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The vascular endothelial growth factor (VEGF) family of genes has been implicated in the clinical development of Alzheimer’s Disease (AD). A previous study identified associations between gene expression of VEGF family members in the prefrontal cortex and cognitive performance and AD pathology. This study explored if those associations were also observed in the blood. Consistent with previous observations in brain tissue, higher blood gene expression of placental growth factor (PGF) was associated with a faster rate of memory decline (p=0.04). Higher protein abundance of FMS-related receptor tyrosine kinase 4 (FLT4) in blood was associated with biomarker levels indicative of lower amyloid and tau pathology, opposite the direction observed in brain. Also, higher gene expression of VEGFB in blood was associated with better baseline memory (p=0.008). Notably, we observed that higher gene expression of VEGFB in blood was associated with lower expression of VEGFB in the brain (r=−0.19, p=0.02). Together, these results suggest that the VEGFB, FLT4, and PGF alterations in the AD brain may be detectable in the blood compartment.

Ischaemic brain infarction can occur without acute neurological symptoms (covert strokes) or with symptoms (overt strokes), both associated with poor health outcomes. We conducted a pilot study of the incidence of preoperative and postoperative (intraoperative or postoperative) covert strokes, and explored the relationship of postoperative ischaemic brain injury to blood levels of neurofilament light, a biomarker of neuronal damage.We analysed 101 preoperative (within 2 weeks of surgery) and 58 postoperative research MRIs on postoperative days 2-9 from two prospective cohorts collected at the University of Wisconsin (NCT01980511 and NCT03124303). Participants were aged65 yr and undergoing non-intracranial, non-carotid surgery.Preoperative covert stroke was identified in 2/101 participants (2%; Bayesian 95% confidence interval [CI], 0.2-5.4). This rate was statistically different from the postoperative ischaemic brain injury rate of 7/58 (12%, 4.9-21.3%; P=0.01) based on postoperative imaging. However, in a smaller group of participants with paired imaging (n=30), we did not identify the same effect (P=0.67). Patients with postoperative brain injury had elevated peak neurofilament light levels (median [inter-quartile range], 2.34 [2.24-2.64] logAlthough limited by a small sample size, these data suggest that preoperative covert stroke occurs more commonly than previously anticipated. Plasma neurofilament light is a potential screening biomarker for postoperative ischaemic brain injury.

A neuroimaging-based biomarker termed the brain age is thought to reflect variability in the brain's ageing process and predict longevity. Using Insight 46, a unique narrow-age birth cohort, we aimed to examine potential drivers and correlates of brain age.Participants, born in a single week in 1946 in mainland Britain, have had 24 prospective waves of data collection to date, including MRI and amyloid PET imaging at approximately 70 years old. Using MRI data from a previously defined selection of this cohort, we derived brain-predicted age from an established machine-learning model (trained on 2001 healthy adults aged 18-90 years); subtracting this from chronological age (at time of assessment) gave the brain-predicted age difference (brain-PAD). We tested associations with data from early life, midlife, and late life, as well as rates of MRI-derived brain atrophy.Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. We included 456 participants (225 female), with a mean chronological age of 70·7 years (SD 0·7; range 69·2 to 71·9). The mean brain-predicted age was 67·9 years (8·2, 46·3 to 94·3). Female sex was associated with a 5·4-year (95% CI 4·1 to 6·8) younger brain-PAD than male sex. An increase in brain-PAD was associated with increased cardiovascular risk at age 36 years (β=2·3 [95% CI 1·5 to 3·0]) and 69 years (β=2·6 [1·9 to 3·3]); increased cerebrovascular disease burden (1·9 [1·3 to 2·6]); lower cognitive performance (-1·3 [-2·4 to -0·2]); and increased serum neurofilament light concentration (1·2 [0·6 to 1·9]). Higher brain-PAD was associated with future hippocampal atrophy over the subsequent 2 years (0·003 mL/year [0·000 to 0·006] per 5-year increment in brain-PAD). Early-life factors did not relate to brain-PAD. Combining 12 metrics in a hierarchical partitioning model explained 33% of the variance in brain-PAD.Brain-PAD was associated with cardiovascular risk, and imaging and biochemical markers of neurodegeneration. These findings support brain-PAD as an integrative summary metric of brain health, reflecting multiple contributions to pathological brain ageing, and which might have prognostic utility.Alzheimer's Research UK, Medical Research Council Dementia Platforms UK, Selfridges Group Foundation, Wolfson Foundation, Wellcome Trust, Brain Research UK, Alzheimer's Association.

It is unclear whether cerebrospinal fluid (CSF) biomarkers of neurodegeneration predict brain atrophy in cognitively healthy older adults, whether these associations can be explained by phosphorylated tau181 (p-tau) and the 42 amino acid form of amyloid-β (Aβ42) biomarkers, and which neural substrates may drive these associations. We addressed these questions in 2 samples of cognitively healthy older adults who underwent longitudinal structural MRI up to 7 years and had baseline CSF levels of heart-type fatty-acid binding protein (FABP3)=, total-tau, neurogranin, and neurofilament light (NFL) (n = 189, scans = 721). The results showed that NFL, total-tau, and FABP3 predicted entorhinal thinning and hippocampal atrophy. Brain atrophy was not moderated by Aβ42 and the associations between NFL and FABP3 with brain atrophy were independent of p-tau. The spatial pattern of cortical atrophy associated with the biomarkers overlapped with neurogenetic profiles associated with expression in the axonal (total-tau, NFL) and dendritic (neurogranin) components. CSF biomarkers of neurodegeneration are useful for predicting specific features of brain atrophy in older adults, independently of amyloid and tau pathology biomarkers.

INTRODUCTION: Amyloid-β (Aβ) deposition is common in dementia with Lewy bodies (DLB) and has been associated with more rapid disease progression. An effective biomarker that identified the presence of significant brain Aβ in people with DLB may be useful to identify and stratify participants for research studies and to inform prognosis in clinical practice. Plasma biomarkers are emerging as candidates to fulfil this role. METHODS: Thirty-two participants with DLB had brain amyloid (18F-florbetapir) PET, of whom 27 also had an MRI to enable the calculation of 18F-florbetapir SUVR. Plasma Aβ42/40, phosphorylated tau (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) were measured using single molecule array (Simoa). The plasma biomarkers were investigated for correlation with 18F-florbetapir SUVR, discriminant ability to identify Aβ-positive cases based on a predefined SUVR threshold of 1.10 and correlation with subsequent cognitive decline over one year. RESULTS: All four plasma markers significantly correlated with 18F-florbetapir SUVR (|β| = 0.40-0.49; p < .05). NfL had the greatest area under the receiver operating characteristic curve to identify Aβ-positive cases (AUROC 0.84 (95% CI 0.66, 1); β = 0.46, p = .001), whereas Aβ42/40 had the smallest (AUROC 0.73 (95% CI 0.52, 0.95); β = -0.47, p = .01). Accuracy was highest when combining all four biomarkers (AUROC 0.92 (95% CI 0.80, 1)). Lower plasma Aβ42/40 was significantly associated with more rapid decline in cognition (β = 0.53, p < .01). CONCLUSIONS: Plasma biomarkers have the potential to identify Aβ deposition in DLB. Further work in other cohorts is required to determine and validate optimal cut-offs for these biomarkers.

Case-control studies have associated delirium with blood-brain barrier (BBB) permeability. However, this approach cannot determine whether delirium is attributable to high pre-existing permeability or to perioperative changes. We tested whether perioperative changes in cerebrospinal fluid/plasma albumin ratio (CPAR) and plasma S100B were associated with delirium severity.Participants were recruited to two prospective cohort studies of non-intracranial surgery (NCT01980511, NCT03124303, and NCT02926417). Delirium severity was assessed using the Delirium Rating Scale-98. Delirium incidence was diagnosed with the 3D-Confusion Assessment Method (3D-CAM) or CAM-ICU (CAM for the ICU). CSF samples from 25 patients and plasma from 78 patients were analysed for albumin and S100B. We tested associations between change in CPAR (n=11) and S100B (n=61) and delirium, blood loss, CSF interleukin-6 (IL-6), and CSF lactate.The perioperative increase in CPAR and S100B correlated with delirium severity (CPAR ρ=0.78, P=0.01; S100B ρ=0.41, P0.001), delirium incidence (CPAR P=0.012; S100B P0.001) and CSF IL-6 (CPAR ρ=0.66 P=0.04; S100B ρ=0.75, P=0.025). Linear mixed-effect analysis also showed that decreased levels of S100B predicted recovery from delirium symptoms (P=0.001). Linear regression demonstrated that change in plasma S100B was independently associated with surgical risk, cardiovascular surgery, blood loss, and hypotension. Blood loss also correlated with CPAR (ρ=0.64, P=0.04), S100B (ρ=0.70, P0.001), CSF lactate (R=0.81, P=0.01), and peak delirium severity (ρ=0.36, P=0.01).Postoperative delirium is associated with a breakdown in the BBB. This increased permeability is dynamic and associated with a neuroinflammatory and lactate response. Strategies to mitigate blood loss may protect the BBB.

Considerable advancements have been made in the quantification of biofluid-based biomarkers for traumatic brain injury (TBI), which provide a clinically accessible window to investigate disease mechanisms and progression. Methods with improved analytical sensitivity compared with standard immunoassays are increasingly used, and blood tests are being used in the diagnosis, monitoring, and outcome prediction of TBI. Most work to date has focused on acute TBI diagnostics, while the literature on biomarkers for long-term sequelae is relatively scarce. In this review, we give an update on the latest developments in biofluid-based biomarker research in TBI and discuss how acute and prolonged biomarker changes can be used to detect and quantify brain injury and predict clinical outcome and neuropsychiatric sequelae.

Objectives To assess the ability of the biomarkers neuron-specific enolase (NSE), tau, neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP) to predict postoperative cognitive dysfunction (POCD) at discharge in patients who underwent cardiac surgery. Design Post hoc analyses (with tests being prespecified before data analyses) from a randomized clinical trial. Setting Single-center study from a primary heart center in Denmark. Participants Adult patients undergoing elective or subacute on-pump coronary artery bypass grafting and/or aortic valve replacement. Interventions Blood was collected before induction of anesthesia, after 24 hours, after 48 hours, and at discharge from the surgical ward. The International Study of Postoperative Cognitive Dysfunction test battery was applied to diagnose POCD at discharge and after three months. Linear mixed models of covariance were used to assess whether repeated measurements of biomarker levels were associated with POCD. Receiver operating characteristic (ROC) curves were applied to assess the predictive value of each biomarker measurement for POCD. Measurements and Main Results A total of 168 patients had biomarkers measured at baseline, and 47 (28%) fulfilled the POCD criteria at discharge. Patients with POCD at discharge had significantly higher levels of tau (p = 0.02) and GFAP (p = 0.01) from baseline to discharge. The biomarker measurements achieving the highest area under the ROC curve for prediction of POCD at discharge were NFL measured at discharge (AUC, 0.64; 95% confidence interval [CI], 0.54-0.73), GFAP measured 48 hours after induction (AUC, 0.64; 95% CI, 0.55-0.73), and GFAP measured at discharge (AUC, 0.64; 95% CI, 0.54-0.74), corresponding to a moderate predictive ability. Conclusions Postoperative serum levels of tau and GFAP were significantly elevated in cardiac surgery patients with POCD at discharge, however, the biomarkers achieved only modest predictive abilities for POCD at discharge. Postoperative levels of NSE were not associated with POCD at discharge.

Objectives While there is growing evidence of an association between depressive symptoms and postoperative delirium, the underlying pathophysiological mechanisms remain unknown. The goal of this study was to explore the association between depression and postoperative delirium in hip fracture patients, and to examine Alzheimer's disease (AD) pathology as a potential underlying mechanism linking depressive symptoms and delirium. Methods Patients 65 years old or older (N = 199) who were undergoing hip fracture repair and enrolled in the study “A Strategy to Reduce the Incidence of Postoperative Delirium in Elderly Patients” completed the 15-item Geriatric Depression Scale (GDS-15) preoperatively. Cerebrospinal fluid (CSF) was obtained during spinal anesthesia and assayed for amyloid-beta (Aβ) 40, 42, total tau (t-tau), and phosphorylated tau (p-tau)181. Results For every one point increase in GDS-15, there was a 13% increase in odds of postoperative delirium, adjusted for baseline cognition (MMSE), age, sex, race, education and CSF AD biomarkers (OR = 1.13, 95%CI = 1.02–1.25). Both CSF Aβ42/t-tau (β = −1.52, 95%CI = −2.1 to −0.05) and Aβ42/p-tau181 (β = −0.29, 95%CI = −0.48 to −0.09) were inversely associated with higher GDS-15 scores, where lower ratios indicate greater AD pathology. In an analysis to identify the strongest predictors of delirium out of 18 variables, GDS-15 had the highest classification accuracy for postoperative delirium and was a stronger predictor of delirium than both cognition and AD biomarkers. Conclusions In older adults undergoing hip fracture repair, depressive symptoms were associated with underlying AD pathology and postoperative delirium. Mild baseline depressive symptoms were the strongest predictor of postoperative delirium, and may represent a dementia prodrome.

Schizophrenia is thought to be a neurodevelopmental disorder with neuronal migration, differentiation and maturation disturbances. Tau is a microtubule-associated protein with a crucial role in these processes. Lower circulating tau levels have been reported in adults with schizophrenia, but this association has not been investigated in adolescent psychosis. We aimed to test the hypotheses that a) adolescents with early-onset psychosis (EOP; age of onset

Background Biochemical markers of brain pathology could potentially contribute to diagnosis and prediction in epilepsy. We describe levels of five brain injury markers in adults with new-onset seizures, and assess group differences in patients with a single seizure, epilepsy, and poststroke epilepsy. Methods In this prospective observational study, adults with new-onset seizures were recruited at Sahlgrenska University Hospital, Sweden, and concentrations of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), microtubule-associated protein tau (tau), S100 calcium-binding protein (S100B), and neuron-specific enolase (NSE) were measured. Participants were categorized as epilepsy, poststroke epilepsy (PSE), or single seizure (no additional seizures). Patients were followed until a diagnosis of epilepsy or PSE, or for at least two years in single seizure cases. Results The cohort included 23 (37%) individuals with a single seizure, 24 (39%) with epilepsy, and 15 (24%) with PSE. The concentrations of S100B were higher in patients with epilepsy and PSE than in single seizures (p = 0.0023 and p = 0.0162, respectively). The concentrations of NfL were higher in patients with PSE than in single seizures (p=0.0027). After age-normalization, levels of S100B were higher in patients with epilepsy and levels of NfL were higher in patients with PSE (p = 0.0021 and p = 0.0180). Conclusion Levels of S100B and NfL were higher in patients with epilepsy or PSE than patients with single seizures. Further studies are needed to investigate the biomarker potential of brain injury markers as predictors of epilepsy course or indicators of epileptogenesis.

Background: Plasma tau phosphorylated at threonine 217 (p-tau217) and plasma tau phosphorylated at threonine 181 (p-tau181) are associated with Alzheimer's disease tau pathology. We compared the diagnostic value of both biomarkers in cognitively unimpaired participants and patients with a clinical diagnosis of mild cognitive impairment, Alzheimer's disease syndromes, or frontotemporal lobar degeneration (FTLD) syndromes. Methods: In this retrospective multicohort diagnostic performance study, we analysed plasma samples, obtained from patients aged 18–99 years old who had been diagnosed with Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, or posterior cortical atrophy), FTLD syndromes (corticobasal syndrome, progressive supranuclear palsy, behavioural variant frontotemporal dementia, non-fluent variant primary progressive aphasia, or semantic variant primary progressive aphasia), or mild cognitive impairment; the participants were from the University of California San Francisco (UCSF) Memory and Aging Center, San Francisco, CA, USA, and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL; 17 sites in the USA and two in Canada). Participants from both cohorts were carefully characterised, including assessments of CSF p-tau181, amyloid-PET or tau-PET (or both), and clinical and cognitive evaluations. Plasma p-tau181 and p-tau217 were measured using electrochemiluminescence-based assays, which differed only in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid-PET and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses were tested with the Delong test. Findings: Data were collected from 593 participants (443 from UCSF and 150 from ARTFL, mean age 64 years [SD 13], 294 [50%] women) between July 1 and Nov 30, 2020. Plasma p-tau217 and p-tau181 were correlated (r=0·90, pdiff=0·31) and in pathology-confirmed Alzheimer's disease (n=15, mean age 73 years [SD 12]) versus pathologically confirmed FTLD (n=68, mean age 67 years [SD 8]; AUC=0·96 [0·92–1·00] for p-tau217, AUC=0·91 [0·82–1·00] for p-tau181; p diff=0·22). P-tau217 outperformed p-tau181 in differentiating patients with Alzheimer's disease syndromes (n=75) from those with FTLD syndromes (n=274, mean age 67 years [SD 9]; AUC=0·93 [0·91–0·96] for p-tau217, AUC=0·91 [0·88–0·94] for p-tau181; p diff=0·01). P-tau217 was a stronger indicator of amyloid-PET positivity (n=146, AUC=0·91 [0·88–0·94]) than was p-tau181 (n=214, AUC=0·89 [0·86–0·93]; p diff=0·049). Tau-PET binding in the temporal cortex was more strongly associated with p-tau217 than p-tau181 (r=0·80 vs r=0·72; p diff

Objectives The aim was to investigate the correlation between biomarkers of brain injury and long-term neurocognitive outcome, and the interplay with intrathecal inflammation and neuronal autoimmunity, in patients with herpes simplex encephalitis (HSE). Methods A total of 53 adult/adolescent HSE patients were included from a prospective cohort in a randomized placebo-controlled trial investigating the effect of a 3-month follow-up treatment with valaciclovir. Study subjects underwent repeated serum/cerebrospinal fluid (CSF) sampling and brain magnetic resonance imaging in the first 3 months along with cognitive assessment using the Mattis Dementia Rating Scale (MDRS) at 24 months. CSF samples were analysed for biomarkers of brain injury, inflammation and synaptic autoimmunity. The predefined primary analysis was the correlation between peak CSF neurofilament protein (NFL), a biomarker of neuronal damage, and MDRS at 24 months. Results Impaired cognitive performance significantly correlated with NFL levels (rho = –0.36, p=0.020). Development of IgG anti-N-methyl-D-aspartate receptor (NDMAR) antibodies was associated with a broad and prolonged proinflammatory CSF response. In a linear regression model, lower MDRS at 24 months was associated with previous development of IgG anti-N-methyl-D-aspartate receptor (NMDAR) (beta = –0.6249, p=0.024) and age (z-score beta = –0.2784, p=0.024), but not CSF NFL, which however significantly correlated with subsequent NMDAR autoimmunization (p = 0.006). Discussion Our findings show that NFL levels are predictive of long-term neurocognitive outcome in HSE, and suggest a causative chain of events where brain tissue damage increases the risk of NMDAR autoimmunisation and subsequent prolongation of CSF inflammation. The data provides guidance for a future intervention study of immunosuppressive therapy administered in the recovery phase of HSE.

Pituitary tumors and subsequent treatment with endoscopic transsphenoidal surgery (ETSS) may cause injury to suprasellar structures, causing long-term fatigue and neurocognitive impairment. A method to quantify brain injury after ETSS is not available. In this prospective, exploratory study of patients undergoing ETSS for pituitary tumors, a novel approach to detect possible neuronal damage is presented. Plasma concentrations of brain injury biomarkers (glial fibrillary acidic protein [GFAP], tau, and neurofilament light [NFL]) were measured the day before surgery, immediately after surgery, at day 1 and 5, and at 6 and 12 months after surgery, using enzyme-linked immunosorbent assays. The association between the increase of biomarkers with preoperative tumor extension and postoperative patient-perceived fatigue was evaluated. Suprasellar tumor extension was assessed from MRI scans, and self-perceived fatigue was assessed using the Multidimensional Fatigue Inventory before and 6 months after surgery. Thirty-five patients were included in the analysis. Compared to baseline, GFAP showed a maximal increase at day 1 after surgery (p = 0.0005), tau peaked postoperatively on the day of surgery (p = 0.019), and NFL reached its maximum at day 5 after surgery (p < 0.0001). The increase in GFAP correlated with preoperative chiasmal compression (p = 0.020). The increase in tau was correlated with preoperative chiasmal (p = 0.011) and hypothalamus compression (p = 0.016), and fatigue score 6 months after surgery (p = 0.016). In conclusion, the concentrations of brain injury biomarkers in blood increased after ETSS for pituitary tumors. The results indicate that postoperative plasma GFAP and tau might reflect astroglial and neuronal damage after ETSS.

The association between cerebrospinal fluid (CSF) amyloid beta (Aβ) Aβ38 or Aβ40 and brain grey- and white matter integrity is poorly understood. We studied this in 213 cognitively normal 70-year-olds, and in subgroups defined by presence/absence of the APOE ε4 allele and Aβ pathology: Aβ-/APOE-, Aβ+/APOE-, Aβ-/APOE+ and Aβ+/APOE+. CSF Aβ was quantified using ELISA and genotyping for APOE was performed. Low CSF Aβ42 defined Aβ plaque pathology. Brain volumes were assessed using Freesurfer-5.3, and white matter integrity using tract-based statistics in FSL. Aβ38 and Aβ40 were positively correlated with cortical thickness, some subcortical volumes and white matter integrity in the total sample, and in 3 of the subgroups: Aβ-/APOE-, Aβ+/APOE- and Aβ-/APOE+. In Aβ+/APOE+ subjects, higher Aβ38 and Aβ40 were linked to reduced cortical thickness and subcortical volumes. We hypothesize that production of all Aβ species decrease in brain regions with atrophy. In Aβ+/APOE+, Aβ-dysregulation may be linked to cortical atrophy in which high Aβ levels is causing pathological changes in the gray matter of the brain.

BACKGROUND: Myocardial and neuronal injury occur commonly after noncardiac surgery. We examined whether patients who had perioperative myocardial injury (PMI) also incurred neuronal injury, and whether myocardial and neuronal injury were associated with similar changes in inflammatory markers or overlapping clinical predictors. METHODS: A total of 114 individuals >65 yr old were recruited from two ongoing perioperative cohort studies (NCT02926417; NCT03124303). Plasma samples were collected before and daily after surgery to process assays for troponin I (PMI), neurofilament light (NfL; neuronal injury) and multiplexed plasma cytokines (inflammation). The primary outcome was the change in NfL in individuals with PMI (>40 pg ml(−1) increase in troponin above preoperative values). We conducted logistic regression to identify if there were shared clinical predictors for myocardial and neuronal injury. RESULTS: Ninety-six patients had paired NfL and troponin data. Twenty-three of 94 subjects (24%) with PMI had greater increases in NfL (median [inter-quartile range, IQR]: 29 pg ml(−1) [3–95 pg ml(−1)]; 2.8-fold increase) compared with subjects with no troponin increase (8 pg ml(−1) [3–20]; 1.3-fold increase; P=0.008). PMI was associated with increased interleukin (IL)-1ra (P=0.005), IL-2 (P=0.045), IL-8 (P=0.002), and IL-10 (P

To develop therapies for Alzheimer's disease, we need accurate in vivo diagnostics. Multiple proteomic studies mapping biomarker candidates in cerebrospinal fluid (CSF) resulted in little overlap. To overcome this shortcoming, we apply the rarely used concept of proteomics meta-analysis to identify an effective biomarker panel. We combine ten independent datasets for biomarker identification: seven datasets from 150 patients/controls for discovery, one dataset with 20 patients/controls for down-selection, and two data -sets with 494 patients/controls for validation. The discovery results in 21 biomarker candidates and down -selection in three, to be validated in the two additional large-scale proteomics datasets with 228 diseased and 266 control samples. This resulting 3-protein biomarker panel differentiates Alzheimer's disease (AD) from controls in the two validation cohorts with areas under the receiver operating characteristic curve (AUROCs) of 0.83 and 0.87, respectively. This study highlights the value of systematically re-analyzing pre-viously published proteomics data and the need for more stringent data deposition.

BACKGROUND: Postoperative delirium is associated with increases in the neuronal injury biomarker, neurofilament light (NfL). Here we tested whether two other biomarkers, glial fibrillary acidic protein (GFAP) and tau, are associated with postoperative delirium. METHODS: A total of 114 surgical patients were recruited into two prospective biomarker cohort studies with assessment of delirium severity and incidence. Plasma samples were sent for biomarker analysis including tau, NfL, and GFAP, and a panel of 10 cytokines. We determined a priori to adjust for interleukin-8 (IL-8), a marker of inflammation, when assessing associations between biomarkers and delirium incidence and severity. RESULTS: GFAP concentrations showed no relationship to delirium. The change in tau from preoperative concentrations to postoperative Day 1 was greater in patients with postoperative delirium (P

To explore if electrographic status epilepticus (ESE) after cardiac arrest causes additional secondary brain injury reflected by serum levels of two novel biomarkers of brain injury: neurofilament light chain (NfL) originating from neurons and glial fibrillary acidic protein (GFAP) from glial cells.Simplified continuous EEG (cEEG) and serum levels of NfL and GFAP, sampled at 24, 48 and 72 h after cardiac arrest, were collected during the Target Temperature Management (TTM)-trial. Two statistical methods were used: multivariable regresssion analysis; and a matched control group of patients without ESE matched for early predictors of poor neurological outcome.128 patients had available biomarkers and cEEG. Twenty-six (20%) patients developed ESE, the majority (69%) within 24 h. ESE was an independent predictor of elevated serum NfL (p 0.001) but not of serum GFAP (p = 0.16) at 72 h after cardiac arrest. Compared to a control group matched for early predictors of poor neurological outcome, patients who developed ESE had higher levels of serum NfL (p = 0.03) and GFAP (p = 0.04) at 72 h after cardiac arrest.ESE after cardiac arrest is associated with higher levels of serum NfL which may suggest increased secondary neuronal injury compared to matched patients without ESE but similar initial brain injury. Associations with GFAP reflecting glial injury are less clear. The study design cannot exclude imperfect matching or other mechanisms of secondary brain injury contributing to the higher levels of biomarkers of brain injury seen in the patients with ESE.

The optimum priming fluid for the cardiopulmonary bypass (CPB) circuit is still debated. We compared a new hyperoncotic priming solution containing dextran 40, which has an electrolyte composition that mimics extracellular fluid, with a standard crystalloid-based prime.Eighty cardiac surgery patients were included in this double-blind, randomized, single-center study. Patients were randomized to either a dextran-based prime or a crystalloid prime containing Ringer's acetate and mannitol. The primary end point was colloid oncotic pressure in serum during CPB. Secondary end points included fluid balance, bleeding and transfusion requirements, pulmonary function, hemolysis, systemic inflammation, and markers of renal, hepatic, myocardial, and brain injury. Blood samples were collected before, during, and after CPB.Colloid oncotic pressure was higher in the dextran group than in the crystalloid prime group during CPB (18.8 ± 2.9 versus 16.4 ± 2.9 mm Hg; P.001) and 10 minutes after CPB (19.2 ± 2.7 versus 16.8 ± 2.9 mm Hg; P.001). Patients in the dextran group required less intravenous fluid during CPB (1090 ± 499 versus 1437 ± 543 mL; P = .004) and net fluid balance was less positive 12 hours after surgery (1431 ± 741 versus 1901 ± 922 mL; P = .014). Plasma-free hemoglobin was significantly lower in the dextran group 2 hours after CPB (0.18 ± 0.11 versus 0.41 ± 0.33; P = .001). There were no significant differences in bleeding, transfusion requirements, organ function, systemic inflammation, or brain and myocardial injury markers between groups at any time point.Our results suggest that a hyperoncotic dextran-based priming solution preserves intraoperative colloid oncotic pressure compared with crystalloid prime. Larger studies with clinically valid end points are necessary to evaluate hyperoncotic prime solutions further.

Brain changes occurring in aging can be indexed by biomarkers. We used cluster analysis to identify subgroups of cognitively unimpaired individuals (n = 99, 64–93 years) with different profiles of the cerebrospinal fluid biomarkers beta amyloid 1–42 (Aβ42), phosphorylated tau (P-tau), total tau, chitinase-3-like protein 1 (YKL-40), fatty acid binding protein 3 (FABP3), and neurofilament light (NFL). Hippocampal volume and memory were assessed across multiple follow-up examinations covering up to 6.8 years. Clustering revealed one group (39%) with more pathological concentrations of all biomarkers, which could further be divided into one group (20%) characterized by tauopathy and high FABP3 and one (19%) by brain β-amyloidosis, high NFL, and slightly higher YKL-40. The clustering approach clearly outperformed classification based on Aβ42 and P-tau alone in prediction of memory decline, with the individuals with most tauopathy and FABP3 showing more memory decline, but not more hippocampal volume change. The results demonstrate that older adults can be classified based on biomarkers beyond amyloid and tau, with improved prediction of memory decline.

CSF and PET biomarkers of amyloid β and tau accurately detect Alzheimer's disease pathology, but the invasiveness, high cost, and poor availability of these detection methods restrict their widespread use as clinical diagnostic tools. CSF tau phosphorylated at threonine 181 (p-tau181) is a highly specific biomarker for Alzheimer's disease pathology. We aimed to assess whether blood p-tau181 could be used as a biomarker for Alzheimer's disease and for prediction of cognitive decline and hippocampal atrophy.We developed and validated an ultrasensitive blood immunoassay for p-tau181. Assay performance was evaluated in four clinic-based prospective cohorts. The discovery cohort comprised patients with Alzheimer's disease and age-matched controls. Two validation cohorts (TRIAD and BioFINDER-2) included cognitively unimpaired older adults (mean age 63-69 years), participants with mild cognitive impairment (MCI), Alzheimer's disease, and frontotemporal dementia. In addition, TRIAD included healthy young adults (mean age 23 years) and BioFINDER-2 included patients with other neurodegenerative disorders. The primary care cohort, which recruited participants in Montreal, Canada, comprised control participants from the community without a diagnosis of a neurological condition and patients referred from primary care physicians of the Canadian National Health Service for specialist care. Concentrations of plasma p-tau181 were compared with established CSF and PET biomarkers and longitudinal measurements using Spearman correlation, area under the curve (AUC), and linear regression analyses.We studied 37 individuals in the discovery cohort, 226 in the first validation cohort (TRIAD), 763 in the second validation cohort (BioFINDER-2), and 105 in the primary care cohort (n=1131 individuals). In all cohorts, plasma p-tau181 showed gradual increases along the Alzheimer's disease continuum, from the lowest concentrations in amyloid β-negative young adults and cognitively unimpaired older adults, through higher concentrations in the amyloid β-positive cognitively unimpaired older adults and MCI groups, to the highest concentrations in the amyloid β-positive MCI and Alzheimer's disease groups (p0·001, Alzheimer's disease vs all other groups). Plasma p-tau181 distinguished Alzheimer's disease dementia from amyloid β-negative young adults (AUC=99·40%) and cognitively unimpaired older adults (AUC=90·21-98·24% across cohorts), as well as other neurodegenerative disorders, including frontotemporal dementia (AUC=82·76-100% across cohorts), vascular dementia (AUC=92·13%), progressive supranuclear palsy or corticobasal syndrome (AUC=88·47%), and Parkinson's disease or multiple systems atrophy (AUC=81·90%). Plasma p-tau181 was associated with PET-measured cerebral tau (AUC=83·08-93·11% across cohorts) and amyloid β (AUC=76·14-88·09% across cohorts) pathologies, and 1-year cognitive decline (p=0·0015) and hippocampal atrophy (p=0·015). In the primary care cohort, plasma p-tau181 discriminated Alzheimer's disease from young adults (AUC=100%) and cognitively unimpaired older adults (AUC=84·44%), but not from MCI (AUC=55·00%).Blood p-tau181 can predict tau and amyloid β pathologies, differentiate Alzheimer's disease from other neurodegenerative disorders, and identify Alzheimer's disease across the clinical continuum. Blood p-tau181 could be used as a simple, accessible, and scalable test for screening and diagnosis of Alzheimer's disease.Alzheimer Drug Discovery Foundation, European Research Council, Swedish Research Council, Swedish Alzheimer Foundation, Swedish Dementia Foundation, Alzheimer Society Research Program.

Using a single integrated analysis, we examined the relationship between brain networks and molecular pathways in a cohort of elderly individuals at risk for Alzheimer's disease. In 205 subjective memory complainers (124 females, mean age: 75.7 ± 3.4), individual functional connectome was computed for a total of 3081 functional connections (set A) and 6 core plasma biomarkers of Alzheimer's disease (set B) were assessed. Partial least squares correlation analysis identified one dimension of population covariation between the 2 sets (p < 0.006), which we named bioneural mode. Five core plasma biomarkers and 190 functional connections presented bootstrap ratios greater than the critical value |1.96|. T-tau protein showed a trend toward significance (bootstrap resampling = 1.64). The salience, the language, the visuospatial, and the default mode networks were the strongest significant networks. We detected a strong association between network dynamics and core pathophysiological blood biomarkers. Innovative composite biomarkers, such as the bioneural mode, are promising to provide outcomes and better inform drug development and clinical practice for neurodegenerative diseases.

Cerebrospinal fluid (CSF) tau and phospho-tau are well established biomarkers of Alzheimer’s disease. While these measures are conventionally referred to as ‘total tau’ (T-tau) and ‘phospho-tau’ (P-tau), several truncated and modified tau forms exist that may relay additional diagnostic information. We evaluated the diagnostic performance of an endogenous tau peptide in CSF, tau 175–190, in the phosphorylated and non-phosphorylated state. A liquid chromatography-mass spectrometry (LC-MS) method was established to measure these peptides in CSF and was used to analyze two independent clinical cohorts; the first cohort included patients with Alzheimer’s disease (AD, n = 15), Parkinson’s disease (PD, n = 15), progressive supranuclear palsy (PSP, n = 15), and healthy controls (n = 15), the second cohort included AD patients (n = 16), and healthy controls (n = 24). In both cohorts T-tau and P-tau concentrations were determined by immunoassay. While tau 175–190 and P-tau 175–190 did not differentiate the study groups, the separation of AD and controls by T-tau (area under the ROC Curve (AUC) = 95%) and P-tau (AUC = 92%) was improved when normalizing the ELISA measurements to the concentrations of the endogenous peptides: T-tau/tau 175–190 (AUC = 100%), P-tau/P-tau 175–190 (AUC = 95%). The separation between patients and controls by T-tau (AUC = 88%) and P-tau (AUC = 82%) was similarly improved in the second cohort by taking the ratios of T-tau/tau 175–190 (AUC = 97%) and P-tau/P-tau 175–190 (AUC = 98%). In conclusion, our results suggest that the performance of the AD biomarkers T-tau and P-tau could be improved by normalizing their measurements to the endogenous peptides tau 175–190 and P-tau 175–190, possibly because these endogenous tau peptides serve to normalize for physiological, and disease-independent, secretion of tau from neurons to the extracellular space and the CSF. Finally, the observations made here add to the general applicability of mass spectrometry as a tool for rapid identification and accurate quantification of biomarker candidates.

Background Several lines of evidence are pointing towards an involvement of the vascular endothelial growth factor (VEGF) in the pathophysiology of depression. There are studies analyzing blood levels of VEGF in patients with depression compared to controls, but a data on cerebrospinal fluid (CSF) levels of VEGF in patients with depression are lacking. Method CSF VEGF levels were measured in patients (n = 12) with a severe, treatment-resistant depressive episode before and after the antidepressant treatment by a course of electroconvulsive therapy (ECT) and compared to age- and sex-matched controls (n = 20). Results The patients with depression showed lower mean VEGF levels in the CSF prior to ECT than the controls (p = 0.041). Regarding the patients, CSF VEGF concentration at baseline and after the complete ECT treatment did not differ from each other (p = 0.78). Limitations Major limitations of this study are the small sample size and that data from corresponding serum levels cannot be provided. Another limitation is that the controls were not completely healthy, as they were recruited from a memory clinic with subjective complaints. The timing of the second sample might have been suboptimal, when taking into account that there might be an on-going phase of re-equilibrating after ECT. Conclusions CSF VEGF concentrations were lower in a clinical sample of patients with treatment-resistant depression compared with matched controls. Additionally, no change in CSF VEGF levels during a course of ECT could be detected.

While the molecular mechanisms underlying Alzheimer's disease (AD) remain largely unknown, abnormal accumulation and deposition of beta amyloid (Aβ) peptides into plaques has been proposed as a critical pathological process driving disease progression. Over the last years, neuronal lipid species have been implicated in biological mechanisms underlying amyloid plaque pathology. While these processes comprise genetic features along with lipid signaling as well as direct chemical interaction of lipid species with Aβ mono- and oligomers, more efforts are needed to spatially delineate the exact lipid-Aβ plaque interactions in the brain. Chemical imaging using mass spectrometry (MS) allows to probe the spatial distribution of lipids and peptides in complex biological tissues comprehensively and at high molecular specificity. As different imaging mass spectrometry (IMS) modalities provide comprehensive molecular and spatial information, we here describe a multimodal ToF-SIMS- and MALDI-based IMS strategy for probing lipid and Aβ peptide changes in a transgenic mouse model of AD (tgAPPArcSwe). Both techniques identified a general AD-associated depletion of cortical sulfatides, while multimodal MALDI IMS revealed plaque specific lipid as well as Aβ peptide isoforms. In addition, MALDI IMS analysis revealed chemical features associated with morphological heterogeneity of individual Aβ deposits. Here, an altered GM1 to GM2/GM3 ganglioside metabolism was observed in the diffuse periphery of plaques but not in the core region. This was accompanied by an enrichment of Aβ1-40arc peptide at the core of these deposits. Finally, a localization of arachidonic acid (AA) conjugated phosphatidylinositols (PI) and their corresponding degradation product, lyso-phosphatidylinositols (LPI) to the periphery of Aβ plaques was observed, indicating site specific macrophage activation and ganglioside processing.

Background: There is no tool to accurately predict who is at risk of developing neurologic complications of preeclampsia, and there is no objective method to determine disease severity. Objective: We assessed whether plasma concentrations of the cerebral biomarkers neurofilament light, tau, and glial fibrillary acidic protein could reflect disease severity in several phenotypes of preeclampsia. Furthermore, we compared the cerebral biomarkers with the angiogenic biomarkers soluble fms-like tyrosine kinase 1, placental growth factor, and soluble endoglin. Study Design: In this observational study, we included women from the South African Preeclampsia Obstetric Adverse Events biobank. Plasma samples taken at diagnosis (preeclampsia cases) or admission for delivery (normotensive controls) were analyzed for concentrations of neurofilament light, tau, glial fibrillary acidic protein, placental growth factor, soluble fms-like tyrosine kinase 1, and soluble endoglin. The cerebrospinal fluid concentrations of inflammatory markers and albumin were analyzed in a subgroup of 15 women. Analyses were adjusted for gestational age, time from seizures and delivery to sampling, maternal age, and parity. Results: Compared with 28 women with normotensive pregnancies, 146 women with preeclampsia demonstrated 2.18-fold higher plasma concentrations of neurofilament light (95% confidence interval, 1.64-2.88), 2.17-fold higher tau (95% confidence interval, 1.49-3.16), and 2.77-fold higher glial fibrillary acidic protein (95% confidence interval, 2.06-3.72). Overall, 72 women with neurologic complications (eclampsia, cortical blindness, and stroke) demonstrated increased plasma concentrations of tau (2.99-fold higher; 95% confidence interval, 1.92-4.65) and glial fibrillary acidic protein (3.22-fold higher; 95% confidence interval, 2.06-5.02) compared with women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications (n=31). Moreover, angiogenic markers were higher, but to a lesser extent. Women with hemolysis, elevated liver enzymes, and low platelet count (n=20) demonstrated increased plasma concentrations of neurofilament light (1.64-fold higher; 95% confidence interval, 1.06-2.55), tau (4.44-fold higher; 95% confidence interval, 1.85-10.66), and glial fibrillary acidic protein (1.82-fold higher; 95% confidence interval, 1.32-2.50) compared with women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications. There was no difference shown in the angiogenic biomarkers. There was no difference between 23 women with preeclampsia complicated by pulmonary edema and women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications for any of the biomarkers. Plasma concentrations of tau and glial fibrillary acidic protein were increased in women with several neurologic complications compared with women with eclampsia only. Conclusion: Plasma neurofilament light, glial fibrillary acidic, and tau were candidate biomarkers for the diagnosis and possibly prediction of cerebral complications of preeclampsia.

Fatigue is the major cause of disability in MS. Fatigue has been suggested to be primary, part of the neurological disease; it can also be secondary to other diseases outside the CNS or exist as a separate comorbidity. The only forms of measurement currently available are through subjective standardized questionnaires, which are not able to identify primary MS-related fatigue. Therefore, there is a need for objective biomarkers of fatigue in MS. This study explored the viability of 17 possible biomarkers of primary fatigue in MS. Our chosen biomarker panel represents the function and health of different parts of the CNS.We evaluated 31 MS patients and 17 healthy controls using the Fatigue Severity Scale (FSS) and Insomnia Severity Index (ISI). We assessed clinical parameters and collected CSF from all participants to analyze 17 biomarkers, some of which in multiple targeted sequences, reflecting structural and functional changes in the brain. Based on FSS scores, MS was divided into MS-Fatigue (MS-F, FSS ≥ 4) and MS-NoFatigue (MS-NoF, FSS4).MS-F had significantly lower levels of amyloid precursor protein (APP) peptides than MS-NoF (p = 0.005, p = 0.011). The only biomarker correlating with FSS in any group was APP in MS (r = -0.47, -0.52; p = 0.007, 0.002). APP did not correlate with any clinical parameter in MS but correlated with multiple markers. In MS, FSS correlated with the ISI and months since diagnosis.Although the mechanisms remain unknown, altered APP metabolism in MS seems to be associated with fatigue. APP should be evaluated as a biomarker of the role of structural MS pathology in the development of fatigue in individual MS patients.

Background Several biochemical markers in blood correlate with the magnitude of brain injury and may be used to predict neurological outcome after cardiac arrest. We present a protocol for the evaluation of prognostic accuracy of brain injury markers after cardiac arrest. The aim is to define the best predictive marker and to establish clinically useful cut-off levels for routine implementation. Methods Prospective international multicenter trial within the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial in collaboration with Roche Diagnostics International AG. Samples were collected 0, 24, 48, and 72 hours after randomisation (serum) and 0 and 48 hours after randomisation (plasma), and pre-analytically processed at each site before storage in a central biobank. Routine markers neuron-specific enolase (NSE) and S100B, and neurofilament light, total-tau and glial fibrillary acidic protein will be batch analysed using novel Elecsys® electrochemiluminescence immunoassays on a Cobas e601 instrument. Results Statistical analysis will be reported according to the Standards for Reporting Diagnostic accuracy studies (STARD) and will include comparisons for prediction of good versus poor functional outcome at six months post-arrest, by modified Rankin Scale (0–3 vs. 4–6), using logistic regression models and receiver operating characteristics curves, evaluation of mortality at six months according to biomarker levels and establishment of cut-off values for prediction of poor neurological outcome at 95–100% specificities. Conclusions This prospective trial may establish a standard methodology and clinically appropriate cut-off levels for the optimal biomarker of brain injury which predicts poor neurological outcome after cardiac arrest.

Contexte Neuregulin1 (Nrg1) est un substrat presynaptique de la beta-secretase 1 (BACE1) qui peut notamment activer les recepteurs ErbB4 post-synaptiques. Le gene Nrg1 a ete associe a la schizophrenie. L’activation de la voie Nrg1/ErbB4 peut induire la synaptogenese et la plasticite, ameliorer l’expression des recepteurs NMDA et GABA et est neuroprotectrice. Cette voie de signalisation peut induire une neuroinflammation et egalement alterer la formation de la memoire. Dans la maladie d’Alzheimer (MA), Nrg1 est associees avec les plaques neuritiques. Alors que plusieurs etudes ont montre une augmentation de BACE1 dans le cerveau et le liquide cerebrospinal (LCS) des patients atteints de MA, aucune etude n’a evalue les niveaux de Nrg1 dans le LCS des patients atteints de MA ou des patients pre-Alzheimer (mild cognitive impairement [MCI]-MA) lie a la MA. Methode Cent soixante-douze patients souffrant de MA (56), MCI-MA (21), MCI non-MA (32) demences non-MA (36) et des controles neurologiques (27) ont ete inclus retrospectivement dans cette etude. Des examens neurologiques, une IRM et des evaluations neuropsychologiques ont ete effectuees. Les LCS de tous les patients ont ete evalues par dosages ELISA pour Aβ1-42, Aβ1-40, tau, tau phosphoryle (ptau), BACE1 et Nrg1. Resultats Les concentrations de Nrg1 dans le LCS etaient significativement augmentees chez les patients MA et MCI-MA par rapport aux MCI non-MA, aux autres demences non-MA et aux controles neurologiques. De plus, les niveaux de Nrg1 etaient correles positivement avec les niveaux de tau, ptau, Aβ 1-40, BACE1 et negativement avec les scores MMSE. Conclusions La neurotoxicite induite par Aβ entraine une perte synaptique avec une augmentation des taux de BACE1 et Nrg1 dans le LCS. Nrg1 est un nouveau biomarqueur qui pourrait refleter l’activite BACE1 et intervenir dans le declin cognitif chez les patients atteints de MA.