CLINICAL-CELL BIOLOGICAL STUDIES IN ALZHEIMER'S DISEASE

此LEAD应用程序的目的是测试检查 患者神经外组织中的细胞和分子异常 阿尔茨海默病（DAT）。 它将测试是否报告 异常与DAT的临床综合征或 它的某些亚组（家族性与散发性，早发与迟发， 与无帕金森综合征、肌阵挛、抑郁症或早期失语症相比）。 DAT 患者和疾病以及年龄和性别相当的完整对照将全部 接受详细的检查，包括神经心理测试; 在可能的情况下，将进行尸检。 皮肤细胞培养包括 活检将严格标准化，以确保DAT和控制 在相同的条件下研究细胞， 文化中的年龄 在培养物中测量的参数将包括两个 与DAT脑中积累的物质相关：淀粉样前体 蛋白质和与成对螺旋抗体反应的材料 长丝（PHF）。 （PI及其同事最近的研究表明， 皮肤细胞在生长条件下积累抗PHF活性物质 在特定条件下，DAT细胞比对照组多得多）。 其他 据报告， 至少两个实验室：异丙肾上腺素刺激的环AMP合成， 细胞钙稳态和[U-14 C]谷氨酰胺氧化。 数据将 存储在关系数据库（SIR软件）中， 详细分析临床和实验室检查结果（SAS统计 软件）。 罗纳德布莱克博士，神经学助理教授，将开发 定量抗PHF反应性物质的方法，比较 这些材料在受影响的可溶性和不溶性部分中， 未受影响的DAT区域和控制大脑，然后比较它们的数量 在培养的DAT和对照细胞中。 他将获得临床专业知识， 以及痴呆症的实验室研究， 临床评价。 一项初步研究将检查抗APP反应性的可能增加， DAT粒细胞中的物质，以及第二种可能的异常 在培养的DAT皮肤细胞中的磷酸激酶活性。 未来的飞行员将 也研究其他潜在的标记。 拟议的调查将扩大PI正在进行的机制， 对培养的DAT细胞异常的研究。 他们将直接测试 研究的异常是否与临床 DAT综合征或DAT亚组。

The aim of this LEAD application is to test the value of examining cellular and molecular abnormalities in extra-neural tissues from patients with Alzheimer's disease (DAT). It will test whether or not reported abnormalities relate to the presence of -the clinical syndrome of DAT or certain of its subgroups (familial vs sporadic, early vs.late onset, with vs without Parkinsonism, myoclonus, depression, or early aphasia). DAT patients and disease and intact controls of comparable age and sex will all receive detailed examination including neuropsychological testing; follow-up where possible will be to autopsy. Skin cell cultures including biopsy will be meticulously standardized to ensure that DAT and control cells are studied under identical conditions including identical biological age in culture. Parameters measured in the cultures will include two related to the materials which accumulate in DAT brain: amyloid precursor protein, and materials which react with antibodies to paired helical filaments (PHF). (Recent studies by the PI and co-workers indicate that skin cells accumulate anti-PHF reactive materials when grown under specified conditions, much more in DAT cells than in controls). Other parameters to be measured have been reported abnormal in DAT calls in at least two laboratories: isoproterenol-stimulated cyclic AMP synthesis, cellular calcium homeostasis, and [U-14C]glutamine oxidation. Data will be stored in a relational data base (SIR-software) and relations among clinical and laboratory findings analyzed in detail (SAS statistical software). Dr Ronald Black, an assistant professor of Neurology, will develop methods to quantitate anti-PHF reactive materials, compare the amounts of these materials in soluble and insoluble fractions of affected and unaffected areas of DAT and control brains, and then compare their amounts in cultured DAT and control cells. He will gain expertise in clinical as well as laboratory research in dementias by participating actively in the clinical evaluations. One pilot study will examine a possible increase in anti-APP reactive materials in DAT granulocytes, and a second possible abnormalities in phosphokinase activities in cultured DAT skin cells. Future pilots will also study other potential markers. The proposed investigations will extend the PI's ongoing mechanistic studies of abnormalities in cultured DAT cells. They will test directly whether or not the abnormalities studied relate closely to the clinical syndrome of DAT or to DAT subgroups.