المؤلفون: Garland, Patrick, Morton, Matt, Zolnourian, Ardalan, Durnford, Andrew, Gaastra, Ben, Toombs, Jamie, Heslegrave, Amanda J, More, John, Zetterberg, Henrik, Bulters, Diederik O, Galea, Ian

المساهمون: Medical Research Council, Engineering and Physical Sciences Research Council, Bio Products Laboratory Limited, Smile for Wessex, Royal College of Surgeons of Edinburgh, University of Southampton, Swedish Research Council, European Research Council, Swedish State Support for Clinical Research, Alzheimer Drug Discovery Foundation, UK Dementia Research Institute

المصدر: Brain ; volume 144, issue 3, page 761-768 ; ISSN 0006-8950 1460-2156

الوصف: To improve outcome prediction following subarachnoid haemorrhage (SAH), we sought a biomarker integrating early brain injury and multiple secondary pathological processes in a prospective study of 42 non-traumatic SAH patients and 19 control individuals. Neurofilament light (NF-L) was elevated in CSF and serum following SAH. CSF and serum NF-L on Days 1–3 post-SAH strongly predicted modified Rankin score at 6 months, independent of World Federation of Neurosurgical Societies (WFNS) score. NF-L from Day 4 onwards also had a profound impact on outcome. To link NF-L to a SAH-specific pathological process, we investigated NF-L’s relationship with extracellular haemoglobin. Most CSF haemoglobin was not complexed with haptoglobin, yet was able to be bound by exogenous haptoglobin i.e. haemoglobin was scavengeable. CSF scavengeable haemoglobin was strongly predictive of subsequent CSF NF-L. Next, we investigated NF-L efflux from the brain after SAH. Serum and CSF NF-L correlated positively. The serum/CSF NF-L ratio was lower in SAH versus control subjects, in keeping with glymphatic efflux dysfunction after SAH. CSF/serum albumin ratio was increased following SAH versus controls. The serum/CSF NF-L ratio correlated negatively with the CSF/serum albumin ratio, indicating that transfer of the two proteins across the blood–brain interface is dissociated. In summary, NF-L is a strong predictive marker for SAH clinical outcome, adding value to the WFNS score, and is a promising surrogate end point in clinical trials.

الإتاحة: https://doi.org/10.1093/brain/awaa451Test
http://academic.oup.com/brain/article-pdf/144/3/761/37036751/awaa451.pdfTest

المؤلفون: Garland, Patrick, Morton, Matthew J, Haskins, William, Zolnourian, Ardalan, Durnford, Andrew, Gaastra, Ben, Toombs, Jamie, Heslegrave, Amanda J, More, John, Okemefuna, Azubuike I, Teeling, Jessica L, Graversen, Jonas H, Zetterberg, Henrik, Moestrup, Soren K, Bulters, Diederik O, Galea, Ian

المساهمون: Medical Research Council

المصدر: Brain Communications ; volume 2, issue 1 ; ISSN 2632-1297

الوصف: After subarachnoid haemorrhage, prolonged exposure to toxic extracellular haemoglobin occurs in the brain. Here, we investigate the role of haemoglobin neurotoxicity in vivo and its prevention. In humans after subarachnoid haemorrhage, haemoglobin in cerebrospinal fluid was associated with neurofilament light chain, a marker of neuronal damage. Most haemoglobin was not complexed with haptoglobin, an endogenous haemoglobin scavenger present at very low concentration in the brain. Exogenously added haptoglobin bound most uncomplexed haemoglobin, in the first 2 weeks after human subarachnoid haemorrhage, indicating a wide therapeutic window. In mice, the behavioural, vascular, cellular and molecular changes seen after human subarachnoid haemorrhage were recapitulated by modelling a single aspect of subarachnoid haemorrhage: prolonged intrathecal exposure to haemoglobin. Haemoglobin-induced behavioural deficits and astrocytic, microglial and synaptic changes were attenuated by haptoglobin. Haptoglobin treatment did not attenuate large-vessel vasospasm, yet improved clinical outcome by restricting diffusion of haemoglobin into the parenchyma and reducing small-vessel vasospasm. In summary, haemoglobin toxicity is of clinical importance and preventable by haptoglobin, independent of large-vessel vasospasm.

الإتاحة: https://doi.org/10.1093/braincomms/fcz053Test
http://academic.oup.com/braincomms/article-pdf/2/1/fcz053/33640052/fcz053.pdfTest

المؤلفون: Pace, Adrian, Mitchell, Sophie, Casselden, Elizabeth, Zolnourian, Ardalan, Glazier, James, Foulkes, Lesley, Bulters, Diederik, Galea, Ian

المصدر: Brain ; volume 141, issue 4, page 1111-1121 ; ISSN 0006-8950 1460-2156

الإتاحة: https://doi.org/10.1093/brain/awy003Test
http://academic.oup.com/brain/article-pdf/141/4/1111/24583662/awy003.pdfTest

المؤلفون: Pegasiou, Chrysia M, Zolnourian, Ardalan, Gomez-Nicola, Diego, Deinhardt, Katrin, Nicoll, James A R, Ahmed, Aminul I, Vajramani, Girish, Grundy, Paul, Verhoog, Matthijs B, Mansvelder, Huibert D, Perry, V H, Bulters, Diederik, Vargas-Caballero, Mariana

المساهمون: Institute for Life Sciences, University of Southampton, Wessex Medical Research, Gerald Kerkut Trust

المصدر: Cerebral Cortex ; volume 30, issue 7, page 4246-4256 ; ISSN 1047-3211 1460-2199

الوصف: The molecular processes underlying the aging-related decline in cognitive performance and memory observed in humans are poorly understood. Studies in rodents have shown a decrease in N-methyl-D-aspartate receptors (NMDARs) that contain the GluN2B subunit in aging synapses, and this decrease is correlated with impaired memory functions. However, the age-dependent contribution of GluN2B-containing receptors to synaptic transmission in human cortical synapses has not been previously studied. We investigated the synaptic contribution of GluN2A and GluN2B-containing NMDARs in adult human neurons using fresh nonpathological temporal cortical tissue resected during neurosurgical procedures. The tissue we obtained fulfilled quality criteria by the absence of inflammation markers and proteomic degradation. We show an age-dependent decline in the NMDA/AMPA receptor ratio in adult human temporal cortical synapses. We demonstrate that GluN2B-containing NMDA receptors contribute to synaptic responses in the adult human brain with a reduced contribution in older individuals. With previous evidence demonstrating the critical role of synaptic GluN2B in regulating synaptic strength and memory storage in mice, this progressive reduction of GluN2B in the human brain during aging may underlie a molecular mechanism in the age-related decline in cognitive abilities and memory observed in humans.

الإتاحة: https://doi.org/10.1093/cercor/bhaa052Test
http://academic.oup.com/cercor/article-pdf/30/7/4246/33332702/bhaa052.pdfTest