Testing a longitudinal compensation model in premanifest Huntington's disease.
Testing a longitudinal compensation model in premanifest Huntington's disease.
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DOI：
10.1093/brain/awy122
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发表时间：
2018-07-01
期刊：
影响因子：
--
通讯作者：
Track-On investigators
中科院分区：
文献类型：
--
作者：
Gregory S;Long JD;Klöppel S;Razi A;Scheller E;Minkova L;Johnson EB;Durr A;Roos RAC;Leavitt BR;Mills JA;Stout JC;Scahill RI;Tabrizi SJ;Rees G;Track-On investigators
由于代偿过程，神经退行性变的初始阶段以正常表现为特征，尽管存在病理。 Gregory 等人使用他们的显式数学模型。报告了对神经退行性疾病随时间的补偿的首次实证检查，显示了亨廷顿病队列中运动和认知补偿的证据。尽管存在结构性脑病理学，但神经退行性变的初始阶段通常以正常水平的认知和运动表现为标志。人们普遍认为补偿可以解释这种保留的行为，但尽管这个概念表面上很简单，但事实证明要证明这种现象并将其与疾病相关的病理学区分开来是极其困难的。最近，我们开发了一种补偿模型，其中大脑激活、行为和病理学（理解补偿的关键组成部分）在三个进展阶段具有特定的纵向轨迹。在这里，我们通过测试神经退行性疾病中随时间的补偿的存在来实证验证我们的显式数学模型。亨廷顿病是检查神经变性纵向补偿的理想模型，因为它是单基因且完全渗透的，因此可以在诊断前多年监测疾病进展和潜在补偿。我们将补偿条件定义为存在线性神经元变性的情况下大脑活动和表现的非线性纵向轨迹，并将我们的补偿模型应用于来自多站点 Track-On HD 研究的大量纵向队列的前期和早期亨廷顿病患者。我们专注于认知和运动网络，整合了神经退行性疾病进展的三个连续阶段的渐进性容量损失、任务和静息状态功能性 MRI 以及认知和运动行为，并根据遗传病负荷进行了调整。拟合多元线性混合模型并测试每个变量的轨迹。我们对补偿的概念化是在不同级别的某些运动和认知网络中部分实现的。我们发现了几个重要的网络趋势，它们比我们模型中假设的更为复杂。这些趋势表明我们的理论模型发生了变化，其中网络效应相对于性能效应而言是延迟的。有证据表明，补偿主要存在于认知网络的前额叶部分，左右背外侧前额叶皮层之间的有效连接性增强。在开发了一个用于神经变性纵向补偿的显式测试的操作模型后，我们框架的一般模式似乎与经验数据一致。通过所提出的修改，我们的补偿操作模型可用于测试与亨廷顿舞蹈病具有相似模式的神经退行性疾病的横截面和纵向补偿。
Owing to compensatory processes, the initial stages of neurodegeneration are marked by normal performance despite the presence of pathology. Using their explicit mathematical model, Gregory et al. report the first empirical examination of compensation over time in neurodegeneration, showing evidence of motor and cognitive compensation in a Huntington’s disease cohort. The initial stages of neurodegeneration are commonly marked by normal levels of cognitive and motor performance despite the presence of structural brain pathology. Compensation is widely assumed to account for this preserved behaviour, but despite the apparent simplicity of such a concept, it has proven incredibly difficult to demonstrate such a phenomenon and distinguish it from disease-related pathology. Recently, we developed a model of compensation whereby brain activation, behaviour and pathology, components key to understanding compensation, have specific longitudinal trajectories over three phases of progression. Here, we empirically validate our explicit mathematical model by testing for the presence of compensation over time in neurodegeneration. Huntington’s disease is an ideal model for examining longitudinal compensation in neurodegeneration as it is both monogenic and fully penetrant, so disease progression and potential compensation can be monitored many years prior to diagnosis. We defined our conditions for compensation as non-linear longitudinal trajectories of brain activity and performance in the presence of linear neuronal degeneration and applied our model of compensation to a large longitudinal cohort of premanifest and early-stage Huntington’s disease patients from the multisite Track-On HD study. Focusing on cognitive and motor networks, we integrated progressive volume loss, task and resting state functional MRI and cognitive and motor behaviour across three sequential phases of neurodegenerative disease progression, adjusted for genetic disease load. Multivariate linear mixed models were fitted and trajectories for each variable tested. Our conceptualization of compensation was partially realized across certain motor and cognitive networks at differing levels. We found several significant network trends that were more complex than that hypothesized in our model. These trends suggest changes to our theoretical model where the network effects are delayed relative to performance effects. There was evidence of compensation primarily in the prefrontal component of the cognitive network, with increased effective connectivity between the left and right dorsolateral prefrontal cortex. Having developed an operational model for the explicit testing of longitudinal compensation in neurodegeneration, it appears that general patterns of our framework are consistent with the empirical data. With the proposed modifications, our operational model of compensation can be used to test for both cross-sectional and longitudinal compensation in neurodegenerative disease with similar patterns to Huntington’s disease.
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影响因子：
3.7
作者：
Malejko, Kathrin;Weydt, Patrick;Abler, Birgit
通讯作者：
Abler, Birgit
DOI：
10.1159/000339528
发表时间：
2013
期刊：
Neuro-degenerative diseases
影响因子：
--
作者：
Dogan I;Eickhoff SB;Schulz JB;Shah NJ;Laird AR;Fox PT;Reetz K
通讯作者：
Reetz K
影响因子：
4.8
作者：
Owen, AM;McMillan, KM;Bullmore, ET
通讯作者：
Bullmore, ET
DOI：
10.1016/s0197-2456(98)00037-3
发表时间：
1998-12-01
期刊：
CONTROLLED CLINICAL TRIALS
影响因子：
--
作者：
Dupont, WD;Plummer, WD
通讯作者：
Plummer, WD
DOI：
10.1016/s0169-2607(02)00017-2
发表时间：
2002-11-01
影响因子：
6.1
作者：
Thiébaut, R;Jacqmin-Gadda, H;Commenges, D
通讯作者：
Commenges, D