Modeling seeding and neuroanatomic spread of pathology in amyotrophic lateral sclerosis.
Modeling seeding and neuroanatomic spread of pathology in amyotrophic lateral sclerosis.
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DOI：
10.1016/j.neuroimage.2022.118968
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发表时间：
2022-05-01
期刊：
影响因子：
5.7
通讯作者：
Raj, Ashish
中科院分区：
文献类型：
--
作者：
Pandya, Sneha;Maia, Pedro D.;Freeze, Benjamin;Menke, Ricarda A. L.;Talbot, Kevin;Turner, Martin R.;Raj, Ashish
神经退行性疾病肌萎缩性侧索硬化症（ALS）的特征在于上运动神经元和下运动神经元的进行性丧失，在额颞叶痴呆（FTD）的临床病理谱中伴有大脑运动区和运动区外的病理受累。一个关键的未解决的问题是ALS中病理的非随机分布如何反映差异网络脆弱性，包括分子因素，如区域基因表达或病理通过解剖学连接的优先传播。基于在死后大脑中观察到的TDP-43病理学区域负担的ALS组织病理学分期系统在一定程度上得到了体内结构MRI变化分布分析的支持。在本文中，使用网络扩散模型（NDM）的计算建模被用来调查是否局灶性病理“播种”的过程中，其次是结构网络为基础的传播概括死后的组织病理学分期，其次，这是否有任何相关性的一组基因的表达模式在ALS在整个健康的大脑。研究ALS患者（基线n = 79）的区域分组T1加权MRI数据与健康对照结构连接体和相关区域脑基因表达数据库的关系。NDM为ALS区域病理扩散的结构网络基础提供了强有力的支持，但与ALS相关基因在健康大脑中的空间分布没有简单的关系。有趣的是，OPTN基因被确定为网络基因相互作用模型（LASSO）中一个重要但较弱的非NDM贡献者。有趣的是，在模型中传播的关键种子区域不在初级运动皮层内，而是基底神经节、丘脑和丘脑，NDM在这些区域概括了死后组织病理学分期系统的各个方面。在ALS-FTD临床病理学范围内，非原发性运动结构可能是脑病理学的最早部位。
The neurodegenerative disorder amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper and lower motor neurons, with pathological involvement of cerebral motor and extra-motor areas in a clinicopathological spectrum with frontotemporal dementia (FTD). A key unresolved issue is how the non-random distribution of pathology in ALS reflects differential network vulnerability, including molecular factors such as regional gene expression, or preferential spread of pathology via anatomical connections. A system of histopathological staging of ALS based on the regional burden of TDP-43 pathology observed in postmortem brains has been supported to some extent by analysis of distribution of in vivo structural MRI changes. In this paper, computational modeling using a Network Diffusion Model (NDM) was used to investigate whether a process of focal pathological ‘seeding’ followed by structural network-based spread recapitulated postmortem histopathological staging and, secondly, whether this had any correlation to the pattern of expression of a panel of genes implicated in ALS across the healthy brain. Regionally parcellated T1-weighted MRI data from ALS patients (baseline n = 79) was studied in relation to a healthy control structural connectome and a database of associated regional cerebral gene expression. The NDM provided strong support for a structural network-based basis for regional pathological spread in ALS, but no simple relationship to the spatial distribution of ALS-related genes in the healthy brain. Interestingly, OPTN gene was identified as a significant but a weaker non-NDM contributor within the network-gene interaction model (LASSO). Intriguingly, the critical seed regions for spread within the model were not within the primary motor cortex but basal ganglia, thalamus and insula, where NDM recapitulated aspects of the postmortem histopathological staging system. Within the ALS-FTD clinicopathological spectrum, non-primary motor structures may be among the earliest sites of cerebral pathology.
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影响因子：
14.5
作者：
Freeze, Benjamin;Pandya, Sneha;Raj, Ashish
通讯作者：
Raj, Ashish
肌萎缩性侧硬化症中的广泛感觉运动和额叶皮质萎缩。
影响因子：
2.6
作者：
Grosskreutz, Julian;Kaufmann, Joern;Fraedrich, Julia;Dengler, Reinhard;Heinze, Hans-Jochen;Peschel, Thomas
通讯作者：
Peschel, Thomas
DOI：
10.1016/s1474-4422(17)30401-5
发表时间：
2018-01
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Chia R;Chiò A;Traynor BJ
通讯作者：
Traynor BJ
影响因子：
4.3
作者：
Jackson WS
通讯作者：
Jackson WS
影响因子：
--
作者：
Braak, H.;Neumann, M.;Del Tredici, K.
通讯作者：
Del Tredici, K.