Observational study of long-term persistent elevation of neurodegeneration markers after cardiac surgery

Abstract

Surgery and anesthesia induce inflammatory changes in the central nervous system, which ultimately lead to neuronal damage concomitant with an increase in the level of neurodegeneration markers. Despite some experimental data showing prolonged activation of the immune system post-surgery, no study has determined the extent of long-term elevation of neurodegeneration markers. The purpose of this study was to investigate the serum levels of tau protein, ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), neurofilament light (NF-L), and glial fibrillary acidic protein (GFAP) after elective cardiac surgery with the implementation of cardiopulmonary bypass (CPB). The serum levels of these markers from 30 patients were compared longitudinally to the baseline (pre-surgery or t 0 ), at 24 hours (t +24 ), at 7 days (t +7d ), and at 3 months (t +3m ). The secondary outcome was the production of macrophage-colony stimulating factor (M-CSF) and tumor necrosis factor-α (TNF-α) in vitro by isolated monocytes in response to lipopolysaccharide (LPS) as the measure of immune system activation. The tertiary outcome was the serum level of C-reactive protein (CRP), serum amyloid P (SAP), and α-2-macroglobulin (A2M). Serum levels of tau protein increased 24 hours after surgery (p = 0.0015) and remained elevated at 7 days ( p = 0.0017) and three months ( p = 0.036). Serum levels of UCH-L1 peaked at 24 hours ( p = 0.00055) and normalized at 3 months. In vitro secretion of M-CSF by LPS-stimulated peripheral monocytes, but not TNFα, correlated highly ( r = 0.58; p = 0.04) with persistent elevation of serum tau levels at 3 months. The serum CRP and SAP increases correlated with tau post-CPB levels significantly at 3 months. We demonstrated that elevation of serum tau levels at 24 hours, 7 days, and 3 months after heart surgery is concomitant with some traits of inflammation after CPB. The elevation of tau several weeks into recovery is significantly longer than expected.

Plasma neurofilament light chain and glial fibrillary acidic protein predict stroke in CADASIL

“…The initial manifestations or reasons for screening for NOTCH3 mutation in these patients were as follows: stroke in 52 patients, cognitive or gait deterioration in 7, headache or dizziness in 5, asymptomatic family members of known CADASIL patients in 3, and incidentally found marked leukoaraiosis in 1. The patients' blood collected from different hospitals underwent genetic diagnosed centrally by combining p.R544C hot-spot mutation screening followed by sequencing of the most frequently mutated NOTCH3 exons (3,4,5,6,11,18) if p.R544C was not detected. Sixty-five patients (96%) had NOTCH3 mutation on exon 11 p.R544C.…”

“…Recently, a panel of ultra-sensitive immunoassays targeting the aforementioned blood-based biomarkers has been developed [18][19][20][21]. It has the advantages of assessing multiple biomarkers at once and comparing their performance based on the clinical interests.…”

Plasma neurofilament light chain and glial fibrillary acidic protein predict stroke in CADASIL

“…(22) The initial manifestations or reasons for screening for NOTCH3 mutation in these patients were as follows, stroke in 52 patients, cognitive or gait deterioration in 7, headache or dizziness in 5, asymptomatic family members of known CADASIL patients in 3, and incidentally found marked leurkoaraiosis in 1. The patients' blood collected from different hospitals underwent genetic diagnosed centrally by combining p.R544C hot-spot mutation screening followed by sequencing of the most frequently mutated NOTCH3 exons (3,4,5,6,11,18) weighted imaging signal intensities through computed tomography (CT) or magnetic resonance imaging (MRI), respectively, that corresponded to the clinical presentations. ICH was defined as the sudden onset of focal neurological deficit with non-traumatic intraparenchymal hemorrhage observed on head CT or MRI scans.…”

“…(16,17) Recently, a panel of ultra-sensitive immunoassays targeting the aforementioned blood-based biomarkers has been developed. (18)(19)(20)(21) It has the advantages of assessing multiple biomarkers at once and comparing their performance based on the clinical interests. We aimed to use this panel to investigate whether these blood-based biomarkers can reflect disease severity, correctly identify stroke event, and predict its incidence in CADASIL patients.…”

“…The blood samples were analyzed through the Neurology 4-Plex assay established by the Simoa platform (Quanterix; Lexington, MA, USA). The assay could quantify the plasma concentrations of NfL, GFAP, tau, and UCHL1simultaneously, and the measurement details are as described previously (18,19). Measurements were performed by board-certified laboratory technicians who were blinded to the clinical groups.…”