EP02.38: The rate of change in cervical length between mid‐trimester and symptom onset is associated with intra‐amniotic and systemic inflammation

A blood-based biomarker able to track early neurodegeneration in Alzheimer’s disease would be valuable. Serum neurofilament-light (NfL) is elevated in familial Alzheimer’s disease (FAD) mutation carriers prior to symptom onset, but exactly how early NfL becomes abnormal and whether it can track change within individuals is uncertain.We recruited 18 symptomatic carriers of autosomal dominant FAD mutations, 19 presymptomatic carriers, and 11 non-carriers. Blood was taken at baseline, and 26 participants also gave at least one follow-up sample (mean interval=2.5 years). Serum NfL was measured on the SIMOA platform. A longitudinal mixed effects framework was used to model change in NfL over time.Serum NfL was increased (p<0.05) in mutation carriers compared with non-carriers 11 years before the estimated time of symptom onset, with rate of change in NfL becoming significantly different 12 years before. However, there was high variability in the inter-individual rate of change in NfL between participants.Serum NfL concentration, and its rate of change, are sensitive, at the group level at least, to very early AD-neurodegenration. However, the high variability between individuals in NfL rate of change may make it difficult at present to use this measure to track early change in individual patients.

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Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation

Blood Advances ◽

10.1182/bloodadvances.2020001500 ◽

2020 ◽

Vol 4 (7) ◽

pp. 1340-1349 ◽

Cited By ~ 1

Author(s):

Christian Valladolid ◽

Marina Martinez-Vargas ◽

Nitin Sekhar ◽

Fong Lam ◽

Cameron Brown ◽

...

Keyword(s):

Systemic Inflammation ◽

Rate Of Change ◽

Fibrin Polymerization ◽

Fibrin Formation ◽

Microvascular Thrombosis ◽

Healthy Humans ◽

Increased Risk ◽

Clot Structure ◽

A2 Domain

Abstract Systemic inflammation can lead to coagulopathy and disseminated intravascular coagulation (DIC). In prior studies, the recombinant A2 domain of human von Willebrand factor (VWF; A2 protein) attenuated DIC and decreased mortality in lipopolysaccharide (LPS)-treated mice. Here, we performed studies to dissect the mechanism by which the A2 protein moderates DIC. We used confocal microscopy to analyze the fibrin clot structure in plasma from healthy humans and endotoxemic mice, turbidity assays to examine fibrin polymerization, and a murine model for LPS-induced DIC and introduced a loss-of-function mutation into the A2 protein for fibrin. The mutation of the residue E1567 located in the α2 helix of the folded A2 domain of VWF inhibited binding activity for fibrin, possibly mapping a novel region containing a putative binding site for fibrin. The A2 protein increased the initial rate of change of fibrin polymerization, intercalated into the fibrin network, and modified the resultant clot structure in vitro. Furthermore, ex vivo experiments using plasma from mice with endotoxemia treated with the A2 protein revealed an increased rate of fibrin formation and an altered clot structure as compared with plasma from nontreated sick animals. Moreover, and in contrast to the A2 mutant, the A2 protein improved survival and reduced fibrin deposition and microvascular thrombosis in mice with endotoxemia-induced DIC. Importantly, in vivo and in vitro studies indicated that the A2 protein did not affect experimental thrombosis. Thus, we provide evidence for a novel treatment to attenuate systemic inflammation-induced coagulopathy/DIC via targeting fibrin formation, without an increased risk for bleeding.

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Rate of Change in Cervical Length in Women With Vaginal Bleeding During Pregnancy

Obstetrics and Gynecology ◽

10.1097/aog.0b013e31827d8e1b ◽

2013 ◽

Vol 121 (2, PART 1) ◽

pp. 260-264 ◽

Cited By ~ 5

Author(s):

Nicholas Behrendt ◽

Ronald S. Gibbs ◽

Anne Lynch ◽

Jan Hart ◽

Nancy A. West ◽

...

Keyword(s):

Vaginal Bleeding ◽

Cervical Length ◽

Rate Of Change

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Early immune pathology and persistent dysregulation characterise severe COVID-19

10.1101/2021.01.11.20248765 ◽

2021 ◽

Author(s):

Laura Bergamaschi ◽

Federica Mescia ◽

Lorinda Turner ◽

Aimee Hanson ◽

Prasanti Kotagiri ◽

...

Keyword(s):

Systemic Inflammation ◽

Symptom Onset ◽

Immune Cell ◽

Adaptive Responses ◽

Robust Immune Response ◽

Mild Disease ◽

Preventative Intervention ◽

Cellular Abnormalities ◽

Immune Pathology ◽

Inflammatory Changes

SummaryIn a study of 207 SARS-CoV2-infected individuals with a range of severities followed over 12 weeks from symptom onset, we demonstrate that an early robust immune response, without systemic inflammation, is characteristic of asymptomatic or mild disease. Those presenting to hospital had delayed adaptive responses and systemic inflammation already evident at around symptom onset. Such early evidence of inflammation suggests immunopathology may be inevitable in some individuals, or that preventative intervention might be needed before symptom onset. Viral load does not correlate with the development of this pathological response, but does with its subsequent severity. Immune recovery is complex, with profound persistent cellular abnormalities correlating with a change in the nature of the inflammatory response, where signatures characteristic of increased oxidative phosphorylation and reactive-oxygen species-associated inflammation replace those driven by TNF and IL-6. These late immunometabolic inflammatory changes and unresolved immune cell defects, if persistent, may contribute to “long COVID”.

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White matter hyperintensities and CSF Alzheimer disease biomarkers in preclinical Alzheimer disease

Neurology ◽

10.1212/wnl.0000000000008864 ◽

2019 ◽

Vol 94 (9) ◽

pp. e950-e960 ◽

Cited By ~ 7

Author(s):

Anja Soldan ◽

Corinne Pettigrew ◽

Yuxin Zhu ◽

Mei-Cheng Wang ◽

Abhay Moghekar ◽

...

Keyword(s):

White Matter ◽

Alzheimer Disease ◽

Symptom Onset ◽

White Matter Hyperintensities ◽

Cox Regression ◽

Rate Of Change ◽

Csf Biomarkers ◽

Risk Of Progression ◽

Fluid Attenuated Inversion Recovery ◽

T Tau

ObjectiveRecent studies suggest that white matter hyperintensities (WMH) on MRI, which primarily reflect small vessel cerebrovascular disease, may play a role in the evolution of Alzheimer disease (AD). In a longitudinal study, we investigated whether WMH promote the progression of AD pathology, or alter the association between AD pathology and risk of progression from normal cognition to mild cognitive impairment (MCI).MethodsTwo sets of analyses were conducted. The relationship between whole brain WMH load, based on fluid-attenuated inversion recovery MRI, obtained in initially cognitively normal participants (n = 274) and time to onset of symptoms of MCI (n = 60) was examined using Cox regression models. In a subset of the participants with both MRI and CSF data (n = 204), the interaction of WMH load and CSF AD biomarkers was also evaluated.ResultsBaseline WMH load interacted with CSF total tau (t-tau) with respect to symptom onset, but not with CSF β-amyloid 1–42 or phosphorylated tau (p-tau) 181. WMH volume was associated with time to symptom onset of MCI among individuals with low t-tau (hazard ratio [HR] 1.35, confidence interval [CI] 1.06–1.73, p = 0.013), but not those with high t-tau (HR 0.86, CI 0.56–1.32, p = 0.47). The rate of change in the CSF biomarkers over time was not associated with the rate of change in WMH volumes.ConclusionThese results suggest that WMH primarily affect the risk of progression when CSF measures of neurodegeneration or neuronal injury (as reflected by t-tau) are low. However, CSF biomarkers of amyloid and p-tau and WMH appear to have largely independent and nonsynergistic effects on the risk of progression to MCI.

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