Biomarkers Of Neuronal Injury Research Articles

Blood Pressure Variability and Plasma Biomarkers of Neuronal Injury and Alzheimer's Disease: A Clinic-Based Study of Patients with Diseases Along the Heart-Brain Axis.

Higher blood pressure variability (BPV) predisposes to cognitive decline. To investigate underlying mechanisms, we measured 24-h ambulatory BPV, nocturnal dipping and orthostatic hypotension in 518 participants with vascular cognitive impairment, carotid occlusive disease, heart failure, or reference participants. We determined cross-sectional associations between BPV indices and plasma biomarkers of neuronal injury (neurofilament light chain) and Alzheimer's disease (phosphorylated-tau-181 and Aβ42/Aβ40). None of the BPV indices were significantly associated with any of the biomarkers. Hence, in patients with diseases along the heart-brain axis, we found no evidence for an association between BPV and selected markers of neuronal injury or Alzheimer's disease.

Association of Biomarkers of Neuronal Injury and Inflammation With Insomnia Trajectories After Traumatic Brain Injury: A TRACK-TBI Study.

Insomnia affects about one-third of patients with traumatic brain injury and is associated with worsened outcomes after injury. We hypothesized that higher levels of plasma neuroinflammation biomarkers at the time of TBI would be associated with worse 12-month insomnia trajectories. Participants were prospectively enrolled from 18 level-1 trauma centers participating in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study from February 26, 2014, to August 8, 2018. Plasma glial fibrillary acidic protein (GFAP), high-sensitivity C-reactive protein (hsCRP), S100b, neuron-specific enolase (NSE), and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) were collected on days 1 (D1) and 14 (D14) after TBI. The insomnia severity index was collected at 2 weeks, 3, 6, and 12 months postinjury. Participants were classified into insomnia trajectory classes based on a latent class model. We assessed the association of biomarkers with insomnia trajectories, controlling for medical and psychological comorbidities and demographics. Two thousand twenty-two individuals with TBI were studied. Elevations in D1 hsCRP were associated with persistent insomnia (severe, odds ratio [OR] = 1.33 [1.11, 1.59], p = 0.002; mild, OR = 1.10 [1.02, 1.19], p = 0.011). Similarly, D14 hsCRP elevations were associated with persistent insomnia (severe, OR = 1.27 [1.02, 1.59], p = 0.03). Of interest, D1 GFAP was lower in persistent severe insomnia (median [Q1, Q3]: 154 [19, 445] pg/mL) compared with resolving mild (491 [154, 1,423], p < 0.001) and persistent mild (344 [79, 1,287], p < 0.001). D14 GFAP was similarly lower in persistent (11.8 [6.4, 19.4], p = 0.001) and resolving (13.9 [10.3, 20.7], p = 0.011) severe insomnia compared with resolving mild (20.6 [12.4, 39.6]. Accordingly, increases in D1 GFAP were associated with reduced likelihood of having persistent severe (OR = 0.76 [95% CI 0.63-0.92], p = 0.004) and persistent mild (OR = 0.88 [0.81, 0.96], p = 0.003) compared with mild resolving insomnia. No differences were found with other biomarkers. Elevated plasma hsCRP and, surprisingly, lower GFAP were associated with adverse insomnia trajectories after TBI. Results support future prospective studies to examine their utility in guiding insomnia care after TBI. Further work is needed to explore potential mechanistic connections between GFAP levels and the adverse insomnia trajectories.

Nonalcoholic Fatty Liver Disease and Longitudinal Change in Imaging and Plasma Biomarkers of Alzheimer Disease and Vascular Pathology.

Prospective measures of plasma and cerebral MRI biomarkers of Alzheimer disease (AD) and vascular neuropathology provide an opportunity to investigate possible mechanisms linking liver disease and dementia. We aimed to quantify the association of midlife nonalcoholic fatty liver disease (NAFLD) with change in plasma and brain MRI biomarkers of AD and vascular neuropathology. We included participants from the Atherosclerosis Risk in Communities Study with brain MRI measurements of white matter hyperintensity (WMH) volume and temporal-parietal lobe cortical thickness meta region of interest (ROI) at up to 2 different visits, in 2011-13 and 2016-19, and plasma biomarkers of β-amyloid (Aβ)42:40, phosphorylated tau at threonine 181, and neurofilament light (NfL) were measured up to 3 times in 1993-95, 2011-13, and 2016-19. NAFLD was categorized using the fatty liver index in 1990-92. Multivariate linear regression was performed for associations between midlife NAFLD and change in plasma and brain MRI biomarkers of AD and vascular neuropathology. The primary models adjusted for demographics, Apolipoprotein E, alcohol use, and kidney function. Among 1,706 participants (mean age 56 years, 62% female, 28% Black), midlife NAFLD vs no NAFLD was associated with greater late-life WMH volume (difference per SD 0.19, 95% CI 0.06-0.31) and faster late-life WMH increase over 6 years (difference in annual change, SD 0.28, 95% CI 0.05-0.51), suggesting accumulating vascular pathology. Midlife NAFLD vs no NAFLD was also associated with AD biomarkers in midlife (lower Aβ42:40 [SD -0.21, 95% CI -0.39 to -0.04] measured in 1993-95) and late life (lower Aβ42:40 [SD -0.13, 95% CI -0.23 to -0.03] and lower temporal-parietal lobe cortical thickness meta ROI [SD -0.16, 95% CI -0.28 to -0.05] measured in 2011-13). Although midlife NfL was lower in individuals with vs without midlife NAFLD, those with NAFLD exhibited a faster rate of NfL increase that accelerated over time. Midlife NAFLD shows associations with AD and accumulating vascular pathology, revealing potential pathways linking liver function to dementia. Plasma biomarkers of neuropathology and neuronal injury may serve as easily measurable and dynamic indicators for monitoring the impacts of impaired liver function on brain health.

Plasma neurofilament light chain is not elevated in people with first-episode psychosis or those at ultra-high risk for psychosis

IntroductionNeurofilament light chain (NfL), a blood biomarker of neuronal injury, shows promise in distinguishing neurodegenerative disorders from psychiatric conditions. This is especially relevant in psychosis, given neurological conditions such as autoimmune encephalitis and Niemann Pick Type C disease (NPC) may initially present with psychotic symptoms. Whilst NfL levels have been studied in established schizophrenia cases, their levels in first-episode psychosis (FEP) and ultra-high risk (UHR) for psychosis individuals remain largely unexplored. This study aimed to compare plasma NfL in people with FEP or UHR with healthy controls, as well as explore its associations with clinical data. MethodWe retrospectively analysed plasma NfL in 63 participants, consisting of 29 individuals with FEP, 10 individuals with UHR, and 24 healthy controls. We used general linear models (GLM), which were bootstrapped, to compute bias-corrected and accelerated (BCa) 95 % confidence intervals (CIs). ResultsMean NfL levels were 5.2 pg/mL in FEP, 4.9 pg/mL in UHR, and 5.9 pg/mL in healthy controls. Compared to healthy controls, there were no significant differences in NfL levels in the FEP group (β = −0.22, 95 % CI [−0.86, 0.39], p = 0.516) nor UHR group (β = −0.37, 95 % CI [−0.90, 0.19], p = 0.182). There were no significant associations between NfL levels and clinical variables in the FEP group. DiscussionOur study is the first to demonstrate that plasma NfL levels are not significantly elevated in individuals at UHR for psychosis compared to healthy controls, a finding also observed in the FEP cohort. These findings bolster the potential diagnostic utility of NfL in differentiating between psychiatric and neurodegenerative disorders.

Clinical variables contributing to the identification of biologically defined subgroups within cognitively unimpaired and mild cognitive impairment individuals.

A lack of consensus exists in linking demographic, behavioral, and cognitive characteristics to biological stages of dementia, defined by the ATN (amyloid, tau, neurodegeneration) classification incorporating amyloid, tau, and neuronal injury biomarkers. Using a random forest classifier we investigated whether 27 demographic, behavioral, and cognitive characteristics allowed distinction between ATN-defined groups with the same cognitive profile. This was done separately for three cognitively unimpaired (CU) (112 A-T-N-; 46 A+T+N+/-; 65 A-T+/-N+/-) and three mild cognitive impairment (MCI) (128 A-T-N-; 223 A+T+N+/-; 94 A-T+/-N+/-) subgroups. Classification-balanced accuracy reached 39% for the CU and 52% for the MCI subgroups. Logical Delayed Recall (explaining 16% of the variance), followed by the Alzheimer's Disease Assessment Scale 13 (14%) and Everyday Cognition Informant (10%), were the most relevant characteristics for classification of the MCI subgroups. Race and ethnicity, marital status, and Everyday Cognition Patient were not relevant (0%). The demographic, behavioral, and cognitive measures used in our model were not informative in differentiating ATN-defined CU profiles. Measures of delayed memory, general cognition, and activities of daily living were the most informative in differentiating ATN-defined MCI profiles; however, these measures alone were not sufficient to reach high classification performance.

Neurofilament light-chain (NfL) and 18 kDa translocator protein in early psychosis and its putative high-risk

Evidence of elevated peripheral Neurofilament light-chain (NfL) as a biomarker of neuronal injury can be utilized to reveal nonspecific axonal damage, which could reflect altered neuroimmune function. To date, only a few studies have investigated NfL as a fluid biomarker in schizophrenia primarily, though none in its putative prodrome (Clinical High-Risk, CHR) or in untreated first-episode psychosis (FEP). Further, it is unknown whether peripheral NfL is associated with 18 kDa translocator protein (TSPO), a validated neuroimmune marker. In this secondary study, we investigated for the first time (1) serum NfL in early stages of psychosis including CHR and FEP as compared to healthy controls, and (2) examined its association with brain TSPO, using [18F]FEPPA positron emission tomography (PET). Further, in the exploratory analyses, we aimed to assess associations between serum NfL and symptom severity in patient group and cognitive impairment in the combined cohort. A large cohort of 84 participants including 27 FEP (24 antipsychotic-naive), 41 CHR (34 antipsychotic-naive) and 16 healthy controls underwent structural brain MRI and [18F]FEPPA PET scan and their blood samples were obtained and assessed for serum NfL concentrations. We found no significant differences in serum NfL levels across clinical groups, controlling for age. We also found no significant association between NfL levels and brain TSPO in the entire cohort. We observed a negative association between serum NfL and negative symptom severity in CHR. Our findings suggest that neither active neuroaxonal deterioration as measured with NfL nor associated neuroimmune activation (TSPO) is clearly identifiable in an early mostly untreated psychosis sample including its putative high-risk.

DNL310 normalizes primary storage substrates, corrects biomarkers of lysosomal dysfunction and reduces biomarkers of neuronal injury (neurofilament light chain) in MPS II: 2-year interim analysis of a phase 1/2 study

DNL310 normalizes primary storage substrates, corrects biomarkers of lysosomal dysfunction and reduces biomarkers of neuronal injury (neurofilament light chain) in MPS II: 2-year interim analysis of a phase 1/2 study

Fluid biomarkers of the neurovascular unit in cerebrovascular disease and vascular cognitive disorders: A systematic review and meta-analysis

BackgroundThe disruption of the neurovascular unit (NVU), which maintains the integrity of the blood brain barrier (BBB), has been identified as a critical mechanism in the development of cerebrovascular and neurodegenerative disorders. However, the understanding of the pathophysiological mechanisms linking NVU dysfunction to the disorders is incomplete, and reliable blood biomarkers to measure NVU dysfunction are yet to be established. This systematic review and meta-analysis aimed to identify biomarkers associated with BBB dysfunction in large vessel disease, small vessel disease (SVD) and vascular cognitive disorders (VCD). MethodsA literature search was conducted in PubMed, EMBASE, Scopus and PsychINFO to identify blood biomarkers related to dysfunction of the NVU in disorders with vascular pathologies published until 20 November 2023. Studies that assayed one or more specific markers in human serum or plasma were included. Quality of studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. Effects were pooled and methodological heterogeneity examined using the random effects model. ResultsA total of 112 studies were included in this review. Where study numbers allowed, biomarkers were analysed using random effect meta-analysis for VCD (1 biomarker; 5 studies) and cerebrovascular disorders, including stroke and SVD (9 biomarkers; 29 studies) while all remaining biomarkers (n = 17 biomarkers; 78 studies) were examined through qualitative analysis. Results of the meta-analysis revealed that cerebrospinal fluid/serum albumin quotient (Q-Alb) reliably differentiates VCD patients from healthy controls (MD = 2.77; 95 % CI = 1.97–3.57; p < 0.0001) while commonly measured biomarkers of endothelial dysfunction (VEGF, VCAM-1, ICAM-1, vWF and E-selectin) and neuronal injury (NfL) were significantly elevated in vascular pathologies. A qualitative assessment of non-meta-analysed biomarkers revealed NSE, NfL, vWF, ICAM-1, VCAM-1, lipocalin-2, MMP-2 and MMP-9 levels to be upregulated in VCD, although these findings were not consistently replicated. ConclusionsThis review identifies several promising biomarkers of NVU dysfunction which require further validation. A panel of biomarkers representing multiple pathophysiological pathways may offer greater discriminative power in distinguishing possible disease mechanisms of VCD.

Elevated Plasma Protein Carbonyl Concentration Is Associated with More Abnormal White Matter in People with HIV.

Structural brain abnormalities, including those in white matter (WM), remain common in people with HIV (PWH). Their pathogenesis is uncertain and may reflect multiple etiologies. Oxidative stress is associated with inflammation, HIV, and its comorbidities. The post-translational carbonylation of proteins results from oxidative stress, and circulating protein carbonyls may reflect this. In this cross-sectional analysis, we evaluated the associations between protein carbonyls and a panel of soluble biomarkers of neuronal injury and inflammation in plasma (N = 45) and cerebrospinal fluid (CSF, n = 32) with structural brain MRI. The volume of abnormal WM was normalized for the total WM volume (nAWM). In this multisite project, all regression models were adjusted for the scanner. The candidate covariates included demographics, HIV disease characteristics, and comorbidities. Participants were PWH on virally suppressive antiretroviral therapy (ART) and were mostly white (64.4%) men (88.9%), with a mean age of 56.8 years. In unadjusted analyses, more nAWM was associated with higher plasma protein carbonyls (p = 0.002) and higher CCL2 (p = 0.045). In the adjusted regression models for nAWM, the association with plasma protein carbonyls remained significant (FDR p = 0.018). Protein carbonyls in plasma may be a valuable biomarker of oxidative stress and its associated adverse health effects, including within the central nervous system. If confirmed, these findings would support the hypothesis that reducing oxidative stress could treat or prevent WM injury in PWH.

Self‐reported COVID‐19 and biomarkers of Alzheimer’s disease: interim analyses from an Alzheimer’s disease risk‐enriched cohort

AbstractBackgroundCOVID‐19‐related SARS‐CoV‐2 infection has been linked with brain abnormalities and cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD), neuroinflammation, and neuronal injury. Whether COVID‐19 increases the brain’s vulnerability to the development of AD is unclear. In participants at an increased risk of AD, we investigated the association of COVID‐19 with pre‐ and post‐pandemic AD biomarkers.MethodWe included 132 cognitively unimpaired adults from the ALFA+ cohort (52‐71 years, 61.4% women) who provided retrospective self‐reported data on SARS‐CoV‐2 infection (with COVID‐19 vs. without COVID‐19). As of February 2022, 125 (94.7%) participants had available CSF biomarkers (measured with exploratory Roche NeuroToolKit or Elecsys® immunoassays, Roche Diagnostics International Ltd, Rotkreuz, Switzerland) and 76 (57.6%) had [18F]flutemetamol‐PET data acquired before (pre‐pandemic) and after (post‐pandemic) the beginning of the COVID‐19 pandemic (average time lapse between the assessments: 3.5±0.6 years). [18F]flutemetamol PET SUVR maps were obtained using the whole cerebellum as the reference region. First, we performed ANCOVA models to investigate whether COVID‐19 was associated with post‐pandemic CSF biomarkers of core AD pathology (Aβ42/40 and p‐tau), neuronal injury (NfL), and neuroinflammation (sTREM2, GFAP, and IL‐6), while controlling for pre‐pandemic biomarker levels. Covariates were age, sex, years of education, APOE‐ε4 status, and time lapse between the biomarker assessments. Second, we performed a voxel‐wise analysis in SPM‐12 using a matched‐group comparison design (with COVID‐19 vs. without COVID‐19 matched by pre‐pandemic Centiloid values, age, and APOE‐ε4 status) with the post‐pandemic amyloid‐PET scans as the outcome of interest.ResultFifteen (12%) participants included in ANCOVA reported COVID‐19. Eleven (14.5%) with amyloid‐PET scans reported COVID‐19 and were matched with 11 participants without COVID‐19 for voxel‐wise analysis. In ANCOVA models, no significant association between COVID‐19 and post‐pandemic CSF biomarkers was found (Table 1). Results from the t‐test voxel‐wise analysis also did not show any differences between participants with vs. without COVID‐19 on [18F]flutemetamol‐PET uptake after correction with false discovery rate.ConclusionOur interim analyses did not show any association between self‐reported COVID‐19 and post‐pandemic biomarkers of AD pathology, neuronal injury, and neuroinflammation. The results are pending confirmation of COVID‐19 status using serology data (n = 181) and complete sample size.

Cerebrospinal fluid biomarkers at presentation associate with etiologic diagnosis and treatment responsiveness in patients with rapidly progressive dementia

AbstractBackgroundThe causes of rapidly progressive dementia are heterogeneous, including neurodegenerative, vascular, and autoimmune/inflammatory diseases. Overlap in presenting symptoms and signs, results of cognitive testing, and findings on brain imaging and other common diagnostic tests confounds the etiologic diagnosis, contributing to diagnostic delays, missed opportunities for treatment, and poorer outcomes in patients with RPD. New tools and approaches are needed to improve diagnostic accuracy, with particular emphasis on improving early recognition of patients with potentially treatable causes of RPD.MethodsEstablished and emerging biomarkers of Alzheimer disease neuropathology (Aβ42/40, p‐tau181, p‐tau231), neuroaxonal and neuronal injury (neurofilament light [NfL], VILIP‐1, total tau), neuroinflammation (YKL‐40, sTREM2, GFAP, MCP‐1), and synaptic dysfunction (SNAP‐25, neurogranin) were measured in cerebrospinal fluid obtained at presentation from 78 prospectively accrued patients with RPD due to neurodegenerative (n = 35), vascular (n = 9), and autoimmune/inflammatory (n = 34) diseases, and 72 age‐ and sex‐similar cognitively normal individuals (controls). Causes of RPD were further classified as potentially treatment‐responsive or nonresponsive, referencing the extant literature. Biomarker levels were compared across etiologic diagnoses and by treatment responsiveness, referencing control values. Analyses were adjusted for the effects of age (ANCOVA).ResultsAlzheimer disease biomarkers (low Aβ42/40 and elevated p‐tau181 and p‐tau231) were associated with neurodegenerative causes of RPD (ANCOVA, p = 0.02 p = 0.30, p = 0.15), while high NfL (p = 0.61), low VILIP‐1 (p = 0.009), and elevated markers of inflammation (sTREM2, p = 0.009; YKL‐40, p&lt;0.001) identified patients with autoimmune/inflammatory diseases (Figure). MCP‐1 levels were highest in patients with vascular causes of RPD (p = 0.08). 44 patients (56.4%) had potentially treatment‐responsive causes of RPD. Treatment responsiveness was associated with higher levels of CSF Aβ42/40 (p = 0.003), NfL (p&lt;0.001), sTREM2 (p&lt;0.001) and YKL‐40 (p&lt;0.001); and lower levels of p‐tau‐181 and p‐tau231 (p&lt;0.001, p&lt;0.001) and VILIP‐1 (p&lt;0.001).ConclusionSelected biomarkers measured in CSF at presentation associate with etiologic diagnosis and treatment responsiveness in patients with neurodegenerative, vascular, and autoimmune/inflammatory causes of RPD. Biomarker panels may be adapted to improve recognition of patients with treatment‐responsive causes of RPD early in the symptomatic course when treatments may be most effective.

Association of plasma Alzheimer’s and neurodegenerative disease biomarkers with brain volume loss and cognitive decline

AbstractBackgroundAlthough plasma Alzheimer’s disease (AD) and neurodegenerative disease biomarkers have been associated with reduced cognition and lower brain volume, few studies have examined whether plasma biomarkers measured in predominately cognitively unimpaired adults are associated with longitudinal brain volume loss and cognitive decline. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether plasma biomarkers of AD pathology (Aß42/40, phosphorylated tau [pTau‐181]), reactive astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal brain volume loss and cognitive decline.MethodPlasma biomarkers (Aß42/40, pTau‐181, GFAP, NfL) were measured using Quanterix SIMOA assays. Baseline visits were considered the earliest visits that had concurrent 3T MRI scans and plasma biomarker measurements, and the earliest visits that had concurrent cognitive assessments and plasma biomarker measurements. Composite Z scores were computed to reflect 5 cognitive domains (Figure 1). Linear mixed effects models adjusted for baseline age, sex, race, education, estimated glomerular filtration rate, and total intracranial volume (brain volume analyses), were used to examine the association of plasma biomarkers with baseline and longitudinal brain volume and cognition. False Discovery Rate correction was used to adjust for multiple comparisons.ResultBrain volume analyses included 628 participants (mean age±SD: 71.0±10.2; Table 1) with an average of 3.3 MRI scans over 4.7 years. Cognition analyses included 686 participants (mean age±SD: 71.4±10.1) with an average of 3.9 cognitive assessments over 5.7 years. Although Aß42/40 was unrelated to brain volume changes, higher pTau‐181 was associated with longitudinal declines in total gray matter volume and regional declines in medial temporal regions. Higher GFAP was associated with longitudinal increases in ventricular volume, whereas NfL was not associated with brain volume change (Table 2). Both lower Aß42/40 and higher pTau‐181 were associated with a decline in verbal memory. Additionally, lower Aß42/40 was associated with a decline in visuospatial performance. Further, higher GFAP was associated with a decline in verbal fluency (Figure 1).ConclusionPlasma biomarkers of AD pathology and astrogliosis may serve as markers of future brain atrophy and cognitive decline.

Serum biomarkers and disease progression in CT-negative mild traumatic brain injury.

Blood proteins are emerging as potential biomarkers for mild traumatic brain injury (mTBI). Molecular pathology of mTBI underscores the critical roles of neuronal injury, neuroinflammation, and vascular health in disease progression. However, the temporal profile of blood biomarkers associated with the aforementioned molecular pathology after CT-negative mTBI, their diagnostic and prognostic potential, and their utility in monitoring white matter integrity and progressive brain atrophy remain unclear. Thus, we investigated serum biomarkers and neuroimaging in a longitudinal cohort, including 103 CT-negative mTBI patients and 66 matched healthy controls (HCs). Angiogenic biomarker vascular endothelial growth factor (VEGF) exhibited the highest area under the curve of 0.88 in identifying patients from HCs. Inflammatory biomarker interleukin-1β and neuronal cell body injury biomarker ubiquitin carboxyl-terminal hydrolase L1 were elevated in acute-stage patients and associated with deterioration of cognitive function from acute-stage to 6-12mo post-injury period. Notably, axonal injury biomarker neurofilament light (NfL) was elevated in acute-stage patients, with higher levels associated with impaired white matter integrity in acute-stage and progressive gray and white matter atrophy from 3- to 6-12mo post-injury period. Collectively, our findings emphasized the potential clinical value of serum biomarkers, particularly NfL and VEGF, in diagnosing mTBI and monitoring disease progression.

Serum spectrin breakdown product and neurofilament heavy in predicting outcome after cardiac arrest: A diagnostic accuracy study

ObjectivesSpectrin breakdown products 145 kDa (SBDP145) and neurofilament heavy chain (Nf-H) have been identified as potential biomarkers of neuronal injury. However, their ability to predict hypoxic-ischemic brain injury following cardiac arrest in humans is not well understood. This study aimed to investigate whether SBDP145 and Nf-H could be used as biomarkers to predict neurological outcomes after cardiac arrest. MethodsThis prospective study was conducted at two academic hospitals and included adults who survived after cardiac arrest. Blood samples were collected at 0, 24, and 48 h after the return of spontaneous circulation, and biomarker analyses were performed to measure SBDP145 and Nf-H. Poor neurological outcome was defined as a modified Rankin Score of 4–6, and diagnostic performance was determined by receiver-operating characteristics analysis. ResultsA total of 56 patients were included in this study. There were no significant differences in levels of SBDP145 or Nf-H between the poor and good outcome groups at any time point. Areas under the receiver-operating characteristics curve of SBDP145 and Nf-H were small, ranging from 0.51 to 0.7. At 0, 24, and 48 h, SBDP145 showed very low sensitivity (18.61 %, 13.89 %, and 13.79 %, respectively) and accuracy (33.93 %, 36.74 %, and 39.02 %, respectively) at a cut-off value for 100 % specificity. Nf-H also showed very low sensitivity (9.30 %, 16.67 %, and 0 %, respectively) and accuracy (29.09 %, 36.74 %, and 30.95 %, respectively). ConclusionsSBDP145 and Nf-H were found to be poor predictors of poor neurological outcomes six months after cardiac arrest.

Proteomic Indicators of Health Predict Alzheimer's Disease Biomarker Levels and Dementia Risk.

Few studies have comprehensively examined how health and disease risk influence Alzheimer's disease (AD) biomarkers. The present study examined the association of 14 protein-based health indicators with plasma and neuroimaging biomarkers of AD and neurodegeneration. In 706 cognitively normal adults, we examined whether 14 protein-based health indices (ie, SomaSignal® tests) were associated with concurrently measured plasma-based biomarkers of AD pathology (amyloid-β [Aβ]42/40 , tau phosphorylated at threonine-181 [pTau-181]), neuronal injury (neurofilament light chain [NfL]), and reactive astrogliosis (glial fibrillary acidic protein [GFAP]), brain volume, and cortical Aβ and tau. In a separate cohort (n = 11,285), we examined whether protein-based health indicators associated with neurodegeneration also predict 25-year dementia risk. Greater protein-based risk for cardiovascular disease, heart failure mortality, and kidney disease was associated with lower Aβ42/40 and higher pTau-181, NfL, and GFAP levels, even in individuals without cardiovascular or kidney disease. Proteomic indicators of body fat percentage, lean body mass, and visceral fat were associated with pTau-181, NfL, and GFAP, whereas resting energy rate was negatively associated with NfL and GFAP. Together, these health indicators predicted 12, 31, 50, and 33% of plasma Aβ42/40 , pTau-181, NfL, and GFAP levels, respectively. Only protein-based measures of cardiovascular risk were associated with reduced regional brain volumes; these measures predicted 25-year dementia risk, even among those without clinically defined cardiovascular disease. Subclinical peripheral health may influence AD and neurodegenerative disease processes and relevant biomarker levels, particularly NfL. Cardiovascular health, even in the absence of clinically defined disease, plays a central role in brain aging and dementia. ANN NEUROL 2024;95:260-273.

Novel Fluid Biomarkers for Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.

Mild cognitive impairment (MCI) is a well-established prodromal stage of dementia (e.g., Alzheimer's disease) that is often accompanied by early signs of neurodegeneration. To facilitate a better characterization of the underlying pathophysiology, we assessed the available literature to evaluate potential fluid biomarkers in MCI. Peer-reviewed articles that measured cerebrospinal fluid (CSF) and/or peripheral biomarkers of neuronal injury (total-tau [T-tau], neurofilament light chain [NfL], heart-type fatty acid binding protein [HFABP], neuron-specific enolase, ubiquitin C-terminal hydrolase L1) and/or astroglial pathology (glial fibrillary acidic protein [GFAP], S100 calcium-binding protein B) in MCI and healthy controls were assessed. Group differences were summarized by standardized mean differences (SMDs) and 95% confidence intervals calculated using a random-effects model. Heterogeneity was quantified using I2. A total of 107 studies were included in the meta-analysis and 10 studies were qualitatively reviewed. In CSF, concentrations of NfL (SMD = 0.69 [0.56, 0.83]), GFAP (SMD = 0.41 [0.07, 0.75]), and HFABP (SMD = 0.57 [0.26, 0.89]) were elevated in MCI. In blood, increased concentrations of T-tau (SMD = 0.19 [0.09, 0.29]), NfL (SMD = 0.41 [0.32, 0.49]), and GFAP (SMD = 0.39 [0.23, 0.55]) were found in MCI. Heterogeneity that was identified in all comparisons was explored using meta-regression and subgroup analysis. Elevated NfL and GFAP can be detected in both CSF and peripheral blood. Monitoring these biomarkers in clinical settings may provide important insight into underlying neurodegenerative processes in MCI.

Blood biomarkers of neuronal injury in paediatric cerebral malaria and severe malarial anaemia

Abstract Persistent neurodisability is a known complication in paediatric survivors of cerebral malaria and severe malarial anaemia. Tau, ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein have proven utility as biomarkers that predict adverse neurologic outcomes in adult and paediatric disorders. In paediatric severe malaria, elevated tau is associated with mortality and neurocognitive complications. We aimed to investigate whether a multi-analyte panel including ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein can serve as biomarkers of brain injury associated with mortality and neurodisability in cerebral malaria and severe malarial anaemia. In a prospective cohort study of Ugandan children, 18 months to 12 years of age with cerebral malaria (n = 182), severe malarial anaemia (n = 158), and asymptomatic community children (n = 118), we measured admission blood levels of ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein. We investigated differences in biomarker levels, associations with mortality, blood–brain barrier integrity, neurodeficits and cognitive Z-scores in survivors up to 24-month follow-up. Admission ubiquitin C-terminal hydrolase-L1 levels were elevated &amp;gt;95th percentile of community children in 71 and 51%, and neurofilament-light chain levels were elevated &amp;gt;95th percentile of community children in 40 and 37% of children with cerebral malaria and severe malarial anaemia, respectively. Glial fibrillary acidic protein was not elevated in disease groups compared with controls. In cerebral malaria, elevated neurofilament-light chain was observed in 16 children who died in hospital compared with 166 survivors (P = 0.01); elevations in ubiquitin C-terminal hydrolase-L1 levels were associated with degree of blood–brain barrier disruption (P = 0.01); and the % predictive value for neurodeficits over follow-up (discharge, 6-, 12-, and 24 months) increased for ubiquitin C-terminal hydrolase-L1 (60, 67, 72, and 83), but not neurofilament-light chain (65, 68, 60, and 67). In cerebral malaria, elevated ubiquitin C-terminal hydrolase-L1 was associated with worse memory scores in children &amp;lt;5 years at malaria episode who crossed to over 5 years old during follow-up cognitive testing [β −1.13 (95% confidence interval −2.05, −0.21), P = 0.02], and elevated neurofilament-light chain was associated with worse attention in children ≥5 years at malaria episode and cognitive testing [β −1.08 (95% confidence interval −2.05, −1.05), P = 0.03]. In severe malarial anaemia, elevated ubiquitin C-terminal hydrolase-L1 was associated with worse attention in children &amp;lt;5 years at malaria episode and cognitive testing [β −0.42 (95% confidence interval −0.76, −0.07), P = 0.02]. Ubiquitin C-terminal hydrolase-L1 and neurofilament-light chain levels are elevated in paediatric cerebral malaria and severe malarial anaemia. In cerebral malaria, elevated neurofilament-light chain is associated with mortality whereas elevated ubiquitin C-terminal hydrolase-L1 is associated with blood–brain barrier dysfunction and neurodeficits over follow-up. In cerebral malaria, both markers are associated with worse cognition, while in severe malarial anaemia, only ubiquitin C-terminal hydrolase-L1 is associated with worse cognition.

COVID-19 Recovery: Consistent Absence of Cerebrospinal Fluid Biomarker Abnormalities in Patients With Neurocognitive Post-COVID Complications.

To investigate evidence of residual viral infection, intrathecal immune activation, central nervous system (CNS) injury, and humoral responses in cerebrospinal fluid (CSF) and plasma in patients recovering from coronavirus disease 2019 (COVID-19), with or without neurocognitive post-COVID condition (PCC). Thirty-one participants (25 with neurocognitive PCC) underwent clinical examination, lumbar puncture, and venipuncture ≥3 months after COVID-19 symptom onset. Healthy volunteers were included. CSF and plasma severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid and spike antigen (N-Ag, S-Ag), and CSF biomarkers of immune activation and neuronal injury were analyzed. SARS-CoV-2 N-Ag or S-Ag were undetectable in all samples and no participant had pleocytosis. We detected no significant differences in CSF and plasma cytokine concentrations, albumin ratio, IgG index, neopterin, β2M, or in CSF biomarkers of neuronal injury and astrocytic damage. Furthermore, principal component analysis (PCA1) analysis did not indicate any significant differences between the study groups in the marker sets cytokines, neuronal markers, or anti-cytokine autoantibodies. We found no evidence of ongoing viral replication, immune activation, or CNS injury in plasma or CSF in patients with neurocognitive PCC compared with COVID-19 controls or healthy volunteers, suggesting that neurocognitive PCC is a consequence of events suffered during acute COVID-19 rather than persistent viral CNS infection or residual CNS inflammation.

Preliminary study of neurofilament light chain as a biomarker for hypoxia-induced neuronal injury in dogs.

Neurofilament light chain (NfL) is a neuroaxonal protein in the nervous system. NfL has recently been demonstrated to be a biomarker for various neurological diseases. In this study, we investigated the potential role of NfL in hypoxia-induced neuronal injury in dogs. Serum NfL levels were determined using a single-molecule array. Serum NfL concentrations were significantly higher in hypoxemic dogs without neurological signs (n = 6, 175.5 pg/mL) than in healthy dogs (n = 15, 15.9 pg/mL; p < 0.0001). Therefore, neuronal injury should be considered in dogs with hypoxemia caused by cardiopulmonary diseases, even in the absence of neurological signs.

Neuro-Specific and Immuno-Inflammatory Biomarkers in Umbilical Cord Blood in Neonatal Hypoxic-Ischemic Encephalopathy

Objectives: The aim of the study was to evaluate neuronal injury and immuno-inflammatory biomarkers in umbilical cord blood (UCB) at birth, in cases with perinatal asphyxia with or without hypoxic-ischemic encephalopathy (HIE), compared with healthy controls and to assess their ability to predict HIE. Study Design: In this case-control study, term infants with perinatal asphyxia were recruited at birth. UCB was stored at delivery for batch analysis. HIE was diagnosed by clinical Sarnat staging at 24 h. Glial fibrillary acidic protein (GFAP), the neuronal biomarkers tau and neurofilament light protein (NFL), and a panel of cytokines were analyzed in a total of 150 term neonates: 50 with HIE, 50 with asphyxia without HIE (PA), and 50 controls. GFAP, tau, and NFL concentrations were measured using ultrasensitive single-molecule array (Simoa) assays, and a cytokine screening panel was applied to analyze the immuno-inflammatory and infectious markers. Results: GFAP, tau, NFL, and several cytokines were significantly higher in newborns with moderate and severe HIE compared to a control group and provided moderate prediction of HIE II/III (AUC: 0.681–0.827). Furthermore, the levels of GFAP, tau, interleukin-6 (IL-6), and interleukin-8 (IL-8) were higher in HIE II/III cases compared with cases with PA/HIE I. IL-6 was also higher in HIE II/III compared with HIE I cases. Conclusions: Biomarkers of brain injury and inflammation were increased in umbilical blood in cases with asphyxia. Several biomarkers were higher in HIE II/III versus those with no HIE or HIE I, suggesting that they could assist in the prediction of HIE II/III.