Blood–Brain Barrier Permeability Post-Ischemia: Comparison
Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Ryszard Pluta.

The impact of post-ischemic brain damage on the function of the BBB is the subject of intensive research, among others, in the context of preventing or treating neurodegenerative changes with the use of substances that would pass through the barrier to the damaged brain tissue. An ischemia-reperfusion episode causes a series of changes that increase the permeability of the BBB to cellular and non-cellular blood components, lead to the opening of tight junctions, and sometimes to diffuse leakage of all blood elements through the necrotic vessel wall.

  • brain ischemia
  • Alzheimer’s disease
  • blood–brain barrier

1. BBB Permeability Post-Ischemia

The impact of post-ischemic brain damage on the function of the BBB is currently the subject of intensive research, among others, in the context of preventing or treating neurodegenerative changes with the use of substances that would pass through the barrier to the damaged brain tissue. An ischemia-reperfusion episode causes a series of changes that increase the permeability of the BBB to cellular and non-cellular blood components, lead to the opening of tight junctions, and sometimes to diffuse leakage of all blood elements through the necrotic vessel wall [6,34,36,56,57,58,59,60,61,62,63][1][2][3][4][5][6][7][8][9][10][11]. In ischemia-reperfusion injury of the BBB, two abnormal and characteristic features deserve attention. One is important given the chronic effects of extravasated substances, such as the neurotoxic β-amyloid peptide, in generating neurodegenerative irreversible neuropathology, and the other concerns the leakage of cellular elements of the blood e.g., platelets, resulting in acute, massive, and mechanical destruction of brain parenchyma [6,64,65][1][12][13]. On the other hand, cells of peripheral tissues and organs are known to continuously produce the neurotoxic β-amyloid peptide [66][14]. The ability of the β-amyloid peptide to cross the damaged BBB may lead to local neurotoxic effects on certain neuronal cell populations, including increased production and accumulation of β-amyloid peptide in the brain parenchyma [27,30][15][16]. Circulating β-amyloid peptide can be delivered to ischemic brain parenchyma and its microcirculation, and thus may contribute to brain amyloidosis after an ischemia-reperfusion episode in stroke patients [27,30,67,68,69,70,71,72,73][15][16][17][18][19][20][21][22][23].

2. Permeability of Non-Cellular Blood Elements through the Ischemic BBB in the Gray Matter

One year after transient cerebral ischemia in rats, brain slices demonstrated multifocal areas of extravasated horseradish peroxidase in gray matter used to assess the permeability of the BBB [6,32,33,34,35,56,57][1][2][4][5][24][25][26]. Light microscopic examination of vibratome brain sections revealed many diffuse and focal staining in the cortical layers of horseradish peroxidase. Many penetrating blood vessels also showed a reaction to horseradish peroxidase of the vessel walls. Horseradish peroxidase was seen in endothelial cells and outside the vessels. In other brain structures, such as the hippocampus, thalamus, basal ganglia, and cerebellum, diffuse as well as isolated multiple extravasation sites of horseradish peroxidase were found. The permeability of the BBB post-ischemia was not restricted to a specific gray matter brain structure, but was mainly dominated by the branching and bifurcation of blood vessels [6][1]. Overall, following cerebral ischemia, animals exhibited random and focal changes in gray matter in the BBB. Extravasations of horseradish peroxidase were localized in the perivascular space of microvessels, arterioles, and venules. Extravasations of horseradish peroxidase around the leaking vessels resembled “puffs of smoke”. The above changes in the ischemic BBB were accompanied by atrophy of the brain cortex and especially of the hippocampus [31,74,75][27][28][29].
Human β-amyloid peptide 1–42 was found after intravenous injection in the vascular walls and perivascular space in rat post-ischemic cortex with a survival of 3 months [27,28,30,51][15][16][30][31]. It should be noted that the β-amyloid peptide alone can cause dysfunction of BBB by disrupting endothelial functions and/or endothelial cell death [76,77,78][32][33][34].
Six months post-ischemia, animals showed increased perivascular immunoreactivity in gray matter for all parts of the amyloid protein precursor [9,74][28][35]. At survival times greater than 6 months, staining of only the β-amyloid peptide and C-terminal of amyloid protein precursor has been noted [31,32,33,34,35,79][2][24][25][26][27][36]. Staining of different parts of the precursor was mainly observed in the extracellular space in gray matter such as the cortex and hippocampus. Numerous extracellular accumulations of C-terminal of amyloid protein precursor and β-amyloid peptide adhered to or mainly embraced capillaries, spreading multifocally in gray matter. The accumulations had an irregular shape and were of various sizes and very well outlined.
The perivascular fragments of the amyloid protein precursor that surrounded the cerebral vessels formed perivascular cuffs or “puff of smoke”-like areas. In addition, the vascular lumen and pericytes and the inner and outer sides of the capillary walls accumulated fragments of the amyloid protein precursor. Accumulation of amyloid and C-terminal of amyloid protein precursor around cortex vessels indicates diffusion of the C-terminal of amyloid protein precursor and β-amyloid peptide from the microcirculatory compartment [27,30,34][2][15][16]. Strong perivascular and vascular amyloid accumulation has been demonstrated in the entorhinal cortex, hippocampus, and brain cortex.

3. Permeability of Non-Cellular Blood Elements through the Ischemic BBB in the White Matter

Post-ischemia BBB in the white matter showed progressive and chronic insufficiency [35,36,62][3][10][26]. Micro BBB changes predominated in periventricular and subcortical white matter and were random and spotty [35,36,62,80][3][10][26][37]. Extravasation of horseradish peroxidase was observed around the capillaries, arterioles, and venules [36][3]. Damaged endothelial cells and pericytes filled with horseradish peroxidase were less observed than in gray matter [6,56,57][1][4][5]. Perivascular immunoreactivity to all amyloid protein precursor fragments was evident in rats’ white matter up to 6 months post-ischemia [31,79][27][36]. After cerebral ischemia-reperfusion with a survival of >6 months, both the toxic C-terminal of the amyloid protein precursor and β-amyloid peptide around the BBB vessels, developing perivascular cuffs with rarefaction of the adjacent white matter and parallel oligodendrocyte staining were noted [31,32,33,34,35,36][2][3][24][25][26][27]. Accumulation of the C-terminal fragment of amyloid protein precursor and β-amyloid peptide dominated in the corpus callosum, subcortical region, and around the lateral ventricles [36,80][3][37]. These observations of BBB permeability were confirmed after intravenous administration of human β-amyloid peptide 1–42 after cerebral ischemia in a rat [27,28,29,30][15][16][30][38].

4. Permeability of Cellular Blood Elements through the Ischemic BBB in the Gray Matter

Platelet aggregation in cortical blood vessels has been observed for 1 year post-ischemia [10,32,34,75][2][24][29][39]. As a result of these changes, there were several vessels partially or completely blocked by platelets [10,32][24][39] and/or platelets with their membranous remnants [56][4]. Platelets were also visualized outside the microvessels in gray matter [10,32,34][2][24][39]. In the areas already presented, the endfeet of the astrocytes were heavily swollen [32][24]. Platelets in the vascular lumen dominated in capillaries and venules. The platelets usually had well-developed pseudopodia, which in many cases were in direct contact with the endothelium [10][39]. In addition, the projection of endothelial microvilli was directed toward the platelets in the lumen of the vessels [4][40]. The presented changes occurred in arterioles, venules, and capillaries, regardless of survival time after brain ischemia. In contrast, some data suggest that cerebral ischemia triggers the creation of platelet and leukocyte aggregates, which often interact with endothelial cells [81,82][41][42]. Many years of research indicate that leukocytes play a key role in cerebral ischemic episodes [64,65,83,84,85,86,87][12][13][43][44][45][46][47]. It is believed that leukocytes with platelets block microcirculation, which promotes the development of hypoperfusion and no-reflow phenomenon after cerebral ischemia [88][48]. Leukocytes cause pathological changes in neurons through the release and interaction of different types of inflammatory molecules [65,89,90][13][49][50]. Some data suggest that leukocytes, most likely neutrophils, are the key cellular source of matrix metalloproteinase-9 after cerebral ischemia [87][47]. Neutrophil matrix metalloproteinase-9 recruited to ischemic brain gray matter promotes further recruitment of neutrophils to the same areas of the brain in a positive feedback fashion and causes secondary alterations to the BBB [65][13]. Thus, neutrophil-derived matrix metalloproteinase-9 directly contributes to post-ischemic brain damage [87][47]. Studies of the BBB using an electron microscope allowed the identification of polymorphonuclear and mononuclear leukocytes adhering to the endothelial cells of capillaries and venules from the lumen side [86][46]. Observations of the projection of pseudopodia of leukocytes and endothelium facing each other indicate the attachment and adhesion of endothelial cells to white blood cells [86][46]. It is assumed that this phenomenon probably plays an important role in the passage of white blood cells through the endothelium. Leukocytes may reduce local cerebral blood flow by constricting and/or blocking cerebral blood vessels [58,91][6][51]. Increased neutrophil endothelial adhesion mediators and cytokines promote the migration of white blood cells across the ischemic BBB [92][52]. In this way, the recruitment of white blood cells appears to activate molecular mechanisms that lead to endothelial tight junction disruption, BBB insufficiency, and ultimately progressive brain gray matter damage with microbleeding [24,92,93,94,95,96][52][53][54][55][56][57].

5. Permeability of Cellular Blood Elements through the Ischemic BBB in the White Matter

Electron microscopy studies after cerebral ischemia-reperfusion injury with survival of up to 1 year have shown single platelet aggregates in and out of capillaries, venules, and arterioles in the white matter [32][24]. The platelets inside and outside the cerebral vessels were irregularly shaped and had numerous pseudopodia. Platelets were often attached to leaky microvascular endothelial cells. Single vessels were completely blocked by aggregating platelets and their membranous remnants [32,34][2][24].
Platelet aggregation along with red and white blood cells caused microblading and complete microcirculation occlusion, resulting in local areas without recirculation after cerebral ischemia [10,24,32,34,75,81,82,94,95,96,97][2][24][29][39][41][42][53][55][56][57][58]. The no-reflow phenomenon [88][48] persisted all the time after the resumption of circulation in the brain following focal ischemia and caused a systematic increase in infarct volume [32,97][24][58]. These observations confirm the important role of blood cells in neuropathology during acute and chronic periods of recirculation and their negative impact on the neurological outcome after ischemia with reperfusion.


  1. Goulay, R.; Mena Romo, L.; Hol, E.M.; Dijkhuizen, R.M. From stroke to dementia: A Comprehensive review exposing tight interactions between stroke and amyloid-β formation. Transl. Stroke Res. 2020, 11, 601–614.
  2. Pluta, R. Alzheimer’s disease connected genes in the post-ischemic hippocampus and temporal cortex. Genes 2022, 13, 1059.
  3. Dickstein, D.L.; Biron, K.E.; Ujiie, M.; Pfeifer, C.G.; Jeffries, A.R.; Jefferies, W.A. Aβ peptide immunization restores blood-brain barrier integrity in Alzheimer disease. FASEB J. 2006, 20, 426–433.
  4. Mossakowski, M.J.; Lossinsky, A.S.; Pluta, R.; Wisniewski, H.M. Changes in cerebral microcirculation system following experimentally induced cardiac arrest: A SEM and TEM study. In Microcirculatory Stasis in the Brain; Tomita, M., Ed.; Elsevier Science Publishers B.V.: Amsterdam, The Netherlands, 1993; pp. 99–106.
  5. Mossakowski, M.J.; Lossinsky, A.S.; Pluta, R.; Wisniewski, H.M. Abnormalities of the blood-brain barrier in global cerebral ischemia in rats due to experimental cardiac arrest. Acta Neurochir. Suppl. 1994, 60, 274–276.
  6. Wisniewski, H.M.; Pluta, R.; Lossinsky, A.S.; Mossakowski, M.J. Ultrastructural studies of cerebral vascular spasm after cardiac arrest-related global cerebral ischemia in rats. Acta Neuropathol. 1995, 90, 432–440.
  7. Ueno, M.; Akiguchi, I.; Hosokawa, M.; Shinnou, M.; Sakamoto, H.; Takemura, M.; Higuchi, K. Age-related changes in the brain transfer of blood-borne horseradish peroxidase in the hippocampus of senescence-accelerated mouse. Acta Neuropathol. 1997, 93, 233–240.
  8. Shinnou, M.; Ueno, M.; Sakamoto, H.; Ide, M. Blood-brain barrier damage in reperfusion following ischemia in the hippocampus of the Mongolian gerbil brain. Acta Neurol. Scand. 1998, 98, 406–411.
  9. Lippoldt, A.; Kniesel, U.; Liebner, S.; Kalbacher, H.; Kirsch, T.; Wolburg, H.; Haller, H. Structural alterations of tight junctions are associated with loss of polarity in stroke-prone spontaneously hypertensive rat blood-brain barrier endothelial cells. Brain Res. 2000, 885, 251–261.
  10. Ueno, M.; Tomimoto, H.; Akiguchi, I.; Wakita, H.; Sakamoto, H. Blood-brain barrier disruption in white matter lesions in a rat model of chronic cerebral hypoperfusion. J. Cereb. Blood Flow Metab. 2002, 22, 97–104.
  11. Ueno, M.; Sakamoto, H.; Liao, Y.J.; Onodera, M.; Huang, C.L.; Miyanaka, H.; Nakagawa, T. Blood-brain barrier disruption in the hypothalamus of young adult spontaneously hypertensive rats. Histochem. Cell Biol. 2004, 122, 131–137.
  12. Hallenbeck, J.M.; Dutka, A.J.; Tanishima, T.; Kochanek, P.M.; Kumaroo, K.K.; Thompson, C.B.; Obrenovitch, T.P.; Contreras, T.J. Polymorphonuclear leukocyte accumulation in brain regions with low blood flow during the early postischemic period. Stroke 1986, 17, 246–253.
  13. Pluta, R.; Januszewski, S.; Czuczwar, S.J. Neuroinflammation in post-ischemic neurodegeneration of the brain: Friend; foe; or both? Int. J. Mol. Sci. 2021, 22, 4405.
  14. Mehta, P.D.; Prittila, T. Biological markers of Alzheimer’s disease. Drug Dev. Res. 2002, 56, 74–84.
  15. Pluta, R.; Ułamek, M.; Łuczyk, W.; Hodun, R.; Niczyporuk, P.; Smyrgała, B.; Januszewski, S. Chronic blood-brain barrier opening following ischemia-reperfusion brain injury with 1-year survival. J. Cereb. Blood Flow Metab. 2003, 23 (Suppl. 1), 165.
  16. Pluta, R.; Ułamek, M.; Januszewski, S. Micro-blood-brain barrier openings and cytotoxic fragments of amyloid precursor protein accumulation in white matter after ischemic brain injury in long-lived rats. Acta Neurochir. Suppl. 2006, 96, 267–271.
  17. Jendroska, K.; Poewe, W.; Daniel, S.E.; Pluess, J.; Iwerssen-Schmidt, H.; Paulsen, J.; Barthel, S.; Schelosky, L.; Cervos-Navarr, J.; DeArmond, S.J. Ischemic stress induces deposition of amyloid beta immunoreactivity in human brain. Acta Neuropathol. 1995, 90, 461–466.
  18. Wisniewski, H.M.; Maslinska, D. Beta-protein immunoreactivity in the human brain after cardiac arrest. Folia Neuropathol. 1996, 34, 65–71.
  19. Jendroska, K.; Hoffmann, O.M.; Patt, S. Amyloid β peptide and precursor protein (APP) in mild and severe brain ischemia. Ann. N. Y. Acad. Sci. 1997, 826, 401–405.
  20. Lee, P.H.; Bang, O.Y.; Hwang, E.M.; Lee, J.S.; Joo, U.S.; Mook-Jung, I.; Huh, K. Circulating beta amyloid protein is elevated in patients with acute ischemic stroke. J. Neural. Transm. 2005, 112, 1371–1379.
  21. Qi, J.; Wu, H.; Yang, Y.; Wand, D.; Chen, Y.; Gu, Y.; Liu, T. Cerebral ischemia and Alzheimer’s disease: The expression of amyloid-β and apolipoprotein E in human hippocampus. J. Alzheimers Dis. 2007, 12, 335–341.
  22. Zetterberg, H.; Mörtberg, E.; Song, L.; Chang, L.; Provuncher, G.K.; Patel, P.P.; Ferrell, E.; Fournier, D.R.; Kan, C.W.; Campbell, T.G.; et al. Hypoxia due to cardiac arrest induces a time-dependent increase in serum amyloid β levels in humans. PLoS ONE 2011, 6, e28263.
  23. Liu, Y.H.; Cao, H.Y.; Wang, Y.R.; Jiao, S.S.; Bu, X.L.; Zeng, F.; Wang, G.; Li, J.; Deng, J.; Zhou, H.D.; et al. Serum Aβ is predictive for short-term neurological deficits after acute ischemic stroke. Neurotox. Res. 2015, 27, 292–299.
  24. Pluta, R.; Januszewski, S.; Czuczwar, S.J. Brain ischemia as a prelude to Alzheimer’s disease. Front Aging Neurosci. 2021, 13, 636653.
  25. Elman-Shina, K.; Efrati, S. Ischemia as a common trigger for Alzheimer’s disease. Front. Aging Neurosci. 2022, 14, 1012779.
  26. Pluta, R. Brain ischemia as a bridge to Alzheimer’s disease. Neural. Regen. Res. 2022, 17, 791–792.
  27. Salminen, A.; Kauppinen, A.; Kaarniranta, K. Hypoxia/ischemia activate processing of amyloid precursor protein: Impact of vascular dysfunction in the pathogenesis of Alzheimer’s disease. J. Neurochem. 2017, 140, 536–549.
  28. Pluta, R.; Ułamek, M.; Jabłoński, M. Alzheimer’s mechanisms in ischemic brain degeneration. Anat. Rec. 2009, 292, 1863–1881.
  29. Jabłoński, M.; Maciejewski, R.; Januszewski, S.; Ułamek, M.; Pluta, R. One year follow up in ischemic brain injury and the role of Alzheimer factors. Physiol. Res. 2011, 60 (Suppl. 1), S113–S119.
  30. Pluta, R. Pathological opening of the blood-brain barrier to horseradish peroxidase and amyloid precursor protein following ischemia-reperfusion brain injury. Chemotherapy 2005, 51, 223–226.
  31. Pluta, R.; Misicka, A.; Barcikowska, M.; Spisacka, S.; Lipkowski, A.W.; Januszewski, S. Possible reverse transport of β-amyloid peptide across the blood-brain barrier. Acta Neurochir. Suppl. 2000, 76, 73–77.
  32. Farkas, I.G.; Czigner, A.; Farkas, E.; Dobo, E.; Soos, K.; Penke, B.; Endresz, V.; Mihaly, A. Beta-amyloid peptide-induced blood-brain barrier disruption facilitates T-cell entry into the rat brain. Acta Histochem. 2003, 105, 115–125.
  33. Paris, D.; Patel, N.; DelleDonne, A.; Quadros, A.; Smeed, R.; Mullan, M. Impaired angiogenesis in a transgenic mouse model of cerebral amyloidosis. Neurosci. Lett. 2004, 366, 80–85.
  34. Paris, D.; Townsend, K.; Quadros, A.; Humphrey, J.; Sun, J.; Brem, S.; Wotoczek-Obadia, M.; DellaDonne, A.; Patel, N.; Obergon, D.F.; et al. Inhibition of angiogenesis by Aβ peptides. Angiogenesis 2004, 7, 75–85.
  35. Blennow, K.; Wallin, A.; Fredman, P.; Karlsson, I.; Gottfries, C.G.; Svennerholm, L. Blood-brain barrier disturbance in patients with Alzheimer’s disease is related to vascular factors. Acta Neurol. Scand. 1990, 81, 323–326.
  36. Pluta, R. Proteins associated with Alzheimer’s disease in conditions predisposing to Alzheimer’s-type neurodegeneration. J. Cereb. Blood Flow Metab. 2001, 21 (Suppl. 1), S424.
  37. Pluta, R.; Januszewski, S.; Ułamek, M. Ischemic blood–brain barrier and amyloid in white matter as etiological factors in leukoaraiosis. Acta Neurochir. Suppl. 2008, 102, 353–356.
  38. Pluta, R.; Januszewski, S.; Ułamek, M. Chronic blood-brain barrier insufficiency and cytotoxic fragment of amyloid precursor protein activity in white matter following ischemia-reperfusion brain injury in long-lived animals. J. Cereb. Blood Flow Metab. 2005, 25, S251.
  39. Zipser, B.D.; Johanson, C.E.; Gonzalez, L.; Berzin, T.M.; Tavares, R.; Hultte, C.M.; Vitek, M.P.; Hovanesian, V.; Stopa, E.G. Microvascular injury and blood-brain barrier leakage in Alzheimer’s disease. Neurobiol. Aging 2007, 28, 977–986.
  40. Pluta, R.; Lossinsky, A.S.; Walski, M.; Wisniewski, H.M.; Mossakowski, M.J. Platelet occlusion phenomenon after short- and long-term survival following complete cerebral ischemia in rats produced by cardiac arrest. J. Brain Res. 1994, 35, 463–471.
  41. Ishikawa, M.; Cooper, D.; Arumugam, T.V.; Zhang, J.H.; Nanda, A.; Granger, D.N. Platelet-leukocyte-endothelial cell interactions after middle cerebral artery occlusion and reperfusion. J. Cereb. Blood Flow Metab. 2004, 24, 907–915.
  42. Ritter, L.S.; Stempel, K.M.; Coull, B.M.; McDonagh, P.F. Leukocyte-platelet aggregates in rat peripheral blood after ischemic stroke and reperfusion. Biol. Res. Nurs. 2005, 6, 281–288.
  43. Del Zoppo, G.J.; Schmid-Schonbein, G.W.; Mori, E.; Copeland, B.R.; Chang, C.M. Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 1991, 22, 1276–1283.
  44. Kochanek, P.M.; Hallenbeck, J.M. Polymorphonuclear leukocytes and mnocytes/macrophages in the pathogenesis of cerebral ischemia and stroke. Stroke 1992, 23, 1367–1379.
  45. Mori, E.; Del Zoppo, G.J.; Chambers, J.D.; Copeland, B.R.; Arfors, R.E. Inhibition of polymorphonuclear leukocyte adherence suppresses no-reflow after focal cerebral ischemia in baboons. Stroke 1992, 23, 712–718.
  46. Caceres, M.J.; Schleien, C.L.; Kuluz, J.W.; Gelman, B.; Dietrich, W.D. Early endothelial damage and leukocyte accumulation in piglet brains following cardiac arrest. Acta Neuropathol. 1995, 90, 582–591.
  47. Gidday, J.M.; Gasche, Y.G.; Copin, J.C.; Shah, A.R.; Perez, R.S.; Shapiro, S.D.; Chan, P.H.; Park, T.S. Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am. J. Physiol. Heart Circ. Physiol. 2005, 289, H558–H568.
  48. Ames, A.; Wright, R.L.; Kowada, M.; Thurston, J.M.; Majno, G. Cerebral ischemia. II. The no-reflow phenomenon. Am. J. Pathol. 1968, 52, 437–453.
  49. Saito, K.; Suyama, K.; Nishida, K.; Sei, Y.; Basile, A.S. Early increases in TNF-alpha; IL-6 and IL-1 beta levels following transient cerebral ischemia in gerbil brain. Neurosci. Lett. 1996, 206, 149–152.
  50. Boutin, H.; LeFeuvre, R.A.; Horai, R.; Asano, M.; Iwakura, Y.; Rothwell, N.J. Role of IL-1α and IL-1β in ischemic brain damage. J. Neurosci. 2001, 21, 5528–5534.
  51. Hart, M.N.; Sokoll, M.D.; Davies, L.R.; Henriquez, E. Vascular spasm in cat cerebral cortex following ischemia. Stroke 1978, 9, 52–57.
  52. Nimmo, A.J.; Cernak, I.; Heath, D.L.; Hu, X.; Bennett, C.J.; Vink, R. Neurogenic inflammation is associated with development of edema and functional deficits following traumatic brain injury in rats. Neuropeptides 2004, 38, 40–47.
  53. Pluta, R.; Barcikowska, M.; Misicka, A.; Lipkowski, A.W.; Spisacka, S.; Januszewski, S. Ischemic rats as a model in the study of the neurobiological role of human β-amyloid peptide. Time-dependent disappearing diffuse amyloid plaques in brain. NeuroReport 1999, 10, 3615–3619.
  54. Zhang, R.L.; Chopp, M.; Liu, Y.; Zaloga, C.; Jiang, N.; Jones, M.L.; Miyasaka, M.; Ward, P.A. Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat. Neurology 1994, 44, 1747–1751.
  55. Jiang, Y.; Yin, D.; Xu, D.; Men, W.; Cao, R.; Li, B.; Fan, M. Investigating microbleeding in cerebral ischemia rats using susceptibility-weighted imaging. Magn. Reson. Imaging 2015, 33, 102–109.
  56. Leeuwis, A.E.; Prins, N.D.; Hooghiemstra, A.M.; Benedictus, M.R.; Scheltens, P.; Barkhof, F.; van der Flier, W.M. Microbleeds are associated with depressive symptoms in Alzheimer’s disease. Alzheimers Dement. 2017, 10, 112–120.
  57. Chen, Y.; Ye, M. Risk factors and their correlation with severity of cerebral microbleed in acute large artery atherosclerotic cerebral infarction patients. Clin. Neurol. Neurosurg. 2022, 221, 107380.
  58. Hossmann, V.; Hossmann, K.A.; Takagi, S. Effect of intravascular platelet aggregation on blood recirculation following prolonged ischemia of the cat brain. J. Neurol. 1980, 222, 159–170.
Video Production Service