| Parkinson’s disease is a kind of nervous system degenerative diseases and elderly is susceptible. Four mainly movement symptoms are included,which is static tremor, bradykinesia, myotonia and posture gait disorder, and non-motor symptoms including:cognitive dysfunction, sleep disorders, mental disorders, autonomic nerve dysfunction.Not only the symptoms of movement disorders,but also motor symptoms of cognitive dysfunction bring much trouble into patients’ daily life. Parkinson’s disease with Cognitive impairment include mild cognitive impairment in Parkinson’s disease and Parkinson’s disease dementia.Cognitive dysfunction can appear in early stage of PD. incidence of accounted for about 20% to 50%, Which has been shown to be a predictor of cognitive decline that can potentially lead to dementia.The PD-MCI, and subsequent worsening of cognitive functions, not only significantly contributes to the morbidity and mortality associated with PD.but also aggravate the burden of the patients’family., main performance of PD-MCI includ:executive function, attention, memory, visual space, etc. With more attention to the PD-MCI,2012,the international movement disorders association redefined the definition of PD-MCI. For the early detection the change of cognitive function in PD, many imaging tools were used to explore relationship between cognitive dysfunction and writer matter changes. Our Research Team early found patients with PD-D and PD-MCI showed significant FA reduction in the left frontal and right temporal white matter as well as in the bilateral anterior cingulate bundles,compared to patients of the control group;patients with PD-D showed significant FA reductions in the left anterior cingulate bundle and corpus callosum splenium compared to PD-MCI by diffusion Tensor Imaging (Difusion Tensor Imaging, DTI) technology.Besides,this research further found that the PD-MCI is associated with cerebral white matter fiber integrity, mainly include:superior parietal lobule, precuneus, Middle Occipital Gyrus, middle temporal gyrus. Based on above research, we think the brain white matter fiber integrity is associated with cognitive function in patients with PD, and accelerate progressof cognitive dysfunction in PD.Leukoaraios,or white matter hyperintensities,is a phenomena of writer matter changes. Leukoaraios has been reported by Hachinski in 1987,which has a dcrease(signal on the Tl-weighted and an increased signal on the T2-weighted (or FLAIR) magnetic resonance imaging(MRI) sequences of the brain.Recent study found brain white matter hyperintensities have relations to the decline of cognitive function in alzheimer’s disease and normal old people, especially the lateral cerebral ventricles of brain white matter hyperintensities, the degree of white matter hyperintensities is positively correlated with decreased cognitive function. Studies have also found the hyperintensities of frontal lobe, parietal lobe, occipital lobe lead to the cognitie decline in PD patients especially deep brain white matter hyperintensities, especially parietal lobe, which is related to executive function damage.Longitudinal studies have shown that subjective memory impairment might be a strong predictor of PD-MCI. Memory impairment brings many puzzles for activities of daily living. Incidence of the memory impairment is about 13% in PD.Petersen Classified PD-MCI four subtypes:aMCI-SD, amnestic single-domain MCI;naMCI-SD, nonamnestic single-domain MCI; aMCI-MD, amnestic multiple-domain MCI; naMCI-MD, nonamnestic multiple-domain MCI. The research of Apostolova in Parkinson’s disease has found amnestic single-domain of Parkinson’s patients with left occipital horn larger trend. Some research found the increase of the lateral ventricle was connected with lateral ventricle hyperintensities. Lee, etc. have found frontal lobe, parietal lobe,occipital lobe and lateral ventricle hyperintensities indicated the decline of immediate and delayed memory in PD. white matter hyperintensities often appear in the lateral ventricle lateral,which is composed of corpus callosum and basal ganglia region, the region is associated with memory, emotion and so on.so lateral ventricle hyperintensities cause fiber disruption of the inside edge of the loop, basal lateral edge of the loop, defense loop, eventually lead to memory impairment.white matter hyperintensities is ofen due to ischemia, low perfusion, blood brain barrier damage, lateral ventricle is supplied much by terminal artery bloodthat is lack of collateral circulation, called the watershed area, when cerebral blood flow decline, ischemia will happen in ventricle white matter, eventually lead to white matter damage. white matter hyperintensities is the pathological process of chronic hypoperfusion, but the changes of brain white matter fibers may appear in the early stages of cerebral hypoperfusion. Therefore, this study combined with animal experiments, which discusses the relationship between white matter changes and cognitive dysfunction in PD. a mouse model of PD was finished and mouse of cognitive dysfunction were acquired by Morris water maze, open field test and Pole test. PD with cerebral hypoperfusion mouse model is builded by narrowing bilateral common carotid artery in the mouse of PD.We can reseach the connection of among cerebral hypoperfusion,white matter fiber changes and cognitive function by immune histological technology.Leukoaraios is the pathological process of cerebral hypoperfusion, when patients have the symptoms of cognitive dysfunction due to Leukoaraios, then,the change of white matter fiber is irreversible. the integrity of white matter fiber can be observed early by functional magnetic resonance imaging (such as:DTI), but imaging tool cannot stop the process of white matter fiber change.So we should explore the mechanism of white matter fiber change from the molecular level in PD. At present the research thinks brain white matter damage is associated with some biological markers in CSF, such as metal matrix protease (MMPs), myelin basic protein (MBP), nerve filament protein light chain. A LADIS study found attention and executive function is relation to metal matrix protease (MMPs), including MMP9 that associated with the progress of white matter changes, MMP3that associated with brain atrophyin vascular dementia patients. MMP3 is known as that it can degrade the degradation of extracellular matrix proteins, participate in the blood-brain barrier damage and regeneration of new blood vessels.Besides, activation of MMP3 also can activate MMP9. The study found that MMP3 plays an important role in the process of glial cell activation, T lymphocyte infiltration, blood-brain barrier damage. in PD patients. In addition, MMP3 also take participate in the growth of axons, glial cell migration and the learning and memory of synaptic plasticity. So some research thinked MMP3 and MMP9 destruct the blood-brain barrier, which in turn cause white matter edema, fiber demyelination.The activation of metal matrix protease is often associated with the activation of glial cells, Oligodendrocyte Precursor Cells(OPCs) is a kind of glial cells,which has the function of differentiate, they could differentiate into oligodendrocytes, and oligodendrocytes is an important part of the myelin, therefore the activation, proliferation and differentiation of OPCsplay an important role in white matter fiber myelin. In 2012, Ji HaeSeo found the increase expression of MMP9 in cerebral white matter lesions area in the rat brain low perfusion model, MMP9 that cause damagement of blood brain barrier, lead to white matter fibers demyelination and cognitive function decline. At the same time, We reseached the influence of OPCs proliferation and migration, MMP3 and MMP9 expression in the brain white matter to white matter change and cognitive by immunohistochemical technology,WB and ELISA test in the model.This research includes the following main contents:1. Analysis of Leukoaraios in Parkinson’s disease patients with amnestic mild cognitive impairment.2. Reseach of Oligodendrocyte Precursor Cells (OPCs)and related metal matrix protease protease (MMP3 and MMP9) in the mouse model of Parkinson’s disease cognitive dysfunction and hypoperfusion.Part I:Analysis of leukoaraios in Parkinson’s disease patients with amnestic mild cognitive impairmentObjective:To evaluate Leukoaraios in Parkinson’s disease (PD)_patients with amnestic mild cognitive impairment(MCI). Methods:According the neuropsychological assessment, one hundred and two Parkinson’s disease (PD) patiens was divided into PD without mild cognitive impairment (PD-CN) group (n=37), amnestic PD-MCI group(aPD-MCI,n=30) and Nonamnestic PD-MCI group(naPD-MCI,n=35). All patients underwent 3.0-T magnetic resonance imaging(MRI). Leukoaraios was rated using the scheltens semiquantitative visual rating system to analysis different characteristic in three groups. Results: leukoaraios level of periventricular and frontal lobe in aPD-MCI group was significantly higher than naPD-MCI and PD-CN group(P<0.05), especially in anterior horns of the lateral ventricles (P<0.05). Mini-Mental state Examination(MMSE) and Montreal cognitive Assessment(MoCA) scores in aPD-MCI and naPD-MCI groups were postively lower than PD-CN group. Conclusions:1.Periventricular leukoaraios cause memory impaired in PD-MCI. 2. Education level may be cognitive reserve in Parkinson’s disease patients with mild cognitive impairment, the higher degree of education, impaired memory is relatively gently.PartⅡ:Analysis of white matter changes between Oligodendrocyte Precursor cells proliferation,metal matrix protease expression under the effect of hypoperfusion in Parkinson’s disease with cognitive impairmentObjective:Reseaching the influence of OPCS proliferation and migration, MMP3 and MMP9 expression in the brain white matter to white matter change and cognitive Methods:Fristly a mouse model of PD was finished and mouse of PD combined cognitive dysfunction were acquired by Morris water maze, open field test and Pole test. The mouse model of PD combined cognitive dysfunction with hypoperfusion was builded by narrowing bilateral common carotid artery, narrowing bilateral common carotid artery 3 days is 3days group; narrowing bilateral common carotid artery 28days is 28days group.3days group mouse was divided into seven groups,as follow:(1).control group,8 mouses (2).sham group,9 mouses (3). PD with mild cognitive impairment (PD-MCI) group,6mouses (4). PD without mild cognitive impairment (PD-CN)group,6mouses (5). Bilateral common carotid artery stenosis(BCCAs) group,6mouses (6). PD-MCI+B group,6 mouses (7). PD-CN+B group,6mouses, Same to the 3 days,28 days group was divided: (1).control group,10 mouses (2).sham group,9 mouses (3). PD with mild cognitive impairment (PD-MCI) group,9 mouses (4). PD without mild cognitive impairment (PD-CN)group,10 mouses (5). Bilateral common carotid artery stenosis(BCCAs) group,8 mouses (6). PD-MCI+B group,8 mouses (7). PD-CN+B group,7 mouses.we dealed with 7 groups as the time of narrowing bilateral common carotid artery. We reseached the distribution of Oligodendrocyte Precursor and matrix protease protease 3 and 9,changes of writer matter fiber of 7 groups by immunohistochemical technology.we observe expression of NG2, matrix protease protease 3 and 9 by Western bloting.Detection of serum matrix protease protease 3 and 9 by ELISA test in the model. Results:(1) the mouse model of Parkinson’s disease cognitive dysfunction and hypoperfusion. Is finished successfully. (2) In PD-MCI+B group and PD-MCI group NG2 immune protein fluorescence intensity is much more obvouris than PD-CN+B group and PD-CN. longer duration of low cerebral blood flow perfusion immune fluorescence intensity is bigger. (3) in corpus callosum area,PD-MCI+B group and PD-MCI group cerebral white matter fiber appear more vacuoles, or Myelin fracture heavier than PD-CN+B group and PD-CN cerebral, longer duration of low cerebral blood flow perfusion and cerebral white matter fiber change is heavier. (4) the expression of MMP3 and MMP9 in PD-MCI+B group and PD-MCI group is biger than PD-CN+B group and PD-CN group obviously, and longer duration of low cerebral blood flow perfusion expression is much more,The distribution of corpus callosum MMP3 and MMP9 also have similarities, but 28 days PD-MCI+B group and PD-CN+B group the difference is no difference. (5) Proliferation of OPCs is significant, expression of MMP9 and MMP3 is much more in PD-MCI+B group and PD-MCI group of Chronic hypoperfusion group (28 days),Proliferation OPCs, were positively correlated expression of MMP9 and MMP3 Conclusions:1. The firstly build cognitive impairment in Parkinson’s disease with low cerebral blood flow perfusion model.2. OPCs proliferation may influence cognitive function in Parkinson’s disease rat.3. cerebral white matter fiber changes by Low cerebral blood flow perfusion were associated with cognitive impairment in Parkinson’s disease, and the longer of low perfusion the more serious the change of cerebral white matter fiber.4. By Low cerebral blood flow perfusion 5the expression of MMP3 and MMP9 caused a decline in cognitive function in mouse Parkinson’s disease, may be because of that the expression of MMP9 and MMP3 lead to cerebral white matter fiber changes, leading to cognitive disfunction in Parkinson’s disease in mice. 5. Low cerebral blood flow perfusion can activate the OPCs, which generate MMP3.OPCs proliferation,OPCs take participate in series of reactions,such as:the apoptosis of dopaminergic neurons,blood-brain barrier damage and fiber demyelination, at last, it participates in pathological mechanism of Parkinson’s disease and Parkinson’s disease cognitive impairment... |
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