Brain multiphysics最新文献

Two for tau: Automated model discovery reveals two-stage tau aggregation dynamics in Alzheimer’s disease 两个 tau：自动模型发现揭示了阿尔茨海默病的两阶段 tau 聚集动力学

Q3 Engineering

Brain multiphysics

Pub Date : 2024-11-12 DOI: 10.1016/j.brain.2024.100103

Charles A. Stockman , Alain Goriely , Ellen Kuhl , Alzheimer’s Disease Neuroimaging Initiative

Alzheimer’s disease is a neurodegenerative disorder characterized by the presence of amyloid-

β

plaques and the accumulation of misfolded tau proteins and neurofibrillary tangles in the brain. A thorough understanding of the local accumulation of tau is critical to develop effective therapeutic strategies. Tau pathology has traditionally been described using reaction–diffusion models, which succeed in capturing the global spread, but fail to accurately describe the local aggregation dynamics. Current mathematical models enforce a single-peak behavior in tau aggregation, which does not align well with clinical observations. Here we identify a more accurate description of tau aggregation that reflects the complex patterns observed in patients. We propose an innovative approach that uses constitutive neural networks to autonomously discover bell-shaped aggregation functions with multiple peaks from clinical positron emission tomography (PET) data of misfolded tau protein. Our method reveals previously overlooked two-stage aggregation dynamics by uncovering a two-term ordinary differential equation that links the local accumulation rate to the tau concentration. When trained on data from amyloid-

β

positive and negative subjects, the neural network clearly distinguishes between both groups and uncovers a more subtle relationship between amyloid-

β

and tau than previously postulated. In line with the amyloid–tau dual pathway hypothesis, our results show that the presence of toxic amyloid-

β

influences the accumulation of tau, particularly in the earlier disease stages. We expect that our approach to autonomously discover the accumulation dynamics of pathological proteins will improve simulations of tau dynamics in Alzheimer’s disease and provide new insights into disease progression.

Significance Statement

In Alzheimer’s disease, understanding the local dynamics of tau protein aggregation is crucial for developing effective treatments. Traditional models for tau protein dynamics use reaction–diffusion models that fail to accurately capture these local patterns. Our study introduces a novel approach that leverages constitutive neural networks to autonomously discover the complex, multi-peak aggregation dynamics from clinical PET data. This method reveals a previously overlooked two-stage tau accumulation process and a nuanced relationship between amyloid-

β

and tau. By distinguishing between amyloid-

β

positive and negative subjects, our model supports the amyloid–tau dual pathway hypothesis and offers novel insights into tau protein aggregation that have the potent to advance our understanding of Alzheimer’s disease progression.

阿尔茨海默氏症是一种神经退行性疾病，其特征是大脑中存在淀粉样β斑块以及折叠错误的 tau 蛋白和神经纤维缠结的积累。透彻了解 tau 蛋白的局部积聚对于制定有效的治疗策略至关重要。传统上，人们使用反应扩散模型来描述 Tau 病理学，这种模型能成功捕捉全球扩散，但却无法准确描述局部聚集动态。目前的数学模型在 Tau 聚集中强制执行单峰行为，这与临床观察结果不符。在此，我们确定了一种更准确的 tau 聚集描述方法，它能反映在患者身上观察到的复杂模式。我们提出了一种创新方法，利用构成神经网络从折叠错误的 tau 蛋白的临床正电子发射断层扫描（PET）数据中自主发现具有多个峰值的钟形聚集函数。我们的方法揭示了以前被忽视的两阶段聚集动力学，发现了一个将局部积累率与 tau 蛋白浓度联系起来的双项常微分方程。在对淀粉样蛋白-β阳性和阴性受试者的数据进行训练时，神经网络能清楚地区分这两个组别，并揭示出淀粉样蛋白-β和tau之间比以前推测的更微妙的关系。与淀粉样蛋白-tau 双通道假说一致，我们的研究结果表明，毒性淀粉样蛋白-β的存在会影响 tau 的积累，尤其是在疾病的早期阶段。我们预计，我们自主发现病理蛋白积累动态的方法将改善对阿尔茨海默氏症中tau动态的模拟，并为疾病进展提供新的见解。传统的 tau 蛋白动态模型使用的是反应扩散模型，无法准确捕捉这些局部模式。我们的研究引入了一种新方法，利用组成神经网络从临床 PET 数据中自主发现复杂的多峰聚集动态。这种方法揭示了以前被忽视的两阶段 tau 积累过程以及淀粉样蛋白-β 和 tau 之间的微妙关系。通过区分淀粉样蛋白-β阳性和阴性受试者，我们的模型支持了淀粉样蛋白-tau双通道假说，并提供了对tau蛋白聚集的新见解，这些见解有望促进我们对阿尔茨海默病进展的理解。

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引用次数: 0

Diffusive secondary injuries in neuronal networks following a blast impact: A morphological and electrophysiological study using a TBI-on-a-Chip model 爆炸冲击后神经元网络的弥散性继发性损伤：利用创伤性脑损伤芯片模型进行形态学和电生理学研究

Q3 Engineering

Brain multiphysics

Pub Date : 2024-11-12 DOI: 10.1016/j.brain.2024.100104

Timothy B. Beauclair , Edmond A. Rogers , Jhon Martinez , Shatha J. Mufti , Nikita Krishnan , Riyi Shi

Traumatic brain injury (TBI) is a worldwide health issue. Increasing prevalence of blast-induced TBI (bTBI), a predominantly combat-related injury, is an alarming trend necessitating a better understanding of the associated pathogenesis to develop treatments. Further, most bTBI injuries are mild and undiagnosed, permitting secondary biochemical injuries to propagate beyond possible intervention. Unfortunately, few treatment options are available due to a limited understanding of the underlying mechanisms. Additional investigative tools are urgently needed to elucidate the mechanisms behind immediate and long-term bTBI-induced damage. Therefore, we introduce “bTBI-on-a-Chip,” an in vitro blast injury model, capable of simultaneous morphological, biochemical, and bioelectrical assessments before, during, and after blast injury. We show correlated increases in markers of oxidative stress (acrolein) and inflammation (TNF-α) accompanied by electrophysiological deficits post-blast injury. Additionally, we show that these pathological consequences are mitigated by acrolein scavenging. We also show that injury products released by cultures post-injury diffuse through culture media and instigate biochemical injury in uninjured neuronal networks. Furthermore, we show that acrolein, a diffusive component of post-TBI secondary injury, is sufficient to increase inflammation in uninjured cultures. These findings validate bTBI-on-a-Chip as an appropriate model for recapitulating and investigating blast injury in vitro by showing its capabilities of recreating primary and secondary bTBI, monitoring biochemical and electrophysiological responses to injury, and screening possible pharmacological interventions post-injury. We expect that this model could provide insights into the pathological biochemical mechanisms that will be critical in developing future diagnostic and treatment strategies for bTBI patients.

Statement of Significance

The findings in the current study validate bTBI-on-a-Chip as an appropriate model for recapitulating and investigating blast injury in vitro by demonstrating its capabilities of recreating primary and secondary bTBI, monitoring biochemical and electrophysiological responses to injury, and screening possible pharmacological interventions post-injury. We expect that this model could provide insights into the pathological biochemical mechanisms that will be critical in developing future diagnostic and treatment strategies for bTBI patients.

创伤性脑损伤（TBI）是一个全球性的健康问题。爆炸诱发的创伤性脑损伤（bTBI）是一种主要与战斗有关的损伤，其发病率不断上升的趋势令人担忧，因此有必要更好地了解相关的发病机制，以开发治疗方法。此外，大多数 bTBI 伤情较轻且未被确诊，这使得继发性生化损伤的传播超出了可能的干预范围。遗憾的是，由于对潜在机制的了解有限，可供选择的治疗方法很少。我们迫切需要更多的研究工具来阐明 bTBI 引起的直接和长期损伤背后的机制。因此，我们引入了 "bTBI-on-a-Chip"--一种体外爆炸损伤模型，能够在爆炸损伤前、中、后同时进行形态学、生物化学和生物电评估。我们发现氧化应激标记物（丙烯醛）和炎症标记物（TNF-α）的相关性增加伴随着爆炸损伤后的电生理缺陷。此外，我们还发现清除丙烯醛可减轻这些病理后果。我们还表明，损伤后培养物释放的损伤产物会通过培养基扩散，并引发未损伤神经元网络的生化损伤。此外，我们还发现，创伤后继发性损伤的扩散成分丙烯醛足以增加未损伤培养物中的炎症反应。这些研究结果表明，bTBI-on-a-Chip 能够再现原发性和继发性 bTBI，监测生化和电生理对损伤的反应，并筛选损伤后可能的药物干预措施，从而验证了 bTBI-on-a-Chip 是在体外再现和研究爆炸损伤的合适模型。我们希望该模型能让我们深入了解病理生化机制，这对未来为 bTBI 患者制定诊断和治疗策略至关重要。当前研究的结果验证了 bTBI-on-a-Chip 是在体外重现和研究爆炸损伤的合适模型，证明它具有重现原发性和继发性 bTBI、监测损伤的生化和电生理反应以及筛选损伤后可能的药物干预措施的能力。我们希望该模型能让我们深入了解病理生化机制，这对未来为 bTBI 患者制定诊断和治疗策略至关重要。

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引用次数: 0

Scaling in the brain 大脑中的缩放

Q3 Engineering

Brain multiphysics

Pub Date : 2024-11-02 DOI: 10.1016/j.brain.2024.100102

D. Le Bihan

Proper scaling is an important concept in physics. It allows theoretical frameworks originally developed to address a specific question to be generalized or recycled to solve another problem at a different scale. The rescaling of the theory of heat to link diffusion and Brownian motion is a famous example set out by Einstein. We have recently shown how the special and general relativity theories could be scaled down to the action potential propagation speed in the brain to explain some of its functioning: Functional “distances” between neural nodes (geodesics), depend on both the spatial distances between nodes and the time to propagate between them, through a connectome spacetime with four intricated dimensions. This spacetime may further be curved by neural activity suggesting how conscious activity could act in a similar the gravitational field curved the physical spacetime. Indeed, the apparent gap between the microscopic and macroscopic connectome scales may find an echo in the AdS/CFT correspondence. Applied to the brain connectome, this means that consciousness may appear as the emergence in a 5D spacetime of the neural activity present as its boundaries, the 4D cortical spacetime, as a holographic 5D construction by our inner brain. We explore here how the conflict between ‘consciousness and matter’ could be resolved by considering that the spacetime of our cerebral connectome has five dimensions, the fifth dimension allowing the natural, immaterial emergence of consciousness as a dual form of the 4D spacetime embedded in our material cerebral cortex.

Statement Of Significance

Scaling to the brain the AdS/CFT framework which shows how the General Gravity framework, hence gravitation, naturally (mathematically) emerges from a “flat”, gravitationless Quantum 4D spacetime once a fifth dimension is considered, we conjecture that the conflict between ‘consciousness and matter’ might be ill-posed and could be resolved by considering that the spacetime of our cerebral connectome has five dimensions, the fifth dimension allowing the natural, immaterial (mind, private) emergence of consciousness as a dual form of the 4D spacetime activity embedded in our material (body, public) cerebral cortex.

适当缩放是物理学中的一个重要概念。它允许将原本为解决特定问题而开发的理论框架加以推广或再造，以解决不同尺度上的另一个问题。爱因斯坦提出了一个著名的例子，即重新调整热理论的尺度，将扩散和布朗运动联系起来。最近，我们展示了如何将狭义相对论和广义相对论缩小到大脑中的动作电位传播速度，以解释大脑的某些功能：神经节点之间的功能 "距离"（大地线）取决于节点之间的空间距离和节点之间的传播时间，并通过一个具有四个复杂维度的连接体时空传播。这个时空可能会被神经活动进一步弯曲，这表明有意识的活动是如何以类似于引力场弯曲物理时空的方式发挥作用的。事实上，微观和宏观连接组尺度之间的明显差距可能在 AdS/CFT 对应中找到了呼应。应用于大脑连接组，这意味着意识可能是作为其边界的神经活动在 5D 时空中的出现，即 4D 大脑皮层时空，是我们大脑内部的全息 5D 构建。我们在此探讨如何通过考虑我们大脑连接体的时空有五个维度来解决 "意识与物质 "之间的冲突，第五维度允许意识作为嵌入我们物质大脑皮层的 4D 时空的双重形式自然、非物质地出现。意义声明将 AdS/CFT 框架扩展到大脑，表明一旦考虑到第五维度，广义引力框架（即引力）是如何从 "平坦"、无引力的量子四维时空中自然（数学地）产生的、我们猜想，"意识与物质 "之间的冲突可能是不恰当的，可以通过考虑我们大脑连接体的时空有五个维度来解决，第五维度允许自然、非物质（心灵、私人）的意识出现，作为嵌入我们物质（身体、公共）大脑皮层的四维时空活动的双重形式。

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引用次数: 0

Quantifying CSF Dynamics disruption in idiopathic normal pressure hydrocephalus using phase lag between transmantle pressure and volumetric flow rate 利用跨端面压力和容积流量之间的相位滞后量化特发性正常压力脑积水的脑脊液动力学紊乱情况

Q3 Engineering

Brain multiphysics

Pub Date : 2024-10-01 DOI: 10.1016/j.brain.2024.100101

Pragalv Karki , Stephanie Sincomb , Matthew C. Murphy , Jeffrey L. Gunter , Matthew L. Senjem , Jonathan Graff-Radford , David T. Jones , Hugo Botha , Jeremy K. Cutsforth-Gregory , Benjamin D. Elder , John Huston III , Petrice M. Cogswell

Background and purpose

Idiopathic normal pressure hydrocephalus (iNPH) is a cerebrospinal fluid (CSF) dynamics disorder as evidenced by the delayed ascent of radiotracers over the cerebral convexity on radionuclide cisternography. However, the exact mechanism causing this disruption remains unclear. Elucidating the pathophysiology of iNPH is crucial, as it is a treatable cause of dementia. Improving the diagnosis and treatment prognosis rely on the better understanding of this disease. In this study, we calculated the pulsatile transmantle pressure and investigated the phase lag between this pressure and the volumetric CSF flow rate as a novel biomarker of CSF dynamics disruption in iNPH.

Methods

44 iNPH patients and 44 age- and sex-matched cognitively unimpaired (CU) control participants underwent MRI scans on a 3T Siemens scanner. Pulsatile transmantle pressure was calculated analytically and computationally using volumetric CSF flow rate, cardiac frequency, and aqueduct dimensions as inputs. CSF flow rate through the aqueduct was acquired using phase-contrast MRI. The aqueduct length and radius were measured using 3D T1-weighted anatomical images.

Results

Peak pressure amplitudes and the pressure load (integrated pressure exerted over a cardiac cycle) were similar between the groups, but the non-dimensionalized pressure load (adjusted for anatomical factors) was significantly lower in the iNPH group (p<0.001, Welch's t-test). The phase lag between the pressure and the flow rate, arising due to viscous drag, was significantly higher in the iNPH group (p<0.001).

Conclusion

The increased phase lag is a promising new biomarker for quantifying CSF dynamics dysfunction in iNPH.

Statement of Significance

The exact mechanism causing the disruption of CSF circulation in idiopathic normal pressure hydrocephalus (iNPH) remains unclear. Elucidating the pathophysiology of iNPH is crucial, as it is a treatable cause of dementia. In this study, we provided an analytical and a computational method to calculate the pulsatile transmantle pressure and the phase lag between the pressure and the volumetric CSF flow rate across the cerebral aqueduct. The phase lag was significantly higher in iNPH patients than in controls and may serve as a novel biomarker of CSF dynamics disruption in iNPH.

背景和目的特发性正常压力脑积水（iNPH）是一种脑脊液（CSF）动力学障碍，表现为放射性核素贮水池造影中放射性核素延迟上升至脑凸面。然而，导致这种紊乱的确切机制仍不清楚。阐明 iNPH 的病理生理学至关重要，因为它是一种可治疗的痴呆病因。改善诊断和治疗预后有赖于更好地了解这种疾病。方法44 名 iNPH 患者和 44 名年龄和性别匹配的认知功能未受损（CU）对照组患者在 3T 西门子扫描仪上接受了 MRI 扫描。以 CSF 容积流速、心脏频率和导水管尺寸为输入，通过分析和计算得出搏动性跨阈压力。通过相位对比核磁共振成像获取了通过导水管的 CSF 流速。结果两组之间的峰值压力振幅和压力负荷（一个心动周期内施加的综合压力）相似，但 iNPH 组的无量纲化压力负荷（根据解剖学因素调整）明显较低（p<0.001，韦尔奇 t 检验）。由粘滞阻力引起的压力与流速之间的相位滞后在 iNPH 组明显更高（p<0.001）。阐明 iNPH 的病理生理学至关重要，因为它是一种可治疗的痴呆症病因。在这项研究中，我们提供了一种分析和计算方法来计算搏动性跨幔压力以及压力与跨脑导水管 CSF 容积流速之间的相位滞后。iNPH患者的相位滞后明显高于对照组，可作为iNPH患者CSF动力学紊乱的新型生物标志物。

{"title":"Quantifying CSF Dynamics disruption in idiopathic normal pressure hydrocephalus using phase lag between transmantle pressure and volumetric flow rate","authors":"Pragalv Karki , Stephanie Sincomb , Matthew C. Murphy , Jeffrey L. Gunter , Matthew L. Senjem , Jonathan Graff-Radford , David T. Jones , Hugo Botha , Jeremy K. Cutsforth-Gregory , Benjamin D. Elder , John Huston III , Petrice M. Cogswell","doi":"10.1016/j.brain.2024.100101","DOIUrl":"10.1016/j.brain.2024.100101","url":null,"abstract":"<div><h3>Background and purpose</h3><div>Idiopathic normal pressure hydrocephalus (iNPH) is a cerebrospinal fluid (CSF) dynamics disorder as evidenced by the delayed ascent of radiotracers over the cerebral convexity on radionuclide cisternography. However, the exact mechanism causing this disruption remains unclear. Elucidating the pathophysiology of iNPH is crucial, as it is a treatable cause of dementia. Improving the diagnosis and treatment prognosis rely on the better understanding of this disease. In this study, we calculated the pulsatile transmantle pressure and investigated the phase lag between this pressure and the volumetric CSF flow rate as a novel biomarker of CSF dynamics disruption in iNPH.</div></div><div><h3>Methods</h3><div>44 iNPH patients and 44 age- and sex-matched cognitively unimpaired (CU) control participants underwent MRI scans on a 3T Siemens scanner. Pulsatile transmantle pressure was calculated analytically and computationally using volumetric CSF flow rate, cardiac frequency, and aqueduct dimensions as inputs. CSF flow rate through the aqueduct was acquired using phase-contrast MRI. The aqueduct length and radius were measured using 3D T1-weighted anatomical images.</div></div><div><h3>Results</h3><div>Peak pressure amplitudes and the pressure load (integrated pressure exerted over a cardiac cycle) were similar between the groups, but the non-dimensionalized pressure load (adjusted for anatomical factors) was significantly lower in the iNPH group (<em>p<0.001</em>, Welch's t-test). The phase lag between the pressure and the flow rate, arising due to viscous drag, was significantly higher in the iNPH group (<em>p<0.001</em>).</div></div><div><h3>Conclusion</h3><div>The increased phase lag is a promising new biomarker for quantifying CSF dynamics dysfunction in iNPH.</div></div><div><h3>Statement of Significance</h3><div>The exact mechanism causing the disruption of CSF circulation in idiopathic normal pressure hydrocephalus (iNPH) remains unclear. Elucidating the pathophysiology of iNPH is crucial, as it is a treatable cause of dementia. In this study, we provided an analytical and a computational method to calculate the pulsatile transmantle pressure and the phase lag between the pressure and the volumetric CSF flow rate across the cerebral aqueduct. The phase lag was significantly higher in iNPH patients than in controls and may serve as a novel biomarker of CSF dynamics disruption in iNPH.</div></div>","PeriodicalId":72449,"journal":{"name":"Brain multiphysics","volume":"7 ","pages":"Article 100101"},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142418243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Increased hindbrain motion in Chiari I malformation patients measured through 3D amplified MRI (3D aMRI) 通过三维放大磁共振成像（3D aMRI）测量 Chiari I 畸形患者后脑运动增加的情况

Q3 Engineering

Brain multiphysics

Pub Date : 2024-09-28 DOI: 10.1016/j.brain.2024.100100

Javid Abderezaei , Fargol Rezayaraghi , Aymeric Pionteck , Ya-Chen Chuang , Alejandro Carrasquilla , Gizem Bilgili , Tianyi Ren , Tyson Lam , Tse-An Lu , Miriam Scadeng , Patrick Fillingham , Peter Morgenstern , Michael R. Levitt , Richard G. Ellenbogen , Yang Yang , Samantha J. Holdsworth , Raj Shrivastava , Mehmet Kurt

Chiari Malformation type 1 (CM-I) is a neurological disorder characterized by morphological defects including excessive cerebellar tonsillar ectopia and associated manifestations. We used 3D amplified MRI on a cohort of healthy and CM-I subjects to investigate the brain’s intrinsic motion, its association with the morphology and patient’s symptomatology, and surgical outcomes. We observed that the regional brain motion in CM-I was significantly higher than that of the healthy subjects, with anterior-posterior (AP) and superior-inferior (SI) displacements in cerebellar tonsils and medulla having the highest differences between the healthy and CM-I (

\sim

45%–

\sim

73% increased motion in the CM-I group). Interestingly, we found the ratio of neural tissue in the foramen magnum to be directly correlated with the SI tonsillar motion (

r = 0.58

). Tonsillar herniation was directly correlated with the AP motion of the tonsils (

r = 0.61

), and AP and medial-lateral (ML) motions of the medulla (

r = 0.66

, and

r = 0.57

). Subjects with higher tonsillar ML motion prior to surgery showed improved outcome (

p = 0.03

, and

A U C = 0.95

). Although we did not observe a significant correlation between the brains motion and morphometrics on the CM-I symptoms (perhaps due to our small sample size), illustrative cases increase our hope for the development of a future tool based on brain biomechanics.

Chiari 畸形 1 型（CM-I）是一种神经系统疾病，其特征是形态缺陷，包括小脑扁桃体过度异位及相关表现。我们使用三维放大核磁共振成像技术对一组健康和 CM-I 患者进行了研究，以了解大脑的固有运动、其与形态学和患者症状的关联以及手术效果。我们观察到，CM-I 患者的大脑区域运动明显高于健康受试者，其中小脑扁桃体和延髓的前后（AP）和上下（SI）位移在健康和 CM-I 之间的差异最大（CM-I 组的运动增加了 45%～73%）。有趣的是，我们发现枕骨大孔中神经组织的比例与扁桃体SI运动直接相关（r=0.58）。扁桃体疝与扁桃体的 AP 运动（r=0.61）以及髓质的 AP 和内外侧（ML）运动（r=0.66 和 r=0.57）直接相关。手术前扁桃体 ML 运动较高的受试者预后较好（P=0.03，AUC=0.95）。虽然我们没有观察到大脑运动与 CM-I 症状上的形态计量学之间存在明显的相关性（可能是由于我们的样本量较小），但说明性的病例增加了我们对未来开发基于大脑生物力学的工具的希望。

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引用次数: 0

Exploring tau protein and amyloid-beta propagation: A sensitivity analysis of mathematical models based on biological data 探索 tau 蛋白和淀粉样蛋白-β 的传播：基于生物数据的数学模型敏感性分析

Q3 Engineering

Brain multiphysics

Pub Date : 2024-08-27 DOI: 10.1016/j.brain.2024.100098

Mattia Corti

Alzheimer’s disease is the most common dementia worldwide. Its pathological development is well known to be connected with the accumulation of two toxic proteins: tau protein and amyloid- $β$ . Mathematical models and numerical simulations can predict the spreading patterns of misfolded proteins in this context. However, the calibration of the model parameters plays a crucial role in the final solution. In this work, we perform a sensitivity analysis of heterodimer and Fisher–Kolmogorov models to evaluate the impact of the equilibrium values of protein concentration on the solution patterns. We adopt advanced numerical methods such as the IMEX-DG method to accurately describe the propagating fronts in the propagation phenomena in a polygonal mesh of sagittal patient-specific brain geometry derived from magnetic resonance images. We calibrate the model parameters using biological measurements in the brain cortex for the tau protein and the amyloid- $β$ in Alzheimer’s patients and controls. Finally, using the sensitivity analysis results, we discuss the applicability of both models in the correct simulation of the spreading of the two proteins.

Statement of significance: Alzheimer’s disease is related to the accumulation of tau protein and amyloid- $β$ . Mathematical models to predict the spreading patterns require accurate parameter calibration. In this work, we perform a sensitivity analysis of heterodimer and Fisher–Kolmogorov models to evaluate the impact of the equilibrium values of protein concentration on the solution patterns obtained with advanced numerical simulations on patient-specific brain geometry derived from magnetic resonance images. By using biological measurements in the brain cortex for the proteins in Alzheimer’s patients and controls, we use sensitivity analysis to discuss the applicability of models in simulating protein spreading.

阿尔茨海默病是全球最常见的痴呆症。众所周知，其病理发展与两种有毒蛋白质的积累有关：tau 蛋白和淀粉样蛋白-β。在这种情况下，数学模型和数值模拟可以预测错误折叠蛋白的扩散模式。然而，模型参数的校准对最终解决方案起着至关重要的作用。在这项工作中，我们对异源二聚体模型和 Fisher-Kolmogorov 模型进行了敏感性分析，以评估蛋白质浓度平衡值对溶液模式的影响。我们采用先进的数值方法（如 IMEX-DG 方法），在根据磁共振图像得出的矢状患者特定脑几何形状的多边形网格中精确描述传播现象中的传播前沿。我们利用对阿尔茨海默氏症患者和对照组大脑皮层中 tau 蛋白和淀粉样蛋白-β 的生物测量结果来校准模型参数。最后，我们利用敏感性分析结果，讨论了两种模型在正确模拟两种蛋白质扩散方面的适用性：阿尔茨海默病与 tau 蛋白和淀粉样蛋白-β 的积累有关。预测扩散模式的数学模型需要精确的参数校准。在这项工作中，我们对异源二聚体模型和费舍尔-科尔莫哥罗夫模型进行了敏感性分析，以评估蛋白质浓度平衡值对根据磁共振图像得出的患者特定大脑几何形状进行高级数值模拟所获得的溶液模式的影响。通过在大脑皮层对阿尔茨海默氏症患者和对照组的蛋白质进行生物测量，我们利用敏感性分析讨论了模型在模拟蛋白质扩散方面的适用性。

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引用次数: 0

Erratum: Bok's equi-volume principle: Translation, historical context, and a modern perspective 勘误：博克的等体积原则：翻译、历史背景和现代视角

Q3 Engineering

Brain multiphysics

Pub Date : 2024-08-21 DOI: 10.1016/j.brain.2024.100099

Jack Consolini , Nagehan Demirci , Andrew Fulwider , Jeffrey J. Hutsler , Maria A. Holland

引用次数: 0

Numerical modelling of multiple sclerosis: A tissue-scale model of brain lesions 多发性硬化症的数值建模：脑损伤组织尺度模型

Q3 Engineering

Brain multiphysics

Pub Date : 2024-08-08 DOI: 10.1016/j.brain.2024.100097

H Hutchison , AC Szekely-Kohn , W Li , DET Shepherd , DM Espino

Multiple Sclerosis (MS) is an autoimmune condition leading to the degeneration of brain tissue, occurring when the immune system attacks the myelin sheath surrounding axons of white brain matter thereby disrupting brain signals. This study aimed to evaluate how MS lesions alter stress distribution through grey and white brain matter with lesions (active, chronic, and inactive). A linear viscoelastic model represents the tissue-scale dynamic deformation and time dependency of brain tissue. A Prony series expansion was used to model viscous effects including stress relaxation. An elastic modulus, within the viscoelastic model, was either reduced by 11 % for active lesions, or increased by 35 % increase for inactive lesions. These material properties were then implemented to model healthy tissue, active, chronically inflamed, and inactive lesions. Finite element analysis enabled stress evaluation in response to a peak cyclic displacement of 0.5 mm (1 % strain) with the healthy model acting as a control model. Chronic lesions had the largest effect on stress induced, in terms of high (171 Pa) and low stress (108 Pa). Inactive lesions induced an increase in stress of 11 Pa with areas of low stress (105 Pa). Active lesions caused the least deviation in peak induced stress (7 Pa). In conclusion, a hierarchy in stress induced across the lesion types has been found, from highest to lowest: chronic, inactive and active, with potential implications for lesion progression. In conclusion, MS lesions within brain tissue should model lesions, avoid assuming homogeneity during degeneration, and should distinguish between active and passive lesions.

多发性硬化症（MS）是一种导致脑组织变性的自身免疫性疾病，当免疫系统攻击白色脑物质轴突周围的髓鞘时，就会破坏脑信号。本研究旨在评估多发性硬化症病变（活动性、慢性和非活动性）如何改变脑灰质和脑白质的应力分布。线性粘弹性模型表示了脑组织的组织尺度动态变形和时间依赖性。普罗尼序列扩展用于模拟粘性效应，包括应力松弛。在粘弹性模型中，活跃病变的弹性模量降低了 11%，不活跃病变的弹性模量增加了 35%。这些材料特性随后被应用于健康组织、活跃病变、慢性炎症病变和非活跃病变的建模。通过有限元分析，可以对 0.5 毫米（1% 应变）的峰值循环位移进行应力评估，健康模型作为对照模型。慢性病变对应力的影响最大，包括高应力（171 帕）和低应力（108 帕）。非活动性病变引起的应力增加了 11 帕，低应力区域为 105 帕。活性病变引起的峰值应力偏差最小（7 Pa）。总之，我们发现不同病变类型引起的应力从高到低：慢性病变、非活动性病变和活动性病变，这对病变的进展具有潜在的影响。总之，脑组织内的多发性硬化病变应建立病变模型，避免假定退化过程中的同质性，并应区分活动性和被动性病变。

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引用次数: 0

Alzheimer’s disease and the mathematical mind 阿尔茨海默病与数学思维

Q3 Engineering

Brain multiphysics

Pub Date : 2024-04-25 DOI: 10.1016/j.brain.2024.100094

Travis B. Thompson, Bradley Z. Vigil, Robert S. Young

Throughout the 19th and 20th centuries, aided by advances in medical imaging, discoveries in physiology and medicine have added nearly 25 years to the average life expectancy. This resounding success brings with it a need to understand a broad range of age-related health conditions, such as dementia. Today, mathematics, neuroimaging and scientific computing are being combined with fresh insights, from animal models, to study the brain and to better understand the etiology and progression of Alzheimer’s disease, the most common cause of age-related dementia in humans. In this manuscript, we offer a brief primer to the reader interested in engaging with the exciting field of mathematical modeling and scientific computing to advance the study of the brain and, in particular, human AD research.

Statement of Significance Modeling Alzheimer’s disease is a highly interdisciplinary field and finding an effective starting point can be a considerable challenge. To address this challenge, this manuscript briefly highlights some central components of AD related protein pathology, useful classes of mathematical models for brain and AD research and effective computational resources for the practical prospective practitioner.

在 19 世纪和 20 世纪，借助医学成像技术的进步，生理学和医学方面的发现使人类的平均寿命延长了近 25 年。这一巨大成功带来了了解老年痴呆症等一系列与年龄有关的健康问题的需求。如今，数学、神经影像学和科学计算正与动物模型的新见解相结合，用于研究大脑，更好地了解阿尔茨海默病的病因和发展过程，阿尔茨海默病是人类最常见的老年痴呆症。在本手稿中，我们将为有兴趣参与数学建模和科学计算这一令人兴奋的领域以推进大脑研究，特别是人类阿尔茨海默病研究的读者提供一个简短的入门指南。意义声明阿尔茨海默病建模是一个高度跨学科的领域，找到一个有效的起点可能是一个相当大的挑战。为了应对这一挑战，本手稿简要介绍了与阿兹海默症相关的蛋白质病理学的一些核心组成部分、大脑和阿兹海默症研究中有用的数学模型类别，以及供实用的前瞻性实践者使用的有效计算资源。

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引用次数: 0

Revealing the heterogeneity of plasma protein and cognitive decline trajectory among Mild Cognitive Impairment patients by clustering of brain atrophy features 通过脑萎缩特征聚类揭示血浆蛋白与轻度认知障碍患者认知能力下降轨迹的异质性

Q3 Engineering

Brain multiphysics

Pub Date : 2024-03-29 DOI: 10.1016/j.brain.2024.100093

My Nguyen , Bao Pham , Toi Vo , Huong Ha

Alzheimer's disease (AD) is suggested to be a heterogeneous disorder, but limited studies explore the heterogeneity of the Mild Cognitive Impairment (MCI) stage. This study aimed to tackle such problems using the CIMLR (Cancer Integration via Multikernel Learning) algorithm to cluster brain structural features extracted from T1-weighted Magnetic Resonance Images of MCI patients from Alzheimer's Disease Neuroimaging Initiative. The demographic and cognitive results, characteristics of brain structural features, plasma biomarkers, and longitudinal cognitive trajectory were analyzed for each cluster. The CIMLR clustering analysis revealed four distinct clusters. Cluster 1 is the oldest group but has had mild atrophy and moderate progression with elevated Tumor Necrosis Factor Receptor 2 level; and low Brain-Derived Neurotrophic Factor and CD40 Ligand levels. Cluster 2 showed the highest risk for aggressive MCI progression, with abnormal Leptin, Adiponectin, and Creatine kinase-MB values. Cluster 3 exhibited a low level of Monokine Induced by Gamma Interferon and mild atrophy that shared similar patterns with Cluster 1. Cluster 4 represented the healthiest group during longitudinal tracking, with the mildest Parahippocampal atrophy, which was found to be positively correlated with cognitive impairment and amino acid levels. The longitudinal analyses showed the potential of Hepatocyte Growth Factor as a marker for slow cognitive impairment; Cortisol and Neurofilament Light Polypeptide as prognosis markers for aggressive MCI progression. These findings may lay out new suggestions for further research contributing to the accurate diagnosis and precision medicine for dementia and AD.

阿尔茨海默病（AD）被认为是一种异质性疾病，但探讨轻度认知障碍（MCI）阶段异质性的研究却很有限。本研究旨在利用 CIMLR（通过多核学习的癌症整合）算法对阿尔茨海默病神经影像计划中 MCI 患者的 T1 加权磁共振图像中提取的脑结构特征进行聚类，从而解决此类问题。对每个聚类的人口统计学和认知结果、脑结构特征、血浆生物标志物和纵向认知轨迹进行了分析。CIMLR 聚类分析揭示了四个不同的聚类。聚类1是年龄最大的一组，但有轻度萎缩和中度进展，肿瘤坏死因子受体2水平升高；脑源神经营养因子和CD40配体水平较低。第 2 组显示侵袭性 MCI 进展风险最高，瘦素、脂肪连接蛋白和肌酸激酶-MB 值异常。第 3 组显示出低水平的伽马干扰素诱导的单克隆和轻度萎缩，其模式与第 1 组相似。第 4 组代表了纵向追踪过程中最健康的一组，其副海马萎缩程度最轻，并发现其与认知障碍和氨基酸水平呈正相关。纵向分析表明，肝细胞生长因子可作为缓慢认知功能损害的标志物；皮质醇和神经丝杠轻多肽可作为侵袭性 MCI 进展的预后标志物。这些发现为进一步研究提出了新的建议，有助于痴呆症和注意力缺失症的精确诊断和精准医疗。

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引用次数: 0