CLINICAL-CELL BIOLOGICAL STUDIES IN ALZHEIMER'S DISEASE

这个LEAD应用程序的目的是测试检查细胞的价值， 和神经外组织的分子异常 阿尔茨海默病（DAT）。 它将测试是否报告 异常与DAT临床综合征的存在有关，或 它的某些亚组（家族性与散发性，早发与迟发， vs.没有帕金森综合征、肌阵挛、抑郁症或早期失语症）。 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，包括神经心理学测试;遵循- 可能的话会送去验尸 皮肤细胞培养，包括活检 将被精心标准化，以确保DAT和控制细胞 在相同的条件下研究，包括相同的生物年龄， 文化 在培养物中测量的参数将包括两个相关参数， 在DAT脑中积累的物质：淀粉样前体蛋白， 以及与成对螺旋丝的抗体反应的材料 （PHF）。 （PI及其同事最近的研究表明，皮肤细胞 当在规定的温度下生长时， 条件下，DAT细胞比对照组多得多。） 其他参数以 据报道，在至少两个国家的DAT细胞中， 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， 详细分析实验室检查结果（SAS统计软件）。 博士神经学助理教授罗纳德布莱克将开发方法， 为了定量抗PHF反应性物质，比较这些物质的量 受影响和未受影响的可溶性和不溶性组分中的物质 DAT和对照大脑的区域，然后比较它们在培养的 DAT和对照细胞。 他将获得临床专业知识， 通过积极参与痴呆症的临床研究， 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， 研究培养的DAT细胞中的异常。 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 cells 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.