沃爾特·M·切斯納特 Martins et al. Show Network-Structured Brain Changes in Post-COVID Syndrome, Informing a Hypothesis of Systemic Neurodegenerative-Like Pathology Just as in Parkinson’s Disease, the Spike Protein appears to be influencing several connectomes of the body, inducing multiple pathological conditions. WALTER M CHESNUT JAN 19
Network diffusion modelling results. Upper left panel shows beta optimization, identifying the best diffusion coefficient (β = 0.010) based on maximum mean Spearman correlation. Upper right panel illustrates optimized Spearman correlation (R) curves over time across all potential seed regions. The lower left panel maps seed likelihood (maximum Spearman correlation) across brain regions, with higher likelihood regions indicated in red. The lower right panel demonstrates the significant positive correlation between seed likelihood and empirical cortical thickness changes (Spearman ρ = 0.703, p < 0.001). Permutation testing against scrambled connectomes and Euclidean distance models confirmed the significance of these findings (p < 0.05).
Four years ago, I proposed the hypothesis that the SARS-CoV-2 Spike Protein, or downstream biological consequences of its presence, could initiate a multi-system condition resembling a “whole-body” neurodegenerative process. The Martins et al. preprint does not directly demonstrate Spike protein localization or propagation. However, it provides evidence that structural brain changes in PCS follow connectivity-constrained patterns, a property shared with several neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease.
Network diffusion modelling results from Martins et al. illustrate this principle. The optimized diffusion coefficient (β = 0.010) produced simulated structural deviation patterns that significantly correlated with empirical cortical thickness changes across patients with PCS. Importantly, regions within the posterior temporoparietal cortex emerged as high-likelihood “seeds” in the model. These “seeds” should be understood as mathematical initial conditions, not as direct evidence of viral entry points or Spike Protein movement. Still – things spread.
Network diffusion modelling demonstrated that structural deviations in PCS are not randomly distributed but follow pathways consistent with structural connectivity. The optimized model (β = 0.010) produced simulated deviation patterns that significantly correlated with empirical data (Figure 4). Posterior-temporoparietal regions emerged as likely “seeds” for network-wide propagation, showing the highest seed likelihood scores. These regions are involved in multisensory integration and attention and may represent key vulnerability nodes in PCS. Permutation testing confirmed that these findings exceeded chance expectations (p < 0.05), with simulations based on scrambled connectomes and Euclidean distance metrics showing significantly lower correspondence with empirical data.
Indeed, the Spike Protein has already been shown to travel along neurons in retrograde and antegrade fashion.
Although experimental evidence regarding SARS-CoV-2 neuroinvasiveness is still lacking (33), post-mortem studies evidenced the virus’s presence in the brain microvasculature, cerebrospinal fluid, even neurons (4, 26, 34). Also, studies demonstrated that the ACE-2 receptor is expressed on neuron and glial cells of structures such as the olfactory epithelium, cortex, striatum, substantia nigra, and the brain stem (35), supporting the SARS-CoV-2 potential to infect cells throughout the CNS. Therefore, there are suggested mechanisms for coronaviruses neuroinvasion (Figure 1), including the neuronal anterograde and retrograde spreading in the transcribial route (8, 16) and (19, 33) the hematogenous route (36). The neuronal retrograde/anterograde transport and the trans-synaptic transfer are supported by in vitro studies where the SARS-CoV-2 is detected within neuronal soma and neurites using human brain organoids (31, 37).
Furthermore, the Spike Protein “propagates” in a most interesting way. Its peptides virtually transform itself into the misfolded proteins of prionopathies – by creating them.
Emerging evidence suggests that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may have long-term deleterious effects on the central nervous system and even contribute to post-COVID neurological syndromes. Interestingly, inflammation-induced proteolytic processing of the Spike protein of SARS-CoV-2 leads to the generation of peptides capable of aggregating into amyloid fibrils in vitro. Herein, we investigate the in vitro effect of a fibrillogenic fragment of the Spike protein [Spike 194–203 (S194)] on the aggregation and toxicity of the Parkinson’s disease (PD) protein α-synuclein (αSyn). Our results indicate that S194 fibrils stimulate in a concentration-dependent manner the fibrillation of αSyn monomer, resulting in aggregates with increased capacity of inducing lipid vesicle leakage and toxicity to neuroblastoma cells, in comparison with either αSyn or S194 alone.
What I would like to add to this discussion is drawing a comparison to Parkinsons’ Disease as an analogy for what we observe occurring with SARS-CoV-2 and its Spike Protein. Like the Spike Protein, Parkinson’s occurs through “prion-like” travel of α-synuclein through parts of the brain – from an originating point.
The pathological assembly of Aβ, tau, and α-synuclein is at the heart of Alzheimer’s and Parkinson’s diseases. Extracellular deposits of Aβ and intraneuronal tau inclusions define Alzheimer’s disease, whereas intracellular inclusions of α-synuclein make up the Lewy pathology of Parkinson’s disease. Most cases of disease are sporadic, but some are inherited in a dominant manner. Mutations frequently occur in the genes encoding Aβ, tau, and α-synuclein. Overexpression of these mutant proteins can give rise to disease-associated phenotypes. Protein assembly begins in specific regions of the brain during the process of Alzheimer’s and Parkinson’s diseases, from where it spreads to other areas.
NEURODEGENERATION. Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein https://pubmed.ncbi.nlm.nih.gov/26250687/
Now, in addition to invading the brain/CNS, as in Parkinson’s, the Spike Protein may invade, prion-like into other (all?) areas of the body through a similar mechanism. Again, Parkinson’s can serve as an analogy as it can have a brain-first – and a body-first(!) mode of propagation.
Recent studies suggest the existence of brain-first and body-first subtypes within the Lewy body disorder (LBD) spectrum, including Parkinson’s disease. These studies primarily focused on α-synuclein propagation through the parasympathetic vagal and olfactory bulb routes, leaving the possibility of a sympathetic nervous system spreading route unexplored. In the present study, we analyzed two postmortem datasets, which included 173 and 129 cases positive for Lewy pathology. We observed a clear distinction between brain-first and body-first subtypes in early prediagnostic cases with mild Lewy pathology. Brain-first cases displayed minimal peripheral organ pathology in prediagnostic phases, contrasting with marked autonomic involvement in prediagnostic body-first cases. Utilizing the SuStaIn machine learning algorithm, we identified two distinct body-first subtypes, one with vagal predominance and another with sympathetic predominance, in equal proportions. Our study supports the existence of three prediagnostic LBD subtypes and highlights the sympathetic nervous system alongside the parasympathetic system in LBD onset and progression.
We need to study the entire population; we need to determine if this is the cause of Long COVID, and, as I stated years ago, is it hanging in the balance for all of us? After all, Parkinson’s can take years or decades to develop as it silently spreads.
Parkinson’s Disease (PD) has long been associated with its cardinal motor symptoms: the tell-tale tremor, the stiffness that creeps in, the slowness of movement that makes everyday tasks a challenge, and the precarious dance of balance.
These are the signs that often lead to a diagnosis, the outward manifestations of a neurodegenerative process unfolding within the brain. However, the reality of Parkinson’s is far more nuanced, its onset is often heralded by subtle, seemingly unrelated changes that can precede the hallmark motor symptoms by months, years, or even decades.
I will continue to investigate this theory. As readers of this Substack know, the prion-like abilities of the Spike Protein I predicted from the very start. Clearly, last week’s preprint was alarming. We will continue to seek understanding and therapeutics. Please have a blessed week.
馬丁斯等人。 顯示新冠肺炎後綜合徵中的網路結構大腦變化，告知系統性神經退行性樣病理的假設
就像帕金森病一樣，尖峰蛋白似乎正在影響身體的幾個連線體，誘發多種病理狀況。
沃爾特·M·切斯納特
Martins et al. Show Network-Structured Brain Changes in Post-COVID Syndrome, Informing a Hypothesis of Systemic Neurodegenerative-Like Pathology
Just as in Parkinson’s Disease, the Spike Protein appears to be influencing several connectomes of the body, inducing multiple pathological conditions.
WALTER M CHESNUT
JAN 19
https://substack.com/@wmcresearch/note/p-185059232
Network diffusion modelling results.
Upper left panel shows beta optimization, identifying the best diffusion coefficient (β = 0.010) based on maximum mean Spearman correlation. Upper right panel illustrates optimized Spearman correlation (R) curves over time across all potential seed regions. The lower left panel maps seed likelihood (maximum Spearman correlation) across brain regions, with higher likelihood regions indicated in red. The lower right panel demonstrates the significant positive correlation between seed likelihood and empirical cortical thickness changes (Spearman ρ = 0.703, p < 0.001). Permutation testing against scrambled connectomes and Euclidean distance models confirmed the significance of these findings (p < 0.05).
Four years ago, I proposed the hypothesis that the SARS-CoV-2 Spike Protein, or downstream biological consequences of its presence, could initiate a multi-system condition resembling a “whole-body” neurodegenerative process. The Martins et al. preprint does not directly demonstrate Spike protein localization or propagation. However, it provides evidence that structural brain changes in PCS follow connectivity-constrained patterns, a property shared with several neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease.
AN INFILTRATIVE DISEASE, AN ALZHEIMER’S OF THE BODY: IS INFILTRATION OF THE SARS-CoV-2 SPIKE PROTEIN INTO ORGAN TISSUE THE CAUSE OF LONG COVID? AND DOES IT AWAIT US ALL?
https://wmcresearch.substack.com/p/an-infiltrative-disease-an-alzheimers
Network diffusion modelling results from Martins et al. illustrate this principle. The optimized diffusion coefficient (β = 0.010) produced simulated structural deviation patterns that significantly correlated with empirical cortical thickness changes across patients with PCS. Importantly, regions within the posterior temporoparietal cortex emerged as high-likelihood “seeds” in the model. These “seeds” should be understood as mathematical initial conditions, not as direct evidence of viral entry points or Spike Protein movement. Still – things spread.
Network diffusion modelling demonstrated that structural deviations in PCS are not randomly distributed but follow pathways consistent with structural connectivity. The optimized model (β = 0.010) produced simulated deviation patterns that significantly correlated with empirical data (Figure 4). Posterior-temporoparietal regions emerged as likely “seeds” for network-wide propagation, showing the highest seed likelihood scores. These regions are involved in multisensory integration and attention and may represent key vulnerability nodes in PCS. Permutation testing confirmed that these findings exceeded chance expectations (p < 0.05), with simulations based on scrambled connectomes and Euclidean distance metrics showing significantly lower correspondence with empirical data.
Molecular, cellular and network mapping of brain structural deviations in patients with Post-COVID19 syndrome
https://www.biorxiv.org/content/10.64898/2026.01.12.699045v1.full
Indeed, the Spike Protein has already been shown to travel along neurons in retrograde and antegrade fashion.
Although experimental evidence regarding SARS-CoV-2 neuroinvasiveness is still lacking (33), post-mortem studies evidenced the virus’s presence in the brain microvasculature, cerebrospinal fluid, even neurons (4, 26, 34). Also, studies demonstrated that the ACE-2 receptor is expressed on neuron and glial cells of structures such as the olfactory epithelium, cortex, striatum, substantia nigra, and the brain stem (35), supporting the SARS-CoV-2 potential to infect cells throughout the CNS. Therefore, there are suggested mechanisms for coronaviruses neuroinvasion (Figure 1), including the neuronal anterograde and retrograde spreading in the transcribial route (8, 16) and (19, 33) the hematogenous route (36). The neuronal retrograde/anterograde transport and the trans-synaptic transfer are supported by in vitro studies where the SARS-CoV-2 is detected within neuronal soma and neurites using human brain organoids (31, 37).
Infection Mechanism of SARS-COV-2 and Its Implication on the Nervous System
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.621735/full
Furthermore, the Spike Protein “propagates” in a most interesting way. Its peptides virtually transform itself into the misfolded proteins of prionopathies – by creating them.
Emerging evidence suggests that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may have long-term deleterious effects on the central nervous system and even contribute to post-COVID neurological syndromes. Interestingly, inflammation-induced proteolytic processing of the Spike protein of SARS-CoV-2 leads to the generation of peptides capable of aggregating into amyloid fibrils in vitro. Herein, we investigate the in vitro effect of a fibrillogenic fragment of the Spike protein [Spike 194–203 (S194)] on the aggregation and toxicity of the Parkinson’s disease (PD) protein α-synuclein (αSyn). Our results indicate that S194 fibrils stimulate in a concentration-dependent manner the fibrillation of αSyn monomer, resulting in aggregates with increased capacity of inducing lipid vesicle leakage and toxicity to neuroblastoma cells, in comparison with either αSyn or S194 alone.
An Amyloidogenic Fragment of the Spike Protein from SARS-CoV-2 Virus Stimulates the Aggregation and Toxicity of Parkinson’s Disease Protein Alpha-Synuclein
https://pubs.acs.org/doi/10.1021/acschemneuro.5c00478
What I would like to add to this discussion is drawing a comparison to Parkinsons’ Disease as an analogy for what we observe occurring with SARS-CoV-2 and its Spike Protein. Like the Spike Protein, Parkinson’s occurs through “prion-like” travel of α-synuclein through parts of the brain – from an originating point.
The pathological assembly of Aβ, tau, and α-synuclein is at the heart of Alzheimer’s and Parkinson’s diseases. Extracellular deposits of Aβ and intraneuronal tau inclusions define Alzheimer’s disease, whereas intracellular inclusions of α-synuclein make up the Lewy pathology of Parkinson’s disease. Most cases of disease are sporadic, but some are inherited in a dominant manner. Mutations frequently occur in the genes encoding Aβ, tau, and α-synuclein. Overexpression of these mutant proteins can give rise to disease-associated phenotypes. Protein assembly begins in specific regions of the brain during the process of Alzheimer’s and Parkinson’s diseases, from where it spreads to other areas.
NEURODEGENERATION. Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein
https://pubmed.ncbi.nlm.nih.gov/26250687/
Now, in addition to invading the brain/CNS, as in Parkinson’s, the Spike Protein may invade, prion-like into other (all?) areas of the body through a similar mechanism. Again, Parkinson’s can serve as an analogy as it can have a brain-first – and a body-first(!) mode of propagation.
Recent studies suggest the existence of brain-first and body-first subtypes within the Lewy body disorder (LBD) spectrum, including Parkinson’s disease. These studies primarily focused on α-synuclein propagation through the parasympathetic vagal and olfactory bulb routes, leaving the possibility of a sympathetic nervous system spreading route unexplored. In the present study, we analyzed two postmortem datasets, which included 173 and 129 cases positive for Lewy pathology. We observed a clear distinction between brain-first and body-first subtypes in early prediagnostic cases with mild Lewy pathology. Brain-first cases displayed minimal peripheral organ pathology in prediagnostic phases, contrasting with marked autonomic involvement in prediagnostic body-first cases. Utilizing the SuStaIn machine learning algorithm, we identified two distinct body-first subtypes, one with vagal predominance and another with sympathetic predominance, in equal proportions. Our study supports the existence of three prediagnostic LBD subtypes and highlights the sympathetic nervous system alongside the parasympathetic system in LBD onset and progression.
Sympathetic and parasympathetic subtypes of body-first Lewy body disease observed in postmortem tissue from prediagnostic individuals
https://www.nature.com/articles/s41593-025-01910-9
We need to study the entire population; we need to determine if this is the cause of Long COVID, and, as I stated years ago, is it hanging in the balance for all of us? After all, Parkinson’s can take years or decades to develop as it silently spreads.
Parkinson’s Disease (PD) has long been associated with its cardinal motor symptoms: the tell-tale tremor, the stiffness that creeps in, the slowness of movement that makes everyday tasks a challenge, and the precarious dance of balance.
These are the signs that often lead to a diagnosis, the outward manifestations of a neurodegenerative process unfolding within the brain. However, the reality of Parkinson’s is far more nuanced, its onset is often heralded by subtle, seemingly unrelated changes that can precede the hallmark motor symptoms by months, years, or even decades.
Subtle Signs of Parkinson’s: Before The Visible Tremors
https://photopharmics.com/subtle-signs-of-parkinsons-before-the-visible-tremors/
I will continue to investigate this theory. As readers of this Substack know, the prion-like abilities of the Spike Protein I predicted from the very start. Clearly, last week’s preprint was alarming. We will continue to seek understanding and therapeutics. Please have a blessed week.
网络扩散模型结果
左上角面板显示了β优化，基于最大平均斯皮尔曼相关系数（Spearman correlation）确定了最佳扩散系数（β = 0.010）。右上角面板展示了所有潜在种子区域在时间上的优化斯皮尔曼相关系数（R）曲线。左下角面板绘制了大脑区域中种子可能性（最大斯皮尔曼相关性），较高可能性区域用红色标出。右下角面板展示了种子可能性与实测皮层厚度变化之间显著的正相关（斯皮尔曼ρ = 0.703，p < 0.001）。对比随机连接组网和欧氏距离模型的排列检验确认了这些发现的显著性（p < 0.05）。
四年前，我提出了假设，认为SARS-CoV-2的刺突蛋白（Spike Protein）或其存在的下游生物学后果，可能会引发一种类似“全身”神经退行性过程的多系统疾病。Martins等人的预印本没有直接展示刺突蛋白的定位或传播，但提供了证据表明，PCS（后遗症综合症）中的大脑结构变化遵循连接约束模式，这种特性与多种神经退行性疾病，如阿尔茨海默病和帕金森病，具有相似之处。
一种渗透性疾病，身体的阿尔茨海默病：SARS-CoV-2刺突蛋白渗透到器官组织中是否是长新冠的原因？它是否也在等待我们每个人？
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Martins等人的网络扩散建模结果说明了这一原理。优化的扩散系数（β = 0.010）产生的模拟结构偏差模式，与PCS患者实测的皮层厚度变化显著相关。重要的是，模型中后颞顶皮层区域成为高可能性“种子”区域。这些“种子”应被理解为数学初始条件，而非病毒进入点或刺突蛋白传播的直接证据。尽管如此——事情依然在扩散。
网络扩散建模表明，PCS中的结构偏差并非随机分布，而是遵循与结构连接一致的路径。优化的模型（β = 0.010）产生的模拟偏差模式与实测数据显著相关（图4）。后颞顶区域成为网络传播的潜在“种子”，显示出最高的种子可能性得分。这些区域涉及多感官整合和注意力，可能是PCS的关键易损节点。排列检验确认，这些发现超出了随机期望（p < 0.05），基于随机连接组网和欧氏距离度量的模拟与实测数据的对应关系显著较低。
后COVID-19综合症患者的大脑结构偏差的分子、细胞和网络映射
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事实上，已有研究表明，刺突蛋白沿着神经元进行逆行和顺行传播。
尽管关于SARS-CoV-2神经侵袭性的实验证据仍然缺乏（33），但尸检研究证明了病毒存在于大脑微血管、脑脊液甚至神经元中（4, 26, 34）。另外，研究显示，ACE-2受体在嗅上皮、皮层、纹状体、黑质和脑干等结构的神经元和胶质细胞中表达（35），支持SARS-CoV-2有可能感染整个中枢神经系统的细胞。因此，已经提出了冠状病毒神经侵袭的机制（图1），包括神经元的顺行和逆行传播、经脊髓传播途径（8, 16）以及血行传播途径（36）。逆行/顺行运输和跨突触转移在体外研究中得到了支持，研究表明SARS-CoV-2可以在人体脑类器官中被检测到，存在于神经元体和神经突起内（31, 37）。
SARS-CoV-2感染机制及其对神经系统的影响
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此外，刺突蛋白“传播”的方式非常有趣。其肽几乎转变为类似于普里昂病（prionopathies）的错误折叠蛋白——通过产生它们来实现。
有新兴证据表明，严重急性呼吸综合症冠状病毒2型（SARS-CoV-2）感染可能对中枢神经系统产生长期的有害影响，甚至可能导致后COVID神经系统综合症。有趣的是，SARS-CoV-2刺突蛋白的炎症诱导蛋白水解处理，导致了能在体外聚集成淀粉样纤维的肽的产生。在这项研究中，我们探讨了SARS-CoV-2刺突蛋白的一个纤维化片段[Spike 194-203（S194）]对帕金森病（PD）蛋白α-突触核蛋白（αSyn）聚集和毒性的影响。我们的结果表明，S194纤维能够依赖浓度促进αSyn单体的纤维化，生成的聚集体比单独的αSyn或S194更具有诱导脂质小泡泄漏和神经母细胞瘤细胞毒性的能力。
来自SARS-CoV-2病毒的刺突蛋白的淀粉样形成片段刺激帕金森病蛋白α-突触核蛋白的聚集和毒性
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我想在这次讨论中添加的一点是，将SARS-CoV-2刺突蛋白的作用与帕金森病进行对比，作为一种类比来帮助理解我们观察到的现象。就像刺突蛋白一样，帕金森病是通过α-突触核蛋白在大脑中各部分的“普里昂样”传播——从一个起始点传播到其他地方。
Aβ、tau和α-突触核蛋白的病理组装是阿尔茨海默病和帕金森病的核心。Aβ的细胞外沉积和tau的神经元内包涵物定义了阿尔茨海默病，而α-突触核蛋白的细胞内包涵物构成了帕金森病的路易小体病理。大多数病例为散发性，但也有部分是显性遗传的。Aβ、tau和α-突触核蛋白的基因经常发生突变，过度表达这些突变蛋白可能导致与疾病相关的表型。在阿尔茨海默病和帕金森病的过程中，蛋白质组装通常从大脑特定区域开始，并传播到其他区域。
神经退行性疾病：阿尔茨海默病与帕金森病：与Aβ、tau和α-突触核蛋白组装相关的普里昂概念
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现在，除了侵入大脑/中枢神经系统（如帕金森病一样），刺突蛋白可能通过类似机制侵入身体的其他（所有？）部位。同样，帕金森病可以作为类比，因为它可以先在大脑传播，也可以先在身体传播（！）。
最近的研究表明，路易小体病（LBD）谱系中存在大脑优先型和身体优先型亚型，包括帕金森病。这些研究主要集中在α-突触核蛋白通过副交感迷走神经和嗅球路线的传播，尚未探讨交感神经系统传播的可能性。在这项研究中，我们分析了两个尸检数据集，分别包括173例和129例具有路易小体病理的病例。我们观察到，在早期诊断前的轻度路易小体病理病例中，大脑优先型和身体优先型亚型之间存在明显的区别。大脑优先型病例在诊断前期显示外周器官病理最小，而身体优先型病例则在诊断前期表现出明显的自主神经系统受累。通过SuStaIn机器学习算法，我们确定了两种不同的身体优先型亚型，一种以迷走神经为主，另一种以交感神经为主，比例相等。我们的研究支持了三