Kivistö Ville, Englert Benjamin, Tuimala Jarno, Kok Eloise, Puttonen Henri, Raunio Anna, Karhunen Pekka J, Lehtinen Maria K, Borghammer Per, Ahvenainen Ella, Colangelo Kia, Savola Sara, Tanskanen Maarit, Kaivola Karri, Tienari Pentti J, Kumar Darshan, Paetau Anders, Tynninen Olli, Mäyränpää Mikko I, Polvikoski Tuomo, Myllykangas Liisa
Department of Pathology, University of Helsinki, 00014, Helsinki, Finland.
HUS Diagnostic Center at Helsinki University Hospital, 00029, Helsinki, Finland.
Acta Neuropathol. 2025 Aug 1;150(1):11. doi: 10.1007/s00401-025-02918-y.
Cardiac manifestations are associated with Lewy body disease, but studies addressing the underlying histopathological mechanisms at the myocardial level are sparse. Here, we generated an artificial intelligence-based algorithm to quantify tyrosine hydroxylase (TH)-immunoreactive sympathetic distal axons at the myocardial level. This novel tool was applied to septal samples of the Vantaa 85 + study (n = 138), which is a population-based autopsy study representing all subjects aged 85 years or older living in the city of Vantaa (southern Finland) in 1991. In addition, the tool was applied to left ventricle samples of the Helsinki Biobank (n = 87) and the forensic Tampere Sudden Death Study (TSDS, n = 127). The level of myocardial TH reactivity was compared between subjects with and without Lewy pathology in the central nervous system in all datasets. In the Vantaa 85 + study, TH reactivity was also compared between subjects with caudo-rostral and amygdala-based subtypes, and potential confounding factors (age at death, sex, myocardial infarction, senile systemic amyloidosis, and diabetes medication) were controlled for using multiple linear regression models. Presence of Lewy pathology was strongly associated with loss of TH reactivity at the myocardial level in all three autopsy cohorts (Vantaa 85 + p = 0.001, Helsinki Biobank p < 0.001, TSDS p < 0.001)). In the Vantaa 85 + study, the caudo-rostral subtype (p < 0.001), but not the amygdala-based subtype (p = 0.60), was associated with myocardial denervation/dysfunction, and this association was independent of other known causes of sympathetic denervation/dysfunction. Caudo-rostral subtype and myocardial infarction were the strongest predictors of myocardial sympathetic denervation/dysfunction in the oldest-old population (Vantaa 85 +). In conclusion, our results show that Lewy pathology in the central nervous system, and particularly its caudo-rostral subtype, is strongly associated with loss of sympathetic distal axons at the myocardial level. We also provide evidence that the caudo-rostral subtype is one of the strongest predictors of myocardial sympathetic denervation/dysfunction in the oldest-old population.
心脏表现与路易体病相关，但针对心肌层面潜在组织病理学机制的研究较少。在此，我们生成了一种基于人工智能的算法，用于在心肌层面量化酪氨酸羟化酶（TH）免疫反应性交感神经远端轴突。这种新工具应用于万塔85+研究（n = 138）的间隔样本，该研究是一项基于人群的尸检研究，代表了1991年居住在芬兰南部万塔市所有85岁及以上的受试者。此外，该工具还应用于赫尔辛基生物银行（n = 87）的左心室样本和坦佩雷猝死法医研究（TSDS，n = 127）。在所有数据集中，比较了中枢神经系统有无路易体病理改变的受试者之间的心肌TH反应水平。在万塔85+研究中，还比较了具有尾-头型和杏仁核型亚型的受试者之间的TH反应性，并使用多元线性回归模型控制了潜在混杂因素（死亡年龄、性别、心肌梗死、老年系统性淀粉样变和糖尿病用药）。在所有三个尸检队列中，路易体病理改变的存在与心肌层面TH反应性的丧失密切相关（万塔85+研究p = 0.001，赫尔辛基生物银行p < 0.001，TSDS p < 0.001）。在万塔85+研究中，尾-头型亚型（p < 0.001）而非杏仁核型亚型（p = 0.60）与心肌去神经支配/功能障碍相关，且这种关联独立于其他已知的交感神经去神经支配/功能障碍原因。在最年长人群（万塔85+）中，尾-头型亚型和心肌梗死是心肌交感神经去神经支配/功能障碍的最强预测因素。总之，我们的结果表明，中枢神经系统中的路易体病理改变，尤其是其尾-头型亚型，与心肌层面交感神经远端轴突的丧失密切相关。我们还提供了证据表明，尾-头型亚型是最年长人群中心肌交感神经去神经支配/功能障碍的最强预测因素之一。
