  Google Scholar 

  163. Egle, M. et al. Neurofilament light chain predicts future dementia risk in cerebral small vessel disease. J. Neurol. Neurosurg. Psychiatry 92, 582–589 (2021).

    PubMed  Google Scholar 

  164. Escartin, C. et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat. Neurosci. 24, 312–325 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Mecocci, P. et al. Serum autoantibodies against glial fibrillary acidic protein in brain aging and senile dementias. Brain Behav. Immun. 6, 286–292 (1992).

    CAS  PubMed  Google Scholar 

  166. Gattringer, T. et al. Serum glial fibrillary acidic protein is sensitive to acute but not chronic tissue damage in cerebral small vessel disease. J. Neurol. 270, 320–327 (2023).

    CAS  PubMed  Google Scholar 

  167. Fortin, L. J. & Genest, J. Jr. Measurement of homocyst(e)ine in the prediction of arteriosclerosis. Clin. Biochem. 28, 155–162 (1995).

    CAS  PubMed  Google Scholar 

  168. Moretti, R., Giuffré, M., Caruso, P., Gazzin, S. & Tiribelli, C. Homocysteine in neurology: a possible contributing factor to small vessel disease. Int. J. Mol. Sci. 22, 2051 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Zhang, F., Slungaard, A., Vercellotti, G. M. & Iadecola, C. Superoxide-dependent cerebrovascular effects of homocysteine. Am. J. Physiol. 274, R1704–R1711 (1998).

    CAS  PubMed  Google Scholar 

  170. Weekman, E. M., Woolums, A. E., Sudduth, T. L. & Wilcock, D. M. Hyperhomocysteinemia-induced gene expression changes in the cell types of the brain. ASN Neuro 9, 1759091417742296 (2017).

    PubMed  PubMed Central  Google Scholar 

  171. Malaguarnera, M. et al. Homocysteine, vitamin B12 and folate in vascular dementia and in Alzheimer disease. Clin. Chem. Lab. Med. 42, 1032–1035 (2004).

    CAS  PubMed  Google Scholar 

  172. Lehmann, M., Gottfries, C. G. & Regland, B. Identification of cognitive impairment in the elderly: homocysteine is an early marker. Dement. Geriatr. Cogn. Disord. 10, 12–20 (1999).

    CAS  PubMed  Google Scholar 

  173. Nagga, K. et al. Cobalamin, folate, methylmalonic acid, homocysteine, and gastritis markers in dementia. Dement. Geriatr. Cogn. Disord. 16, 269–275 (2003).

    CAS  PubMed  Google Scholar 

  174. Davis, G. K. et al. Potential biomarkers for dementia in Trinidad and Tobago. Neurosci. Lett. 424, 27–30 (2007).

    CAS  PubMed  Google Scholar 

  175. Davis, G., Baboolal, N., Nayak, S. & McRae, A. Sialic acid, homocysteine and CRP: potential markers for dementia. Neurosci. Lett. 465, 282–284 (2009).

    CAS  PubMed  Google Scholar 

  176. Zhang, L., Liu, N., Zhang, J., Zhang, H. & Zhang, Y. Clinical research of homocysteine, high-sensitive C-reactive protein and D-Dimer in patients with vascular dementia. Pak. J. Pharm. Sci. 30, 1445–1447 (2017).

    PubMed  Google Scholar 

  177. Kloppenborg, R. P. et al. Homocysteine and progression of generalized small-vessel disease: the SMART-MR study. Neurology 82, 777–783 (2014).

    CAS  PubMed  Google Scholar 

  178. Seshadri, S. et al. Association of plasma total homocysteine levels with subclinical brain injury: cerebral volumes, white matter hyperintensity, and silent brain infarcts at volumetric magnetic resonance imaging in the Framingham Offspring Study. Arch. Neurol. 65, 642–649 (2008).

    PubMed  PubMed Central  Google Scholar 

  179. Yoo, J. S. et al. Homocysteinemia is associated with the presence of microbleeds in cognitively impaired patients. J. Stroke Cerebrovasc. Dis. 29, 105302 (2020).

    PubMed  Google Scholar 

  180. Pavlovic, A. M. et al. Increased total homocysteine level is associated with clinical status and severity of white matter changes in symptomatic patients with subcortical small vessel disease. Clin. Neurol. Neurosurg. 113, 711–715 (2011).

    CAS  PubMed  Google Scholar 

  181. Björkhem, I. et al. Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. J. Lipid Res. 39, 1594–1600 (1998).

    PubMed  Google Scholar 

  182. Lutjohann, D. et al. Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J. Lipid Res. 41, 195–198 (2000).

    CAS  PubMed  Google Scholar 

  183. Zuliani, G. et al. Plasma 24S-hydroxycholesterol levels in elderly subjects with late onset Alzheimer’s disease or vascular dementia: a case-control study. BMC Neurol. 11, 121 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Ference, B. A. et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur. Heart J. 38, 2459–2472 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Schilling, S. et al. Plasma lipids and cerebral small vessel disease. Neurology 83, 1844–1852 (2014).

    CAS  PubMed  Google Scholar 

  186. Axelsson, E., Wallin, A. & Svensson, J. Patients with the subcortical small vessel type of dementia have disturbed cardiometabolic risk profile. J. Alzheimers Dis. 73, 1373–1383 (2020).

    CAS  PubMed  Google Scholar 

  187. McGrath, E. R. et al. Circulating ceramide ratios and risk of vascular brain aging and dementia. Ann. Clin. Transl. Neurol. 7, 160–168 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Liu, Y. et al. Plasma lipidomic biomarker analysis reveals distinct lipid changes in vascular dementia. Comput. Struct. Biotechnol. J. 18, 1613–1624 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Guo, Q. et al. miR-130b-3p regulates M1 macrophage polarization via targeting IRF1. J. Cell Physiol. 236, 2008–2022 (2021).

    CAS  PubMed  Google Scholar 

  190. Varendi, K., Kumar, A., Härma, M. A. & Andressoo, J. O. miR-1, miR-10b, miR-155, and miR-191 are novel regulators of BDNF. Cell Mol. Life Sci. 71, 4443–4456 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Ragusa, M. et al. miRNAs plasma profiles in vascular dementia: biomolecular data and biomedical implications. Front. Cell Neurosci. 10, 51 (2016).

    PubMed  PubMed Central  Google Scholar 

  192. Liang, C. et al. MicroRNA-146a switches microglial phenotypes to resist the pathological processes and cognitive degradation of Alzheimer’s disease. Theranostics 11, 4103–4121 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Dong, H. et al. Serum microRNA profiles serve as novel biomarkers for the diagnosis of Alzheimer’s disease. Dis. Markers 2015, 625659 (2015).

    PubMed  PubMed Central  Google Scholar 

  194. Bai, Y. Y. & Niu, J. Z. miR-222 regulates brain injury and inflammation following intracerebral hemorrhage by targeting ITGB8. Mol. Med. Rep. 21, 1145–1153 (2020).

    CAS  PubMed  Google Scholar 

  195. Ouyang, Y. B. et al. Astrocyte-enriched miR-29a targets PUMA and reduces neuronal vulnerability to forebrain ischemia. Glia 61, 1784–1794 (2013).

    PubMed  Google Scholar 

  196. Barbagallo, C. et al. Specific signatures of serum miRNAs as potential biomarkers to discriminate clinically similar neurodegenerative and vascular-related diseases. Cell Mol. Neurobiol. 40, 531–546 (2020).

    CAS  PubMed  Google Scholar 

  197. Shigemizu, D. et al. Risk prediction models for dementia constructed by supervised principal component analysis using miRNA expression data. Commun. Biol. 2, 77 (2019).

    PubMed  PubMed Central  Google Scholar 

  198. Joo, H. S., Jeon, H. Y., Hong, E. B., Kim, H. Y. & Lee, J. M. Exosomes for the diagnosis and treatment of dementia. Curr. Opin. Psychiatry 36, 119–125 (2023).

    PubMed  Google Scholar 

  199. Han, X. et al. Circulating exo-miR-154-5p regulates vascular dementia through endothelial progenitor cell-mediated angiogenesis. Front. Cell Neurosci. 16, 881175 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Zhao, W. et al. Exosomal miRNA-223-3p as potential biomarkers in patients with cerebral small vessel disease cognitive impairment. Ann. Transl. Med. 9, 1781 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Chabriat, H., Joutel, A., Dichgans, M., Tournier-Lasserve, E. & Bousser, M. G. Cadasil. Lancet Neurol. 8, 643–653 (2009).

    PubMed  Google Scholar 

  202. Cho, B. P. H. et al. Association of vascular risk factors and genetic factors with penetrance of variants causing monogenic stroke. JAMA Neurol. 79, 1303–1311 (2022).

    PubMed  PubMed Central  Google Scholar 

  203. Chen, C. H., Cheng, Y. W., Chen, Y. F., Tang, S. C. & Jeng, J. S. Plasma neurofilament light chain and glial fibrillary acidic protein predict stroke in CADASIL. J. Neuroinflammation 17, 124 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Gravesteijn, G. et al. Serum neurofilament light correlates with CADASIL disease severity and survival. Ann. Clin. Transl. Neurol. 6, 46–56 (2019).

    CAS  PubMed  Google Scholar 

  205. Pescini, F. et al. Circulating biomarkers in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy patients. J. Stroke Cerebrovasc. Dis. 26, 823–833 (2017).

    PubMed  Google Scholar 

  206. Rufa, A. et al. Plasma levels of asymmetric dimethylarginine in cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy. Cerebrovasc. Dis. 26, 636–640 (2008).

    CAS  PubMed  Google Scholar 

  207. Primo, V. et al. Blood biomarkers in a mouse model of CADASIL. Brain Res. 1644, 118–126 (2016).

    CAS  PubMed  Google Scholar 

  208. Yamamoto, Y., Liao, Y. C., Lee, Y. C., Ihara, M. & Choi, J. C. Update on the epidemiology, pathogenesis, and biomarkers of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J. Clin. Neurol. 19, 12–27 (2023).

    PubMed  PubMed Central  Google Scholar 

  209. Yamamoto, Y., Craggs, L., Baumann, M., Kalimo, H. & Kalaria, R. N. Review: molecular genetics and pathology of hereditary small vessel diseases of the brain. Neuropathol. Appl. Neurobiol. 37, 94–113 (2011).

    CAS  PubMed  Google Scholar 

  210. Branyan, K. et al. Elevated TGFβ signaling contributes to cerebral small vessel disease in mouse models of Gould syndrome. Matrix Biol. 115, 48–70 (2023).

    CAS  PubMed  Google Scholar 

  211. Dagonnier, M., Donnan, G. A., Davis, S. M., Dewey, H. M. & Howells, D. W. Acute stroke biomarkers: are we there yet? Front. Neurol. 12, 619721 (2021). A review of biomarkers associated with stroke.

    PubMed  PubMed Central  Google Scholar 

  212. Bjerke, M. et al. Subcortical vascular dementia biomarker pattern in mild cognitive impairment. Dement. Geriatr. Cogn. Disord. 28, 348–356 (2009).

    PubMed  Google Scholar 

  213. Staszewski, J., Piusinska-Macoch, R., Brodacki, B., Skrobowska, E. & Stepien, A. IL-6, PF-4, sCD40 L, and homocysteine are associated with the radiological progression of cerebral small-vessel disease: a 2-year follow-up study. Clin. Interv. Aging 13, 1135–1141 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Rosenberg, G. A. et al. Validation of biomarkers in subcortical ischaemic vascular disease of the Binswanger type: approach to targeted treatment trials. J. Neurol. Neurosurg. Psychiatry 86, 1324–1330 (2015).

    PubMed  Google Scholar 

  215. Winder, Z. et al. Hierarchical clustering analyses of plasma proteins in subjects with cardiovascular risk factors identify informative subsets based on differential levels of angiogenic and inflammatory biomarkers. Front. Neurosci. 14, 84 (2020).

    PubMed  PubMed Central  Google Scholar 

  216. Kong, D. H., Kim, Y. K., Kim, M. R., Jang, J. H. & Lee, S. Emerging roles of vascular cell adhesion molecule-1 (VCAM-1) in immunological disorders and cancer. Int. J. Mol. Sci. 19, 1057 (2018).

    PubMed  PubMed Central  Google Scholar 

  217. Singh, J., Lee, Y. & Kellum, J. A. A new perspective on NO pathway in sepsis and ADMA lowering as a potential therapeutic approach. Crit. Care 26, 246 (2022).

    PubMed  PubMed Central  Google Scholar 

  218. Steinert, M., Ramming, I. & Bergmann, S. Impact of Von Willebrand factor on bacterial pathogenesis. Front. Med. 7, 543 (2020).

    Google Scholar 

  219. Saki, N., Javan, M., Moghimian-Boroujeni, B. & Kast, R. E. Interesting effects of interleukins and immune cells on acute respiratory distress syndrome. Clin. Exp. Med. https://doi.org/10.1007/s10238-023-01118-w (2023).

  220. Hachinski, V. et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 37, 2220–2241 (2006).

    PubMed  Google Scholar 

  221. Sachdev, P. S. et al. The neuropsychological profile of vascular cognitive impairment in stroke and TIA patients. Neurology 62, 912–919 (2004).

    CAS  PubMed  Google Scholar 

  222. Au, R. et al. Association of white matter hyperintensity volume with decreased cognitive functioning: the Framingham Heart Study. Arch. Neurol. 63, 246–250 (2006).

    PubMed  Google Scholar 

  223. Sachdev, P. S. et al. Classifying neurocognitive disorders: the DSM-5 approach. Nat. Rev. Neurol. 10, 634–642 (2014).

    PubMed  Google Scholar 

  224. Markus, H. S. et al. Framework for Clinical Trials in Cerebral Small Vessel Disease (FINESSE): a review. JAMA Neurol. 79, 1187–1198 (2022).

    PubMed  Google Scholar 

  225. Banks, W. A., Reed, M. J., Logsdon, A. F., Rhea, E. M. & Erickson, M. A. Healthy aging and the blood-brain barrier. Nat. Aging 1, 243–254 (2021).

    PubMed  PubMed Central  Google Scholar 

  226. Davis, K. D. et al. Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities. Nat. Rev. Neurol. 16, 381–400 (2020).

    PubMed  PubMed Central  Google Scholar 

  227. Custodero, C. et al. Role of inflammatory markers in the diagnosis of vascular contributions to cognitive impairment and dementia: a systematic review and meta-analysis. Geroscience 44, 1373–1392 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Hosoki, S., Tanaka, T. & Ihara, M. Diagnostic and prognostic blood biomarkers in vascular dementia: from the viewpoint of ischemic stroke. Neurochem. Int. 146, 105015 (2021). A review of biomarkers associated with VCID and stroke.

    CAS  PubMed  Google Scholar 

  229. Ihara, M. & Yamamoto, Y. Transcriptomic mapping of the human cerebrovasculature. Nat. Rev. Neurol. 18, 319–320 (2022).

    CAS  PubMed  Google Scholar 

  230. van Dyck, C. H. et al. Lecanemab in early Alzheimer’s disease. N. Engl. J. Med. 388, 9–21 (2023).

    PubMed  Google Scholar 

  231. Sperling, R. A. et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 7, 367–385 (2011).

    PubMed  PubMed Central  Google Scholar 

  232. Dichgans, M., Beaufort, N., Debette, S. & Anderson, C. D. Stroke genetics: turning discoveries into clinical applications. Stroke 52, 2974–2982 (2021).

    PubMed  PubMed Central  Google Scholar 

  233. Román, G. C. et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 43, 250–260 (1993).

    PubMed  Google Scholar 

  234. Sachdev, P. et al. Diagnostic criteria for vascular cognitive disorders: a VASCOG statement. Alzheimer Dis. Assoc. Disord. 28, 206–218 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Skrobot, O. A. et al. Progress toward standardized diagnosis of vascular cognitive impairment: guidelines from the Vascular Impairment of Cognition Classification Consensus Study. Alzheimers Dement. 14, 280–292 (2018).

    PubMed  Google Scholar 

  236. Adams, H. P. Jr. et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24, 35–41 (1993).

    PubMed  Google Scholar 

  237. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edn (American Psychiatric Association, 1994).

  238. World Health Organization. The ICD-10 Classification of Mental and Behavioral Disorders (World Health Organization, 1992).

  239. Chui, H. C. et al. Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer’s Disease Diagnostic and Treatment Centers. Neurology 42, 473–480 (1992).

    CAS  PubMed  Google Scholar 

  240. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 5th edn (American Psychiatric Association, 2013).

  241. Rost, N. S. et al. Post-stroke cognitive impairment and dementia. Circ. Res. 130, 1252–1271 (2022).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The search strategies were peer reviewed by the UNSW librarian.

Author information

Authors and Affiliations

  1. Centre for Healthy Brain Ageing, Discipline of Psychiatry and Mental Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia

    Satoshi Hosoki, Gurpreet K. Hansra, Tharusha Jayasena, Anne Poljak, Karen A. Mather, Vibeke S. Catts & Perminder S. Sachdev

  2. Department of Neurology, National Cerebral and Cardiovascular Center, Osaka, Japan

    Satoshi Hosoki & Masafumi Ihara

  3. Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, NSW, Australia

    Anne Poljak

  4. Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Ruslan Rust, Abhay Sagare & Berislav V. Zlokovic

  5. Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA

    Jason C. Kovacic

  6. Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia

    Jason C. Kovacic

  7. St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia

    Jason C. Kovacic

  8. Department of Neurology, Royal Melbourne Hospital, Parkville, VIC, Australia

    Amy Brodtmann

  9. Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Anders Wallin

Authors
  1. Satoshi Hosoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gurpreet K. Hansra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tharusha Jayasena
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anne Poljak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Karen A. Mather
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vibeke S. Catts
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ruslan Rust
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Abhay Sagare
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jason C. Kovacic
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Amy Brodtmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Anders Wallin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Berislav V. Zlokovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Masafumi Ihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Perminder S. Sachdev
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.H. and P.S.S. conceived the idea of the Review. S.H. performed the literature search, prepared the original figures and tables, and wrote the first draft. G.K.H. and T.J. assisted with the literature search by assessing manuscripts against the review criteria. A.P., K.A.M., V.S.C., R.R., A.S., J.C.K., A.B., A.W., B.V.Z., M.I. and P.S.S. critically revised the manuscript.

Corresponding author

Correspondence to Perminder S. Sachdev.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Neurology thanks G. J. Biessels and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Review criteria

We searched for papers using PubMed, Embase and Scopus with the terms (‘vascular dementia’ [Text Word]) OR (‘Vascular cognitive impairment’ [Text Word]) OR (‘vascular contributions to cognitive impairment and dementia’ [Text Word]) OR (‘Vascular cognitive impairment and Dementia’ [Text Word]) OR (Dementia, Vascular [Mesh]) OR (Cerebral Small Vessel Diseases [Mesh]) AND (Biomarker [Text Word] OR Biomarkers [Mesh] OR RNA [Text Word] OR RNA [Mesh]) AND (Plasma [Text Word] OR Serum [Mesh] OR Blood [Text Word] OR Cerebrospinal Fluid [Mesh] OR Circulating [Text Word]) on 16th December 2022. The reference lists of identified papers were used to identify additional papers on VCID biomarkers.

Supplementary information

Glossary

Cerebral microbleeds

Small areas of signal void with associated blooming on T2*-weighted MRI or susceptibility-weighted imaging.

Lacunes

Round or ovoid subcortical, fluid-filled cavities of 3–15 mm in diameter; the MRI signal is similar to that of cerebrospinal fluid.

Perivascular spaces

Fluid-filled spaces that surround blood vessels in the grey or white matter.

White matter hyperintensities

Abnormalities of variable size in the white matter that appear as hyperintensity without cavitation on T2-weighted MRI.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hosoki, S., Hansra, G.K., Jayasena, T. et al. Molecular biomarkers for vascular cognitive impairment and dementia. Nat Rev Neurol 19, 737–753 (2023). https://doi.org/10.1038/s41582-023-00884-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-023-00884-1

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research