Publications by authors named "Eyiyemisi C Damisah"

12 Publications

  • Page 1 of 1

Increased branched-chain amino acids at baseline and hours before a spontaneous seizure in the human epileptic brain.

Epilepsia 2021 Jun 5;62(6):e88-e97. Epub 2021 May 5.

Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.

The objective of this study was to monitor the extracellular brain chemistry dynamics at baseline and in relation to spontaneous seizures in human patients with refractory epilepsy. Thirty patients with drug-resistant focal epilepsy underwent intracranial electroencephalography and concurrent brain microdialysis for up to 8 continuous days. Extracellular brain glutamate, glutamine, and the branched-chain amino acids (BCAAs) valine, leucine, and isoleucine were quantified in the dialysis samples by liquid chromatography-tandem mass spectrometry. Extracellular BCAAs and glutamate were chronically elevated at baseline by approximately 1.5-3-fold in brain regions of seizure onset and propagation versus regions not involved by seizures. Moreover, isoleucine increased significantly above baseline as early as 3 h before a spontaneous seizure. BCAAs play important roles in glutamatergic neurotransmission, mitochondrial function, neurodegeneration, and mammalian target of rapamycin signaling. Because all of these processes have been implicated in epilepsy, the results suggest a novel role of BCAAs in the pathogenesis of spontaneous seizures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16920DOI Listing
June 2021

Case Report: Suprasellar Pituitary Adenoma Presenting With Temporal Lobe Seizures.

Front Surg 2020 1;7:598138. Epub 2020 Dec 1.

Department of Neurosurgery, Yale School of Medicine, New Haven, CT, United States.

Seizures in patients with pituitary pathology are uncommon and typically secondary to electrolyte disturbances. Rarely, seizures have been described from mass effect related to large prolactinomas undergoing medical treatment. We describe a 54 year-old male who presented with a first-time generalized seizure, secondary to a pituitary macroadenoma compressing the left temporal lobe. His seizures abated after endoscopic endonasal debulking of the tumor. This report highlights isolated seizures as a potential sole presenting symptom of pituitary macroadenomas without visual or endocrine dysfunction. Prompt surgical debulking to relieve mass effect on the temporal lobe may effectively prevent further seizure activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fsurg.2020.598138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736041PMC
December 2020

Imaging and optogenetic modulation of vascular mural cells in the live brain.

Nat Protoc 2021 01 9;16(1):472-496. Epub 2020 Dec 9.

Department of Neurology, Yale School of Medicine, New Haven, CT, USA.

Mural cells (smooth muscle cells and pericytes) are integral components of brain blood vessels that play important roles in vascular formation, blood-brain barrier maintenance, and regulation of regional cerebral blood flow (rCBF). These cells are implicated in conditions ranging from developmental vascular disorders to age-related neurodegenerative diseases. Here we present complementary tools for cell labeling with transgenic mice and organic dyes that allow high-resolution intravital imaging of the different mural cell subtypes. We also provide detailed methodologies for imaging of spontaneous and neural activity-evoked calcium transients in mural cells. In addition, we describe strategies for single- and two-photon optogenetics that allow manipulation of the activity of individual and small clusters of mural cells. Together with measurements of diameter and flow in individual brain microvessels, calcium imaging and optogenetics allow the investigation of pericyte and smooth muscle cell physiology and their role in regulating rCBF. We also demonstrate the utility of these tools to investigate mural cells in the context of Alzheimer's disease and cerebral ischemia mouse models. Thus, these methods can be used to reveal the functional and structural heterogeneity of mural cells in vivo, and allow detailed cellular studies of the normal function and pathophysiology of mural cells in a variety of disease models. The implementation of this protocol can take from several hours to days depending on the intended applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41596-020-00425-wDOI Listing
January 2021

Astrocytes and microglia play orchestrated roles and respect phagocytic territories during neuronal corpse removal in vivo.

Sci Adv 2020 Jun 26;6(26):eaba3239. Epub 2020 Jun 26.

Department of Neurology, Yale School of Medicine, New Haven, CT, USA.

Cell death is prevalent throughout life; however, the coordinated interactions and roles of phagocytes during corpse removal in the live brain are poorly understood. We developed photochemical and viral methodologies to induce death in single cells and combined this with intravital optical imaging. This approach allowed us to track multicellular phagocytic interactions with precise spatiotemporal resolution. Astrocytes and microglia engaged with dying neurons in an orchestrated and synchronized fashion. Each glial cell played specialized roles: Astrocyte processes rapidly polarized and engulfed numerous small dendritic apoptotic bodies, while microglia migrated and engulfed the soma and apical dendrites. The relative involvement and phagocytic specialization of each glial cell was plastic and controlled by the receptor tyrosine kinase . In aging, there was a marked delay in apoptotic cell removal. Thus, a precisely orchestrated response and cross-talk between glial cells during corpse removal may be critical for maintaining brain homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.aba3239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319765PMC
June 2020

TREM2: Modulator of Lipid Metabolism in Microglia.

Neuron 2020 03;105(5):759-761

Department of Neurology, Yale School of Medicine, New Haven, CT, USA; Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA. Electronic address:

Lipid-processing mechanisms during demyelination are poorly understood. In this issue of Neuron,Nugent et al. (2020) show by cell-specific lipidomics that Trem2 deficiency leads to cholesterol ester (CE) overload in microglia. This is mediated by misregulation of lipid metabolism genes and is rescued by modulating CE synthesis or efflux.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuron.2020.02.008DOI Listing
March 2020

Cerebrospinal fluid untargeted metabolomic profiling of aneurysmal subarachnoid hemorrhage: an exploratory study.

Br J Neurosurg 2018 Dec 26;32(6):637-641. Epub 2018 Dec 26.

d Division of Neurosurgery , University of Connecticut Health Center , Farmington , CT , USA.

Introduction: Despite advancements in medical and surgical therapies, clinical outcomes of aneurysmal subarachnoid hemorrhage (aSAH) continue to be poor. Currently, aSAH pathophysiology remains poorly understood. No aSAH biomarkers are commonly used in the clinical setting. This exploratory study used metabolomics profiling to identify global metabolic changes and metabolite predictors of long-term outcome using cerebrospinal fluid (CSF) samples of aSAH patients.

Methods And Methods: Gas chromatography time-of-flight mass spectrometry was applied to CSF samples collected from 15 consecutive high-grade aSAH patients (modified Fisher grade 3 or 4). Collected CSF samples were analyzed at two time points (admission and the anticipated vasospasm timeframe). Metabolite levels at both time points were compared and correlated with vasospasm status and Glasgow Outcome Scale (GOS) of patients at 1 year post-aSAH. Significance level was defined as p < 0.05 with false discovery rate correction for multiple comparisons.

Results: Of 97 metabolites identified, 16 metabolites, primarily free amino acids, significantly changed between the two time points. These changes were magnified in modified Fisher grade 4 compared with grade 3. Six metabolites (2-hydroxyglutarate, tryptophan, glycine, proline, isoleucine, and alanine) correlated with GOS at 1 year post-aSAH independent of vasospasm status. When predicting patients who had low disability (GOS 5 vs. GOS ≤4), 2-hydroxyglutarate had a sensitivity and specificity of 0.89 and 0.83 respectively.

Conclusions: Our preliminary study suggests that specific metabolite changes occur in the brain during the course of aSAH and that quantification of specific CSF metabolites may be used to predict long-term outcome in patients with aSAH. This is the first study to implicate 2-hydroxyglutarate, a known marker of tissue hypoxia, in aSAH pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/02688697.2018.1519107DOI Listing
December 2018

Targeted two-photon chemical apoptotic ablation of defined cell types in vivo.

Nat Commun 2017 06 16;8:15837. Epub 2017 Jun 16.

Department of Neurology, Yale School of Medicine, New Haven, Connecticut 06511, USA.

A major bottleneck limiting understanding of mechanisms and consequences of cell death in complex organisms is the inability to induce and visualize this process with spatial and temporal precision in living animals. Here we report a technique termed two-photon chemical apoptotic targeted ablation (2Phatal) that uses focal illumination with a femtosecond-pulsed laser to bleach a nucleic acid-binding dye causing dose-dependent apoptosis of individual cells without collateral damage. Using 2Phatal, we achieve precise ablation of distinct populations of neurons, glia and pericytes in the mouse brain and in zebrafish. When combined with organelle-targeted fluorescent proteins and biosensors, we uncover previously unrecognized cell-type differences in patterns of apoptosis and associated dynamics of ribosomal disassembly, calcium overload and mitochondrial fission. 2Phatal provides a powerful and rapidly adoptable platform to investigate in vivo functional consequences and neural plasticity following cell death as well as apoptosis, cell clearance and tissue remodelling in diverse organs and species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms15837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501159PMC
June 2017

A fluoro-Nissl dye identifies pericytes as distinct vascular mural cells during in vivo brain imaging.

Nat Neurosci 2017 Jul 15;20(7):1023-1032. Epub 2017 May 15.

Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA.

Pericytes and smooth muscle cells are integral components of the brain microvasculature. However, no techniques exist to unambiguously identify these cell types, greatly limiting their investigation in vivo. Here we show that the fluorescent Nissl dye NeuroTrace 500/525 labels brain pericytes with specificity, allowing high-resolution optical imaging in the live mouse. We demonstrate that capillary pericytes are a population of mural cells with distinct morphological, molecular and functional features that do not overlap with precapillary or arteriolar smooth muscle actin-expressing cells. The remarkable specificity for dye uptake suggests that pericytes have molecular transport mechanisms not present in other brain cells. We demonstrate feasibility of longitudinal pericyte imaging during microvascular development and aging and in models of brain ischemia and Alzheimer's disease. The ability to easily label pericytes in any mouse model opens the possibility of a broad range of investigations of mural cells in vascular development, neurovascular coupling and neuropathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nn.4564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550770PMC
July 2017

Novel biomarker identification using metabolomic profiling to differentiate radiation necrosis and recurrent tumor following Gamma Knife radiosurgery.

J Neurosurg 2017 Aug 25;127(2):388-396. Epub 2016 Nov 25.

Departments of 1 Neurosurgery.

OBJECTIVE Following an initial response of brain metastases to Gamma Knife radiosurgery, regrowth of the enhancing lesion as detected on MRI may represent either radiation necrosis (a treatment-related inflammatory change) or recurrent tumor. Differentiation of radiation necrosis from tumor is vital for management decision making but remains difficult by imaging alone. In this study, gas chromatography with time-of-flight mass spectrometry (GC-TOF) was used to identify differential metabolite profiles of the 2 tissue types obtained by surgical biopsy to find potential targets for noninvasive imaging. METHODS Specimens of pure radiation necrosis and pure tumor obtained from patient brain biopsies were flash-frozen and validated histologically. These formalin-free tissue samples were then analyzed using GC-TOF. The metabolite profiles of radiation necrosis and tumor samples were compared using multivariate and univariate statistical analysis. Statistical significance was defined as p ≤ 0.05. RESULTS For the metabolic profiling, GC-TOF was performed on 7 samples of radiation necrosis and 7 samples of tumor. Of the 141 metabolites identified, 17 (12.1%) were found to be statistically significantly different between comparison groups. Of these metabolites, 6 were increased in tumor, and 11 were increased in radiation necrosis. An unsupervised hierarchical clustering analysis found that tumor had elevated levels of metabolites associated with energy metabolism, whereas radiation necrosis had elevated levels of metabolites that were fatty acids and antioxidants/cofactors. CONCLUSIONS To the authors' knowledge, this is the first tissue-based metabolomics study of radiation necrosis and tumor. Radiation necrosis and recurrent tumor following Gamma Knife radiosurgery for brain metastases have unique metabolite profiles that may be targeted in the future to develop noninvasive metabolic imaging techniques.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3171/2016.8.JNS161395DOI Listing
August 2017

5-aminovaleric acid suppresses the development of severe seizures in the methionine sulfoximine model of mesial temporal lobe epilepsy.

Neurobiol Dis 2014 Jul 14;67:18-23. Epub 2014 Mar 14.

Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address:

Mesial temporal lobe epilepsy (MTLE) is one of the most common forms of drug-resistant, localization-related epilepsies in humans. One potential therapeutic target is the brain glutamine-glutamate-GABA metabolic pathway, which is perturbed in patients with MTLE. Loss of glutamine synthetase (GS) in astrocytes may be critically involved in this perturbation, which can be modeled by infusing the GS inhibitor methionine sulfoximine (MSO) into the entorhinal-hippocampal area in rats. Because 5-aminovaleric acid (5-AV) has been implicated in modulation of the glutamine-glutamate-GABA metabolic pathway, we hypothesized that 5-AV would alter the expression of seizures in the MSO model of MTLE. Male Sprague Dawley rats (300-330g) were implanted with an Alzet pump placed subcutaneously in the abdominal region to release either 5-AV (0.05mg/mL, n=6) or phosphate buffered saline (PBS, n=6) at a rate of 2.5μl/h over 28days. Five to 7days after surgery, all rats were implanted with an intracranial pump infusing MSO (2.5mg/mL; 0.25μl/h) unilaterally into the hippocampal formation. Following the second surgery, intracranial EEG was measured from the left and right hemispheres above the dorsal hippocampal formations for a continuous period of 21days. The EEG was correlated with simultaneous video recordings to determine the stage of seizures according to a modified Racine scale. Five-AV-treated rats experienced a 3.5 fold reduction in the number of seizures (6.7±1.4seizures/day) than PBS-treated rats (23.2±6.3seizures/day) during the first 2days following MSO pump placement (p<0.005). Both groups showed similar seizure frequency over days 3-21 (~1seizure/day). However, the fraction of the most severe type of seizures (Racine stages 4 and 5) increased over time in the PBS treated group, but not in the 5-AV treated group. Notably, 5-AV treated rats experienced a 2.3 and 2.6 fold lower fraction of stage 4 and 5 seizures than PBS-treated rats during the 2nd and 3rd weeks of MSO treatment respectively (p<0 .05 and p<0.001 respective to week). Five-AV markedly reduces the number of seizures initially and suppresses the development of the most severe type of seizures in the MSO model of MTLE. These results may have implications for the therapeutic use of 5-AV in treating mesial temporal lobe seizures and for our understanding of the chemical pathology of epileptogenesis and MTLE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2014.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035438PMC
July 2014

Intra-arterial treatment of acute ischemic stroke: the continued evolution.

Curr Treat Options Cardiovasc Med 2014 Feb;16(2):281

Department of Neurosurgery, Yale School of Medicine, 100 York Street Apt 9G, New Haven, CT, 06510, USA,

Opinion Statement: The devastation caused by acute ischemic strokes is evident in every intensive care unit across the world. Although there is no doubt that progress has been made in treatment, it has been slow to come. With the emergence of new technologies in imaging, thrombolysis and endovascular intervention, the treatment modalities of acute ischemic stroke will enter a new era. In this review, we present the concept of the seven evolutionary phases in the treatment of acute ischemic stroke to date.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11936-013-0281-2DOI Listing
February 2014

Linking of bone morphogenetic protein-2 to resorbable fracture plates for enhancing bone healing.

Laryngoscope 2005 Dec;115(12):2232-7

Department of Otolaryngology/Head and Neck Surgery, University of California Irvine School of Medicine, Orange, California 92868, USA.

Objective: To test whether bone morphogenetic protein (BMP)-2 may be covalently linked to resorbable fracture repair plates using an ester-hydrolysis reaction and determining whether the linked compound can facilitate bone growth.

Study Design: Laboratory in vitro experiments.

Method: Resorbable fracture repair plates were partially hydrolyzed using varying concentrations of acid or base. This intermediate was then reacted with EDAC (1-ethyl-3[-3-dimethylamino propyl carbodiimide) to form an EDAC intermediate, which was then reacted with either horseradish peroxidase (HRP), interleukin (IL)-2, or BMP-2. Compound binding to the plate was confirmed by immunofluorescent staining. Confirmation of protein function was determined by the following assays: HRP's ability to cleave peroxide, IL-2's ability to stimulate lymphocytes, and BMP-2's ability to stimulate C3H10T1/2 cells to generate alkaline phosphatase.

Results: Three compounds (HRP, IL-2, and BMP-2) were successfully linked to plates as confirmed by immunofluorescence staining or functional testing. Compounds demonstrated better covalent linking to plates under basic conditions. HRP, IL-2, and BMP-2 retained function after binding as measured by cleaved peroxide levels, lymphocytes proliferation, and alkaline phosphatase production.

Conclusions: Covalent linking of compounds such as HRP, IL-2, and BMP-2 to resorbable plates is possible and represents a novel protein delivery technique. BMP-2 covalently linked to resorbable plates may be used to facilitate bone healing. Covalent linking of compounds to plates represents a novel method for delivering concentrated levels of growth factors to a specific site and potentially extending their half-life. Further investigation into this application for bone healing may lead to quicker healing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.mlg.0000183692.27532.5bDOI Listing
December 2005