08年神经内科及神经科学进展专栏（征译稿 )

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此栏用于动态报道最新的神经内科临床和相关基础实验，首先包括新英格兰杂志，柳叶刀，JAMA、nature。主要以摘要为主。
文章鼓励由战友提供。对于科学性差的临床/基础实验文献（impact factor)低于4分的文献请不予登出。临床病例、病理讨论除外。


请站友注意，2007年的文献不列入本栏目！

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Brain 2008 131(1):277-287; doi:10.1093/brain/awm285
An investigation of the retinal nerve fibre layer in progressive multiple sclerosis using optical coherence tomography

一项进展性多发性硬化视网膜神经纤维层视觉相干X断层扫描的研究
Andrew P. D. Henderson1,2, S. Anand T**1,2, Patricio G. Schlottmann4, Daniel R. Altmann1,3, David F. Garway-Heath4, Gordon T. Plant2 and David H. Miller1
1NMR Research Unit, Institute of Neurology, University College London, London, WC1N 3BG, 2Department of Neuro-Ophthalmology, Moorfields Eye Hospital, City Road, 3Medical Statistics Unit, London School of Hygiene and Tropical Medicine, Keppel Street and 4Glaucoma Research Unit, Moorfields Eye Hospital, City Road, London, UK

Correspondence to: Dr Andrew Henderson, NMR Research Unit, Institute of Neurology, University College London, London, WC1N 3BG, UK E-mail: a.henderson@ion.ucl.ac.uk

Axonal loss is thought to be the predominant cause of disability in progressive multiple sclerosis (MS). The retinal nerve fibre layer (RNFL) is composed largely of unmyelinated axons of retinal ganglion cells, and is accessible to study with optical coherence tomography (OCT), giving a measure of axonal loss. OCT measures of the RNFL thickness (RNFLT) and macular volume were studied in 23 patients with primary progressive multiple sclerosis (primary progressive MS) (13 male; 10 female; mean age 52 years; median EDSS 6.0; mean disease duration 11 years), and 27 patients with secondary progressive multiple sclerosis (secondary progressive MS) (8 male; 19 female; mean age 50 years; median EDSS 6; mean disease duration 22 years). Of the patients with secondary progressive MS, 14 had clinical history of optic neuritis (ON) in a single eye; the remaining patients had not had ON. Twenty healthy controls (11 male; 9 female; mean age 46 years) had RNFLT and macular volume studied. Of the patients’ eyes not previously affected by ON, both the mean RNFL thickness and macular volume were reduced when compared with control values. The mean RNFL thickness and macular volume were significantly reduced in secondary progressive MS, but not in primary progressive MS when compared with control RNFL thickness and macular volume. RNFL loss was most evident in the temporal quadrant, where significant reduction was seen in primary progressive MS versus controls and in secondary versus primary progressive MS. There were significant correlations of decreased RNFLT and macular volume with measures of visual acuity, low contrast visual acuity and visual field mean deviation in the MS patients. There are significant global reductions in RNFLT and macular volume in the eyes of secondary progressive MS patients not previously affected by ON, but not in primary progressive MS patients, compared with controls. This may indicate a difference in the extent of the pathological processes that cause axonal loss in the retina, and by inference the optic nerve, in secondary progressive MS and primary progressive MS.

轴突缺失被认为是进展性多发性硬化残疾形成的首当其冲的原因。视网膜神经纤维层大致由视网膜神经节细胞的无髓轴突组成，并且可以用视觉相干X线断层扫描（OCT）的方法来研究，可测定轴突的缺失。研究了 23名原发进展性多发性硬化患者中的OCT 测定的视网膜神经纤维厚度和黄斑体积， (13 男; 10 女; 平均年龄 52 岁; 平均 EDSS 6.0; 平均患病时间11 年), 以及27名继发的进展性多发性硬化患者(8 男; 19 女; 平均年龄 50 岁; 平均 EDSS 6; 平均患病时间22 年) 在继发的进展性多发性硬化患者中，14名有单眼的视神经炎临床病史；其余患者无视神经炎临床病史。20名健康对照组(11 男; 9女; 平均年龄 46岁) 进行了视网膜神经纤维层和黄斑面积扫描研究。在没有感染过视神经炎的患者中，平均视网膜神经纤维层的厚度和黄斑面积值均低于健康对照组。 继发性进展性多发性硬化患者平均视网膜神经纤维层的厚度和黄斑面积值亦降低，但与原发性进展性多发性硬化相比不降低。视网膜神经纤维层的缺失在颞象限最为明显，在原发性进行性多发性硬化与继发性进行性多发性硬化相比时降低显著。 减少的视网膜神经纤维层和黄斑面积与视觉准确度有明显的相关性，低的视觉对比准确度和视野均差在多发性硬化患者中为低。在未感染视神经炎的继发性的多发性硬化患者眼球视网膜神经纤维的缺失和黄斑面积的降低，但不是在原发进展性多发性硬化患者，与正常对照组相比。 此结果提示原发性和继发性进展性多发性硬化患者，引起视网膜轴突缺失的病理过程程度，及由此推出视神经的病变之间的差异。

请指教！

g***l

Lancet Neurology 2008; 7:41-49

DOI:10.1016/S1474-4422(07)70293-4
Articles
研究原著
Aspirin in Alzheimer's disease (AD2000): a randomised open-label trial
AD2000 Collaborative Group ‡
‡Members listed at end of paper
阿斯匹林在阿尔茨海默病的应用（AD2000）:一个随机开标试验
AD2000 协作组
成员在文章末尾列出
Summary 摘要
Background
Cardiovascular risk factors and a history of vascular disease can increase the risk of Alzheimer's disease (AD). AD is less common in aspirin users than non-users, and there are plausible biological mechanisms whereby aspirin might slow the progression of either vascular or Alzheimer-type pathology. We assessed the benefits of aspirin in patients with AD.
背景:心血管危险因素以及血管病病史可增加AD发病的危险。AD出现在阿司匹林使用者较非阿司匹林使用者少见，并且存在阿司匹林可减慢血管性或阿尔茨海默型（痴呆型）病理的似乎合理的生物学机制。我们评估阿司匹林在AD患者的益处。
Methods
310 community-resident patients who had AD and who had no potential indication or definite contraindication for aspirin were randomly assigned to receive open-label aspirin (n=156; one 75-mg enteric-coated tablet per day, to continue indefinitely) or to avoid aspirin (n=154). Primary outcome measures were cognition (assessed with the mini-mental state examination [MMSE]) and functional ability (assessed with the Bristol activities of daily living scale [BADLS]). Secondary outcomes were time to formal domiciliary or institutional care, progress of disability, behavioural symptoms, caregiver wellbeing, and care time. Patients were assessed at 12-week intervals in the first year and once each year thereafter. Analysis of the primary outcome measures was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN96337233.
方法：我们对310名没有潜在的对阿司匹林适应症或明确禁忌症的社区AD患者随机分为接受开标阿司匹林（n=156,连续口服阿司匹林肠溶片75mg/d而无明确终止时间）组和非阿司匹林组（n=154）。第一检测结果为认知（评估迷你精神状态量表试验MMSE）和功能能力（评估Bristol活动每日生活量表[BADLS]）。第二检测结果为到达家庭或公共机构的时间，残疾的进展，行为症状，看护福利和看护时间。在第一年口服阿司匹林后12周以及以后每年再次进行评估。分析第一个结果为了进行治疗。这个研究登记为国际标准随机对照试验，号码是ISRCTN96337233。

Findings
Patients had a median age of 75 years; 156 patients had mild AD, 154 had moderate AD, and 18 had concomitant vascular dementia. Over the 3 years after randomisation, in patients who took aspirin, mean MMSE score was 0•10 points higher (95% CI −0•37 to 0•57; p=0•7) and mean BADLS score was 0•62 points lower (−1•37 to 0•13; p=0•11) than in patients assigned to aspirin avoidance. There were no obvious differences between the groups in any other outcome measurements. 13 (8%) patients on aspirin and two (1%) patients in the control group had bleeds that led to admission to hospital (relative risk=4•4, 95% CI 1•5–12•8; p=0•007); three (2%) patients in the aspirin group had fatal cerebral bleeds.
结果：患者的平均年龄为75岁，156名患者有轻度AD，154名患者有中度AD，18名患者合并血管性痴呆。3年后，口服阿司匹林患者平均MMSE评分比未口服阿司匹林患者高0.1分（95% 可信区间−0.37 到 0.57; p=0.7），平均BADLS评分比未口服阿司匹林患者低0.62 (95% 可信区间−1.37 到 0.13; p=0.11)。两组之间在其他任何检测结果均没有显著性差异。13名口服阿司匹林患者(8%) 和2名(1%)对照组患者由于出现出血并发症而入院治疗（相对危险度=4.4, 95% 可信区间 1•5–12•8; p=0•007）；3名口服阿司匹林患者(2%)由于脑出血而死亡。
Interpretation
Although aspirin is commonly used in dementia, in patients with typical AD 2 years of treatment with low-dose aspirin has no worthwhile benefit and increases the risk of serious bleeds.
认识：阿司匹林常规给予痴呆患者使用，但典型AD患者2年口服低剂量阿司匹林治疗有带来益处反而增加严重出血风险。

g***l

Each month, Archives of Neurology publishes an
article of particular clinical or public health
importance online 2 months before it appears in
print. This month's article is linked below;
it will appear in print in March 2008 in JAMA&Archives of Neurology.
************************************************
Archives of Neurology Early Releases
for January 14, 2008  
Genome-Wide Pharmacogenomic Analysis of the Response to Interferon Beta Therapy in Multiple Sclerosis
Esther Byun, MD; Stacy J. Caillier, BSc; Xavier Montalban, MD; Pablo Villoslada, MD, PhD; Oscar Fernández, MD; David Brassat, MD; Manuel Comabella, MD, PhD; Joanne Wang, MPH; Lisa F. Barcellos, PhD; Sergio E. Baranzini, PhD; Jorge R. Oksenberg, PhD
Arch Neurol. 2008;65(3)doi:10.1001/archneurol.2008.47).
Objective To identify promising candidate genes linked to interindividual differences in the efficacy of interferon beta therapy. Recombinant interferon beta therapy is widely used to reduce disease activity in multiple sclerosis (MS). However, up to 50% of patients continue to have relapses and worsening disability despite therapy.
Design We used a genome-wide pharmacogenomic approach to identify single-nucleotide polymorphism (SNP) allelic differences associated with interferon beta therapy response.
Setting Four collaborating centers in the Mediterranean Basin. Data Coordination Center at the University of California, San Francisco.
Patients A cohort of 206 patients with relapsing-remitting MS followed up prospectively for 2 years after initiation of treatment.
Intervention DNA was pooled and hybridized to Affymetrix 100K GeneChips. Pooling schemes were designed to minimize confounding batch effects and increase confidence by technical replication.
Main Outcome Measures Single-nucleotide polymorphism detection. Comparison of allelic frequencies between good responders and nonresponders to interferon beta therapy.
Results A multi**ytical approach detected significant associations between several SNPs and treatment response, which were validated by individual DNA genotyping on an independent platform. After the validation stage was complete, 81 additional individuals were added to the **ysis to increase power. We found that responders and nonresponders had significantly different genotype frequencies for SNPs located in many genes, including glypican 5, collagen type XXV 1, hyaluronan proteoglycan link protein, calpastatin, and neuronal PAS domain protein 3.
Conclusions The reported results address the question of genetic heterogeneity in MS and the response to immunotherapy by **ysis of the correlation between different genotypes and clinical response to interferon beta therapy. Many of the detected differences between responders and nonresponders were genes associated with ion channels and signal transduction pathways. The study also suggests that genetic variants in heparan sulfate proteoglycan genes may be of clinical interest in MS as predictors of the response to therapy. In addition to new insights into the mechanistic biology of interferon beta, these results help define the molecular basis of interferon beta therapy response heterogeneity.
多发性硬化对β干扰素治疗反应性的全基因组药物基因组学研究
目的：鉴定个体对β干扰素不同治疗效果相关的候补基因。重组β干扰素被广泛用于控制多发性硬化的疾病活动性。然而，近50％患者经过治疗后还是有复发和病残加重。
试验设计：采用全基因组药物基因组学方法鉴定与β干扰素不同治疗反应相关的单核苷酸多态性等位性差异。
场所：位于地中海盆地的四个合作中心。由加州大学旧金山分校进行数据协调。
对象：206名复发缓解型多发性硬化患者，初次治疗后前瞻性随访2年。
干预措施：DNA混合并杂交到Affymetrix 100K基因芯片，混合方案设计用来将批量混杂效应减小到最小，并通过技术性**增加置信度。
主要测量指标：单核苷酸多态性测定，比较对β干扰素反应良好和不好的患者之间的等位基因频率。
结果：运用多重分析法探测到数个单核苷酸多态性与治疗反应性的显著相关性，并通过个体DNA基因分型进一步证实。验证阶段完成后，又增加了81例患者以增加检验效能。我们发现反应良好者和无反应者许多基因的单核苷酸多态性存在显著的基因型频率差异，这些基因包括glypican 5, collagen type XXV 1, hyaluronan proteoglycan link protein, calpastatin, neuronal PAS domain protein 3.
结论：通过分析不同基因型和对β干扰素治疗反应的关系，我们提出了多发性硬化的基因异质性和对免疫治疗的反应性的问题。有反应和无反应者之间探查到的基因差别主要为与铁离子通道和信号转导通路相关的基因。本研究还显示heparan sulfate proteoglycan基因异质性可能为多发性硬化对治疗反应性的一个预测因子。本研究除了对β干扰素的生物学机制以新的视角进行探讨，还有助于确定产生β干扰素治疗反应异质性的分子学基础。