Alber Jessica, McGarry Kelly, Noto Richard B, Snyder Peter J
Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University & Rhode Island Hospital, Providence, RI, United States.
Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, United States.
Front Aging Neurosci. 2018 Mar 6;10:60. doi: 10.3389/fnagi.2018.00060. eCollection 2018.
Recent genome-wide association screening (GWAS) studies have linked Alzheimer's disease (AD) neuropathology to gene networks that regulate immune function. Kan et al. recently reported that (an anti-inflammatory gene that codes for arginase-1) is expressed in parts of the brain associated with amyloidosis prior to the onset of neuronal loss, suggesting that chronic brain arginine deprivation promotes AD-related neuropathology. They blocked arginine catabolism in their mouse AD model by administration of eflornithine (DFMO) to juvenile animals, effectively blocking the expression of AD-related amyloid pathology as the mice aged. We report results from a single-case study in which DFMO was administered, for the first time, in an attempt to slow progression of AD in a single woman with multi-domain, amnestic MCI who was unable to tolerate an acetylcholinesterase inhibitor. Patient C.S. is a 74-year old female with a 5-year history of cognitive decline who was placed on DFMO (500 mg b.i.d.) for 12 months, with amyloid PET scans (baseline and 12-months), APOE genotyping and neuropsychological exams at baseline, 3, 9, and 12 months. C.S. suffered continued cognitive decline over 12 months, including progressive worsening of orientation, social functions and ability to engage in IADL's. She also showed progressive decline on measures of episodic memory and executive function. Florbetapir PET imaging yielded elevated total neocortical SUVr scores at both baseline (SUVr = 1.55) and at 12 months (SUVr = 1.69). We report a first attempt at using DFMO to slow AD progression. This 12-month single-case trial did not halt continued amyloidosis nor cognitive decline. Although this trial was predicated on data reported by Kan et al. (2015) showing that DFMO administered to AD-prone mice led to diminished amyloid aggregation, this attempt to treat an older mild AD patient may not be a fair test of Kan et al.'s model and results. A future trial might seek to block amyloidosis in young adults who are autosomal gene carriers for early onset AD, or perhaps in adults who are very clearly in the pre-clinical disease stage. This trial was registered as a Compassionate Use IND #128888 with the United States Food and Drug Administration (FDA).
近期的全基因组关联筛查（GWAS）研究已将阿尔茨海默病（AD）神经病理学与调节免疫功能的基因网络联系起来。Kan等人最近报告称，（一种编码精氨酸酶-1的抗炎基因）在神经元丧失发作之前就在与淀粉样变性相关的脑区表达，这表明慢性脑精氨酸缺乏会促进AD相关神经病理学。他们通过给幼年动物施用依氟鸟氨酸（DFMO）来阻断其小鼠AD模型中的精氨酸分解代谢，随着小鼠年龄增长，有效地阻断了AD相关淀粉样病理的表达。我们报告了一项单病例研究的结果，其中首次施用DFMO，试图减缓一名患有多领域、遗忘型轻度认知障碍（MCI）且无法耐受乙酰胆碱酯酶抑制剂的单身女性的AD进展。患者C.S.是一名74岁女性，有5年认知衰退病史，服用DFMO（500毫克，每日两次）12个月，在基线、3个月、9个月和12个月时进行淀粉样蛋白PET扫描（基线和12个月）、APOE基因分型和神经心理学检查。C.S.在12个月内持续出现认知衰退，包括定向、社交功能和参与日常生活活动能力的逐渐恶化。她在情景记忆和执行功能测量方面也显示出逐渐下降。氟代硼吡咯PET成像在基线（SUVr = 1.55）和12个月时（SUVr = 1.69）均显示总新皮质SUVr评分升高。我们报告了首次尝试使用DFMO减缓AD进展的情况。这项为期12个月的单病例试验并未阻止持续的淀粉样变性或认知衰退。尽管该试验基于Kan等人（2015年）报告的数据，即给易患AD的小鼠施用DFMO会导致淀粉样蛋白聚集减少，但此次治疗一名老年轻度AD患者的尝试可能并非对Kan等人模型和结果的公平测试。未来的试验可能会寻求在早发性AD的常染色体基因携带者的年轻成年人中，或者可能在非常明确处于临床前疾病阶段的成年人中阻断淀粉样变性。该试验已在美国食品药品监督管理局（FDA）注册为同情用药IND #128888。
