Plasma markers of neurologic injury and systemic inflammation in individuals with self-reported neurologic post-acute sequelae of SARS-CoV-2 infection (PASC)

Background: The biologic mechanisms underlying neurologic post-acute-sequelae of SARS-CoV-2 infection (PASC) are incompletely understood. Methods: We measured markers of neuronal injury (glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]) and soluble markers of inflammation among a cohort of people with prior confirmed SARS-CoV-2 infection at early and late recovery following the initial illness (defined as less than and greater than 90 days, respectively). The primary clinical outcome was the presence of self-reported central nervous system (CNS) PASC symptoms during the late recovery timepoint. We compared fold-changes in marker values between those with and without CNS PASC symptoms using linear mixed effects models and examined relationships between neurologic and immunologic markers using rank linear correlations. Results: Of 121 individuals, 52 reported CNS PASC symptoms. During early recovery, those who went on to report CNS PASC symptoms had elevations in GFAP (1.3-fold higher mean ratio, 95% CI 1.04-1.63, p=0.02), but not NfL (1.06-fold higher mean ratio, 95% CI 0.89-1.26, p=0.54). During late recovery, neither GFAP nor NfL levels were elevated among those with CNS PASC symptoms. Although absolute levels of NfL did not differ, those who reported CNS PASC symptoms demonstrated a stronger downward trend over time in comparison to those who did not report CNS PASC symptoms (p=0.041). Those who went on to report CNS PASC also exhibited elevations in IL-6 (48% higher during early recovery and 38% higher during late recovery), MCP-1 (19% higher during early recovery), and TNF-alpha (19% higher during early recovery and 13% higher during late recovery). GFAP and NfL correlated with levels of several immune activation markers during early recovery; these correlations were attenuated during late recovery. Conclusions: Self-reported neurologic symptoms present >90 days following SARS-CoV-2 infection are associated with elevations in markers of neurologic injury and inflammation at early recovery timepoints, suggesting that early injury can result in long-term disease. The correlation of GFAP and NfL with markers of systemic immune activation suggests one possible mechanism that might contribute to these symptoms. Additional work is needed to better characterize these processes and to identify interventions to prevent or treat this condition.

Hif1α is required for Wnt regulated gene expression during Xenopus tropicalis tail regeneration

Regeneration of complex tissues is initiated by an injury-induced stress response, eventually leading to activation of developmental signaling pathways, such as Wnt signaling. How early injury cues are interpreted and coupled to activation of these developmental signals and their targets is not well understood. Here, we show that Hif1α, a stress induced transcription factor, is required for tail regeneration in Xenopus tropicalis. We find that Hif1α is required for regeneration of differentiated axial tissues, including axons and muscle. Using RNA-sequencing, we find that Hif1α and Wnt converge on a broad set of genes required for posterior specification and differentiation, including the posterior hox genes. We further show that Hif1α is required for transcription via a Wnt-responsive element, a function that is conserved in both regeneration and early neural patterning. Our findings indicate a regulatory role for Hif1α in Wnt mediated gene expression across multiple tissue contexts.

The engine initiating tissue regeneration: does a common mechanism exist during evolution?

A successful tissue regeneration is a very complex process that requires a precise coordination of many molecular, cellular and physiological events. One of the critical steps is to convert the injury signals into regeneration signals to initiate tissue regeneration. Although many efforts have been made to investigate the mechanisms triggering tissue regeneration, the fundamental questions remain unresolved. One of the major obstacles is that the injury and the initiation of regeneration are two highly coupled processes and hard to separate from one another. In this article, we review the major events occurring at the early injury/regeneration stage in a range of species, and discuss the possible common mechanisms during initiation of tissue regeneration.

Poor Corticospinal Motor Neuron Health Is Associated with Increased Symptom Severity in the Acute Phase Following Repetitive Mild TBI and Predicts Early ALS Onset in Genetically Predisposed Rodents

Traumatic brain injury (TBI) is a well-established risk factor for several neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease, however, a link between TBI and amyotrophic lateral sclerosis (ALS) has not been clearly elucidated. Using the SOD1G93A rat model known to recapitulate the human ALS condition, we found that exposure to mild, repetitive TBI lead ALS rats to experience earlier disease onset and shortened survival relative to their sham counterparts. Importantly, increased severity of early injury symptoms prior to the onset of ALS disease symptoms was linked to poor health of corticospinal motor neurons and predicted worsened outcome later in life. Whereas ALS rats with only mild behavioral injury deficits exhibited no observable changes in corticospinal motor neuron health and did not present with early onset or shortened survival, those with more severe injury-related deficits exhibited alterations in corticospinal motor neuron health and presented with significantly earlier onset and shortened lifespan. While these studies do not imply that TBI causes ALS, we provide experimental evidence that head injury is a risk factor for earlier disease onset in a genetically predisposed ALS population and is associated with poor health of corticospinal motor neurons.

Multimodal brain monitoring following traumatic brain injury: A primer for intensive care practitioners

Traumatic brain injury (TBI) is common and potentially devastating. Traditional examination-based patient monitoring following TBI may be inadequate for frontline clinicians to reduce secondary brain injury through individualized therapy. Multimodal neurologic monitoring (MMM) offers great potential for detecting early injury and improving outcomes. By assessing cerebral oxygenation, autoregulation and metabolism, clinicians may be able to understand neurophysiology during acute brain injury, and offer therapies better suited to each patient and each stage of injury. Hence, we offer this primer on brain tissue oxygen monitoring, pressure reactivity index monitoring and cerebral microdialysis. This narrative review serves as an introductory guide to the latest clinically-relevant evidence regarding key neuromonitoring techniques.

Magnetic Resonance Imaging Features of Early Knee Cartilage Injury in Athletes and Its Significance in Diagnosis

Objective: The objective is to study the application and significance of magnetic resonance imaging (MRI) in the diagnosis of early knee joint cartilage injury in athletes, so as to provide corresponding rehabilitation training. Method: The imaging manifestations of T2 mapping of patellar cartilage in athletes and healthy volunteers are studied. 32 national professional athletes are included. The imaging characteristics of T2 mapping pseudocolor images of normal patellar cartilage are analyzed. The image characteristics of early patellar cartilage injury in T2 mapping pseudocolor images are analyzed, and the comparison of cartilage injury between athletes and ordinary people, as well as the injury of left and right knee cartilage of athletes are obtained. Results: The average value of T2 (T2av) of right patellar cartilage of athletes is higher than that of left patellar cartilage, and there are significant differences. The average T2av of right patellar cartilage is slightly higher than that of left patellar cartilage in healthy volunteers, with no significant differences. With the increase of training years, the color scale of patellar cartilage gradually increases, from the surface to the deep layer. In addition, the damage is aggravated, the blue range is reduced, the green range is expanded, and some yellow areas appear, which are more mixed. The lateral area and deviation to lateral area of right patellar cartilage are more obvious, and the T2 value is increased. Conclusion: T2 mapping can reflect the early injury of articular cartilage sensitively, intuitively and quantitatively. Before the morphological changes, the changes of biochemical structure of degenerative articular cartilage can be found by T2 mapping, which can provide theoretical support for the detection of early injury of knee cartilage in athletes.

Imaging Developmental and Interventional Plasticity Following Perinatal Stroke

ABSTRACT: Perinatal stroke occurs around the time of birth and leads to lifelong neurological disabilities including hemiparetic cerebral palsy. Magnetic resonance imaging (MRI) has revolutionized our understanding of developmental neuroplasticity following early injury, quantifying volumetric, structural, functional, and metabolic compensatory changes after perinatal stroke. Such techniques can also be used to investigate how the brain responds to treatment (interventional neuroplasticity). Here, we review the current state of knowledge of how established and emerging neuroimaging modalities are informing neuroplasticity models in children with perinatal stroke. Specifically, we review structural imaging characterizing lesion characteristics and volumetrics, diffusion tensor imaging investigating white matter tracts and networks, task-based functional MRI for localizing function, resting state functional imaging for characterizing functional connectomes, and spectroscopy examining neurometabolic changes. Key challenges and exciting avenues for future investigations are also considered.