Cerebral Small Vessel Disease: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Others
Contributor:
Jakub Litak

Cerebral small vessel disease (CSVD) represents a cluster of various vascular disorders with different pathological backgrounds. The advanced vasculature net of cerebral vessels, including small arteries, capillaries, arterioles and venules, is usually affected. Processes of oxidation underlie the pathology of CSVD, promoting the degenerative status of the epithelial layer. There are several classifications of cerebral small vessel diseases; some of them include diseases such as Binswanger’s disease, leukoaraiosis, cerebral microbleeds (CMBs) and lacunar strokes.

  • CSVD
  • CMB
  • cerebral microbleeds
  • cerebral small vessel disease

1. Introduction

Cerebral small vessel disease (CSVD) represents a cluster of pathologies with a heterogeneous etiology and a pathomechanism affecting elements of the brain vascular system such as small arteries, capillaries, arterioles and venules. Histopathologic studies demonstrate reduced lumens in affected vessels and also demonstrate the thickening of walls, which impedes perfusion and transmural gas transfer [1]. The disease accounts for 20–30% of cases of ischemic stroke [2][3] and cerebral hemorrhage [4][5]. Moreover, CSVD has been shown to worsen functional outcomes after supra [6] and infratentorial [7] ischemic stroke because it disrupts the reorganization of brain networks that is essential for post-stroke recovery. Certain fluid biomarkers have been identified to correlate with CSVD. Some studies present elevated levels of Low Molecular Weight Neurofilament Protein (NF-L), tissue inhibitor of metalloproteinase-1, metalloproteinase-9 and metalloproteinase-2 in CSVD patients [8]. Imaging examination has revealed a direct relationship between Alzheimer’s Disease occurrence and certain identified cerebral vascular diseases, principally CSVD.

CSVD can be classified according to varied pathological, radiologic and clinical criteria. Most commonly, two types are identified: amyloid and non-amyloid related. CSVD has been recognized as a dynamic condition of the whole brain and as having a diffuse nature, and systems for the visual scoring of MRI images have been introduced to assess the total load of the disease [9][10]. The neuroimaging features are white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), lacunae, subcortical infarcts, microbleeds and brain atrophy. Some researchers include individual disease entities in this group, such as Binswanger’s disease, leukoaraiosis, cerebral microbleeds (CMBs) and lacunar strokes.

2. Classification of Cerebral Small Vessel Disease

CSVD can be divided into six groups:

  • Type I: arteriosclerosis/age-related CSVD;

  • Type II: amyloid-related CSVD;

  • Type III: genetic CSVD distinct from amyloid angiopathy;

  • Type IV: inflammatory/immunologically mediated CSVD;

  • Type V: venous collagenosis;

  • Type VI: other CSVD.

3. Etiology of Cerebral Small Vessel Disease

The deposition of amyloid-beta in the cerebral vessels (cerebral amyloid angiopathy (CAA)) is a common finding in elderly people, a major cause of spontaneous intracerebral hemorrhage (ICH) and an important contributor to age-related mental decline [11]. The accumulation of eosinophilic hyaline material along the basement membranes is accompanied by progressive loss of the smooth muscle layer in the media of arterioles [12]. This results in the formation of microaneurysms and a temporary blockage of the vessel lumen [13]. However, the exact etiology of these lesions remains unknown. Some authors associate amyloid deposition in CAA with its production in smooth muscle cells after earlier damage [14][15]. The neuronal origin of β amyloid, which in the next stage would be transported into the blood along the fluid spaces around the cortical and meningeal arteries, has also been suggested [16][17]. Other theories concern the damage to the blood–brain barrier, which determines the penetration of its molecules [18][19].

The pathological hallmarks of CAA, first described in 1954 by Stefanos Pantelakis, have since been confirmed by more recent studies: the involvement of arterioles of the meninges and cerebral cortex, favoring posterior regions of the brain (occipital lobes), the sparing of white matter vasculature, association with age and dementia, a lack of association with hypertension and atherosclerosis (unlike other CSVD) and independence from systemic amyloidosis [20]. Cerebral microvessels are crucial for the drainage of interstitial fluid of the brain; thus, the accumulation of amyloid-beta is an early sign of clearance failure and has pending hemorrhagic or ischemic consequences [21]. In an autopsy, the condition can be detected in 20–40% of the non-demented and 50–60% of the demented elderly population [22].

Although highly prevalent in patients affected with Alzheimer’s disease (found post-mortem in 85–95% of patients), it is rarely diagnosed during the patient’s lifetime [23]. In MRI, biomarkers of CAA are lobar ICH, lobar microbleeds, cortical superficial siderosis, white matter hyperintensities (periventricular, posterior–predominant), enlarged perivascular spaces in the cerebral white matter and cortical microinfarcts. CAA lesions primarily affect the cortical vessels and those that supply the meninges. This determines the location of the markers detected in imaging tests. It has been shown that, in the case of changes caused by amyloid etiology, microbleeds, which are a sign of CSVD, are usually found in the cerebral and cerebellar lobes, including their cortical and subcortical areas [8]. Localization in the occipital lobe is particularly frequent [2]. It is also worth mentioning that the presence of such changes may also be genetically determined. An analysis of the genotype of apolipoprotein E showed its ε4 isoform to be associated with a greater prevalence of microbleeds. At the same time, it results in a greater ratio of β-amyloid 40 to β-amyloid 42 [24]. CAA has been classified into two pathological types: CAA type 1, characterized by amyloid in cortical capillaries; and CAA type 2, where amyloid deposits are found in leptomeningeal and cortical arteries, but not capillaries [15].

Another key factor in the etiology of cerebral small vessel disease is hypertensive angiopathy—the umbrella term for a spectrum of sporadic non-amyloid small vessel pathologies associated with age, hypertension, diabetes mellitus and other vascular risk factors. Pathologically, it is characterized by the narrowing of the vessel lumen resulting from the collagenous hypertrophy of the vascular wall and exudation of serum proteins [1]. This type of microangiopathy predominantly affects the small perforating arteries of the deep grey nuclei and deep white matter [25]. As a consequence, the bleedings caused by this condition occurs in deep-brain regions (e.g., the basal ganglia, thalamus and brain stem). Distinguishing CAA from hypertensive angiopathy may have clinical implications (which is relevant for treatment decisions concerning antithrombotic use), as CAA-related lobar ICH carries a considerably higher risk of recurrence [26].

Recent studies have proven that oxidative stress is also a major factor influencing different types of CSVD. Oxidative stress is caused by disturbances of the homeostasis between oxidation and antioxidation processes. An imbalance occurs when free radicals increase or antioxidation processes become inefficient [27][28]. Molecular oxygen undoubtedly plays key roles in the biology of every cell, thus affecting tissues and systems and consequently the entire organism; it is necessary for proper functioning and life [29][30][31]. Although oxygen is important as a life-determinant and is also involved in signal transduction, the regulation of gene transcription and the control of other cellular activities, it also has a detrimental effect on biomolecules in the form of reactive oxygen species (ROS) and free radicals. The unfavorable effect of oxygen is due to its monovalent reductive status, which is directly responsible for ROS production [29][30][32]. Oxygen is an irreplaceable entity for all living organisms, although its presence in excess has harmful effects. Therefore, it is required that the consumption and uptake of oxygen be maintained under a high level of control and that the levels are checked by a complex cell system [32][33][34][35]. Uncontrolled redox reactions generate ROS, such as hydroxyl radicals (•OH), superoxide anions (•O2−), peroxyl radicals (ROO•), hydrogen peroxide (H2O2) and nitric oxide (NO•). Hydrogen peroxide (H2O2) and superoxide anion (O2−) constrict vessels, reducing blood flow [36][37][38][39]. Oxygen radicals activate inflammatory processes and the formation of oxidized low-density lipoprotein (LDL), affecting the vascular endothelial part of the vessel walls [40][41][42]. Oxidative stress is an indisputable factor contributing to vascular damage and loss of function. Nitric oxide is another important mediator that could be a target of the destructive influence ROS and carries out a regulatory function on vascular smooth muscle cells. It controls many processes such as proliferation and relaxation, vascular tone intensity, hemodynamics and angiogenesis [43][44]. Oxidative stress and ROS are commonly known as crucial factors in the etiology of CSVD. The endothelium, as a significant structure of the vessel architecture, regulates wall tone and maintains adequate perfusion. Many studies have revealed that the endothelium is the main target of inadequate oxidation, accelerating the degenerative effects on CNS blood flow in CSVD patients. Monovalent reactive forms of free radicals are promoted by arterial hypertension, the oxidation of low-density lipoproteins (oxLDL), diabetes mellitus, a high level of homocysteine, general infections and cigarette smoking. Consequently, excessive ROS formation underlies the pathology of cerebral small vessel disease [45].

4. Detection of Cerebral Small Vessel Disease

The diagnosis of cerebral small vessel disease is based on the detection of neuroimaging markers occurring in the course of its development. They include a number of characteristic lesions that can be observed in imaging tests. This group includes cerebral atrophy, leukoaraiosis, white matter hyperintensities and cerebral microbleeds.

4.1. Cerebral Atrophy

Cerebral atrophy is a kind of condition in which neurons and the connections between them are lost. It causes decreases in brain volume [46][47]. The consequences of this condition manifest in cognitive and neurological problems. Atrophy can be generalized or focal. Focal cerebral atrophy and the corresponding damage affect a particular area of the brain tissue. This type of atrophy can manifest in the corresponding functional impairment of the concerned area of the brain [48][49]. Decreases of brain volume can usually be identified by computed tomography (CT) and magnetic resonance imaging (MRI). Radiological examination may show changes in the brain tissue that are closely related to cerebral atrophy. CT and MRI are equally able to demonstrate cortical atrophy, but MRI is more sensitive to the detection of some types of atrophy, such as focal atrophic changes in the nuclei [50][51][52]. A prospective follow-up study published by Nitkunan et al. showed that brain tissue volume is decreased in patients with cerebral small vessel disease with respect to normal aging subjects. Additionally, this atrophy was associated with cognition decline in 1-year follow-up [53]. Leukoaraiosis research works have proven that decreased brain tissue volume is associated with and facilitates cognitive decline. Brain atrophy due to cerebral small vessel disease is independently related to longitudinal cognitive decline [50]. The size of the white matter located in periventricular and subcortical brain tissue and the number of lacunar infarcts have been associated with the severity of brain atrophy in MRI examination [51][54][55].

Some degree of cerebral atrophy occurs naturally with age. This also applies to many pathological conditions, such as epilepsy, traumatic brain injuries, strokes, multiple sclerosis, Huntington’s disease and cerebral palsy [56][57][58]. An association has been shown between cerebral cortex atrophy and drug and alcohol toxicity, as well as Alzheimer’s disease (AD) [59][60]. A large number of studies have confirmed that cerebral atrophy is the most significant morphological characteristic of AD [61][62][63][64].

4.2. Leukoaraiosis and White Matter Hyperintensities

The term leukoaraiosis was introduced in 1987 by Hachinski, Potter and Merskey to describe bilateral periventricular hypodense areas of white matter seen in CT scans, mostly in the elderly population [65]. It roughly corresponds with white matter hyperintensities (WMH), defined as disseminated regions of white matter changes that are hyperintense in T2-weighted findings and FLAIR in MRI images, predominantly around the ventricles and subcortically. Histologically, the atrophy of axons, as well as a decreased quantity of myelin, is observed. This could be the result of an insufficient blood supply to the deep portions of white matter due to vascular pathology [66][67][68]. Makedonov et al. report that the perfusion of white matter hyperintensities (WMHs), as assessed with SPECT and MRI, is lower than the perfusion of normal-appearing white matter [69]. Other researchers point to an impairment of lymphatic drainage as the suspected mechanism rather than an infarction, because no foamy macrophages are present [70]. In patients with beta-amyloid deposits in the basement membranes of arterioles, the interstitial fluid cannot be sufficiently reabsorbed [71]. White matter hyperintensities can be found in 20% of adults in their sixties and in up to 94% in the population of octogenarians [72][73]. They are a common finding in asymptomatic patients; however, the prevalence is higher in the population affected by AD [74][75]. Likewise, patients with cardiovascular risk factors and symptomatic cerebrovascular disease are more likely to develop WMHs [76]. This has clinical implications, as shown in the Perindopril Protection Against Recurrent Stroke Study, where the WMH volume was successfully reduced after 36 months of treatment with ACE inhibitor [77]. Moreover, in a meta-analysis of nine previous studies, Debette and Markus confirmed a significant association of white matter hyperintensities with incident stroke [78]. Furthermore, recent studies have demonstrated the clinical significance of WMH with regard to bladder dysfunction as well as gait and balance disorders [79].

4.3. Lacunar Strokes

Lacunar strokes (LSs) of the cerebrum result from the occlusion of small perforating arteries. By definition, the diameter of a lacunar stroke lesion is less than 20 mm on the axial plane [80]. They can be classified by their shape, as tubular (resulting from the occlusion of larger perforating vessels and confluence of lesions) or oval, and by their size, which can be as large as 15–20 mm and as small as 0–14 mm [81]. They comprise around 20% of ischemic strokes [82]. The clinical lacunar syndromes are pure motor stroke, pure sensory stroke, mixed sensorimotor stroke, ataxic hemiparesis and dysarthria/clumsy hand. Very often silent, they are found in 20–50% of elderly people [83]. Hypertension and diabetes mellitus have been established as important risk factors [84][85]. Family history data analysis suggests a hereditary predisposition for lacunar stroke [86]. Large artery abnormalities are often observed in LS, and the possibility of artery-to-artery embolism has been indicated, as shown in a study associating calcifications in the carotid siphon and silent LS [87]. Moreover, CSVD and its sequelae LS are observed to co-exist with abnormalities in small vessels of other organs, including kidneys and retina [88][89]. An important pathological mechanism is endothelial dysfunction leading to the vasoconstriction, inflammation and proliferation of the affected vessels. The circulating markers of endothelial activation, namely intercellular adhesion molecule-1 (ICAM) and thrombomodulin, are elevated in patients with LS as compared with age-matched controls [90]. Furthermore, the LS areas show increased brain–blood barrier permeability, which appears as white matter hyperintensities on MRIs. Lacunar stroke is associated with a lower rate of motor disability and urinary incontinence than stroke due to large-vessel occlusion in anterior or posterior cerebral circulation or hemorrhagic stroke. Similarly, depression is more common in survivors of large-vessel disease (52%) than in patients affected by a lacunar stroke [91]. However, intellectual disability is a serious consequence of this type of stroke, as it is often a manifestation of an underlying diffused condition of cerebral vessels. In total, 11–23% of patients with lacunar stroke will develop dementia [92][93], and the risk increases with recurrent lacunar events [94].

5. Conclusions

CSVD is a complex group of diseases associated with cerebrovascular architecture disorders. Their pathogenesis is very complex and varies depending on the specific unit. In most cases, they are associated with amyloid angiopathy or arteriosclerosis, but in some contingencies, genetic considerations may also play an important role. As demonstrated in recent years, the manifestation of CVSD can be of great importance in the diagnosis of patients with cognitive impairment. Genetic considerations also play a similar role in vascular diseases such as stroke. A thorough understanding of the role and ethology of cerebral small vessel disease can allow for the more careful monitoring of these groups of patients and the implementation of measures that will prevent relapse or acceleration of the progression of the disease. Developing an accurate knowledge of the meaning and full characteristics of these issues requires further research.

This entry is adapted from the peer-reviewed paper 10.3390/ijms21249729

References

  1. Pantoni, L. Cerebral small vessel disease: From pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010, 9, 689–701.
  2. Kwon, S.M.; Choi, K.S.; Yi, H.J.; Ko, Y.; Kim, Y.S.; Bak, K.H.; Chun, H.J.; Lee, Y.J.; Lee, J.Y. Impact of brain atrophy on 90-day functional outcome after moderate-vol- ume basal ganglia hemorrhage. Sci. Rep. 2018, 8, 4819.
  3. Zhang, A.-J.; Yu, X.-J.; Wang, M. The clinical manifestations and pathophysiology of cerebral small vessel disease. Neurosci. Bull. 2010, 26, 257–264.
  4. Ryu, W.-S.; Woo, S.-H.; Schellingerhout, D.; Jang, M.U.; Park, K.-J.; Hong, K.-S.; Jeong, S.-W.; Na, J.-Y.; Cho, K.-H.; Kim, J.-T.; et al. Stroke outcomes are worse with larger leukoaraiosis volumes. Brain 2016, 140, 158–170.
  5. Caprio, F.Z.; Maas, M.B.; Rosenberg, N.F.; Kosteva, A.R.; Bernstein, R.A.; Alberts, M.J.; Prabhakaran, S.; Naidech, A.M. Leukoaraiosis on magnetic resonance imaging cor- relates with worse outcomes after spontaneous intracerebral hemorrhage. Stroke 2013, 44, 642–646.
  6. Onteddu, S.R.; Goddeau, R.P., Jr.; Minaeian, A.; Henninger, N. Clinical impact of leukoaraiosis burden and chronological age on neurological de cit recovery and 90-day outcome after minor ischemic stroke. J. Neurol. Sci. 2015, 359, 418–423.
  7. Förster, A.; Griebe, M.; Ottomeyer, C.; Rossmanith, C.; Gass, A.; Kern, R.; Hennerici, M.G.; Szabo, K. Cerebral Network Disruption as a Possible Mechanism for Impaired Recovery after Acute Pontine Stroke. Cerebrovasc. Dis. 2011, 31, 499–505.
  8. Wallin, A.; Kapaki, E.; Boban, M.; Engelborghs, S.; Hermann, D.M.; Huisa, B.; Jonsson, M.; Kramberger, M.G.; Lossi, L.; Malojcic, B.; et al. Biochemical markers in vascular cognitive impairment associ- ated with subcortical small vessel disease—A consensus report. BMC Neurol. 2017, 17, 102–116.
  9. Staals, J.; Makin, S.D.; Doubal, F.N.; Dennis, M.S.; Wardlaw, J.M. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Neurology 2014, 83, 1228–1234.
  10. Xu, X.; Hilal, S.; Collinson, S.L.; Chong, E.J.Y.; Ikram, M.K.; Venketasubramanian, N.; Chen, C.L.H. Association of magnetic resonance imaging markers of cerebro- vascular disease burden and cognition. Stroke 2015, 46, 2808–2814.
  11. Viswanathan, A.; Greenberg, S.M. Cerebral amyloid angiopathy in the elderly. Ann. Neurol. 2011, 70, 871–880.
  12. Attems, J.; Jellinger, K.; Thal, D.; Van Nostrand, W. Review: Sporadic cerebral amyloid angiopathy. Neuropathol. Appl. Neurobiol. 2011, 37, 75–93.
  13. Shams, S.; Granberg, T.; Martola, J.; Li, X.; Shams, M.; Fereshtehnejad, S.-M.; Cavallin, L.; Aspelin, P.; Kristoffersen-Wiberg, M.; Wahlund, L.-O. Cerebrospinal fluid profiles with increasing number of cerebral microbleeds in a continuum of cognitive impairment. Br. J. Pharmacol. 2016, 36, 621–628.
  14. Martinez-Ramirez, S.; Greenberg, S.M.; Viswanathan, A. Cerebral microbleeds: Overview and implications in cognitive impairment. Alzheimer’s Res. Ther. 2014, 6, 33.
  15. Kuhn, J.; Sharman, T. Cerebral Amyloid Angiopathy. In StatPearls; Updated 1 October 2020; StatPearls Publishing: Treasure Island, FL, USA, January 2020. Available online: https://www.ncbi.nlm.nih.gov/books/NBK556105/ (accessed on 20 March 2020).
  16. Charidimou, A.; Gang, Q.; Werring, D.J. Sporadic cerebral amyloid angiopathy revisied: Recent insights into pathophysiology and clinical spectrum. J. Neurol. Neurosurg. Psychiatry 2012, 83, 124–137.
  17. Scharf, J.; Forsting, M.; Sartor, K. Significance of haemorrhagic lacunes on MRI in patients with hypertensive cerebrovascular disease and intracerebral haemorrhage. Neuroradiology 1994, 36, 504–508.
  18. Rensink, A.A.; De Waal, R.M.; Kremer, B.; Verbeek, M.M. Pathogenesis of cerebral amyloid angiopathy. Brain Res. Rev. 2003, 43, 207–223.
  19. Hofman, A.; Ott, A.; Breteler, M.M.; Bots, M.L.; Slooter, A.J.; van Harskamp, F.; van Duijn, C.N.; Van Broeckhoven, C.; Grobbee, D.E. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam Study. Lancet 1997, 349, 151–154.
  20. Pantelakis, S. [A particular type of senile angiopathy of the central nervous system: Congophilic angiopathy, topography and frequency]. Monatsschr. Psychiatr. Neurol. 1954, 128, 219–256.
  21. Keable, A.; Fenna, K.; Yuen, H.M.; Johnston, D.A.; Smyth, N.R.; Smith, C.; Salman, R.A.-S.; Samarasekera, N.; Nicoll, J.A.; Attems, J.; et al. Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy. Biochim. Biophys. Acta (BBA) Mol. Basis Dis. 2016, 1862, 1037–1046.
  22. Keage, H.A.D.; Carare, R.O.; Friedland, R.P.; Ince, P.G.; Love, S.; Nicoll, J.A.R.; Wharton, S.B.; Weller, R.O.; Brayne, C. Population studies of sporadic cerebral amyloid angiopathy and dementia: A systematic review. BMC Neurol. 2009, 9, 3.
  23. Kalaria, R.N.; Ballard, C. Overlap between pathology of Alzheimer disease and vascular dementia. Alzheimer Dis. Assoc. Disord. 1999, 13 (Suppl. 3), S115–S123.
  24. Mendel, T.A. Sporadyczna mózgowa angiopatia amyloidowa—patofizjologia, objawy, diagnostyka i leczenie. Pol. Przegl. Neurol. 2015, 11, 163–172.
  25. Charidimou, A.; Pantoni, L.; Love, S. The concept of sporadic cerebral small vessel disease: A road map on key definitions and current concepts. Int. J. Stroke 2016, 11, 6–18.
  26. Weimar, C.; Benemann, J.; Terborg, C.; Walter, U.; Weber, R.; Diener, H.-C.; German Stroke Study Collaboration. Recurrent Stroke after Lobar and Deep Intracerebral Hemorrhage: A Hospital-Based Cohort Study. Cerebrovasc. Dis. 2011, 32, 283–288.
  27. Liguori, I.; Russo, G.; Curcio, F.; Bulli, G.; Aran, L.; Della-Morte, D.; Gargiulo, G.; Testa, G.; Cacciatore, F.; Bonaduce, D.; et al. Oxidative stress, aging, and diseases. Clin. Interv. Aging 2018, 26, 757–772.
  28. Zhang, L.; Wang, K.; Lei, Y.; Li, Q.; Nice, E.C.; Huang, C. Redox signaling: Potential arbitrator of autophagy and apoptosis in therapeutic response. Free Radic. Biol. Med. 2015, 89, 452–465.
  29. Kawamura, T.; Muraoka, I.; Kawamura, T.; Muraoka, I. Exercise-Induced Oxidative Stress and the Effects of Antioxidant Intake from a Physiological Viewpoint. Antioxidants 2018, 7, 119.
  30. Höhn, A.; Weber, D.; Jung, T.; Ott, C.; Hugo, M.; Kochlik, B.; Kehm, R.; König, J.; Grune, T.; Castro, J.P. Happily (n)ever after: Aging in the context of oxidative stress, proteostasis loss and cellular senescence. Redox Biol. 2017, 11, 482–501.
  31. Rahal, A.; Kumar, A.; Singh, V.; Yadav, B.; Tiwari, R.; Chakraborty, S.; Dhama, K. Oxidative stress, prooxidants, and antioxidants: The interplay. BioMed Res. Int. 2014, 2014, 761264.
  32. Navarro-Yepes, J.; Burns, M.; Anandhan, A.; Khalimonchuk, O.; Del Razo, L.M.; Quintanilla-Vega, B.; Pappa, A.; Panayiotidis, M.I.; Franco, R. Oxidative stress, redox signaling, and autophagy: Cell death versus survival. Antioxid. Redox Signal. 2014, 21, 66–85.
  33. Kapuy, O.; Papp, D.; Vellai, T.; Bánhegyi, G.; Korcsmáros, T. Systems-Level Feedbacks of NRF2 Controlling Autophagy upon Oxidative Stress Response. Antioxidants 2018, 7, 39.
  34. Van’t Erve, T.J. Strategies to decrease oxidative stress biomarker levels in human medical conditions: A meta-analysis on 8-iso-prostaglandin F2α. Redox Biol. 2018, 17, 284–296.
  35. Debevec, T.; Millet, G.P.; Pialoux, V. Hypoxia-Induced Oxidative Stress Modulation with Physical Activity. Front. Physiol. 2017, 8, 84.
  36. Aikens, J.; A Dix, T. Perhydroxyl radical (HOO.) initiated lipid peroxidation. The role of fatty acid hydroperoxides. J. Biol. Chem. 1991, 266, 15091–15098.
  37. Halliwell, B.; Gutteridge, J.M. Free Radicals in Biology and Medicin, 3rd ed.; Oxford University Press: Oxford, UK, 1999.
  38. Dröge, W. Free Radicals in the Physiological Control of Cell Function. Physiol. Rev. 2002, 82, 47–95.
  39. Kupsco, A.; Schlenk, D. Oxidative Stress, Unfolded Protein Response, and Apoptosis in Developmental Toxicity. Int. Rev. Cell Mol. Biol. 2015, 317, 1–66.
  40. González, J. Essential hypertension and oxidative stress: New insights. World J. Cardiol. 2014, 6, 353–566.
  41. Yao, Y.; Wang, Y.; Zhang, Y.; Liu, C. Klotho ameliorates oxidized low density lipoprotein (ox-LDL)-induced oxidative stress via regulating LOX-1 and PI3K/Akt/eNOS pathways. Lipids Health Dis. 2017, 16, 1–10.
  42. Liu, Y.; Chen, X.; Li, J. Resveratrol protects against oxidized low‑density lipoprotein‑induced human umbilical vein endothelial cell apoptosis via inhibition of mitochondrial‑derived oxidative stress. Mol. Med. Rep. 2017, 15, 2457–2464.
  43. Corpas, F.J.; Sandalio, L.M.; Palma, J.M. Impact of Nitric Oxide (NO) on the ROS Metabolism of Peroxisomes. Plants 2019, 8, 37.
  44. Hsieh, H.-J.; Liu, C.-A.; Huang, B.; Tseng, A.H.; Wang, D.L. Shear-induced endothelial mechanotransduction: The interplay between reactive oxygen species (ROS) and nitric oxide (NO) and the pathophysiological implications. J. Biomed. Sci. 2014, 21, 3.
  45. Grochowski, C.; Litak, J.; Kamieniak, P.; Maciejewski, R. Oxidative stress in cerebral small vessel disease. Role of reactive species. Free. Radic. Res. 2017, 52, 1–13.
  46. Beck, C.; Kruetzelmann, A.; Forkert, N.D.; Juettler, E.; Singer, O.C.; Köhrmann, M.; Kersten, J.F.; Sobesky, J.; Gerloff, C.; Fiehler, J.; et al. A simple brain atrophy measure improves the prediction of malignant middle cerebral artery infarction by acute DWI lesion volume. J. Neurol. 2014, 261, 1097–1103.
  47. Whitwell, J.L.; Jack, C.R.; Parisi, J.E.; Knopman, D.S.; Boeve, B.F.; Petersen, R.C.; Ferman, T.J.; Dickson, D.W.; Josephs, K.A. Rates of cerebral atrophy differ in different degenerative pathologies. Brain 2007, 130, 1148–1158.
  48. Muller, M.M.; Appelman, A.P.; Van Der Graaf, Y.; Vincken, K.L.; Mali, W.P.; I Geerlings, M. Brain atrophy and cognition: Interaction with cerebrovascular pathology? Neurobiol. Aging 2011, 32, 885–893.
  49. Thong, J.Y.J.; Hilal, S.; Wang, Y.; Soon, H.W.; Dong, Y.; Collinson, S.L.; Anh, T.T.; Ikram, M.K.; Wong, T.Y.; Venketasubramanian, N.; et al. Association of silent lacunar infarct with brain atrophy and cognitive impairment. J. Neurol. Neurosurg. Psychiatry 2013, 84, 1219–1225.
  50. Caplan, L.R. Binswanger’s disease—Revisited. Neurology 1995, 45, 626–633.
  51. Sala, S.; Agosta, F.; Pagani, E.; Copetti, M.; Comi, G.; Filippi, M. Microstructural changes and atrophy in brain white matter tracts with aging. Neurobiol. Aging 2012, 33, 488–498.e2.
  52. Nitkunan, A.; Lanfranconi, S.; Charlton, R.A.; Barrick, T.R.; Markus, H.S. Brain atrophy and cerebral small vessel disease: A prospective follow-up study. Stroke 2011, 42, 133–138.
  53. Jokinen, H.; Lipsanen, J.; Schmidt, R.; Fazekas, F.; Gouw, A.; Van Der Flier, W.M.; Barkhof, F.; Madureira, S.; Verdelho, A.; Ferro, J.M.; et al. Brain atrophy accelerates cognitive decline in cerebral small vessel disease: The LADIS study. Neurology 2012, 78, 1785–1792.
  54. Wikgren, M.; Karlsson, T.; Söderlund, H.; Nordin, A.; Roos, G.; Nilsson, L.-G.; Adolfsson, R.; Norrback, K.-F. Shorter telomere length is linked to brain atrophy and white matter hyperintensities. Age Ageing 2013, 43, 212–217.
  55. Guo, H.; Song, X.; Vandorpe, R.; Zhang, Y.; Chen, W.; Zhang, N.; Schmidt, M.; Rockwood, K. Evaluation of common structural brain changes in aging and alzheimer disease with the use of an MRI-based brain atrophy and lesion index: A comparison between T1WI and T2WI at 1.5T and 3T. Am. J. Neuroradiol. 2013, 35, 504–512.
  56. Tate, D.F.; Khedraki, R.; Neeley, E.S.; Ryser, D.K.; Bigler, E.D. Cerebral Volume Loss, Cognitive Deficit, and Neuropsychological Performance: Comparative Measures of Brain Atrophy: II. Traumatic Brain Injury. J. Int. Neuropsychol. Soc. 2011, 17, 308–316.
  57. Kassubek, J.; Landwehrmeyer, G.B.; Ecker, D.; Juengling, F.D.; Muche, R.; Schuller, S.; Weindl, A.; Peinemann, A. Global cerebral atrophy in early stages of Huntington’s disease: Quantitative MRI study. Neuroreport 2004, 15, 363–365.
  58. Aribisala, B.S.; Hernández, M.C.V.; Royle, N.A.; Morris, Z.; Maniega, S.M.; Bastin, M.E.; Deary, I.J.; Wardlaw, J.M. Brain atrophy associations with white matter lesions in the ageing brain: The Lothian Birth Cohort 1936. Eur. Radiol. 2013, 23, 1084–1092.
  59. García-Valdecasas-Campelo, E.; González-Reimers, E.; Santolaria-Fernández, F.; De La Vega-Prieto, M.J.; Milena-Abril, A.; Sánchez-Pérez, M.J.; Martínez-Riera, A.; Rodríguez-Rodríguez, E. Brain atrophy in alcoholics: Relationship with alcohol intake; liver disease; nutritional status, and inflammation. Alcohol. Alcohol. 2007, 42, 533–538.
  60. Henny, C.; A Despland, P.; Regli, F. Initial epileptic crisis after the age of 60: Etiology, clinical aspects and EEG. Schweiz. Med. Wochenschr. 1990, 120, 787–792.
  61. Anandh, K.R.; Sujatha, C.M.; Ramakrishnan, S. Atrophy analysis of corpus callosum in Alzheimer brain MR images using anisotropic diffusion filtering and level sets. In Proceedings of the 2014 36th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Chicago, IL, USA, 26–30 August 2014; Volume 2014, pp. 1945–1948.
  62. Sluimer, J.D.; Vrenken, H.; Blankenstein, M.A.; Fox, N.C.; Scheltens, P.; Barkhof, F.; Van Der Flier, W.M. Whole-brain atrophy rate in Alzheimer disease: Identifying fast progressors. Neurology 2008, 70, 1836–1841.
  63. Bokde, A.L.W.; Pietrini, P.; Ibáñez, V.; Furey, M.L.; Alexander, G.E.; Graff-Radford, N.R.; Rapoport, S.I.; Schapiro, M.B.; Horwitz, B. The Effect of Brain Atrophy on Cerebral Hypometabolism in the Visual Variant of Alzheimer Disease. Arch. Neurol. 2001, 58, 480–486.
  64. Henneman, W.; Sluimer, J.D.; Barnes, J.; Van Der Flier, W.M.; Sluimer, I.C.; Fox, N.C.; Scheltens, P.; Vrenken, H.; Barkhof, F. Hippocampal atrophy rates in Alzheimer disease: Added value over whole brain volume measures. Neurology 2009, 72, 999–1007.
  65. Prins, N.D.; Scheltens, P. White matter hyperintensities, cognitive impairment and dementia: An update. Nat. Rev. Neurol. 2015, 11, 157–165.
  66. Pantoni, L. Pathophysiology of age-related cerebral white matter changes. Cerebrovasc. Dis. 2002, 13, 7–10.
  67. Thal, D.R.; Ghebremedhin, E.; Orantes, M.; Wiestler, O.D. Vas-cular pathology in Alzheimer disease: Correlation of cerebral amyloid angiopathy and arteriosclerosis/ lipohyalinosis with cognitive decline. J. Neuropathol. Exp. Neurol. 2003, 62, 1287–1301.
  68. Moody, D.M.; Brown, W.R.; Challa, V.R.; Reboussin, D.M.; Ghazi-Birry, H.S. Cerebral Microvascular Alterations in Aging, Leukoaraiosis, and Alzheimer’s Disease. Ann. N. Y. Acad. Sci. 1997, 826, 103–116.
  69. Makedonov, I.; E Black, S.; MacIntosh, B.J. Cerebral small vessel disease in aging and Alzheimer’s disease: A comparative study using MRI and SPECT. Eur. J. Neurol. 2012, 20, 243–250.
  70. Brown, W.R.; Moody, D.M.; Thore, C.R.; Challa, V.R. Cere- brovascular pathology in Alzheimer’s disease and leukoaraiosis. Ann. N. Y. Acad. Sci. 2000, 903, 39–45.
  71. Smith, E.E. Cerebral amyloid angiopathy as a cause of neurodegeneration. J. Neurochem. 2018, 144, 651–658.
  72. Ylikoski, A.; Erkinjuntti, T.; Raininko, R.; Sarna, S.; Sulkava, R.; Tilvis, R. White Matter Hyperintensities on MRI in the Neurologically Nondiseased Elderly. Stroke 1995, 26, 1171–1177.
  73. Garde, E.; Mortensen, E.L.; Krabbe, K.; Rostrup, E.; Larsson, H.B. Relation between age-related decline in intelligence and cerebral white-matter hyperintensities in healthy octogenarians: A longitudinal study. Lancet 2000, 356, 628–634.
  74. Diaz, J.F.; Merskey, H.; Hachinski, V.; Lee, D.H.; Boniferro, M.; Wong, C.J.; Mirsen, T.R.; Fox, H. Improved Recognition of Leukoaraiosis and Cognitive Impairment in Alzheimer’s Disease. Arch. Neurol. 1991, 48, 1022–1025.
  75. Hermosilla, C.; De Lorena, P.; Sarabia-Cobo, C.; Pérez, V.; Núñez, M.J. Apathy and Leukoaraiosis in Mild Cognitive Impairment and Alzheimer’s Disease: Multicenter Diagnostic Criteria according to the Latest Studies. Dement. Geriatr. Cogn. Disord. Extra 2014, 4, 228–235.
  76. Launer, L.J. Epidemiology of White Matter Lesions. Top. Magn. Reson. Imaging 2004, 15, 365–367.
  77. Dufouil, C.; Chalmers, J.; Coskun, O.; Besancon, V.; Bousser, M.G.; Guillon, P.; Macmahon, S.; Mazoyer, B.; Neal, B.; Woodward, M.; et al. Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: The PROGRESS (Peri- ndopril Protection Against Recurrent Stroke Study) Magnetic Reso- nance Imaging Substudy. Circulation 2005, 112, 1644–1650.
  78. Debette, S.; Markus, H.S. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: Systematic review and meta-analysis. BMJ 2010, 341, c3666.
  79. Baezner, H.; Blahak, C.; Poggesi, A.; Pantoni, L.; Inzitari, D.; Chabriat, H.; Erkinjuntti, T.; Fazekas, F.; Ferro, J.M.; Langhorne, P.; et al. Association of gait and balance disorders with age-related white matter changes: The LADIS study. Neurology 2008, 70, 935–942.
  80. Wardlaw, J.M.; E Smith, E.; Biessels, G.J.; Cordonnier, C.; Fazekas, F.; Frayne, R.; I Lindley, R.; O’Brien, J.T.; Barkhof, F.; Benavente, O.R.; et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013, 12, 822–838.
  81. Del Bene, A.; Makin, S.D.; Doubal, F.N.; Inzitari, D.; Wardlaw, J.M. Variation in Risk Factors for Recent Small Subcortical Infarcts With Infarct Size, Shape, and Location. Stroke 2013, 44, 3000–3006.
  82. Sudlow, C.L.; Warlow, C.P. Comparable studies of the incidence of stroke and its pathological types: Results from an international collaboration. International Stroke Incidence Collaboration. Stroke 1997, 28, 491–499.
  83. E Vermeer, S.; Longstreth, W.T.; Koudstaal, P.J. Silent brain infarcts: A systematic review. Lancet Neurol. 2007, 6, 611–619.
  84. Kase, C.S.; A Wolf, P.; Chodosh, E.H.; Zacker, H.B.; Kelly-Hayes, M.; Kannel, W.B.; D’Agostino, R.B.; Scampini, L. Prevalence of silent stroke in patients presenting with initial stroke: The Framingham Study. Stroke 1989, 20, 850–852.
  85. Rabinstein, A. Differing Risk Factor Profiles of Ischemic Stroke Subtypes: Evidence for a Distinct Lacunar Arteriopathy? Yearb. Neurol. Neurosurg. 2010, 2010, 24–25.
  86. Jerrard-Dunne, P.; Cloud, G.; Hassan, A.; Markus, H.S. Evaluating the genetic component of ischemic stroke subtypes: A family history study. Stroke 2003, 34, 1364–1369.
  87. Del Brutto, O.H.; Mera, R.M.; Gillman, J.; Ha, J.-E.; Zambrano, M. Calcifications in the carotid siphon correlate with silent cerebral small vessel disease in community-dwelling older adults: A population-based study in rural Ecuador. Geriatr. Gerontol. Int. 2015, 16, 1063–1067.
  88. Xiao, L.; Lan, W.; Sun, W.; Dai, Q.; Xiong, Y.; Li, L.; Zhou, Y.; Zheng, P.; Fan, W.; Ma, N.; et al. Chronickidney disease in patients with lacunar stroke: Association with enlarged perivascular spaces and total magnetic resonance imaging burden of cerebral small vessel disease. Stroke 2015, 46, 2081–2086.
  89. Yang, S.; Cai, J.; Lu, R.; Wu, J.; Zhang, M.; Zhou, X. Association Between Serum Cystatin C Level and Total Magnetic Resonance Imaging Burden of Cerebral Small Vessel Disease in Patients With Acute Lacunar Stroke. J. Stroke Cerebrovasc. Dis. 2017, 26, 186–191.
  90. Giwa, M.O.; Williams, J.; Elderfield, K.; Jiwa, N.S.; Bridges, L.R.; Kalaria, R.N.; Markus, H.S.; Esiri, M.M.; Hainsworth, A.H. Neuropathologic evidence of endothelial changes in cerebral small vessel disease. Neurology 2012, 78, 167–174.
  91. Lawrence, E.S.; Coshall, C.; Dundas, R.; Stewart, J.; Rudd, A.G.; Howard, R.; Wolfe, C.D. Estimates of the prevalence of acute stroke impairments and disability in a multiethnic population. Stroke 2001, 32, 1279–1284.
  92. Chen, Y.; Chen, X.; Mok, V.C.; Lam, W.W.; Wong, K.S.; Tang, W.K. Poststroke depression in patients with small subcortical infarcts. Clin. Neurol. Neurosurg. 2009, 111, 256–260.
  93. Ross, G.W.; Petrovitch, H.; White, L.R.; Masaki, K.H.; Li, C.Y.; Curb, J.; Yano, K.; Rodriguez, B.L.; Foley, D.J.; Blanchette, P.L.; et al. Characterization of risk factors for vascular dementia: The Honolulu-Asia Aging Study. Neurology 1999, 53, 337.
  94. Barba, R.; Martinez-Espinosa, S.; Rodríguez-Garcia, E.; Pondal, M.; Vivancos, J.; Del Ser, T. Poststroke dementia: Clinical features and risk factors. Stroke 2000, 31, 1494–1501.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback