Extracellular fluid, cerebrospinal fluid and plasma biomarkers of axonal and neuronal injury following intracerebral hemorrhage

AbstractSpontaneous intracerebral hemorrhage (ICH) is the most devastating form of stroke. To refine treatments, improved understanding of the secondary injury processes is needed. We compared energy metabolic, amyloid and neuroaxonal injury biomarkers in extracellular fluid (ECF) from the perihemorrhagic zone (PHZ) and non-injured (NCX) brain tissue, cerebrospinal fluid (CSF) and plasma. Patients (n = 11; age 61 ± 10 years) undergoing ICH surgery received two microdialysis (MD) catheters, one in PHZ, and one in NCX. ECF was analysed at three time intervals within the first 60 h post- surgery, as were CSF and plasma samples. Amyloid-beta (Aβ) 40 and 42, microtubule associated protein tau (tau), and neurofilament-light (NF-L) were analysed using Single molecule array (Simoa) technology. Median biomarker concentrations were lowest in plasma, higher in ECF and highest in CSF. Biomarker levels varied over time, with different dynamics in the three fluid compartments. In the PHZ, ECF levels of Aβ40 were lower, and tau higher when compared to the NCX. Altered levels of Aβ peptides, NF-L and tau may reflect brain tissue injury following ICH surgery. However, the dynamics of biomarker levels in the different fluid compartments should be considered in the study of pathophysiology or biomarkers in ICH patients.

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Extracellular Fluid, Cerebrospinal Fluid and Plasma Biomarkers of Axonal and Neuronal Injury Following Intracerebral Hemorrhage

10.21203/rs.3.rs-538018/v1 ◽

2021 ◽

Author(s):

Lovisa Tobieson ◽

Henrik Zetterberg ◽

Kaj Blennow ◽

Niklas Marklund

Keyword(s):

Cerebrospinal Fluid ◽

Intracerebral Hemorrhage ◽

Brain Tissue ◽

Single Molecule ◽

Tissue Injury ◽

Extracellular Fluid ◽

Neurofilament Light ◽

Aβ Peptides ◽

Post Surgery ◽

Fluid Compartments

Abstract Background: Spontaneous intracerebral hemorrhage (ICH) is the most devastating form of stroke. To refine treatments, improved understanding of the secondary injury processes is needed. We compared energy metabolic, amyloid and neuroaxonal injury biomarkers in extracellular fluid (ECF) from the perihemorrhagic zone (PHZ) and non-injured (NCX) brain tissue, cerebrospinal fluid (CSF) and plasma. Method: Patients (n=11, age 61 ± 10 years) undergoing ICH surgery received two microdialysis (MD) catheters, one in PHZ, and one in NCX. ECF was analysed at three time intervals within the first 60 hours post- surgery, as were CSF and plasma samples. Amyloid-beta (Aβ) 40 and 42, microtubule associated protein tau (tau), and neurofilament-light (NF-L) were analysed using Single molecule array (Simoa) technology.Results: Median biomarker concentrations were lowest in plasma, higher in ECF and highest in CSF. Biomarker levels varied over time, with different dynamics in the three fluid compartments. In the PHZ, ECF levels of Aβ40 were lower, and tau higher when compared to the NCX.Conclusion: Altered levels of Aβ peptides, NF-L and tau may reflect brain tissue injury following ICH surgery. However, the different biomarker levels, and their dynamics, in the different fluid compartments should be considered when used to monitor ICH patients.

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Leukocyte dynamics after intracerebral hemorrhage in a living patient reveal rapid adaptations to tissue milieu

10.1101/2020.11.10.375675 ◽

2020 ◽

Author(s):

Brittany A. Goods ◽

Michael H. Askenase ◽

Erica Markarian ◽

Hannah E. Beatty ◽

Riley Drake ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Single Cell ◽

Brain Tissue ◽

Cellular Response ◽

Tissue Injury ◽

Brain Inflammation ◽

Therapeutic Interventions ◽

Acute Injury ◽

The Brain ◽

Over Time

ABSTRACTIntracerebral hemorrhage (ICH) is a devastating form of stroke with a high mortality rate and few treatment options. Discovery of therapeutic interventions has been slow given the challenges associated with studying acute injury, particularly over time, in the human brain. Inflammation induced by exposure of brain tissue to blood appears to be a major part of brain tissue injury. Here we longitudinally profiled blood and cerebral hematoma effluent from a patient enrolled in the Minimally Invasive Surgery with Thrombolysis in Intracerebral Haemorrhage Evacuation (MISTIEIII) trial, offering a rare window into the local and systemic immune responses to acute brain injury. Using single-cell RNA-sequencing, we characterized the local cellular response during ICH in the brain of a living patient at single-cell resolution for the first time. Our analysis revealed rapid shifts in the activation states of myeloid and T cells in the brain over time, suggesting that leukocyte responses are dynamically reshaped by the hematoma microenvironment. Interestingly, the patient had an asymptomatic re-bleed (second local exposure to blood) that our transcriptional data indicated occurred more than 30 hours prior to detection by CT scan. This case highlights the rapid immune dynamics in the brain after ICH and suggests that sensitive methods like scRNA-seq can inform our understanding of complex intracerebral events.

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Comparison of Brain Extracellular Fluid, Brain Tissue, Cerebrospinal Fluid, and Serum Concentrations of Antiepileptic Drugs Measured Intraoperatively in Patients with Intractable Epilepsy

Epilepsia ◽

10.1111/j.1528-1167.2006.00504.x ◽

2006 ◽

Vol 47 (4) ◽

pp. 681-694 ◽

Cited By ~ 122

Author(s):

Bernhard Rambeck ◽

Uwe H. Jurgens ◽

Theodor W. May ◽

Heinz Wolfgang Pannek ◽

Friedrich Behne ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Antiepileptic Drugs ◽

Brain Tissue ◽

Intractable Epilepsy ◽

Extracellular Fluid ◽

Serum Concentrations ◽

Brain Extracellular Fluid

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Evaluation of neurofilament light chain in the cerebrospinal fluid and blood as a biomarker for neuronal damage in experimental pneumococcal meningitis

Journal of Neuroinflammation ◽

10.1186/s12974-020-01966-3 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Ngoc Dung Le ◽

Lukas Muri ◽

Denis Grandgirard ◽

Jens Kuhle ◽

David Leppert ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Single Molecule ◽

Light Chain ◽

Pneumococcal Meningitis ◽

Neuronal Damage ◽

Neuronal Injury ◽

Health Concern ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Inflammatory Phase

Abstract Background Pneumococcal meningitis (PM) remains a global public health concern and affects all age groups. If acquired during infancy or childhood, permanent neurofunctional deficits including cognitive impairment, cerebral palsy, and secondary epilepsy are typical sequelae of neuronal injury. Determination of patients at risk for the development of brain injury and subsequent neurofunctional sequelae could help to identify patients for focused management. Neurofilament light chain (NfL) is an axonal cytoskeletal protein released upon neuronal injury into the cerebrospinal fluid (CSF) and blood. As little is known about the course of neurofilament release in the course of PM, we measured CSF and serum NfL levels longitudinally in experimental PM (ePM). Methods Eleven-day-old infant Wistar rats were infected intracisternally with Streptococcus pneumoniae and treated with ceftriaxone. At 18 and 42 h post-infection (hpi), the blood and CSF were sampled for NfL measurements by a single molecule array technology. Inflammatory cytokines and MMP-9 in CSF were quantified by magnetic bead multiplex assay (Luminex®) and by gel zymography, respectively. Results In ePM, CSF and serum NfL levels started to increase at 18 hpi and were 26- and 3.5-fold increased, respectively, compared to mock-infected animals at 42 hpi (p < 0.0001). CSF and serum NfL correlated at 18 hpi (p < 0.05, r = 0.4716) and 42 hpi (p < 0.0001, r = 0.8179). Both CSF and serum NfL at 42 hpi strongly correlated with CSF levels of IL-1β, TNF-α, and IL-6 and of MMP-9 depending on their individual kinetics. Conclusion Current results demonstrate that during the peak inflammatory phase of ePM, NfL levels in CSF and serum are the highest among CNS disease models studied so far. Given the strong correlation of CSF versus serum NfL, and its CNS-specific signal character, longitudinal measurements to monitor the course of PM could be performed based on blood sample tests, i.e., without the need of repetitive spinal taps. We conclude that NfL in the serum should be evaluated as a biomarker in PM.

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Intracerebral Pro-inflammatory Cytokine Increase in Surgically Evacuated Intracerebral Hemorrhage - an Observational Microdialysis Study

10.21203/rs.3.rs-516589/v1 ◽

2021 ◽

Author(s):

Lovisa Tobieson ◽

Anna Gard ◽

Karsten Ruscher ◽

Niklas Marklund

Keyword(s):

Intracerebral Hemorrhage ◽

Brain Tissue ◽

Inflammatory Cytokines ◽

Inflammatory Mediators ◽

Inflammatory Cytokine ◽

Tissue Injury ◽

Treatment Options ◽

Cerebral Microdialysis ◽

Cytokines And Chemokines ◽

Anti Inflammatory

Abstract Background: Treatment options for spontaneous intracerebral hemorrhage (ICH) are limited. A possible inflammatory response in the brain tissue surrounding an ICH may exacerbate the initial injury and could be a target for treatment. Methods: In this observational study, ten patients needing surgical evacuation of supratentorial ICH received two cerebral microdialysis (MD) catheters; one in the perihemorrhagic zone (PHZ), and one in non-eloquent cortex (SNX) remote from the ICH. The microdialysate was analysed for energy metabolites (including lactate/pyruvate ratio (LPR) and glucose) and for inflammatory mediators using a multiplex immunoassay of 27 cytokines and chemokines at 6-10 hours, 20-26 hours and 44-50 hours after surgery. Results: Deranged energy metabolic markers suggestive of a metabolic crisis were found in PHZ compared to SNX, persistent throughout the 50 hours. Pro-inflammatory cytokines IL-8, TNF-α, IL-2, IL-1β, IL-6 and IFN-γ, anti-inflammatory cytokine IL-13, IL-4, and VEGF-A were significantly higher in PHZ compared to SNX, most prominent at 20-26 hours following ICH evacuation.Conclusions: Higher levels of pro- and anti-inflammatory cytokines in the perihemorrhagic brain tissue suggests a role for inflammatory mediators involved in secondary injury cascades potentially exacerbating tissue injury, which may constitute a target for future medical interventions.

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Comparison between plasma and cerebrospinal fluid biomarkers for the early diagnosis and association with survival in prion disease

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2020-323826 ◽

2020 ◽

Vol 91 (11) ◽

pp. 1181-1188 ◽

Cited By ~ 1

Author(s):

Samir Abu-Rumeileh ◽

Simone Baiardi ◽

Anna Ladogana ◽

Corrado Zenesini ◽

Anna Bartoletti-Stella ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Diagnostic Accuracy ◽

Prion Disease ◽

Single Molecule ◽

Clinical Care ◽

Csf Biomarkers ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Lower Accuracy ◽

T Tau

ObjectiveTo compare the diagnostic accuracy and the prognostic value of blood and cerebrospinal fluid (CSF) tests across prion disease subtypes.MethodsWe used a single-molecule immunoassay to measure tau and neurofilament light chain (NfL) protein levels in the plasma and assessed CSF total(t)-tau, NfL and protein 14-3-3 levels in patients with prion disease (n=336), non-prion rapidly progressive dementias (n=106) and non-neurodegenerative controls (n=37). We then evaluated each plasma and CSF marker for diagnosis and their association with survival, taking into account the disease subtype, which is a strong independent prognostic factor in prion disease.ResultsPlasma tau and NfL concentrations were higher in patients with prion disease than in non-neurodegenerative controls and non-prion rapidly progressive dementias. Plasma tau showed higher diagnostic value than plasma NfL, but a lower accuracy than the CSF proteins t-tau and 14-3-3. In the whole prion cohort, both plasma (tau and NfL) and CSF (t-tau, 14-3-3 and NfL) markers were significantly associated with survival and showed similar prognostic values. However, the intrasubtype analysis revealed that only CSF t-tau in sporadic Creutzfeldt-Jakob disease (sCJD) MM(V)1, plasma tau and CSF t-tau in sCJD VV2, and plasma NfL in slowly progressive prion diseases were significantly associated with survival after accounting for covariates.ConclusionsPlasma markers have lower diagnostic accuracy than CSF biomarkers. Plasma tau and NfL and CSF t-tau are significantly associated with survival in prion disease in a subtype-specific manner and can be used to improve clinical trial stratification and clinical care.

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Detection of Cerebrospinal Fluid Neurofilament Light Chain as a Marker for Alpha-Synucleinopathies

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.717930 ◽

2021 ◽

Vol 13 ◽

Author(s):

Sezgi Canaslan ◽

Matthias Schmitz ◽

Anna Villar-Piqué ◽

Fabian Maass ◽

Karin Gmitterová ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Single Molecule ◽

Light Chain ◽

Clinical Symptoms ◽

Alpha Synuclein ◽

Test System ◽

Marker Protein ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Different Types

Alpha-synucleinopathies, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are a class of neurodegenerative diseases. A diagnosis may be challenging because clinical symptoms partially overlap, and there is currently no reliable diagnostic test available. Therefore, we aimed to identify a suitable marker protein in cerebrospinal fluid (CSF) to distinguish either between different types of alpha-synucleinopathies or between alpha-synucleinopathies and controls. In this study, the regulation of different marker protein candidates, such as alpha-synuclein (a-Syn), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and total tau (tau) in different types of alpha-synucleinopathies, had been analyzed by using an ultrasensitive test system called single-molecule array (SIMOA). Interestingly, we observed that CSF-NfL was significantly elevated in patients with DLB and MSA compared to patients with PD or control donors. To differentiate between groups, receiver operating characteristic (ROC) curve analysis resulted in a very good diagnostic accuracy as indicated by the area under the curve (AUC) values of 0.87–0.92 for CSF-NfL. Furthermore, we observed that GFAP and tau were slightly increased either in DLB or MSA, while a-Syn levels remained unregulated. Our study suggests NfL as a promising marker to discriminate between different types of alpha-synucleinopathies or between DLB/MSA and controls.

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E-086 Human intracerebral hemorrhage (ICH): Early hemolysis/erythryolysis, iron overload, perihematomal edema & surviving white matter; translational evidence for brain tissue injury markers on MRI

10.1136/neurintsurg-2021-snis.181 ◽

2021 ◽

Author(s):

N Novakovic ◽

Z Wilseck ◽

T Chenevert ◽

G Xi ◽

R Keep ◽

...

Keyword(s):

White Matter ◽

Intracerebral Hemorrhage ◽

Iron Overload ◽

Brain Tissue ◽

Tissue Injury ◽

Perihematomal Edema

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Serum Neurofilament Light Chain Levels and Myelin Oligodendrocyte Glycoprotein Antibodies in Pediatric Acquired Demyelinating Syndromes

Frontiers in Neurology ◽

10.3389/fneur.2021.754518 ◽

2021 ◽

Vol 12 ◽

Author(s):

Marta Simone ◽

Claudia Palazzo ◽

Mariangela Mastrapasqua ◽

Luca Bollo ◽

Francesco Pompamea ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Single Molecule ◽

Light Chain ◽

Myelin Oligodendrocyte Glycoprotein ◽

Oligoclonal Bands ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Significant Difference ◽

The Relationship

Introduction: The relationship between serum neurofilament light chain (sNfL) and myelin oligodendrocyte glycoprotein antibody (MOG-Ab) status has not been yet investigated in children with the acquired demyelinating syndrome (ADS).Objective and Methods: The sNfL levels and MOG-Abs were measured by ultrasensitive single-molecule array and cell-based assay in a cohort of 37 children with ADS and negativity for serum anti-aquaporin 4 (AQP4) antibodies. The sNfL levels were compared in MOG-Ab+/MOG-Ab– and in two subgroups MOG-Ab+ with/without encephalopathy.Results: About 40% ADS resulted in MOG-Ab+. MOG-Ab+ were younger at sampling (median = 9.8; range = 2.17–17.5 vs. 14.7/9–17; p = 0.002) with lower frequency of cerebrospinal fluid oligoclonal bands positivity (27% vs. 70%; p = 0.013) compared to MOG-Ab–. About 53% of MOG-Ab+ presented encephalopathy at onset, 1/22 of MOG-Ab– (p = 0.0006). Higher sNfL levels (p = 0.0001) were found in MOG-Ab+ (median/range = 11.11/6.8–1,129) and MOG-Ab– (median/range = 11.6/4.3–788) compared to age-matched controls (median/range = 2.98/1–4.53), without significant difference. MOG-Ab+ with encephalopathy resulted significantly younger at sampling (median/range: 4.5/2.17–11.17 vs. 14.16/9.8–17.5; p = 0.004), had higher sNfL levels (median/range:75.24/9.1–1,129 vs. 10.22/6.83–50.53; p = 0.04), and showed a trend for higher MOG-Ab titer (0.28/0.04–0.69 vs. 0.05/0.04–0.28; p = 0.1) in comparison to those without encephalopathy.Discussion: We confirmed high sNfL levels in pediatric ADS independently from the MOG-Ab status. Encephalopathy at onset is associated more frequently with MOG Ab+ children with higher sNfL levels and MOG titer. These findings suggest a role of acute demyelination in association with axonal damage in the pathogenesis of encephalopathy in pediatric ADS.

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