Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: a population-based study of Finns aged 85+
Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: a population-based study of Finns aged 85+
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DOI：
10.1007/s00401-019-02071-3
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发表时间：
2019-11-01
影响因子：
12.7
通讯作者：
Myllykangas, Liisa
中科院分区：
文献类型：
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作者：
Raunio, Anna;Kaivola, Karri;Myllykangas, Liisa
根据普遍接受的概念，路易相关病理学（LRP）遵循分级的尾吻侧进展。LRP也经常伴随阿尔茨海默病（AD）出现，并且已经假设AD相关的LRP形成不同类型的α-突触核蛋白病，其中LRP起源于杏仁核。尚未在基于人群的背景下研究不同形式的LRP进展类型的频率。我们调查了LRP的分布和进展及其与AD病理学和载脂蛋白（APOE）β 4的关系，以人群为基础的样本，年龄超过85岁的芬兰人（N = 304）。对代表11个解剖部位的脊髓至新皮层区域的样品进行化学分析（α-突触核蛋白抗体克隆5G 4）。LRP存在于124人（41%），并根据DLB联盟的指导方针，其中19人被归类为脑干，杏仁核占主导地位的10个，41边缘，43弥漫性新皮质类型，而11个无法分类。为了确定LRP进展模式，通过考虑每个解剖部位的半定量LRP评分的密度进行系统解剖评分。根据该评分，123例（99%）受试者可分为两种进展模式类型：67%显示尾吻侧进展，32%基于杏仁核进展。无监督统计K均值聚类分析用作补充检验，支持存在两种进展模式，与系统解剖学评分方法的总体一致性为90%。重度Braak NFT分期、高CERAD评分和APOE β 4与杏仁核为基础的进展型显著相关（均p < 0.00001），但与尾吻侧进展型无关（均p > 0.2）。这项基于人群的研究显示了两种不同的常见LRP进展模式在非常老年人群。杏仁核为基础的模式与APOE β 4和AD病理学相关。结果证实了以前的进展假设，但也扩大了AD相关LRP的概念。
According to a generally accepted concept Lewy-related pathology (LRP) follows hierarchical caudo-rostral progression. LRP is also frequently present concomitantly with Alzheimer's disease (AD), and it has been hypothesized that AD-associated LRP forms a distinct type of alpha-synucleinopathy, where LRP originates in the amygdala. The frequency of distinct forms of LRP progression types has not been studied in a population-based setting. We investigated the distribution and progression of LRP and its relation to AD pathology and apolipoprotein (APOE) epsilon 4 in a population-based sample of Finns aged over 85 years (N = 304). Samples from spinal cord to neocortical areas representing 11 anatomical sites without any hierarchical selection were analyzed immunohistochemically (alpha-synuclein antibody clone 5G4). LRP was present in 124 individuals (41%) and according to DLB Consortium guidelines 19 of them were categorized as brainstem, 10 amygdala-predominant, 41 limbic, and 43 diffuse neocortical type, whereas 11 could not be classified. To determine the LRP progression patterns, a systematic anatomical scoring was carried out by taking into account the densities of the semiquantitative LRP scores in each anatomic site. With this scoring 123 (99%) subjects could be classified into two progression pattern types: 67% showed caudo-rostral and 32% amygdala-based progression. The unsupervised statistical K-means cluster analysis was used as a supplementary test and supported the presence of two progression patterns and had a 90% overall concordance with the systematic anatomical scoring method. Severe Braak NFT stage, high CERAD score and APOE epsilon 4 were significantly (all p < 0.00001) associated with amygdala-based, but not with caudo-rostral progression type (all p > 0.2). This population-based study demonstrates two distinct common LRP progression patterns in the very elderly population. The amygdala-based pattern was associated with APOE epsilon 4 and AD pathology. The results confirm the previous progression hypotheses but also widen the concept of the AD-associated LRP.