| BackgroundAlzheimer,s disease(AD) which occupies senile dementia from 60% to 70% is the most common subtype of senile dementia. Currently there are more than 12 million patients with AD worldwide, and it is projected that approximately 45 million will be afflicted with the disease in the next 50 years. The therapy and nurse on patients with AD carry a heavy burden on their families and society. It is urgent to prevent and cure AD.Epidemiological studies found that vascular risk factors of cerebrovascular disease, including hypertension, diabetes, hypercholesteremia, atherosclerosis,and so on, can influence the occurrence of AD and increase the risk of AD.According to above studies,we can suppose vascular risk factors may also have an important effect on the progression of AD and ultimately aggravate the cognitive dysfunction of AD.The approach to the role of vascular risk factors in the progression of AD will bring us an important hint to the therapy of AD,that is besides the orthodox anticholinergic drugs ,active control of vascular risk factors by good use of therapeutic drugs such as antihypertensive drugs,hypoglycemic drugs and antihyperpipoproteinemic drugs will slow down ,or prevent,even reverse the progression of AD.What is the mechanism of vascular risk factors affecting the cognitive function of AD?Vascular risk factors result in cerebral arteriosclerosis which induces chronic cerebral hyoperfusion,and seriously leads to cerebral infarction in which lacunar infarction is the most common, and the mechanism of vascular risk factors affecting cognitive function of AD is the acute or chronic cerebral ischemia induced by the above cerebrovascular diseases. Cerebral ischemia induces ischemic change of hippocampal neurons to be functional disorder,even dead, and ultimately leads to cognitive dysfunction. So at present the association between cerebral ischemia and AD is thought highly of increasingly. Epidemiological and neuropathological studies found that about 1/3 of AD diagnosed clinically exhibited the pathological evidence of cerebral infarction at autopsy; cerebral ischemia aggravated the cognitive dysfunction of AD.These entire studies hint there is a close relationship between AD and cerebral ischemia.To approach the effect of cerebral ischemia on the progression of AD will provide a new clue to teat AD.It is important clinically for the therapy and prevention of AD to study the role of vascular risk factors and cerebral ischemia in the development of AD. With regard to this purpose, an clinical study and an experimental study were conducted: (1) to investigate the association between vascular risk factors and the progression of AD in a two years longitudinal prospective study. (2) to explore the effect and mechanism of cerebral ischemia on cognitive function in rats with AD, and to approach the role and mechanism of cerebral ischemia in the progression of AD.Part One A clinical study on the effect of vascular risk factors on the cognitive function of ADObjectives To investigate the association between vascular risk factors and the progression of AD in a prospective study.Subjects and methods(1) Subjects A 2-year follow-up study from 2004 Sep to 2006 Dec was conducted in 163 patients with AD who were diagnosed as possible AD clinically in our department from 2000 Jan to 2004 Aug.(2) Baseline screening At baseline screening, the following data were collected: demographic data, vascular risk factors and medication(by insquiring case history, medical examination, auxiliary examination and blood tests) and neuropsychological test (including MMSE, ADL, FOM, RVR, POD, DS subtest, BS subtest, HDRS and Hachinski score).The diagnose of dementia and AD was made on the basis of DSM-Ⅲ-R and NINCDS-ADRDA respectively. Patients with AD were classified into AD with vascular risk factors and AD without vascular risk factors.(3) Follow-up Subjects were followed up annually.Cognitive status was assessed using the same procedure as baseline screening.(4) Statistical analysis In uivariate analysis, Pearson Chi-square test, Fisher exact test, T-test or the Mann-Whitney U test were used as deemed to be appropriate. In multivariate analysis, Linear stepwise regression analysis was used to evaluate the association between vascular risk factors and the progression of AD.Results(1) Follow-up There were a total of 238 residents in our department who were diagnosed as possible AD clinically from 2000 Jan to 2004 Aug, of which 211(88.7%) were enrolled into the follow-up. The duration of follow-up was 2 years, during which 15(7.1%) died, 22(10.4%) refused or went out, 2(0.9%)moved too far to be interviewed and 9(4.3%) were rejected because of cerebral hemorrhage diagnosed. Only 163(77.3%) patients with AD were enrolled into the study.(2) Baseline characteristics The baseline characteristics of the subjects were compared according to the existence of vascular risk factors. Compared with subjects without vascular risk factros, those with vascular risk factors had older age (82.7±7.9 vs 78.3±6.7, p<0.01)and were more frequent in women (69.4% vs 58.3%, p<0.01).No statistical differences were found in MMSE score(17.6±4.3 vs 18.5±5.1,p=0.426), ADL score(32.8±8.3 vs 32.1±7.7, p=0.896), lower education(≤6 years)(71.6% vs 72.8%, p=0.830), blue-collar occupation(70.1% vs 68.7%, p=0.864) and percent of taking anti-AD medicine(32.7% vs 31.4%, p=0.913) at baseline.(3) Distribution of vascular risk factors in baseline The distribution of vascular risk factors in the patients with AD was hypertension (36.5%), diabetes (28.6%), hypercholesteremia (20.7%), myocardial infarction (3.5%), atrial fibrillation (6.9%), carotid atherosclerotic plaque (25.1%), TIA (11.6%), current smoking (28.2%), drinking wine daily (23.1%).(4) Univariate analysis for the progression of cognitive dysfunction At the end of follow-up subjects with vascular risk factors had lower scores of memory, direction, spatial resolution, abstract thinking, language and social activities than subjects without (P<0.01).Subjects with vascular risk factors had higher rate of cognitive deterioration than subjects without(P<0.01).(5) Multivariate analysis for the association between vascular risk factors and the progression of AD After correcting confusing factors including demographic data and medication, the following vascular risk factors including cerebral infarction(bj'=0.917,P<0.001),TIA (bj'=0.876,P<0.001), diabetes (bj'=0.863,P<0.001), hypertension (bj' = 0.821 , P < 0.01), carotid atherosclerotic plaque (bj ' = 0.749 , P <0.05),hypercholesteremia (bj'=0.736,P<0.05), current smoking (bj'=0.439,P<0.05) and drinking wine daily (bj'=0.323,P<0.05) were associated with the progression of AD.Conclusions(1) Cerebral infarction,TIA, diabetes,hypertension, carotid atherosclerotic plaque , hypercholesteremia, current smoking and drinking wine daily were associated with the progression of cognitive dysfunction of AD. The mechanism of vascular risk factors affecting cognitive function of AD may be that cerebral ischemia caused by vascular risk factors induces ischemic change of hippocampal neurons to be functional disorder,even dead, and ultimately leads to cognitive dysfunction.(2) Active control of vascular risk factors can relieve the progression of AD to some extent.Part Two The effect and mechanism of cerebral ischemia on cognitive function of AD rats Objectives To investigate the change of cognitive function in AD rats established by injection of Aβ1-40 into the hippocampus after exposed to cerebral ischemia established by injection of (Endothelin-1,ET-1) into the right striatum, then to explore the effect and possible mechanism of cerebral ischemia on cognitive function in AD rats. Methods AD rat model was established by hippocampal injection of Aβ1-40.Then AD rats were injected ET-1 into the right striatum to establish cerebral ischemic model of multiple striatal lacunar infarction which is common clinically so as to explore the effect and possible mechanism of cerebral ischemia on cognitive function in AD rats.(1) Evaluation of the AD rat model The AD rat model was evaluated in ethology (by shuttle box and Morris water maze), neuropathology of hippocampus (by Congo red,Nissl,s and HE staining) and the expression of phosphorylated tau protein in neurons (anti-tau(pS202) immunohistochemistry).(2) The effect of cerebral ischemia on cognitive function of AD rats After established the condition of cerebral ischemia, the AD rats were observed for the change of cognitive function, neuropathology of hippocampus and the expression of phosphorylated tau protein in neurons.(3) The inflammatory mechanism of cerebral ischemia on cognitive function in AD rats After establishing the condition of cerebral ischemia to the AD rats, immunohistochemical method was used to analyze the number of astrocytes and the protein expression of inflammatory cytokine IL-1, TNF-αin the hippocampus. In situ hybridization and reverse transcription-polymerase chain reaction were used to evaluate the mRNA expression of IL-1 and TNF-αin the hippocampus by location and quantitation respectively.Results(1) The AD rats showed decreased ability of AAR,PAR and spatial resolution(P<0.01), reduced number of neurons in the region of DG(P<0.01), Aβdepositon in the injected hippocampus and significantly increased expression of phosphorylated tau of ser202 in hippocampal neurons(P < 0.01).All of the above results indicated the successful establishment of the AD rat model. The cerebral ischemic model of multiple striatal lacunar infarction can be established successfully by injecting ET-1 into the right striatum of rats.(2) Compared with the simple AD rats, the AD rats exposed to cerebral ischemia showed deterioration of conitive function(P<0.01), more Aβdeposition in the injected hippocampus(P<0.05), reduced number of neurons in the region of DG(P<0.01) and significantly increased expression of phosphorylated tau of ser202 in hippocampal neurons(P<0.01).(3) The number of astrocytes and the protein expression of inflammatory cytokine IL-1, TNF-αin the hippocampus increased significantly in the group of AD with cerebral ischemia(P<0.01). The mRNA expression of IL-1 and TNF-αin the hippocampus also increased significantly in the group of AD with cerebral ischemia(P<0.01).Conclusions(1) The AD rat model can be established successfully by injection of Aβ1-40 into the hippocampus of rats.(2) The cerebral ischemic model of multiple striatal lacunar infarction which is common clinically can be established successfully by injecting ET-1 into the right striatum of rats.(3) Cerebral ischemia aggravated the cognitive impairment of AD rats, and this conclusion hints active prevention and therapy of cerebral ischemia can relieve the progression of AD to some extent.(4) The astrocyte and expression of inflammatory cytokine including IL-1 and TNF-αin the hippocampus increased obviously after cerebral ischemia, and inflammatory mechaniasm participated in the process that cerebral ischemia enhanced the progression of AD.
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