Tobinick Edward
University of California Los Angeles; Institute for Neurological Research, Los Angeles, California, USA.
Medscape J Med. 2008 Jun 10;10(6):135.
Primary progressive aphasia (PPA) is an uncommon form of progressive dementia for which there exists no established treatment. The underlying pathology may be that of either frontotemporal dementia or Alzheimer's disease. Increasing evidence suggests that excess tumor necrosis factor (TNF) may play a central role in Alzheimer's disease. Additionally, excess TNF has been documented in patients with frontotemporal dementia. Excess TNF may therefore represent a therapeutic target in PPA. Etanercept, an anti-TNF fusion protein, binds to TNF, thereby reducing its biologic effect. Emerging evidence suggests that perispinal administration of etanercept may have therapeutic efficacy for Alzheimer's disease. This evidence, in combination, supports a rationale for the use of perispinal etanercept for the treatment of PPA. This report documents rapid improvement in verbal abilities, beginning within 20 minutes of perispinal etanercept, in a patient with severe PPA. With repeated weekly dosing, sustained improvement at 1 month is documented, with a more than 10-point improvement in the patient's abilities to perform activities of daily living as measured by a standardized instrument, the Alzheimer's Disease Cooperative Study-Activities of Daily Living inventory. Rapid clinical improvement in PPA following perispinal etanercept administration may be related to TNF's role as a gliotransmitter and modulator of synaptic communication in the brain. These results may provide insight into the basic pathophysiologic mechanisms underlying PPA and related forms of dementia and suggest the existence of novel, rapidly reversible, TNF-mediated pathophysiologic mechanisms in both PPA and Alzheimer's disease. Further study of this therapeutic method is indicated.
原发性进行性失语（PPA）是一种罕见的进行性痴呆形式，目前尚无既定的治疗方法。其潜在病理可能是额颞叶痴呆或阿尔茨海默病。越来越多的证据表明，过量的肿瘤坏死因子（TNF）可能在阿尔茨海默病中起核心作用。此外，额颞叶痴呆患者体内也有过量TNF的记录。因此，过量的TNF可能是PPA的一个治疗靶点。依那西普是一种抗TNF融合蛋白，可与TNF结合，从而降低其生物学效应。新出现的证据表明，经脊柱旁给药依那西普可能对阿尔茨海默病有治疗效果。这些证据共同支持了使用脊柱旁依那西普治疗PPA的理论依据。本报告记录了一名重度PPA患者在脊柱旁注射依那西普后20分钟内语言能力迅速改善的情况。每周重复给药一次，1个月时记录到持续改善，通过标准化工具阿尔茨海默病协作研究日常生活活动量表测量，患者的日常生活活动能力提高了10分以上。脊柱旁注射依那西普后PPA的快速临床改善可能与TNF作为神经胶质递质和大脑突触通讯调节剂的作用有关。这些结果可能有助于深入了解PPA及相关痴呆形式的基本病理生理机制，并提示在PPA和阿尔茨海默病中存在新的、快速可逆的、TNF介导的病理生理机制。有必要对这种治疗方法进行进一步研究。
