Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study.
Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study.
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DOI：
10.1016/s1474-4422(11)70156-9
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发表时间：
2011-09
期刊：
影响因子：
48
通讯作者：
Dickson, Dennis W.
中科院分区：
文献类型：
--
作者：
Murray, Melissa E.;Graff-Radford, Neill R.;Ross, Owen A.;Petersen, Ronald C.;Duara, Ranjan;Dickson, Dennis W.
神经病理学在阿尔茨海默病（AD）中具有刻板的进展，其被封装在Braak分期方案中。一些AD病例不符合Braak分期方案，被认为是非典型的。本研究的目的是比较典型AD与具有海马保留（HpSp）和边缘优势（LP）神经系统病理学的非典型AD的临床和病理学特征。根据ThioflavinS荧光显微镜下神经纤维缠结（NFT）计数在三个皮质区和两个Hp区的密度和分布，设计了一种数学算法，将AD病例分为典型、Hp和LP。该算法应用于889例AD患者（409例男性和480例女性;死亡年龄：37-103岁）的NFT计数。根据临床、人口统计学、病理学和遗传学的理由对这样分类的病例进行比较。对113例AD病例的独立系列进行了类似的评价，以验证初始队列的结果。与典型AD相比，HpSp（n=97）在皮质区具有较高的NFT密度，而海马区具有较低的NFT密度，而LP（n=127）在皮质区具有较低的NFT密度，而HP中具有较高的NFT密度。HpSp的Hp萎缩率低于典型AD（11%）和LP（14%）。Hp较年轻，男性比例较高，而LP较年长，女性比例较高。MAPT H1 H1基因型在LP中的分布频率高于HpSp，而在LP和典型AD中的分布频率无明显差异。只有当考虑到发病年龄时，AD亚型之间的APOE ε4等位基因状态才不同。临床表现、发病年龄、病程和下降速度在AD亚型之间存在差异。这些发现在一个重复队列中得到证实。我们的数据支持AD不同临床病理亚型的假设。HpSp和LP AD约占AD的25%，在临床、遗传学、生物标志物和治疗研究中值得考虑。
Neurofibrillary pathology has a stereotypic progression in Alzheimer's disease (AD) that is encapsulated in the Braak staging scheme. Some AD cases do not fit the Braak staging scheme and are considered atypical. The purpose of this study was to compare clinical and pathological features of typical AD with atypical AD that had either hippocampal sparing (HpSp) and limbic-predominant (LP) neurofibrillary pathology. A mathematical algorithm was devised to classify AD cases into typical, HpSp and LP according to the density and distribution of neurofibrillary tangle (NFT) counts from thioflavin S fluorescent microscopy in three cortical regions and two Hp sectors. The algorithm was applied to NFT counts of 889 cases of AD (409 men and 480 women; age at death: 37-103 years). Cases so classified were compared on clinical, demographic, pathological and genetic grounds. An independent series of 113 cases of AD were similarly evaluated to validate findings from the initial cohort. In comparison to typical AD, HpSp (n=97) had higher NFT densities in cortical areas and lower NFT densities in hippocampus, while LP (n=127) had lower NFT densities in cortical areas and higher NFT densities in the Hp. HpSp had less Hp atrophy than typical AD (11%) and LP (14%). HpSp were younger, with a higher proportion of men, whereas LP was older, with a higher proportion of women. MAPT H1H1 genotype was more frequent in LP compared with HpSp, but not between LP and typical AD. APOE ε4 allele status differed among AD subtypes only when age of onset was considered. Clinical presentation, age of onset, disease duration, and rate of decline differed among the AD subtypes. The findings were confirmed in a replication cohort. Our data supports the hypothesis of distinct clinicopathologic subtypes of AD. HpSp and LP AD account for about 25% of AD and are important to consider in clinical, genetic, biomarker and treatment studies.