| 1. |
- Emami Khoonsari, Payam
(författare)
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Proteomics Studies of Subjects with Alzheimer’s Disease and Chronic Pain
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD) is a neurodegenerative disease and the major cause of dementia, affecting more than 50 million people worldwide. Chronic pain is long-lasting, persistent pain that affects more than 1.5 billion of the world population. Overlapping and heterogenous symptoms of AD and chronic pain conditions complicate their diagnosis, emphasizing the need for more specific biomarkers to improve the diagnosis and understand the disease mechanisms.To characterize disease pathology of AD, we measured the protein changes in the temporal neocortex region of the brain of AD subjects using mass spectrometry (MS). We found proteins involved in exo-endocytic and extracellular vesicle functions displaying altered levels in the AD brain, potentially resulting in neuronal dysfunction and cell death in AD.To detect novel biomarkers for AD, we used MS to analyze cerebrospinal fluid (CSF) of AD patients and found decreased levels of eight proteins compared to controls, potentially indicating abnormal activity of complement system in AD.By integrating new proteomics markers with absolute levels of Aβ42, total tau (t-tau) and p-tau in CSF, we improved the prediction accuracy from 83% to 92% of early diagnosis of AD. We found increased levels of chitinase-3-like protein 1 (CH3L1) and decreased levels of neurosecretory protein VGF (VGF) in AD compared to controls.By exploring the CSF proteome of neuropathic pain patients before and after successful spinal cord stimulation (SCS) treatment, we found altered levels of twelve proteins, involved in neuroprotection, synaptic plasticity, nociceptive signaling and immune regulation.To detect biomarkers for diagnosing a chronic pain state known as fibromyalgia (FM), we analyzed the CSF of FM patients using MS. We found altered levels of four proteins, representing novel biomarkers for diagnosing FM. These proteins are involved in inflammatory mechanisms, energy metabolism and neuropeptide signaling.Finally, to facilitate fast and robust large-scale omics data handling, we developed an e-infrastructure. We demonstrated that the e-infrastructure provides high scalability, flexibility and it can be applied in virtually any fields including proteomics. This thesis demonstrates that proteomics is a promising approach for gaining deeper insight into mechanisms of nervous system disorders and find biomarkers for diagnosis of such diseases.
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| 2. |
- Gracias, J., et al.
(författare)
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Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia risk has been associated with the complement component 4 (C4) genes. Here the authors show that C4A is elevated in individuals with schizophrenia. Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ: median 0.41 fmol/ul [CI = 0.34-0.45], FEP-non-SCZ: median 0.29 fmol/ul [CI = 0.22-0.35], healthy controls: median 0.28 [CI = 0.24-0.33]). We show that the CSF elevation of C4A in FEP-SCZ exceeds what can be expected from genetic risk variance in the C4 locus, and in patient-derived cellular models we identify a mechanism dependent on the disease-associated cytokines interleukin (IL)-1beta and IL-6 to selectively increase neuronal C4A mRNA expression. In patient-derived CSF, we confirm that IL-1beta correlates with C4A controlled for genetically predicted C4A RNA expression (r = 0.39; CI: 0.01-0.68). These results suggest a role of C4A in early schizophrenia pathophysiology.
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| 3. |
- Ribom, Dan, et al.
(författare)
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Elevated levels of alpha-2-Heremans-Schmid glycoprotein in CSF of patients with low-grade gliomas
- 2003
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Ingår i: Tumor Biology. - : Springer Science and Business Media LLC. - 1010-4283 .- 1423-0380. ; 24:2, s. 94-99
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about the expression of mitogens and other tumour-related substances in the cerebrospinal fluid (CSF) of glioma patients. The aim of the current study was to determine the presence of aberrant proteins in the CSF of patients with low-grade gliomas. Lumbar puncture was performed in 8 adult patients with supratentorial low-grade gliomas at the time of diagnosis and in 7 controls. Two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionisation time of flight mass spectrometry were used to detect and quantify deviant proteins in the CSF. Two isoforms of alpha(2)-Heremans-Schmid glycoprotein (AHSG) were identified and demonstrated in higher levels in patients with low-grade gliomas compared with the control group consisting of patients with mixed neurological diagnoses (p = 0.001 and p = 0.04, respectively). In 1 patient, the level of AHSG was significantly reduced after gross total resection of the tumour. AHSG appears in the present proteome screening as a novel substance in glioma research. This glycoprotein is expressed in the fetal human brain and is believed to be involved in the embryonic development of the neocortex. Further analyses are planned to determine the significance of the increased levels of AHSG in the CSF of patients with low-grade gliomas.
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| 4. |
- Xu, Chengai, et al.
(författare)
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CSF levels of synaptosomal-associated protein 25 and synaptotagmin-1 in first-episode psychosis subjects.
- 2020
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Ingår i: IBRO reports. - : Elsevier BV. - 2451-8301. ; 8, s. 136-142
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Tidskriftsartikel (refereegranskat)abstract
- Post-mortem studies consistently show evidence of reduced synaptic protein levels in patients with schizophrenia. Clinically high-risk subjects show a steeper decrease in grey matter thickness and in vitro modeling using patient-derived cells implicate excessive synaptic pruning during neurodevelopment as a part of the schizophrenia pathophysiology. However, it is unclear to what extent synapse elimination is present during various stages of the disease, which is of clinical importance as in a real-world setting most subjects received their first-episode psychosis (FEP) diagnosis not until their mid-twenties. In the present study, we measured cerebrospinal fluid (CSF) concentrations of the two pre-synaptic proteins synaptosomal-associated protein 25 (SNAP-25) and synaptotagmin-1 (SYT-1), both of which are increased in conditions of ongoing synaptic degeneration, in 44 FEP subjects (mean age 29.9 years) and 21 healthy controls (25.9 years) using immunoprecipitation mass spectrometry. Neither protein was found to differ between healthy controls and patients, and they showed no correlation with symptom ratings, cognitive performance or antipsychotic medication. Additional studies in high-risk subjects in the early prodromal phase will be needed to address if excessive synapse destruction occurs before the development of overt psychotic symptoms.
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