脑中的铁质或许可以预测阿兹海默氏症的病程


  【24drs.com】一篇新研究认为,脑中的铁质程度可能可以预测带有APOE ε4风险等位基因之阿兹海默氏症(AD)患者的疾病病程。
  
  研究作者、澳洲墨尔本大学Florey神经科学暨心智健康研究院资深研究员Ashley I. Bush博士表示,脑中的铁质是AD疾病病程的一个被低估的驱动因子。
  
  测量脑中铁质可用来预测疾病病程,降低脑中铁质可能可作为一种新的治疗标靶,借以减缓疾病病程。
  
  他们的研究结果发表于二月JAMA Neurology期刊的来函中。
  
  研究者使用Alzheimer's Disease Neuroimaging Initiative (ADNI)资料库的资料,该资料库是始于2003年的公民合办机构。
  
  ADNI的主要目标,是检测serial MRI、正子放射断层摄影、其它生物标记、以及临床和神经心理学评估等是否可以合并使用于测量轻微认知缺损以及初期AD的病程。
  
  目前的研究探讨了脑脊液(CSF)中的铁蛋白程度-代表脑中的铁质负担,根据Bush博士指出,自1950年代就已知,铁质升高是AD的病理特征之一;铁质上升可能会引起氧化压力而损伤神经元。但是,我们以前没有证据指出铁质升高会实际地影响临床表现。
  
  神经病学家最大的挑战之一是,辨识最初期可能阶段的AD患者,Bush博士表示,这些患者最可能对治疗有反应。
  
  为了此篇研究,研究者分析了CSF的amyloid β 1-42 (Aβ 1-42)、tau、APOE、铁蛋白、factor H (发炎标记)以及血红素(血液渗漏标记)的含量。他们依据Rey氏听觉-视觉学习任务(Rey Auditory-Visual Learning Task,RAVLT)以及阿兹海默氏症评估量表-认知分量表(ADAS-Cog13)(Alzheimer's Disease Assessment Scale-Cognitive subset[ADAS-Cog13])之检测结果探讨某段时间的认知。
  
  分析发现,对于认知正常的参与者,铁蛋白值与认知恶化有关,以三种方式和时间与ε4等位基因相互影响(RAVLT: β = –1.58, P = .004; ADAS-Cog13: β = .11, P = .01)。
  
  根据ε4,认知正常个体的分类显示,铁蛋白值与ε4携带者的认知衰退强烈相关(RAVLT: β = –1.4, P < .001; ADAS-Cog13: β = .09, P = .02)。表现有APOE ε4等位基因者具有认知衰退的高风险,不过,并非所有人都会如此。
  
  Bush博士表示,研究发现,表现有APOE ε4风险等位基因的认知正常者中,高CSF铁蛋白值几乎可以完美地预言个人是否会在随后的7年内经历认知衰退。
  
  他表示,铁蛋白的影响远大于最广为人知的生物标记— tau以及amyloid β。
  
  他们的结果也显示,铁质量低的APOE ε4携带者免于认知衰退。
  
  Bush博士表示,这是篇重要研究,因为它显示,CSF的铁蛋白值是预测带有APOE ε4者在可预见的未来是否会恶化的一个极佳生物标记。
  
  Bush博士表示,CSF铁蛋白或其它铁质生物标记 — 例如,MRI技术如定量敏感性映射—可应用于诊间以预测患者之认知能力下降的可能进展。
  
  他表示,这些生物标记也可用于临床试验招募。
  
  Bush博士等人即将启动2b阶段之临床试验,以确认deferiprone这项可通过脑部之螯合铁质的药物是否可以延缓阿兹海默氏症初期患者的疾病病程。
  
  资料来源:http://www.24drs.com/
  
  Native link:Brain Iron May Predict Progression in Alzheimer's
  
  

Brain Iron May Predict Progression in Alzheimer's

By Pauline Anderson
Medscape Medical News

A new study suggests brain iron levels may predict disease progression in patients with Alzheimer's disease (AD) who carry the APOE ε4 risk allele.

Iron in the brain is an "underappreciated driver of disease progression" in AD, study author Ashley I. Bush, MBBS, PhD, senior principal research fellow, Florey Institute of Neuroscience & Mental Health, University of Melbourne, Australia, told Medscape Medical News.

"Measuring brain iron could beused to predict disease progression, and lowering brain iron levels might present as a novel therapeutic target to slowthe disease process."

Their findings were described in a letter published in the January issue of JAMA Neurology.

The researchers used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, which was launched in 2003 as a public–private partnership.

The primary goal of ADNI is to test whether serial MRI, positron emission tomography, other biological markers, and clinical and neuropsychological assessments can be combined to measure the progression of mild cognitive impairment and early AD.

The current study looked at the level of ferritin in cerebrospinal fluid (CSF), which indicates the brain iron load. According to Dr Bush, it has been known since the 1950s that elevated iron is a pathologic feature of AD. Iron elevation, he said, may cause oxidative stress,which damages neurons.

"But wedidn't previously have evidence that iron elevation actually impacts on the clinical presentation,"he said.

Most Likely to Respond

One of the biggest challenges for neurologists is identifying patients with the earliest possible stages of AD. These patients, said Dr Bush, could be the most likely to respond to therapy.

For the study, researchers analysed CSF levels of amyloid β 1-42 (Aβ 1-42), tau, APOE, ferritin, factor H (an inflammatory marker), and hemoglobin (a blood leakage marker). They looked at cognitive performance over time on the Rey Auditory-Visual Learning Task (RAVLT) and the Alzheimer's Disease Assessment Scale-Cognitive subset (ADAS-Cog13).

The analysis found that for cognitively normal participants, the ferritin level was associated with cognitive deterioration in a three-way interaction with time and ε4 allele (RAVLT: β = –1.58, P = .004; ADAS-Cog13: β = .11, P = .01).

Categorization of cognitively normal individuals according to ε4 showed that ferritin level was strongly associated with cognitive decline in ε4 carriers (RAVLT: β = –1.4, P < .001; ADAS-Cog13: β = .09, P = .02).

People who express the APOE ε4 allele are at a high risk for cognitivedecline, although not all will do so.

"The study found that in cognitively normal people who express the APOE ε4 risk allele, high CSF ferritin almost perfectlypredicted whether the individual will experience cognitive decline in the subsequent 7 years," said Dr Bush.

The effect of ferritin "was far greater than the mostestablished biomarkers — tau and amyloid β," he said.

Their results also showed that APOE ε4 carriers who have low iron levels were protected from cognitive decline.

The study is important because it shows that the CSF ferritin level is "an excellent biomarker for predicting whether someone with APOE ε4 might progressin the foreseeable future," said Dr Bush.

CSF ferritin or other iron biomarkers — for example, MRI techniques, such as quantitative susceptibility mapping — could be used in the clinic to predict the likely progression of cognitive decline in patients, said Dr Bush.

These biomarkers could also be used forclinical trial recruitment, he said.

Dr Bush and colleagues will be launching a phase 2b clinical trial to determine whether deferiprone, a brain-permeable drug that chelates iron, can slow disease progression among patients in the early stagesof Alzheimer's disease.

Dr Bush is a shareholder in Prana Biotechnology Pty Ltd, Cogstate Pty Ltd, Eucalyptus Pty Ltd, Mesoblast Pty Ltd, Brighton Biotech LLC, Nextvet Ltd, Grunbiotics Pty Ltd, and Collaborative Medicinal Development LLC and a paid consultant for Collaborative Medicinal Development Pty Ltd. He and the other authors have filed a provisional patent encompassing findings from these data. Dr Bush has received funding relevant to this study from the Australian National Health and Medical Research Council, the Alzheimer's Association, Alzheimer's Research UK, the Michael J. Fox Foundation for Parkinson's Research, the Weston Brain Institute, and the Perpetual-Salteri Foundation.

JAMA Neurol. 2017;74):122-125.

    
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