Neuropathology And Neuroimage Studies For The Ischemic Mechanism Of Leukoaraiosis

Background Leukoaraiosis, which is used to describe the hypodensities on CT or hyperintensities on MRI in the periventricular or deep white matter, has a high prevalence in aged people and has been found to have close association with cognition decline, motor and gait disturbances, depressive symptoms, and urinary disturbances. Leukoaraiosis was an independent predictor of stroke and stroke recurrence. It has also been suggested as an important predictor for disability and mortality of community based subjects. Many ischemic factors, such as hypertension, diabetes mellitus, history of vascular diseases and cigarettes smoking, have close correlation with leukoaraiosis. The strong association between leukoaraiosis and vascular factors implied an ischemic basis of leukoaraiosis. Lacunes, which were used to describe the 3 to 10 mm cerebrospinal fluid-like signals in the basal ganglia or white matter, were frequently observed coincidentally on imaging in older people, and often not clearly associated with discrete neurological symptoms. Leukoaraiosis and lacunes have been recognized as aspects of cerebral small vessel diseases, while lacunes is resulted from occlusion of small arteries and leukoaraiosis is resulted from partial ischemia mainly. The role of large vessel disease in the pathogenesis of leukoaraiosis is still controversial. Although numerous studies had been applied to leukoaraiosis, the pathogenesis remains poorly defined. The object of our research is to gain a preliminary understanding of the pathogenesis of ischemic leukoaraiosis through discussion of pathological basis and clinical characteristics of leukoaraiosis by animal experiments and clinical imaging studies.Methods Two major parts were included in our research: animal experiment and clinical imaging study. For the animal experiment, the main objective is to determine the effect of angiogenesis and angiogenic blood-brain barrier (BBB) damage on the ischemic white matter damage. In the first section of animal experiment, bilateral common carotid artery occlusion (BCCAO) was used to induce hypoperfusion of forebrain to male Wistar rats. White matter change, vessel density and endothelial proliferation in white matter areas, BBB permeability, the mRNA expression of vascular endothelial growth factor and vascular endothelial growth factor receptors were examined. In the second section of animal experiment, rats with hypoperfusion also received anti-angiogenesis treatment to further explore the effect of angiogenesis and angiogenic BBB damage on the ischemic white matter impairment.The main objective of clinical imaging study was to determine the effect of small vessel diseases and large vessel diseases on leukoaraiosis, and the prognosis of leukoaraiosis. For the clinical imaging study, consecutive patients admitted to Department of Neurology, Beijing Military General Hospital were included. Magnetic resonance imaging (MRI) was performed and computer-assisted method was used for quantitative analysis of the volume of white matter hyperintensities (WMH) in bilateral hemispheres. The asymmetric WMH were analyzed with the blood flow dynamic factors of carotid arteries and lacunes. In the research, the effect of leukoaraiosis and lacunes on the outcome and complications were also studied to discuss the clinical characteristics of leukoaraiosis, and the difference between leukoaraiosis and lacunes. Besides, a computer-assisted semi-automated quantitative method for assessment the volume of white matter hyperintensities and an imaging-overlap method were developed and applied successfully.Result In the first section of animal experiment, compared to the controlled rats, fiber densities of cerebral white matter of BCCAO rats were significantly lower and more serious in deep cerebral white matter. Increased vascular surface areas and more palingenetic endothelial cells in white matter areas, higher BBB permeability and upregulation of mRNA expression of VEGF and VEGFRs were also observed in BCCAO rats. A temporal and spatial coincidence was found among the angiogenesis, BBB leakage and white matter changes.In the second section of animal experiment, the anti-angiogenesis rats showed a significant decrease of capillary density, numbers of proliferated endothelial cells in deep white matter areas and BBB permeability compared with those of the ischemia-control group, while the fiber density in deep cerebral white matter of anti-angiogenesis rats is significantly lower than ischemia-control group.In the first part of clinical imaging studies, asymmetric white matter hyperintensities (WMH) had an incidence of 14.2% within all patients. Patients with asymmetric WMH had significantly less age, higher WMH volume, more hypercholesterolemia and more diabetes than those with symmetric WMH. More alcohol drinker and smoker were founded in patients with asymmetric WMH than those with symmetric WMH. Age, alcohol taking and diabetes were independently predictors of asymmetric WMH. The difference of lacunes numbers of bilateral hemisphere was strongly associated with asymmetric WMH (P < 0.001). Stenosis of common carotid arteries had a weak association with asymmetric WMH (P = 0.031).In the second part of clinical imaging studies, Leukoaraiosis was found to be an independent predictor of adverse outcome and chest infection for patients with acute ischemic stroke, while no association between lacunes and adverse outcome or any complications after stroke was observed.Conclusion Six major conclusions were drew from our research as follow:⑴BBB damage and white matter impairment could be induced by chronic cerebral hypoperfusion; Angiogenesis, including upregulation of VEGF and its receptors and formation of palingenetic capillary, could be also prompted by chronic cerebral hypoperfusion;⑵The temporal and spatial association among angiogenesis, BBB damage and white matter impairment implied an possible interaction between such processes in ischemic injury;⑶VEGF and VEGFR contributed to the BBB leakage on chronic hypoperfusion status;⑷Angiogenesis offered beneficial effect on whiter matter with chronic cerebral hypoperfusion more than harmful effect,anti-angiogenesis treatment would bring to severer whiter matter impairment;⑸Cerebral small vessel diseases have important significance for the pathogenesis of leukoaraiosis, while large vessel diseases have less effect on leukoaraiosis. Although lacunes and leukoaraiosis were both main manifestations of small vessel diseases, lacunes may be one of the causes of ischemic leukoaraiosis;⑹leukoaraiosis is an independent predictor of adverse outcome and chest infection for patients with acute ischemic stroke, lacunes had not any significant association with adverse outcome and complications after stroke. The different effects of lacunes and leukoaraiosis on the stroke outcome and incidence of complications may reflect the heterogeneity between them.