| 1. |
- Anckarsäter, Rolf, 1956, et al.
(author)
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Non-neurological surgery results in a neurochemical stress response.
- 2008
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In: Journal of neural transmission (Vienna, Austria : 1996). - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 115:3, s. 397-9
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Journal article (peer-reviewed)abstract
- There is a paucity of studies assessing changes in measures of human neurotransmission during stressful events, such as surgery. Thirty-five patients without any neurological disorders undergoing knee replacements with spinal bupivacaine anaesthesia and propofol sedation had cerebrospinal fluid (CSF) drawn from a spinal catheter before, three hours after and the morning after surgery. The CSF concentrations of the dopamine metabolite homovanillinic acid (HVA) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), which are related to the activity of the dopaminergic and serotonergic systems of the brain, increased sharply during surgery and reached 188% and 166% of their initial concentrations on the morning after the intervention (p < 0.0001). The CSF concentrations of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglucol (MHPG) increased modestly (non-significantly) during and after surgery. The HVA/5-HIAA ratios initially increased but returned to the initial level during the night after surgery. We conclude that non-neurological surgery, in this case to the lower limb, is accompanied by a marked central nervous stress response in spite of a spinal blockade.
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| 2. |
- Blomqvist, Maria K., 1975, et al.
(author)
-
High-throughput analysis of sulfatides in cerebrospinal fluid using automated extraction and UPLC-MS/MS
- 2017
-
In: Journal of Lipid Research. - 0022-2275. ; 58:7, s. 1482-1489
-
Journal article (peer-reviewed)abstract
- Sulfatides (STs) are a group of glycosphingolipids that are highly expressed in brain. Due to their importance for normal brain function and their potential involvement in neurological diseases, development of accurate and sensitive methods for their determination is needed. Here we describe a high-throughput oriented and quantitative method for the determination of STs in cerebrospinal fluid (CSF). The STs were extracted using a fully automated liquid/liquid extraction method and quantified using ultra-performance liquid chromatography coupled to tandem mass spectrometry. With the high sensitivity of the developed method, quantification of 20 ST species from only 100 mu l of CSF was performed. Validation of the method showed that the STs were extracted with high recovery (90%) and could be determined with low inter-and intra-day variation. Our method was applied to a patient cohort of subjects with an Alzheimer's disease biomarker profile. Although the total ST levels were unaltered compared with an age-matched control group, we show that the ratio of hydroxylated/nonhydroxylated STs was increased in the patient cohort. In conclusion, we believe that the fast, sensitive, and accurate method described in this study is a powerful new tool for the determination of STs in clinical as well as preclinical settings.-Blomqvist, M., J. Boren, H. Zetterberg, K. Blennow, J-E. Mansson, and M. Stahlman. High-throughput analysis of sulfatides in cerebrospinal fluid using automated extraction and UPLC-MS/MS.
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| 3. |
- Blomqvist, Maria K., 1975, et al.
(author)
-
Sulfatide in health and disease. The evaluation of sulfatide in cerebrospinal fluid as a possible biomarker for neurodegeneration
- 2021
-
In: Molecular and Cellular Neuroscience. - : Elsevier BV. - 1044-7431. ; 116
-
Journal article (peer-reviewed)abstract
- Sulfatide (3-O-sulfogalactosylceramide, SM4) is a glycosphingolipid, highly multifunctional and particularly enriched in the myelin sheath of neurons. The role of sulfatide has been implicated in various biological fields such as the nervous system, immune system, host-pathogen recognition and infection, beta cell function and haemostasis/thrombosis. Thus, alterations in sulfatide metabolism and production are associated with several human diseases such as neurological and immunological disorders and cancers. The unique lipid-rich composition of myelin reflects the importance of lipids in this specific membrane structure. Sulfatide has been shown to be involved in the regulation of oligodendrocyte differentiation and in the maintenance of the myelin sheath by influencing membrane dynamics involving sorting and lateral assembly of myelin proteins as well as ion channels. Sulfatide is furthermore essential for proper formation of the axo-glial junctions at the paranode together with axonal glycosphingolipids. Alterations in sulfatide metabolism are suggested to contribute to myelin deterioration as well as synaptic dysfunction, neurological decline and inflammation observed in different conditions associated with myelin pathology (mouse models and human disorders). Body fluid biomarkers are of importance for clinical diagnostics as well as for patient stratification in clinical trials and treatment monitoring. Cerebrospinal fluid (CSF) is commonly used as an indirect measure of brain metabolism and analysis of CSF sulfatide might provide information regarding whether the lipid disruption observed in neurodegenerative disorders is reflected in this body fluid. In this review, we evaluate the diagnostic utility of CSF sulfatide as a biomarker for neurodegenerative disorders associated with dysmyelination/demyelination by summarising the current literature on this topic. We can conclude that neither CSF sulfatide levels nor individual sulfatide species consistently reflect the lipid disruption observed in many of the demyelinating disorders. One exception is the lysosomal storage disorder metachromatic leukodystrophy, possibly due to the genetically determined accumulation of non-metabolised sulfatide. We also discuss possible explanations as to why myelin pathology in brain tissue is poorly reflected by the CSF sulfatide concentration. The previous suggestion that CSF sulfatide is a marker of myelin damage has
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| 4. |
- Brinkmalm, Gunnar, et al.
(author)
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An online nano-LC-ESI-FTICR-MS method for comprehensive characterization of endogenous fragments from amyloid β and amyloid precursor protein in human and cat cerebrospinal fluid.
- 2012
-
In: Journal of mass spectrometry : JMS. - : Wiley. - 1096-9888 .- 1076-5174. ; 47:5, s. 591-603
-
Journal article (peer-reviewed)abstract
- Amyloid precursor protein (APP) is the precursor protein to amyloid β (Aβ), the main constituent of senile plaques in Alzheimer's disease (AD). Endogenous Aβ peptides reflect the APP processing, and greater knowledge of different APP degradation pathways is important to understand the mechanism underlying AD pathology. When one analyzes longer Aβ peptides by low-energy collision-induced dissociation tandem mass spectrometry (MS/MS), mainly long b-fragments are observed, limiting the possibility to determine variations such as amino acid variants or post-translational modifications (PTMs) within the N-terminal half of the peptide. However, by using electron capture dissociation (ECD), we obtained a more comprehensive sequence coverage for several APP/Aβ peptide species, thus enabling a deeper characterization of possible variants and PTMs. Abnormal APP/Aβ processing has also been described in the lysosomal storage disease Niemann-Pick type C and the major large animal used for studying this disease is cat. By ECD MS/MS, a substitution of Asp7 → Glu in cat Aβ was identified. Further, sialylated core 1 like O-glycans at Tyr10, recently discovered in human Aβ (a previously unknown glycosylation type), were identified also in cat cerebrospinal fluid (CSF). It is therefore likely that this unusual type of glycosylation is common for (at least) species belonging to the magnorder Boreoeutheria. We here describe a detailed characterization of endogenous APP/Aβ peptide species in CSF by using an online top-down MS-based method.
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| 5. |
- Gustavson, Christina, et al.
(author)
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Platelet Monoamine Oxidase B Activity Did Not Predict Destructive Personality Traits or Violent Recidivism: A Prospective Study in Male Forensic Psychiatric Examinees.
- 2010
-
In: Neuropsychobiology. - : S. Karger AG. - 1423-0224 .- 0302-282X. ; 61:2, s. 87-96
-
Journal article (peer-reviewed)abstract
- Aims: This prospective study was designed to replicate previous findings of an association between the platelet monoamine oxidase B (MAO-B) activity and factors of relevance for criminal behaviour in a well-documented clinical study population. Methods: Subjects (n = 77, aged 17-76 years, median 30 years) were recruited among consecutive perpetrators of severe interpersonal violent and/or sexual crimes referred to forensic psychiatric investigation. Participants were extensively investigated by structured psychiatric, psychological and social workups, including state-of-the-art rating instruments and official records, and with laboratory tests including venous blood sampling for determination of MAO-B activity. A subset of 36 individuals had lumbar punctures to measure cerebrospinal fluid concentrations of monoamine neurotransmitter metabolites. Results: Platelet MAO-B activity did not show any significant correlation with assessments of childhood behavioural disorders, substance abuse, or psychosocial adversity, nor with any crime-related factors, such as scores on the Life History of Aggression Scale, the Psychopathy Checklist or recidivistic violent crime. No significant correlation was found between MAO-B and any of the monoamine metabolites. Analyses in subgroups of smokers/non-smokers did not change this overall result. Conclusions: The findings of the present study did not support the use of MAO-B as a biological marker for aggression-related personality traits or as a predictor for violent recidivism among violent offenders.
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| 6. |
- Krupanek, Janusz, et al.
(author)
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Sectoral Guidance for Chemicals Management in the Surface treatment of metals and plastics Industry : HAZBREF-project Activity 4.1 report
- 2021
-
Reports (other academic/artistic)abstract
- BackgroundThe main instrument on EU level to control industrial releases is the Industrial Emissions Directive (IED), particularly through the publication of BAT reference documents (BREFs) and related BAT Conclusions, which is the reference for setting the permit conditions throughout EU for IED installations. However, the BREFs published so far do not contain adequate information on specific hazardous chemicals used and released from industry which makes the control difficult for the industry and the permitting and supervising authorities.One of the case sectors in the HAZBREF project is the surface treatment of metals and plastics (STM). This sector was chosen due to the use of chemicals, potential emissions, the wide range of products as well as technological processes and the upcoming STM BREF review. The other HAZBREF case sectors are textile industry and chemical industry which are addressed in separate reports.The lack of knowledge on the use and flow of specific hazardous chemicals in the industrial processes makes chemical control and reduction measures difficult. The problem is that often neither plant operators nor authorities know which substances are relevant to be treated and which handling measures are needed. Surface treatment of metals and plastics is covered by the STM BREF document, published in 2006. According to the last work programme of the EIPPCB the review of the EU STM BREF is planned to start in 2021.Purpose of the documentThis sectoral guidance contains information on uses of hazardous chemicals, the best practices in chemical management and recommendations on enhancing the permitting process in the STM sector. This document sums up the findings from HAZBREF project and is based on industrial case studies, interviews with authorities and expert judgment. The aim is to describe good practices in chemical management to be utilized by STM installations as well as environmental and chemical authorities. These include technical, organisational and management aspects and concrete tools supporting chemical management.The report addresses the STM sector as a whole in Europe, although the main part of the findings is generated from HAZBREF case installation and other experiences in the Baltic Sea Region. The document provides also general descriptions of BAT proposals related to management of hazardous chemicals and substances. These findings of the guidance will feed into in the forthcoming revision of the STM BREF. They are also to be used for HELCOM recommendations on how to reduce the discharge of hazardous substances into the Baltic Sea.Moreover, the document provides an overview of applicable legal requirements, procedures and other obligations of installation operators regarding use of chemicals and releases of hazardous substances. This includes guidance for tools to identify and assess relevant hazardous substances used and released from the STM installations.Main findings and proposalsImprovement of chemical management systemA Chemical Management System provides a systematic way of managing chemicals through the whole process on the site. Most of the companies have implemented quality management standards such as ISO 9000, ISO 14000, EMAS and integrated EHS programs which also address certain aspects of chemical management. The quality of chemical management systems in the companies differs depending on the scale of operation, ownership and awareness. Integration of good practices of chemical management within already implemented management systems strengthens the ability to reduce environmental risks. HAZBREF project strongly recommends the establishment and regular use of a chemical management system at IED installations.Development of a chemical inventoryThe establishment and maintenance of a chemical inventory is an importantprerequisite for effective and responsible chemicals management in the STMsector. All chemicals and raw materials along with information on their propertiesused in all processes and activities at the site should be listed in a database. Such adatabase is a key part of chemical management allowing for systematic riskassessment, management of chemicals flows and their storage. The information in the chemical list/database must be searchable and should be updated regularly. Most of the information needed is available in the safety datasheets (SDS). If some information is missing from the SDS, the supplier should be asked to provide this. Good routines to handle new and updated SDSs are crucial to have an up to date and reliable chemical database. These routines should involve on-site handling and updates as well as communication with suppliers on how SDSs are delivered. Well-managed chemical inventories can significantly simplify the environmental permit application process both for the operators and the permitting authorities.Better use of Chemical Management Tools and training of stafNumerous references and tools are available to support STM companies and competent authorities in implementing the good chemical management required in the IED. HAZBREF recommends that operators use proper tools for risk assessment and evaluation of the efficiency of chemical management.Use and improvement of risk assessment tools such as extended SDS and material flow analysis should be promoted among installation operators in this respect. The HAZBREF project has developed a comprehensive tool that helps the operators to identify the site-specific hazardous substances that should be considered in strategic and operational decisions.Awareness raising and training of staff in the use of chemical management tools and systems is crucial for implementation of good chemical management practices at the installations.SubstitutionA regular check aiming at identifying potentially new available and safer alternatives to the hazardous chemicals used is an important measure to minimise chemical risks at the installation. A successful substitution work can be performed in four stages: - Identification of hazardous substances - Screening for possible alternatives - Evaluation and choice of alternatives and Development of new alternatives.Substitution can be aimed for any hazardous chemical used at installation level where it is needed in order to protect environment or human health. However, regrettable substitution (i.e. move to use new chemical that is equally or more hazardous than the substituted chemical or results in cross-media effects) must be avoided.Assessment and improvement of SDSEfficient chemicals management requires high quality of the Safety Data Sheets (SDS). The SDS should sufficiently describe the chemical properties and include information about exposure (including use and emissions), eco-toxicology and proper storage and handling. A SDS must also contain information on whether the chemical product contains substances on the SVHC list, priority substances under the Water Framework Directive WFD and the POPs convention. In case a chemical supplier fails to provide a SDS of sufficient quality, it is the duty of both the operator and the competent authority to demand the missing information. This is already required by law in some countries, e.g. Germany. It is also important that the operators know how to extract and consolidate the relevant information from the SDS to their permit applications and verify the quality of different information sources.The development of an extended SDS including exposure scenarios and improved data on environmental effects would facilitate better risk assessment of individual chemicals used in specific processes. This would lead to more efficient monitoring and help focusing on substances of concern. Improved SDSs for raw materials with information on impurities or additives would facilitate more complete chemical inventories.Continuous improvement of BAT implementation The implementation of BAT needs to be continuously monitored and improved at the installation considering site specific technological, economical and environmental aspects. The findings from Polish HAZBREF case studies is that fulfilment of BAT requirements can be challenging if all improvements need to be done in a short time period. For example, closed-loop systems are considered necessary additional process-integrated techniques that it is important to implementstep by step in the installations.Circular economyThe STM sector is a significant user of non-renewable resources (metals), and recycling of recovered metal containing materials such as metal substrates orelectrolytes back to the process is good practice. Such recovery processes are widely used for basic metals, such as zinc, copper and nickel, which are used as valuable secondary raw materials SRM. High costs of recovery processes and high energy consumption as well as the variety of chemicals and metals used in STM processes often hinders recycling. In cases where recycling is not feasible, pretreatment of contaminated waste water on site and subsequent off-site treatment of generated metal containing sludges is standard practice.Permitting processBeside best practices in chemical management, the project also elaborated recommendations on enhancing the permitting process in the STM sector. It can be concluded that the existing general structure and content of the permit application procedures are as such sufficient to deal with hazardous substances and chemicals. Nevertheless, in practice the permit process could be improved with more communication between the applicant and the permitting authority during the application phase. More co-operation between chemical, environmental and occupational health authorities is suggested to achieve a smooth information flow and reduce double work regarding requirements under different legislations concerning chemicals and hazardous substances. In some countries, for example in Finland, the supervising practices in different parts of a given country need harmonising s
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| 7. |
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| 8. |
- Mattsson, Niklas, 1979, et al.
(author)
-
Amyloid-β metabolism in Niemann-Pick C disease models and patients.
- 2012
-
In: Metabolic brain disease. - : Springer Science and Business Media LLC. - 1573-7365 .- 0885-7490. ; 27:4, s. 573-85
-
Journal article (peer-reviewed)abstract
- Niemann-Pick type C (NPC) is a progressive neurodegenerative lysosomal disease with altered cellular lipid trafficking. The metabolism of amyloid-β (Aβ) - previously mainly studied in Alzheimer's disease - has been suggested to be altered in NPC. Here we aimed to perform a detailed characterization of metabolic products from the amyloid precursor protein (APP) in NPC models and patients. We used multiple analytical technologies, including immunoassays and immunoprecipitation followed by mass spectrometry (IP-MS) to characterize Aβ peptides and soluble APP fragments (sAPP-α/β) in cell media from pharmacologically (U18666A) and genetically (NPC1 ( -/- ) ) induced NPC cell models, and cerebrospinal fluid (CSF) from NPC cats and human patients. The pattern of Aβ peptides and sAPP-α/β fragments in cell media was differently affected by NPC-phenotype induced by U18666A treatment and by NPC1 ( -/- ) genotype. U18666A treatment increased the secreted media levels of sAPP-α, AβX-40 and AβX-42 and reduced the levels of sAPP-β, Aβ1-40 and Aβ1-42, while IP-MS showed increased relative levels of Aβ5-38 and Aβ5-40 in response to treatment. NPC1 ( -/- ) cells had reduced media levels of sAPP-α and Aβ1-16, and increased levels of sAPP-β. NPC cats had altered CSF distribution of Aβ peptides compared with normal cats. Cats treated with the potential disease-modifying compound 2-hydroxypropyl-β-cyclodextrin had increased relative levels of short Aβ peptides including Aβ1-16 compared with untreated cats. NPC patients receiving β-cyclodextrin had reduced levels over time of CSF Aβ1-42, AβX-38, AβX-40, AβX-42 and sAPP-β, as well as reduced levels of the axonal damage markers tau and phosphorylated tau. We conclude that NPC models have altered Aβ metabolism, but with differences across experimental systems, suggesting that NPC1-loss of function, such as in NPC1 ( -/- ) cells, or NPC1-dysfunction, seen in NPC patients and cats as well as in U18666A-treated cells, may cause subtle but different effects on APP degradation pathways. The preliminary findings from NPC cats suggest that treatment with cyclodextrin may have an impact on APP processing pathways. CSF Aβ, sAPP and tau biomarkers were dynamically altered over time in human NPC patients.
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| 9. |
- Mattsson, Niklas, 1979, et al.
(author)
-
Cerebrospinal Fluid Microglial Markers in Alzheimer's Disease: Elevated Chitotriosidase Activity but Lack of Diagnostic Utility
- 2011
-
In: NeuroMolecular Medicine. - : Springer Science and Business Media LLC. - 1535-1084 .- 1559-1174. ; 13:2, s. 151-159
-
Journal article (peer-reviewed)abstract
- Activated microglial cells, which are the resident macrophages of the central nervous system, surround amyloid beta-plaques in Alzheimer's disease (AD) brains. Inflammation including microglial activation may contribute in AD pathogenesis, and biomarkers for this process may thus be of value to study AD pathogenesis and might facilitate development of therapies targeting these cells. We therefore examined cerebrospinal fluid (CSF) biomarkers in patients with AD, other dementias, mild cognitive impairment and in healthy controls. Samples were analyzed for markers with known association to macrophage activity, including chitotriosidase, YKL-40 (CHI3L1, HC gp-39) and chemokine CC motif ligand 2 (CCL2, MCP1). Patients with AD had higher chitotriosidase activity than controls and patients with stable mild cognitive impairment, consistent with the presence of activated microglial cells in AD brains, but with large overlaps between groups. CCL2 and YKL-40 concentrations did not differ among groups. Microglial markers are unlikely to be useful for AD diagnosis, but might be useful for identification of distinct subgroups of patients, and for the development and implementation of drugs targeting microglial pathology.
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| 10. |
- Mattsson, Niklas, 1979, et al.
(author)
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Elevated cerebrospinal fluid levels of prostaglandin E2 and 15-(S)-hydroxyeicosatetraenoic acid in multiple sclerosis.
- 2009
-
In: Journal of internal medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 265:4, s. 459-64
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: To test the hypothesis that the arachodinic acid metabolites prostaglandin E2 (PGE2) and 15-(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in cerebrospinal fluid (CSF) are elevated and reflect neuroinflammation and degenerative changes in multiple sclerosis (MS). PATIENTS AND METHODS: We measured PGE2 and 15(S)-HETE concentrations, as well as markers of axonal and astroglial injury in CSF from 46 MS patients, 46 healthy siblings and 50 controls. RESULTS: We found elevated levels of both PGE2 and 15(S)-HETE in MS compared with the control and sibling groups. Siblings had lower PGE2 levels and higher 15(S)-HETE levels than controls. There were no correlations between either PGE2 or 15(S)-HETE and clinical scores of MS severity or biochemical markers of axonal or astroglial injury. CONCLUSION: These data suggest no direct involvement of PGE2 and 15(S)-HETE in the MS disease process. Rather, the elevated levels reflect a general up-regulation of arachidonic acid metabolism and neuroinflammation.
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| 11. |
- Mattsson, Niklas, 1979, et al.
(author)
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{gamma}-Secretase-dependent amyloid-{beta} is increased in Niemann-Pick type C: A cross-sectional study.
- 2011
-
In: Neurology. - 0028-3878. ; 76:4, s. 366-72
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by intracellular accumulation of lipids such as cholesterol and glycosphingolipids in endosomes and lysosomes. This accumulation induces progressive degeneration of the nervous system. NPC shows some intriguing similarities with Alzheimer disease (AD), including neurofibrillary tangles, but patients with NPC generally lack amyloid-β (Aβ) plaques. Lipids affect γ-secretase-dependent amyloid precursor protein (APP) metabolism that generates Aβ in vitro, but this has been difficult to prove in vivo. Our aim was to assess the effect of altered lipid constituents in neuronal membranes on amyloidogenic APP processing in humans. METHODS: We examined Aβ in CSF from patients with NPC (n = 38) and controls (n = 14). CSF was analyzed for Aβ(38), Aβ(40), Aβ(42), α-cleaved soluble APP, β-cleaved soluble APP, total-tau, and phospho-tau. RESULTS: Aβ release was markedly increased in NPC, with a shift toward the Aβ(42) isoform. Levels of α- and β-cleaved soluble APP were similar in patients and controls. Patients with NPC had increased total-tau. Patients on treatment with miglustat (n = 18), a glucosylceramide synthase blocker, had lower Aβ(42) and total-tau than untreated patients. CONCLUSION: Increased CSF levels of Aβ(38), Aβ(40), and Aβ(42) and unaltered levels of β-cleaved soluble APP are consistent with increased γ-secretase-dependent Aβ release in the brains of patients with NPC. These results provide the first in vivo evidence that neuronal lipid accumulation facilitates γ-secretase-dependent Aβ production in humans and may be of relevance to AD pathogenesis.
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| 12. |
- Mattsson, Niklas, 1979, et al.
(author)
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Miglustat treatment may reduce cerebrospinal fluid levels of the axonal degeneration marker tau in niemann-pick type C.
- 2012
-
In: JIMD reports. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 2192-8304. ; 3, s. 45-52
-
Journal article (peer-reviewed)abstract
- Introduction: Niemann-Pick disease type C (NPC) is a lysosomal storage disorder that leads to progressive neurodegeneration. The glucosylceramide synthase blocker miglustat is being used to treat NPC, but monitoring of disease progression and treatment response is difficult. NPC patients have elevated cerebrospinal fluid (CSF) levels of total-tau (T-tau) indicating axonal degeneration, and increased CSF amyloid β (Aβ) indicating abnormal brain amyloid metabolism, but it is unknown if start of miglustat treatment affects these biomarker levels. Methods: Biomarkers were measured in serial CSF samples from NPC patients who started miglustat between samplings (N=5), were untreated at both samplings (N=5) or received treatment during the whole study (N=6) (median time between samplings 309 days [range 175-644]). CSF was analyzed for Aβ(38), Aβ(40), Aβ(42), α-cleaved soluble APP, β-cleaved soluble APP, T-tau and phospho-tau. Results: T-tau levels decreased in patients who started miglustat treatment (median 955 [range 338-1,271]ng/L at baseline vs. 382 [187-736]ng/L at follow-up, p=0.043). Untreated patients and continuously treated patients had stable levels (p>0.05). No changes were seen in the other biomarkers. Conclusion: Reduced CSF T-tau suggests that miglustat treatment might affect axonal degeneration in NPC. However, the results must be interpreted with caution and verified in future studies, since this pilot study was small, treatment was not randomized, and patients starting treatment had higher baseline CSF T-tau than untreated patients.
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| 13. |
- Molander-Melin, Marie, 1965, et al.
(author)
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Structural membrane alterations in Alzheimer brains found to be associated with regional disease development; increased density of gangliosides GM1 and GM2 and loss of cholesterol in detergent-resistant membrane domains
- 2005
-
In: J Neurochem. - : Wiley. - 0022-3042 .- 1471-4159. ; 92:1, s. 171-82
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Journal article (peer-reviewed)abstract
- The formation of neurotoxic beta-amyloid fibrils in Alzheimer's disease (AD) is suggested to involve membrane rafts and to be promoted, in vitro, by enriched concentrations of gangliosides, particularly GM1, and the cholesterol therein. In our study, the presence of rafts and their content of the major membrane lipids and gangliosides in the temporal cortex, reflecting late stages of AD pathology, and the frontal cortex, presenting earlier stages, has been investigated. Whole tissue and isolated detergent-resistant membrane fractions (DRMs) were analysed from 10 AD and 10 age-matched control autopsy brains. DRMs from the frontal cortex of AD brains contained a significantly higher concentration (micromol/micromol glycerophospholipids), of ganglioside GM1 (22.3 +/- 4.6 compared to 10.3 +/- 6.4, p <0.001) and GM2 (2.5 +/- 1.0 compared to 0.55 +/- 0.3, p <0.001). Similar increases of these gangliosides were also seen in DRMs from the temporal cortex of AD brains, which, in addition, comprised significantly lower proportions of DRMs. Moreover, these remaining rafts were depleted in cholesterol (from 1.5 +/- 0.2 to 0.6 +/- 0.3 micromol/micromol glycerophospholipids, p <0.001). In summary, we found an increased proportion of GM1 and GM2 in DRMs, and accelerating plaque formation at an early stage, which may gradually lead to membrane raft disruptions and thereby affect cellular functions associated with the presence of such membrane domains.
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| 14. |
- Pernber, Zarah, 1969, et al.
(author)
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Altered Distribution of the Gangliosides GM1 and GM2 in Alzheimer's Disease
- 2012
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In: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 33:2-3, s. 174-188
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Journal article (peer-reviewed)abstract
- Background: Alzheimer's disease (AD) is a neurodegenerative disorder where beta-amyloid tends to aggregate and form plaques. Lipid raft-associated ganglioside GM1 has been suggested to facilitate beta-amyloid aggregation; furthermore, GM1 and GM2 are increased in lipid rafts isolated from cerebral cortex of AD cases. Aim/Method: The distribution of GM1 and GM2 was studied by immunohistochemistry in the frontal and temporal cortex of AD cases. Frontotemporal dementia (FTD) was included as a contrast group. Results: The distribution of GM1 and GM2 changes during the process of AD (n = 5) and FTD (n = 3) compared to controls (n = 5). Altered location of the GM1-positive small circular structures seems to be associated with myelin degradation. In the grey matter, the staining of GM1-positive plasma membranes might reflect neuronal loss in the AD/FTD tissue. The GM1-positive compact bundles were only visible in cells located in the AD frontal grey matter, possibly reflecting raft formation of GM1 and thus a pathological connection. Furthermore, our results suggest GM2 to be enriched within vesicles of pyramidal neurons of the AD/FTD brain. Conclusion: Our study supports the biochemical finding of ganglioside accumulation in cellular membranes of AD patients and shows a redistribution of these molecules. Copyright (C) 2012 S. Karger AG, Basel
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| 15. |
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| 16. |
- Tullberg, Mats, 1965, et al.
(author)
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Cerebrospinal fluid markers before and after shunting in patients with secondary and idiopathic normal pressure hydrocephalus.
- 2008
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In: Cerebrospinal fluid research. - : Springer Science and Business Media LLC. - 1743-8454. ; 5
-
Journal article (peer-reviewed)abstract
- ABSTRACT: BACKGROUND: The aim of this study was to explore biochemical changes in the cerebrospinal fluid (CSF) induced by shunt surgery and the relationship between these changes and clinical improvement. METHODS: We measured clinical symptoms and analysed lumbar CSF for protein content, neurodegeneration and neurotransmission markers in patients with secondary (SNPH, n = 17) and idiopathic NPH (INPH, n = 18) before and 3 months after shunt surgery. Patients were divided into groups according to whether or not there was improvement in clinical symptoms after surgery. RESULTS: Preoperatively, the only pathological findings were elevated neurofilament protein (NFL), significantly more so in the SNPH patients than in the INPH patients, and elevated albumin content. Higher levels of NFL correlated with worse gait, balance, wakefulness and neuropsychological performance. Preoperatively, no differences were seen in any of the CSF biomarkers between patients that improved after surgery and those that did not improve. Postoperatively, a greater improvement in gait and balance performance correlated with a more pronounced reduction in NFL. Levels of albumin, albumin ratio, neuropeptide Y, vasoactive intestinal peptide and ganglioside GD3 increased significantly after shunting in both groups. In addition, Gamma amino butyric acid increased significantly in SNPH and tau in INPH. CONCLUSION: We conclude that a number of biochemical changes occur after shunt surgery, but there are no marked differences between the SNPH and INPH patients. The results indicate that NFL may be a marker that can predict a surgically reversible state in NPH.
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| 17. |
- Tullberg, Mats, 1965, et al.
(author)
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CSF sulfatide distinguishes between normal pressure hydrocephalus and subcortical arteriosclerotic encephalopathy.
- 2000
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In: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 0022-3050. ; 69:1, s. 74-81
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Journal article (peer-reviewed)abstract
- To examine the CSF concentrations of molecules reflecting demyelination, neuronal and axonal degeneration, gliosis, monoaminergic neuronal function, and aminergic and peptidergic neurotransmission in a large series of patients with normal pressure hydrocephalus (NPH) or subcortical arteriosclerotic encephalopathy (SAE), to elucidate pathogenic, diagnostic, and prognostic features.CSF concentrations of glycosphingolipid (sulfatide), proteins (neurofilament triplet protein (NFL), glial fibrillary acidic protein (GFAP)), neuropeptides (vasoactive intestinal peptide (VIP), 4-aminobutyric acid (GABA)), and monoamines (homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA), 4-hydroxy-3-methoxyphenylglycol (HMPG)) were analysed in 43 patients with NPH and 19 patients with SAE. The diagnoses of NPH and SAE were based on strict criteria and patients with NPH were subsequently operated on. Twelve clinical variables, psychometric tests measuring perceptual speed, accuracy, learning, and memory and a psychiatric evaluation were performed in all patients and before and after a shunt operation in patients with NPH.The CSF sulfatide concentration was markedly increased in patients with SAE (mean 766, range 300-3800 nmol/l) compared with patients with NPH (mean 206, range 50-400 nmol/l) (p<0.001). 5-HIAA, GABA, and VIP in CSF were higher in patients with SAE than in patients with NPH. The patients with NPH with cerebrovascular aetiology had higher sulfatide concentrations and a poorer outcome after shunt surgery than patients with NPH with other aetiologies.The pathogenesis of the white matter changes in NPH and SAE is different and ischaemic white matter changes can be a part of the NPH state. The markedly increased CSF sulfatide concentrations in patients with SAE indicate ongoing demyelination as an important pathophysiological feature of SAE. The CSF sulfatide concentration distinguished between patients with SAE and those with NPH with a sensitivity of 74% and a specificity of 94%, making it an important diagnostic marker.
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| 18. |
- Tullberg, Mats, 1965, et al.
(author)
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Ventricular cerebrospinal fluid neurofilament protein levels decrease in parallel with white matter pathology after shunt surgery in normal pressure hydrocephalus.
- 2007
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In: European journal of neurology : the official journal of the European Federation of Neurological Societies. - 1468-1331. ; 14:3, s. 248-54
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Journal article (peer-reviewed)abstract
- Normal pressure hydrocephalus (NPH) is characterized by disturbed cerebrospinal fluid (CSF) dynamics and white matter lesions (WML). Although the morphology of these lesions is described, little is known about the biochemistry. Our aim was to explore the relationship between ventricular CSF markers, periventricular WML and postoperative clinical outcome in patients with NPH. We analysed lumbar and ventricular concentrations of 10 CSF markers, 12 clinical symptoms and signs, magnetic resonance imaging (MRI) periventricular white matter hyperintensities (PVH) and ventricular size before and 3 months after shunt surgery in 35 patients with NPH. Higher ventricular CSF neurofilament protein (NFL), an axonal marker, correlated with more extensive PVH. A larger postoperative reduction in NFL correlated with larger reduction in PVH and a more pronounced overall improvement. Albumin ratio, HMPG, NPY, VIP and GD3 increased postoperatively whereas NFL, tau and HVA decreased. Variations in ventricular size were not associated with CSF concentrations of any marker. We conclude that NPH is characterized by an ongoing periventricular neuronal dysfunction seen on MRI as PVH. Clinical improvement after shunt surgery is associated with CSF changes indicating a restitution of axonal function. Other biochemical effects of shunting may include increased monoaminergic and peptidergic neurotransmission, breakdown of blood brain barrier function, and gliosis.
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| 19. |
- Vasiljevic, Natasa, et al.
(author)
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The Bcl-xL inhibitor of apoptosis is preferentially expressed in cutaneous squamous cell carcinoma compared with that in keratoacanthoma.
- 2009
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 124, s. 2361-2366
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Journal article (peer-reviewed)abstract
- Keratoacanthoma (KA) is difficult to histologically distinguish from squamous cell carcinoma (SCC). Therefore, although KA is a benign self-resolving skin lesion, KA is commonly treated as SCC. Biomarkers to distinguish KA and SCC would thus be desirable. In search for specific markers, paraffin-embedded tissue samples from 25 SCC and 64 KA were arranged in a tissue microarray (TMA) and stained for immunologic cell-markers CD3, CD20 and CD68 as well as for proteins considered of relevance in tumorgenesis, namely NFkappaB/p65, IkappaB-alpha, STAT3, p53, TRAP-1, pRB, phosphorylated pRb, Cyld, p21, p16(INK4), Survivin, Bcl-xL, Caspase 3, Bak, FLK-1/VEGF-r2 and Ki-67. In addition, the tumors were tested for presence of human papillomavirus by PCR. We detected that the two lesions differed significantly in expression of Bcl-xL which was present in 84% of the SCC compared with only 15% in the KA (p < 0.001). The lower expression of the antiapoptotic protein Bcl-xL in KA is consistent with a possible role of apoptosis in the regression of KA. (c) 2008 Wiley-Liss, Inc.
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| 20. |
- Winblad, S, et al.
(author)
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Cerebrospinal fluid tau and amyloid beta42 protein in patients with myotonic dystrophy type 1.
- 2008
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In: European journal of neurology : the official journal of the European Federation of Neurological Societies. - : Wiley. - 1468-1331. ; 15:9, s. 947-52
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Journal article (peer-reviewed)abstract
- BACKGROUND: Myotonic dystrophy type 1 (DM1) is associated with brain morphology changes including neurofibrillary degeneration. METHODS: We have examined cerebrospinal fluid (CSF) markers indicative of neuronal degeneration and amyloidogenesis; total tau (T-tau), phosphorylated tau (P-tau) and beta amyloid 1-42 (Abeta42), in 32 patients with DM1. RESULTS AND CONCLUSIONS: Associations between CSF markers and CTG repeat expansion size, brain MRI findings, and neuropsychological test results were analysed. As compared with matched controls Abeta42 was significantly decreased (P = 0.001), whilst levels of T-tau were increased (P < 0.001). No difference was found between measures considering P-tau levels. At present the clinical implications of these findings is unclear, because of an overlap between CSF values of DM1 patients and healthy controls, but also regarding modest associations between CSF markers and other measures. However notably, the Tau pathology, as seen in DM1, differs from Alzheimers disease, considering the lack of increased levels of P-tau.
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