Digitala Vetenskapliga Arkivet

Change search
Refine search result
1234567 1 - 50 of 5414
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Aalto, K
    et al.
    Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
    Korhonen, L
    Department of Neuroscience, Neurobiology, Uppsala University, Box 587, S-75123, Uppsala, Sweden.
    Lahdenne, P
    Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
    Pelkonen, P
    Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
    Lindholm, D
    Department of Neuroscience, Neurobiology, Uppsala University, Box 587, S-75123, Uppsala, Sweden.
    Nerve growth factor in serum of children with systemic lupus erythematosus is correlated with disease activity2002In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 20, no 3, p. 136-139Article in journal (Refereed)
    Abstract [en]

    Nerve growth factor (NGF) is a neurotrophic factor, which is expressed both in the nervous system and in peripheral organs. NGF is also present in mast cells, and in B- and T-lymphocytes, and may play a role in the immune cell development and differentiation. Various cytokines have been shown to affect NGF expression, and NGF is elevated in inflammation and in some autoimmune diseases. Here we have studied NGF concentrations in serum of pediatric patients with systemic lupus erythematosus (SLE) using a two-site enzyme-linked immunosorbent assay (ELISA). We have further correlated the levels of NGF to the inflammatory state of the disease. The mean value of serum NGF in SLE patients was significantly increased compared with controls (3346 vs 627 pg/ml). There was a correlation between the activity of SLE and the levels of NGF. The results show that NGF is elevated in childhood SLE and that the levels are correlated with disease activity. The present results suggest that NGF may play a role in the pathogenesis of SLE and may have a prognostic value in evaluating the course of the disease and in outlining the medication. (C) 2002 Elsevier Science Ltd. All rights reserved.

  • 2.
    Aare, Sudhakar Reddy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Intensive Care Unit Muscle Wasting: Skeletal Muscle Phenotype and Underlying Molecular Mechanisms2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Acute quadriplegic myopathy (AQM), or critical illness myopathy, is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients characterized by generalized muscle wasting and weakness of limb and trunk muscles. A preferential loss of the thick filament protein myosin is considered pathognomonic of this disorder, but the myosin loss is observed relatively late during the disease progression. In attempt to explore the potential role of factors considered triggering AQM in sedated mechanically ventilated (MV) ICU patients, we have studied the early effects, prior to the myosin loss, of neuromuscular blockade (NMB), corticosteroids (CS) and sepsis separate or in combination in a porcine experimental ICU model. Specific interest has been focused on skeletal muscle gene/protein expression and regulation of muscle contraction at the muscle fiber level. This project aims at improving our understanding of the molecular mechanisms underlying muscle specific differences in response to the ICU intervention and the role played by the different triggering factors.

    The sparing of masticatory muscle fiber function was coupled to an up-regulation of heat shock protein genes and down-regulation of myostatin are suggested to be key factors in the relative sparing of masticatory muscles. Up-regulation of chemokine activity genes and down-regulation of heat shock protein genes play a significant role in the limb muscle dysfunction associated with sepsis. The effects of corticosteroids in the development of limb muscle weakness reveals up-regulation of kinase activity and transcriptional regulation genes and the down-regulation of heat shock protein, sarcomeric, cytoskeletal and oxidative stress responsive genes. In contrast to limb and craniofacial muscles, the respiratory diaphragm muscle responded differently to the different triggering factors. MV itself appears to play a major role for the diaphragm muscle dysfunction. By targeting these genes, future experiments can give an insight into the development of innovative treatments expected at protecting muscle mass and function in critically ill ICU patients.

    Download full text (pdf)
    fulltext
  • 3.
    Aaseth, Jan
    et al.
    Innlandet Hospital Trust, Norway; Hedmark University of Appl Science, Norway.
    Alexander, Jan
    Norwegian Institute Public Heatlh, Norway; Norwegian University of Life Science NMBU, Norway.
    Bjorklund, Geir
    Council Nutr and Environm Med, Norway.
    Hestad, Knut
    Innlandet Hospital Trust, Norway; Hedmark University of Appl Science, Norway.
    Dusek, Petr
    Charles University of Prague, Czech Republic; Charles University of Prague, Czech Republic; Gen University Hospital Prague, Czech Republic.
    Roos, Per M.
    Karolinska Institute, Sweden; St Goran Hospital, Sweden.
    Alehagen, Urban
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Treatment strategies in Alzheimers disease: a review with focus on selenium supplementation2016In: Biometals, ISSN 0966-0844, E-ISSN 1572-8773, Vol. 29, no 5, p. 827-839Article in journal (Refereed)
    Abstract [en]

    Alzheimers disease (AD) is a neurodegenerative disorder presenting one of the biggest healthcare challenges in developed countries. No effective treatment exists. In recent years the main focus of AD research has been on the amyloid hypothesis, which postulates that extracellular precipitates of beta amyloid (A beta) derived from amyloid precursor protein (APP) are responsible for the cognitive impairment seen in AD. Treatment strategies have been to reduce A beta production through inhibition of enzymes responsible for its formation, or to promote resolution of existing cerebral A beta plaques. However, these approaches have failed to demonstrate significant cognitive improvements. Intracellular rather than extracellular events may be fundamental in AD pathogenesis. Selenate is a potent inhibitor of tau hyperphosphorylation, a critical step in the formation of neurofibrillary tangles. Some selenium (Se) compounds e.g. selenoprotein P also appear to protect APP against excessive copper and iron deposition. Selenoproteins show anti-inflammatory properties, and protect microtubules in the neuronal cytoskeleton. Optimal function of these selenoenzymes requires higher Se intake than what is common in Europe and also higher intake than traditionally recommended. Supplementary treatment with N-acetylcysteine increases levels of the antioxidative cofactor glutathione and can mediate adjuvant protection. The present review discusses the role of Se in AD treatment and suggests strategies for AD prevention by optimizing selenium intake, in accordance with the metal dysregulation hypothesis. This includes in particular secondary prevention by selenium supplementation to elderly with mild cognitive impairment.

    Download full text (pdf)
    fulltext
  • 4.
    Abas Hashmi, Zaynab
    et al.
    University of Skövde, School of Bioscience.
    Pettersson, Wilma
    University of Skövde, School of Bioscience.
    The Structural Brain Correlates of Psychopathy and Violent Crime2023Independent thesis Basic level (degree of Bachelor), 15 credits / 22,5 HE creditsStudent thesis
    Abstract [en]

    Psychopathy is a frequently reported personality trait among violent offenders, and psychopaths have a higher rate of recidivism than inmates without psychopathic features. This systematic review aimed to investigate whether structural brain differences, measured with magnetic resonance imaging, are observed in violent offenders with psychopathy compared to violent offenders without psychopathy or healthy non-violent controls. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search utilised the academic databases Web of Science and Medline EBSCO and included original peer-reviewed articles written in English and published between 2013 and 2023. Seven articles fulfilling the inclusion criteria were selected for the review. The findings indicated that there are structural differences between violent psychopaths compared to non-violent psychopaths and healthy controls, such as reduced grey matter volume in the prefrontal cortical areas, posterior cingulate cortex and precuneus, and striatal and limbic regions. Further, the degree of structural brain differences in psychopaths correlated with the degree of psychopathic traits. The structural differences found in the brains of violent psychopaths can provide insight into the neurobiological basis and neural mechanisms of psychopathy and elucidate how changes in brain morphology relate to antisocial behaviour and psychopathic personality traits. In addition, the evidence of structural abnormalities in the brain of psychopaths may help develop targeted treatments that could reduce the risk of psychopathic individuals turning to crime and violence or committing repeated violent crimes. 

    Download full text (pdf)
    fulltext
  • 5. Abdelhak, Ahmed
    et al.
    Barba, Lorenzo
    Romoli, Michele
    Benkert, Pascal
    Conversi, Francesco
    D'Anna, Lucio
    Masvekar, Ruturaj R
    Bielekova, Bibiana
    Prudencio, Mercedes
    Petrucelli, Leonard
    Meschia, James F
    Erben, Young
    Furlan, Roberto
    De Lorenzo, Rebecca
    Mandelli, Alessandra
    Sutter, Raoul
    Hert, Lisa
    Epple, Varenka
    Marastoni, Damiano
    Sellner, Johann
    Steinacker, Petra
    Aamodt, Anne Hege
    Heggelund, Lars
    Dyrhol-Riise, Anne Margarita
    Virhammar, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurology.
    Fällmar, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Rostami, Elham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurosurgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Acquired brain injury.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurology.
    Blennow, Kaj
    Zetterberg, Henrik
    Tumani, Hayrettin
    Sacco, Simona
    Green, Ari J
    Otto, Markus
    Kuhle, Jens
    Ornello, Raffaele
    Foschi, Matteo
    Abu-Rumeileh, Samir
    Prognostic performance of blood neurofilament light chain protein in hospitalized COVID-19 patients without major central nervous system manifestations: an individual participant data meta-analysis.2023In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 270, no 7, p. 3315-3328Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: To investigate the prognostic value of blood neurofilament light chain protein (NfL) levels in the acute phase of coronavirus disease 2019 (COVID-19).

    METHODS: We conducted an individual participant data (IPD) meta-analysis after screening on MEDLINE and Scopus to May 23rd 2022. We included studies with hospitalized adult COVID-19 patients without major COVID-19-associated central nervous system (CNS) manifestations and with a measurement of blood NfL in the acute phase as well as data regarding at least one clinical outcome including intensive care unit (ICU) admission, need of mechanical ventilation (MV) and death. We derived the age-adjusted measures NfL Z scores and conducted mixed-effects modelling to test associations between NfL Z scores and other variables, encompassing clinical outcomes. Summary receiver operating characteristic curves (SROCs) were used to calculate the area under the curve (AUC) for blood NfL.

    RESULTS: We identified 382 records, of which 7 studies were included with a total of 669 hospitalized COVID-19 cases (mean age 66.2 ± 15.0 years, 68.1% males). Median NfL Z score at admission was elevated compared to the age-corrected reference population (2.37, IQR: 1.13-3.06, referring to 99th percentile in healthy controls). NfL Z scores were significantly associated with disease duration and severity. Higher NfL Z scores were associated with a higher likelihood of ICU admission, need of MV, and death. SROCs revealed AUCs of 0.74, 0.80 and 0.71 for mortality, need of MV and ICU admission, respectively.

    CONCLUSIONS: Blood NfL levels were elevated in the acute phase of COVID-19 patients without major CNS manifestations and associated with clinical severity and poor outcome. The marker might ameliorate the performance of prognostic multivariable algorithms in COVID-19.

  • 6.
    Abdollahi, Nyayesh
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Modifierad constraint-induced movement therapy förbättrar livskvalitet hos unga stroke-patienter2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 7. Abelein, Axel
    et al.
    Ciofi-Baffoni, Simone
    Mörman, Cecilia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Karolinska Institutet, Sweden.
    Kumar, Rakesh
    Giachetti, Andrea
    Piccioli, Mario
    Biverstål, Henrik
    Molecular Structure of Cu(II)-Bound Amyloid-β Monomer Implicated in Inhibition of Peptide Self-Assembly in Alzheimer’s Disease2022In: JACS Au, E-ISSN 2691-3704, Vol. 2, no 11, p. 2571-2584Article in journal (Refereed)
    Abstract [en]

    Metal ions, such as copper and zinc ions, have been shown to strongly modulate the self-assembly of the amyloid-β (Aβ) peptide into insoluble fibrils, and elevated concentrations of metal ions have been found in amyloid plaques of Alzheimer’s patients. Among the physiological transition metal ions, Cu(II) ions play an outstanding role since they can trigger production of neurotoxic reactive oxygen species. In contrast, structural insights into Cu(II) coordination of Aβ have been challenging due to the paramagnetic nature of Cu(II). Here, we employed specifically tailored paramagnetic NMR experiments to determine NMR structures of Cu(II) bound to monomeric Aβ. We found that monomeric Aβ binds Cu(II) in the N-terminus and combined with molecular dynamics simulations, we could identify two prevalent coordination modes of Cu(II). For these, we report here the NMR structures of the Cu(II)–bound Aβ complex, exhibiting heavy backbone RMSD values of 1.9 and 2.1 Å, respectively. Further, applying aggregation kinetics assays, we identified the specific effect of Cu(II) binding on the Aβ nucleation process. Our results show that Cu(II) efficiently retards Aβ fibrillization by predominately reducing the rate of fibril-end elongation at substoichiometric ratios. A detailed kinetic analysis suggests that this specific effect results in enhanced Aβ oligomer generation promoted by Cu(II). These results can quantitatively be understood by Cu(II) interaction with the Aβ monomer, forming an aggregation inert complex. In fact, this mechanism is strikingly similar to other transition metal ions, suggesting a common mechanism of action of retarding Aβ self-assembly, where the metal ion binding to monomeric Aβ is a key determinant. 

  • 8. Aberg, A. C.
    et al.
    Thorstensson, A.
    Tarassova, O.
    Halvorsen, Kjartan
    KTH, School of Technology and Health (STH).
    Calculations of mechanisms for balance control during narrow and single-leg standing in fit older adults: A reliability study2011In: Gait & Posture, ISSN 0966-6362, E-ISSN 1879-2219, Vol. 34, no 3, p. 352-357Article in journal (Refereed)
    Abstract [en]

    For older people balance control in standing is critical for performance of activities of daily living without falling. The aims were to investigate reliability of quantification of the usage of the two balance mechanisms M(1) 'moving the centre of pressure' and M(2) 'Segment acceleration' and also to compare calculation methods based on a combination of kinetic (K) and kinematic (Km) data, (K-Km), or Km data only concerning M(2). For this purpose nine physically fit persons aged 70-78 years were tested in narrow and single-leg standing. Data were collected by a 7-camera motion capture system and two force plates. Repeated measure ANOVA and Tukey's post hoc tests were used to detect differences between the standing tasks. Reliability was estimated by ICCs, standard error of measurement including its 95% Cl, and minimal detectable change, whereas Pearson's correlation coefficient was used to investigate agreement between the two calculation methods. The results indicated that for the tasks investigated, M(1) and M(2) can be measured with acceptable inter- and intrasession reliability, and that both Km and K-Km based calculations may be useful for M(2), although Km data may give slightly lower values. The proportional M(1) :M(2) usage was approximately 9:1, in both anterio-posterior (AP) and medio-lateral (ML) directions for narrow standing, and about 2:1 in the AP and of 1:2 in the ML direction in single-leg standing, respectively. In conclusion, the tested measurements and calculations appear to constitute a reliable way of quantifying one important aspect of balance capacity in fit older people.

  • 9.
    Abrahamsson, Sebastian
    University of Skövde, School of Bioscience.
    Neuroplasticity induced by exercise2017Independent thesis Basic level (degree of Bachelor), 15 credits / 22,5 HE creditsStudent thesis
    Abstract [en]

    As opposed to earlier beliefs, the brain is altering itself throughout an individual’s life. The process of functional or structural alterations is referred to as plasticity, and can be induced by several factors such as experience or physical exercise. In this thesis, the research area of experience-dependent plasticity, with focus on exercise-induced plasticity is examined critically. Evidence from a vast array of studies are reviewed and compared in order to find whether physical exercise can induce neural plasticity in the human brain, how it may be beneficial, and what some of the plausible mediators of exercise-induced plasticity are. The findings demonstrated in this thesis suggest that although there are knowledge gaps and limitations in the literature, physical exercise can indeed result in exhibited plasticity as well as being beneficial for the human brain in several ways.

    Download full text (pdf)
    fulltext
  • 10.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Rollman Waara, Erik
    BioArctic Neurosci AB, Stockholm, Sweden.
    Möller, Christer
    BioArctic Neurosci AB, Stockholm, Sweden.
    Söderberg, Linda
    BioArctic Neurosci AB, Stockholm, Sweden.
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. BioArctic Neuroscience AB, Stockholm, Sweden.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. BioArctic Neuroscience AB, Stockholm, Sweden.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury2018In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 28, no 4, p. 451-462Article in journal (Refereed)
    Abstract [en]

    Deposition of amyloid-β (Aβ) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for Aβ deposition including monomeric Aβ40, Aβ42 and Aβ oligomers/protofibrils, Aβ species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N-terminally intact and truncated Aβ40 and Aβ42, as well as Aβ oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n = 12; mean age 49.5 ± 19 years) due to life-threatening brain swelling/hemorrhage within one week post-injury. The TBI tissues were compared to post-mortem AD brains (n = 5), to post-mortem tissue of neurologically intact (NI) subjects (n = 4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n = 4). The levels of Aβ40 and Aβ42 were not elevated by TBI. The levels of Aβ oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P < 0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE ε3/4; n = 4) had increased levels of Aβ oligomers/protofibrils (P < 0.05) and of both N-terminally intact and truncated Aβ42 (P < 0.05) compared to APOE ε3/4-negative TBI patients (n = 8). Neuropathological analysis showed insoluble Aβ aggregates (commonly referred to as Aβ plaques) in three TBI patients, all of whom were APOE ε3/4 carriers. We conclude that soluble intermediary Aβ aggregates form rapidly after TBI, especially among APOE ε3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short- and long-term outcome in TBI.

  • 11.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Proteomic Differences Between Focal And Diffuse Traumatic Brain Injury In Human Brain Tissue2018In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A238-A239Article in journal (Other academic)
  • 12.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Proteomic differences between focal and diffuse traumatic brain injury in human brain tissue2018In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 6807Article in journal (Refereed)
    Abstract [en]

    The early molecular response to severe traumatic brain injury (TBI) was evaluated using biopsies of structurally normal-appearing cortex, obtained at location for intracranial pressure (ICP) monitoring, from 16 severe TBI patients. Mass spectrometry (MS; label free and stable isotope dimethyl labeling) quantitation proteomics showed a strikingly different molecular pattern in TBI in comparison to cortical biopsies from 11 idiopathic normal pressure hydrocephalus patients. Diffuse TBI showed increased expression of peptides related to neurodegeneration (Tau and Fascin, p < 0.05), reduced expression related to antioxidant defense (Glutathione S-transferase Mu 3, Peroxiredoxin-6, Thioredoxin-dependent peroxide reductase; p < 0.05) and increased expression of potential biomarkers (e.g. Neurogranin, Fatty acid-binding protein, heart p < 0.05) compared to focal TBI. Proteomics of human brain biopsies displayed considerable molecular heterogeneity among the different TBI subtypes with consequences for the pathophysiology and development of targeted treatments for TBI.

    Download full text (pdf)
    fulltext
  • 13.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Tenovuo, Olli
    Univ Turku, Turku Brain Injury Ctr, Turku, Finland; Turku Univ Hosp, Turku, Finland.
    Peul, Wilco
    Leiden Univ, HAGA, Neurosurg Ctr Holland, HMC, The Hague, Netherlands; Leiden Univ, LUMC, Neurosurg Ctr Holland, HMC, The Hague, Netherlands; Leiden Univ, HAGA, Neurosurg Ctr Holland, HMC, Leiden, Netherlands; Leiden Univ, LUMC, Neurosurg Ctr Holland, HMC, Leiden, Netherlands.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery. Lund Univ, Skåne Univ Hosp, Dept Clin Sci Lund, Neurosurg, Lund, Sweden.
    "Omics" in traumatic brain injury: novel approaches to a complex disease2021In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 163, no 9, p. 2581-2594Article, review/survey (Refereed)
    Abstract [en]

    Background

    To date, there is neither any pharmacological treatment with efficacy in traumatic brain injury (TBI) nor any method to halt the disease progress. This is due to an incomplete understanding of the vast complexity of the biological cascades and failure to appreciate the diversity of secondary injury mechanisms in TBI. In recent years, techniques for high-throughput characterization and quantification of biological molecules that include genomics, proteomics, and metabolomics have evolved and referred to as omics.

    Methods

    In this narrative review, we highlight how omics technology can be applied to potentiate diagnostics and prognostication as well as to advance our understanding of injury mechanisms in TBI.

    Results

    The omics platforms provide possibilities to study function, dynamics, and alterations of molecular pathways of normal and TBI disease states. Through advanced bioinformatics, large datasets of molecular information from small biological samples can be analyzed in detail and provide valuable knowledge of pathophysiological mechanisms, to include in prognostic modeling when connected to clinically relevant data. In such a complex disease as TBI, omics enables broad categories of studies from gene compositions associated with susceptibility to secondary injury or poor outcome, to potential alterations in metabolites following TBI.

    Conclusion

    The field of omics in TBI research is rapidly evolving. The recent data and novel methods reviewed herein may form the basis for improved precision medicine approaches, development of pharmacological approaches, and individualization of therapeutic efforts by implementing mathematical “big data” predictive modeling in the near future.

    Download full text (pdf)
    FULLTEXT01
  • 14.
    Abzhandadze, Tamar
    et al.
    Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Occupational Therapy and Physiotherapy, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lundström, Erik
    Department of Neuroscience, Neurology, Uppsala University, Akademiska Sjukhuset, Uppsala, Sweden.
    Buvarp, Dongni
    Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Eriksson, Marie
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Quinn, Terence J
    Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
    S Sunnerhagen, Katharina
    Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Neurocare, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Development of a short-form Swedish version of the Montreal Cognitive Assessment (s-MoCA-SWE): Protocol for a cross-sectional study2021In: BMJ Open, E-ISSN 2044-6055, Vol. 11, no 5, article id e049035Article in journal (Refereed)
    Abstract [en]

    Introduction: Short forms of the Montreal Cognitive Assessment (MoCA) have allowed quick cognitive screening. However, none of the available short forms has been created or validated in a Swedish sample of patients with stroke.

    The aim is to develop a short-form Swedish version of the MoCA (s-MoCA-SWE) in a sample of patients with acute and subacute stroke. The specific objectives are: (1) to identify a subgroup of MoCA items that have the potential to form the s-MoCA-SWE; (2) to determine the optimal cut-off value of s-MoCA-SWE for predicting cognitive impairment and (3) and to compare the psychometric properties of s-MoCA-SWE with those of previously developed MoCA short forms.

    Methods and analysis: This is a statistical analysis protocol for a cross-sectional study. The study sample will comprise patients from Väststroke, a local stroke registry from Gothenburg, Sweden and Efficacy oF Fluoxetine - a randomisEd Controlled Trial in Stroke (EFFECTS), a randomised controlled trial in Sweden. The s-MoCA-SWE will be developed by using exploratory factor analysis and the boosted regression tree algorithm. The cut-off value of s-MoCA-SWE for impaired cognition will be determined based on binary logistic regression analysis. The psychometric properties of s-MoCA-SWE will be compared with those of other MoCA short forms by using cross-tabulation and area under the receiving operating characteristic curve analyses.

    Ethics and dissemination: The Väststroke study has received ethical approval from the Regional Ethical Review Board in Gothenburg (346-16) and the Swedish Ethical Review Authority (amendment 2019-04299). The handling of data generated within the framework of quality registers does not require written informed consent from patients. The EFFECTS study has received ethical approval from the Stockholm Ethics Committee (2013/1265-31/2 on 30 September 2013). All participants provided written consent. Results will be published in an international, peer-reviewed journal, presented at conferences and communicated to clinical practitioners in local meetings and seminars.

    Download full text (pdf)
    fulltext
  • 15.
    Abzhandadze, Tamar
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Occupat Therapy & Physiotherapy, Gothenburg, Sweden..
    Lundström, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Buvarp, Dongni
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden..
    Eriksson, Marie
    Umeå Univ, Dept Stat, USBE, Umeå, Sweden..
    Quinn, Terence J.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Sunnerhagen, Katharina
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Neurocare, Gothenburg, Sweden..
    Development of a short-form Swedish version of the Montreal Cognitive Assessment (s-MoCA-SWE): protocol for a cross-sectional study2021In: BMJ Open, E-ISSN 2044-6055, Vol. 11, no 5, article id e049035Article in journal (Refereed)
    Abstract [en]

    Introduction Short forms of the Montreal Cognitive Assessment (MoCA) have allowed quick cognitive screening. However, none of the available short forms has been created or validated in a Swedish sample of patients with stroke. The aim is to develop a short-form Swedish version of the MoCA (s-MoCA-SWE) in a sample of patients with acute and subacute stroke. The specific objectives are: (1) to identify a subgroup of MoCA items that have the potential to form the s-MoCA-SWE; (2) to determine the optimal cut-off value of s-MoCA-SWE for predicting cognitive impairment and (3) and to compare the psychometric properties of s-MoCA-SWE with those of previously developed MoCA short forms. Methods and analysis This is a statistical analysis protocol for a cross-sectional study. The study sample will comprise patients from Vaststroke, a local stroke registry from Gothenburg, Sweden and Efficacy oF Fluoxetine-a randomisEd Controlled Trial in Stroke (EFFECTS), a randomised controlled trial in Sweden. The s-MoCA-SWE will be developed by using exploratory factor analysis and the boosted regression tree algorithm. The cut-off value of s-MoCA-SWE for impaired cognition will be determined based on binary logistic regression analysis. The psychometric properties of s-MoCA-SWE will be compared with those of other MoCA short forms by using cross-tabulation and area under the receiving operating characteristic curve analyses. Ethics and dissemination The Vaststroke study has received ethical approval from the Regional Ethical Review Board in Gothenburg (346-16) and the Swedish Ethical Review Authority (amendment 2019-04299). The handling of data generated within the framework of quality registers does not require written informed consent from patients. The EFFECTS study has received ethical approval from the Stockholm Ethics Committee (2013/1265-31/2 on 30 September 2013). All participants provided written consent. Results will be published in an international, peer-reviewed journal, presented at conferences and communicated to clinical practitioners in local meetings and seminars.

    Download full text (pdf)
    FULLTEXT01
  • 16.
    Abzhandadze, Tamar
    et al.
    Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Occupat Therapy & Physiotherapy, Gothenburg, Sweden.;Univ Gothenburg, Inst Neurosci & Physiol, Rehabil Med, Dubbsgatan 14,fl 3, SE-41345 Gothenburg, Sweden..
    Lundström, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurology.
    Buvarp, Dongni
    Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Gothenburg, Sweden..
    Eriksson, Marie
    Umeå Univ, Dept Stat, USBE, Umeå, Sweden..
    Quinn, Terence J.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Scotland..
    Sunnerhagen, Katharina S.
    Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Neurocare, Rehabil Med, Gothenburg, Sweden..
    Development of a Swedish short version of the Montreal Cognitive Assessment for cognitive screening in patients with stroke2023In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 55, article id jrm4442Article in journal (Refereed)
    Abstract [en]

    Objective: The primary objective was to develop a Swedish short version of the Montreal Cognitive Assessment (s-MoCA-SWE) for use with patients with stroke. Secondary objectives were to iden-tify an optimal cut-off value for the s-MoCA-SWE to screen for cognitive impairment and to compare its sensitivity with that of previously developed short forms of the Montreal Cognitive Assessment.

    Design: Cross-sectional study.

    Subjects/patients: Patients admitted to stroke and rehabilitation units in hospitals across Sweden.

    Methods: Cognition was screened using the Mont-real Cognitive Assessment. Working versions of the s-MoCA-SWE were developed using supervised and unsupervised algorithms.

    Results: Data from 3,276 patients were analysed (40% female, mean age 71.5 years, 56% minor stroke at admission). The suggested s-MoCA-SWE compri-sed delayed recall, visuospatial/executive function, serial 7, fluency, and abstraction. The aggregated scores ranged from 0 to 16. A threshold for impai-red cognition & LE; 12 had a sensitivity of 97.41 (95% confidence interval, 96.64-98.03) and positive pre-dictive value of 90.30 (95% confidence interval 89.23-91.27). The s-MoCA-SWE had a higher abso-lute sensitivity than that of other short forms.

    Conclusion: The s-MoCA-SWE (threshold & LE; 12) can detect post-stroke cognitive issues. The high sensitivity makes it a potentially useful "rule-out" tool that may eliminate severe cognitive impair-ment in people with stoke.

    Download full text (pdf)
    FULLTEXT01
  • 17.
    Abzhandadze, Tamar
    et al.
    Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Occupational Therapy and Physiotherapy, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lundström, Erik
    Department of Medical Sciences, Neurology, Akademiska Sjukhuset, Uppsala, Sweden.
    Buvarp, Dongni
    Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Eriksson, Marie
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Quinn, Terence J.
    Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
    Sunnerhagen, Katharina S.
    Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Neurocare, Rehabilitation Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Development of a Swedish short version of the montreal cognitive assessment for cognitive screening in patients with stroke2023In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 55, article id jrm4442Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The primary objective was to develop a Swedish short version of the Montreal Cognitive Assessment (s-MoCA-SWE) for use  with patients with stroke. Secondary objectives were to identify an optimal cut-off value for the s-MoCA-SWE to screen for cognitive impairment and to compare its sensitivity with that of previously developed short forms of the Montreal Cognitive Assessment.

    DESIGN: Cross-sectional study.

    SUBJECTS/PATIENTS: Patients admitted to stroke and rehabilitation units in hospitals across Sweden.

    METHODS: Cognition was screened using the Montreal Cognitive Assessment. Working versions of the s-MoCA-SWE were developed using supervised and unsupervised algorithms.

    RESULTS: Data from 3,276 patients were analysed (40% female, mean age 71.5 years, 56% minor stroke at admission). The suggested s-MoCA-SWE comprised delayed recall, visuospatial/executive function, serial 7, fluency, and abstraction. The aggregated scores ranged from 0 to 16. A threshold for impaired cognition ≤ 12 had a sensitivity of 97.41 (95% confidence interval, 96.64-98.03) and positive predictive value of 90.30 (95% confidence interval 89.23-91.27). The s-MoCA-SWE had a higher absolute sensitivity than that of other short forms.

    CONCLUSION: The s-MoCA-SWE (threshold ≤ 12) can detect post-stroke cognitive issues. The high sensitivity makes it a potentially useful "rule-out" tool that may eliminate severe cognitive impairment in people with stoke.

    Download full text (pdf)
    fulltext
  • 18.
    Acevedo, Juan Pablo
    et al.
    Univ Los Andes, Chile; Cells Cells, Chile.
    Angelopoulos, Ioannis
    Univ Los Andes, Chile; Cells Cells, Chile.
    van Noort, Danny
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering. Univ Los Andes, Chile.
    Khoury, Maroun
    Univ Los Andes, Chile; Cells Cells, Chile; Consorcio Regenero, Chile.
    Microtechnology applied to stem cells research and development2018In: Regenerative Medicine, ISSN 1746-0751, E-ISSN 1746-076X, Vol. 13, no 2, p. 233-248Article, review/survey (Refereed)
    Abstract [en]

    Microfabrication and microfluidics contribute to the research of cellular functions of cells and their interaction with their environment. Previously, it has been shown that microfluidics can contribute to the isolation, selection, characterization and migration of cells. This review aims to provide stem cell researchers with a toolkit of microtechnology (mT) instruments for elucidating complex stem cells functions which are challenging to decipher with traditional assays and animal models. These microdevices are able to investigate about the differentiation and niche interaction, stem cells transcriptomics, therapeutic functions and the capture of their secreted microvesicles. In conclusion, microtechnology will allow a more realistic assessment of stem cells properties, driving and accelerating the translation of regenerative medicine approaches to the clinic.

  • 19.
    Ackerley, Rochelle
    et al.
    Aix Marseille Univ, France.
    Croy, Ilona
    Tech Univ Dresden, Germany.
    Olausson, Håkan
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Clinical Neurophysiology.
    Badre, Gaby
    Gothenburg Univ, Sweden.
    Investigating the Putative Impact of Odors Purported to Have Beneficial Effects on Sleep: Neural and Perceptual Processes2020In: Chemosensory Perception, ISSN 1936-5802, E-ISSN 1936-5810, Vol. 13, no 2, p. 93-105Article in journal (Refereed)
    Abstract [en]

    Introduction Olfaction has an important role in physiological and affective processes, as well as the potential to have profound effects on activities such as sleep and learning. We investigated two commercially manufactured odors ("Deep Sleep" and "Oriental," from This Works) purported to promote sleep, compared with control odor, where we aimed to explore whether neural and behavioral differences existed after odor inhalation. Methods In a neuroimaging study, 30 healthy participants were exposed to the odors via an olfactometer during functional magnetic resonance imaging (fMRI). In a further behavioral study using 12 chronic insomniacs, we investigated whether the commercial odors showed effects on sleep during a double-blind, randomized home evaluation. Results In the neuroimaging, the odors were related to activation of olfactory-relevant areas, such as the orbitofrontal cortex, and we found positive connectivity between the piriform cortex and the hippocampus, amygdala, insula, and middle cingulate cortex. Deep Sleep specifically activated the superior temporal gyrus, whereas Oriental activated the caudate. Further, these commercial odors showed some beneficial impact on sleep. Conclusions The perceptual and neural impacts of the commercial odors showed that olfactory stimulation can potentially aid sleep and modify affective processes in a number of ways. Implications The present work opens up opportunities for further investigations into how different odors may lead to specific behavioral and physiological modifications, such as their impact on sleep and well-being, which may provide non-pharmacological alternative approaches.

    Download full text (pdf)
    fulltext
  • 20. Adami, C.
    et al.
    Qian, J.
    Rupp, M.
    Hintze, Arend
    Keck Graduate Institute of Applied Life Sciences, Claremont, United States; Michigan State University, East Lansing, United States.
    Information content of colored motifs in complex networks2011In: Artificial Life, ISSN 1064-5462, E-ISSN 1530-9185, Vol. 17, no 4, p. 375-390Article in journal (Refereed)
    Abstract [en]

    We study complex networks in which the nodes are tagged with different colors depending on their function (colored graphs), using information theory applied to the distribution of motifs in such networks. We find that colored motifs can be viewed as the building blocks of the networks (much more than the uncolored structural motifs can be) and that the relative frequency with which these motifs appear in the network can be used to define its information content. This information is defined in such a way that a network with random coloration (but keeping the relative number of nodes with different colors the same) has zero color information content. Thus, colored motif information captures the exceptionality of coloring in the motifs that is maintained via selection. We study the motif information content of the C. elegans brain as well as the evolution of colored motif information in networks that reflect the interaction between instructions in genomes of digital life organisms. While we find that colored motif information appears to capture essential functionality in the C. elegans brain (where the color assignment of nodes is straightforward), it is not obvious whether the colored motif information content always increases during evolution, as would be expected from a measure that captures network complexity. For a single choice of color assignment of instructions in the digital life form Avida, we find rather that colored motif information content increases or decreases during evolution, depending on how the genomes are organized, and therefore could be an interesting tool to dissect genomic rearrangements. © 2011 Massachusetts Institute of Technology.

  • 21. Adams, Rick A.
    et al.
    Moutoussis, Michael
    Nour, Matthew M.
    Dahoun, Tarik
    Lewis, Declan
    Illingworth, Benjamin
    Veronese, Mattia
    Mathys, Christoph
    de Boer, Lieke
    Guitart-Masip, Marc
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Max Planck-UCL Centre for Computational Psychiatry and Ageing Research, UK.
    Friston, Karl J.
    Howes, Oliver D.
    Roiser, Jonathan P.
    Variability in Action Selection Relates to Striatal Dopamine 2/3 Receptor Availability in Humans: A PET Neuroimaging Study Using Reinforcement Learning and Active Inference Models2020In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 30, no 6, p. 3573-3589Article in journal (Refereed)
    Abstract [en]

    Choosing actions that result in advantageous outcomes is a fundamental function of nervous systems. All computational decision-making models contain a mechanism that controls the variability of (or confidence in) action selection, but its neural implementation is unclear-especially in humans. We investigated this mechanism using two influential decision-making frameworks: active inference (AI) and reinforcement learning (RL). In AI, the precision (inverse variance) of beliefs about policies controls action selection variability-similar to decision 'noise' parameters in RL-and is thought to be encoded by striatal dopamine signaling. We tested this hypothesis by administering a 'go/no-go' task to 75 healthy participants, and measuring striatal dopamine 2/3 receptor (D2/3R) availability in a subset (n = 25) using [C-11]-(+)-PHNO positron emission tomography. In behavioral model comparison, RL performed best across the whole group but AI performed best in participants performing above chance levels. Limbic striatal D2/3R availability had linear relationships with AI policy precision (P = 0.029) as well as with RL irreducible decision 'noise' (P = 0.020), and this relationship with D2/3R availability was confirmed with a 'decision stochasticity' factor that aggregated across both models (P = 0.0006). These findings are consistent with occupancy of inhibitory striatal D(2/3)Rs decreasing the variability of action selection in humans.

  • 22.
    Adedeji, Dickson O.
    et al.
    Psychiatric Clinic, Vrinnevi Hospital, Norrköping, Sweden.
    Holleman, Jasper
    Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden.
    Juster, Robert-Paul
    Ageing Epidemiology Research Unit (AGE), School of Public Health, Faculty of Medicine, Imperial College London, United Kingdom.
    Udeh-Momoh, Chinedu T.
    Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden.
    Kåreholt, Ingemar
    Jönköping University, School of Health and Welfare, HHJ, Institute of Gerontology. Jönköping University, School of Health and Welfare, HHJ. ARN-J (Aging Research Network - Jönköping).
    Hagman, Göran
    Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden.
    Aspö, Malin
    Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden.
    Adagunodo, Sofia
    Theme Inflammation and Aging, Karolinska University Hospital, Stockholm, Sweden.
    Håkansson, Krister
    Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden.
    Kivipelto, Miia
    Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden.
    Solomon, Alina
    Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden.
    Sindi, Shireen
    Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden.
    Longitudinal study of Alzheimer's disease biomarkers, allostatic load, and cognition among memory clinic patients2023In: Brain, Behavior, and Immunity - Health, ISSN 2666-3546, Vol. 28, article id 100592Article in journal (Refereed)
    Abstract [en]

    Background: Allostatic load (AL) is defined as the cumulative dysregulation of neuroendocrine, immunological, metabolic, and cardiovascular systems that increases the susceptibility to stress-related health problems. Several dementia and Alzheimer's disease (AD) risk factors have been identified, yet little is known about the role of AL and its associations with AD biomarkers (e.g., beta-amyloid (Aβ) or tau) and cognitive function among memory clinic patients. Hence, this study aims to assess the association between AL and AD biomarkers, cognitive performance, and cognitive decline after 3-years of follow-up.

    Methods: Data from 188 memory clinic patients were derived from the Cortisol and Stress in AD (Co-STAR) study in Sweden. Participants underwent baseline assessments including blood tests for AL measures (including cortisol, thyroid stimulating hormone, cobalamin, homocysteine, leukocytes, glycated hemoglobin, albumin, high-density and low-density lipoprotein cholesterol, triglycerides, and creatinine), cerebrospinal fluid (CSF) sampling for AD biomarkers and neuropsychological tests including five cognitive domains. Linear regressions were conducted, adjusting for age, sex, and education.

    Results: Higher AL was associated with lower CSF Aβ1-42 levels (β = −0.175, p = 0.025), reflecting higher brain levels of Aβ1-42. Stratified analyses suggested a significant association among women but not men, although the AL-sex interaction was not statistically significant. AL was not significantly associated with T-tau level (β = −0.030, p = 0.682) and P-tau level (β = 0.091, p = 0.980). There were no significant associations between AL and cognition or cognitive decline after 3 years.

    Conclusion: This study showed that higher AL was associated with increased brain amyloid accumulation. This suggests that AL may play a role in AD/dementia pathophysiology. Potential sex-related differences should be assessed in further larger studies.

  • 23.
    Adey, Brett N.
    et al.
    Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom.
    Cooper-Knock, Johnathan
    Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom.
    Al Khleifat, Ahmad
    Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom.
    Fogh, Isabella
    Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom.
    van Damme, Philip
    Department of Neurosciences, KU Leuven-University of Leuven, Experimental Neurology, Leuven Brain Institute (LBI), Leuven, Belgium; VIB, Center for Brain and Disease Research, Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
    Corcia, Philippe
    UMR 1253, Université de Tours, Inserm, Tours, France; Centre de référence sur la SLA, CHU de Tours, Tours, France.
    Couratier, Philippe
    Centre de référence sur la SLA, CHRU de Limoges, Limoges, France; UMR 1094, Université de Limoges, Inserm, Limoges, France.
    Hardiman, Orla
    Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
    McLaughlin, Russell
    Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
    Gotkine, Marc
    Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; Agnes Ginges Center for Human Neurogenetics, Department of Neurology, Hadassah Medical Center, Jerusalem, Israel.
    Drory, Vivian
    Department of Neurology, Tel-Aviv Sourasky Medical Centre, Tel-Aviv, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
    Silani, Vincenzo
    Department of Neurology and Laboratory of Neuroscience, Istituto Auxologico Italiano, IRCCS, Milan, Italy; Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano, Milan, Italy.
    Ticozzi, Nicola
    Department of Neurology and Laboratory of Neuroscience, Istituto Auxologico Italiano, IRCCS, Milan, Italy; Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano, Milan, Italy.
    Veldink, Jan H.
    Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands.
    van den Berg, Leonard H.
    Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands.
    de Carvalho, Mamede
    Instituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
    Pinto, Susana
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Instituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
    Mora Pardina, Jesus S.
    ALS Unit, Hospital San Rafael, Madrid, Spain.
    Povedano Panades, Mónica
    Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, Barcelona, L’Hospitalet de Llobregat, Spain.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Weber, Markus
    Neuromuscular Diseases Unit/ALS Clinic, St. Gallen, Switzerland.
    Başak, Nazli A.
    Koc University School of Medicine, Translational Medicine Research Center, NDAL, Istanbul, Turkey.
    Shaw, Christopher E.
    Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom.
    Shaw, Pamela J.
    Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom.
    Morrison, Karen E.
    School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, United Kingdom.
    Landers, John E.
    Department of Neurology, University of Massachusetts Medical School, MA, Worcester, United States.
    Glass, Jonathan D.
    Department of Neurology, Emory University School of Medicine, GA, Atlanta, United States.
    Vourc’h, Patrick
    Department of Neurology, University Hospitals Leuven, Leuven, Belgium; Service de Biochimie et Biologie molécularie, CHU de Tours, Tours, France.
    Dobson, Richard J. B.
    Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London, Maudsley NHS Foundation Trust, King’s College London, London, United Kingdom; Institute of Health Informatics, University College London, London, United Kingdom; NIHR Biomedical Research Centre at University College London Hospitals, NHS Foundation Trust, London, United Kingdom.
    Breen, Gerome
    Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom.
    Al-Chalabi, Ammar
    Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; King’s College Hospital, London, United Kingdom.
    Jones, Ashley R.
    Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom.
    Iacoangeli, Alfredo
    Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London, Maudsley NHS Foundation Trust, King’s College London, London, United Kingdom.
    Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival2023In: Frontiers in Cellular Neuroscience, E-ISSN 1662-5102, Vol. 17, article id 1112405Article in journal (Refereed)
    Abstract [en]

    Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts.

    Methods: Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype.

    Results: We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days.

    Discussion: These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion.

    Download full text (pdf)
    fulltext
  • 24.
    Adlerz, Linda
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Processing of the amyloid precursor protein and its paralogues amyloid precursor-like proteins 1 and 22007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Alzheimer’s disease (AD) is a neurodegenerative disorder which is histopathologically characterised by amyloid plaques and neurofibrillary tangles. Amyloid plaques consist of the amyloid β-peptide (Aβ) that can form aggregates in the brain. Aβ is generated from the amyloid precursor protein (APP) through proteolytic cleavage. APP belongs to a conserved protein family that also includes the two paralogues, APP-like proteins 1 and 2 (APLP1 and APLP2). Despite the immense amount of research on APP, motivated by its implication in AD, the function of this protein family has not yet been determined. In this thesis, we have studied the expression and proteolytic processing of the APP protein family. Our results are consistent with previous findings that suggest a role for APP during neuronal development. Treatment of cells with retinoic acid (RA) resulted in increased synthesis. In addition, we observed that RA treatment shifted the processing of APP from the amyloidogenic to the non-amyloidogenic pathway. The proteins in the APP family have been hard to distinguish both with respect to function and proteolytic processing. However, for development of new drugs with APP processing enzymes as targets this is of great importance. Our studies suggest similarities, but also differences in the mechanism regulating the processing of the different paralogues. We found that brain-derived neurotrophic factor (BDNF) had different impact on the members of the APP family. Most interestingly, we also found that the mechanism behind the increased processing in response to IGF-1 was not identical between the homologous proteins. In summary, our results indicate that in terms of regulation APLP1 and APLP2 differ more from each other than from APP. Our studies open up the possibility of finding means to selectively block Aβ production without interfering with the processing and function of the paralogous proteins.

    Download full text (pdf)
    FULLTEXT01
  • 25.
    Adlerz, Linda
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Beckman, Marie
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Holback, Sofia
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Tehranian, Roya
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Cortés Toro, Veronica
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Accumulation of the amyloid precursor-like protein APLP2 and reduction of APLP1 in retinoic acid-differentiated human neuroblastoma cells upon curcumin-induced neurite retraction2003In: Brain Research. Molecular Brain Research, ISSN 0169-328X, E-ISSN 1872-6941, Vol. 119, no 1, p. 62-72Article in journal (Refereed)
    Abstract [en]

    Amyloid precursor protein (APP) belongs to a conserved gene family, also including the amyloid precursor-like proteins, APLP1 and APLP2. The function of these three proteins is not yet fully understood. One of the proposed roles of APP is to promote neurite outgrowth. The aim of this study was to investigate the regulation of the expression levels of APP family members during neurite outgrowth. We observed that retinoic acid (RA)-induced neuronal differentiation of human SH-SY5Y cells resulted in increased expression of APP, APLP1 and APLP2. We also examined the effect of the NFκB, AP-1 and c-Jun N-terminal kinase inhibitor curcumin (diferuloylmethane) on the RA-induced expression levels of these proteins. We found that treatment with curcumin counteracted the RA-induced mRNA expression of all APP family members. In addition, we observed that curcumin treatment resulted in neurite retraction without any effect on cell viability. Surprisingly, curcumin had differential effects on the APLP protein levels in RA-differentiated cells. RA-induced APLP1 protein expression was blocked by curcumin, while the APLP2 protein levels were further increased. APP protein levels were not affected by curcumin treatment. We propose that the sustained levels of APP and the elevated levels of APLP2, in spite of the reduced mRNA expression, are due to altered proteolytic processing of these proteins. Furthermore, our results suggest that APLP1 does not undergo the same type of regulated processing as APP and APLP2.

  • 26.
    Adlerz, Linda
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Soomets, Ursel
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology. University of Tartu, Estonia.
    Holmlund, Linda
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Virland, Saade
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Down-regulation of amyloid precursor protein by peptide nucleic acid oligomer in cultured rat primary neurons and astrocytes2003In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 336, no 1, p. 55-59Article in journal (Refereed)
    Abstract [en]

    The amyloid precursor protein (APP) and its proteolytic cleavage products, the amyloid P peptides, have been implicated as a cause of Alzheimer's disease. Peptide nucleic acids (PNA), the DNA mimics, have been shown to block the expression of specific proteins at both transcriptional and translational levels. Generally, the cellular uptake of PNA is low. However, recent studies have indicated that the effect of unmodified antisense PNA uptake is more pronounced in nervous tissue. In this study we have shown that biotinylated PNA directed to the initiator codon region of the APP mRNA (-4 - +11) was taken up into the cytoplasm of primary rat cerebellar granule cells and cortical astrocytes, using fluorescence and confocal microscopy studies. Uptake of PNA was faster in neurons than in astrocytes. Western blotting analysis showed that APP was strongly down-regulated in both neurons and astrocytes. Thus, unmodified PNA can be used for studies on the function of APP in neurons and astrocytes.

  • 27. Adori, Csaba
    et al.
    Barde, Swapnali
    Bogdanovic, Nenad
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Institutet, Sweden.
    Reinscheid, Rainer R.
    Kovacs, Gabor G.
    Hokfelt, Tomas
    Neuropeptide S- and Neuropeptide S receptor-expressing neuron populations in the human pons2015In: Frontiers in Neuroanatomy, E-ISSN 1662-5129, Vol. 9Article in journal (Refereed)
    Abstract [en]

    Neuropeptide S (NPS) is a regulatory peptide with potent pharmacological effects. In rodents, NPS is expressed in a few pontine cell clusters. Its receptor (NPSR1) is, however, widely distributed in the brain. The anxiolytic and arousal promoting effects of NPS make the NPS NPSR1 system an interesting potential drug target in mood-related disorders. However, so far possible disease-related mechanisms involving NPS have only been studied in rodents. To validate the relevance of these animal studies for i.a. drug development, we have explored the distribution of NPS-expressing neurons in the human pons using in situ hybridization and stereological methods and we compared the distribution of NPS mRNA expressing neurons in the human and rat brain. The calculation revealed a total number of 22,317 +/- 2411 NPS mRNA-positive neurons in human, bilaterally. The majority of cells (84%) were located in the parabrachial area in human: in the extension of the medial and lateral parabrachial nuclei, in the Kolliker-Fuse nucleus and around the adjacent lateral lemniscus. In human, in sharp contrast to the rodents, only very few NPS-positive cells (5%) were found close to the locus coeruleus. In addition, we identified a smaller cell cluster (11% of all NPS cells) in the pontine central gray matter both in human and rat, which has not been described previously even in rodents. We also examined the distribution of NPSR1 mRNA-expressing neurons in the human pons. These cells were mainly located in the rostral laterodorsal tegmental nucleus, the cuneiform nucleus, the microcellular tegmental nucleus region and in the periaqueductal gray. Our results show that both NPS and NPSR1 in the human pons are preferentially localized in regions of importance for integration of visceral autonomic information and emotional behavior. The reported interspecies differences must, however, be considered when looking for targets for new pharmacotherapeutical interventions.

  • 28.
    Adori, Csaba
    et al.
    Karolinska Inst, Dept Neurosci, Retzius Lab, Retzius Vag 8, S-17177 Stockholm, Sweden.
    Barde, Swapnali
    Karolinska Inst, Dept Neurosci, Retzius Lab, Retzius Vag 8, S-17177 Stockholm, Sweden.
    Vas, Szilvia
    Semmelweis Univ, Dept Pharmacodynam, Nagyvarad Ter 4, H-1089 Budapest, Hungary; Hungarian Acad Sci, Neuropsychopharmacol & Neurochem Res Grp, Nagyvarad Ter 4, H-1089 Budapest, Hungary.
    Ebner, Karl
    Leopold Franzens Univ Innsbruck, CMBI, Inst Pharm, Dept Pharmacol & Toxicol, Innrain 80-82-3, A-6020 Innsbruck, Austria.
    Su, Jie
    Karolinska Inst, Dept Physiol & Pharmacol, Nanna Svartz Vag 2, S-17177 Stockholm, Sweden.
    Svensson, Camilla
    Karolinska Inst, Dept Physiol & Pharmacol, Nanna Svartz Vag 2, S-17177 Stockholm, Sweden.
    Mathé, Aleksander A
    Karolinska Inst, Sect Psychiat, Dept Clin Neurosci, Tomtebodavagen 18A, S-17177 Stockholm, Sweden.
    Singewald, Nicolas
    Leopold Franzens Univ Innsbruck, CMBI, Inst Pharm, Dept Pharmacol & Toxicol, Innrain 80-82-3, A-6020 Innsbruck, Austria.
    Reinscheid, Rainer R
    Univ Calif Irvine, Dept Pharmaceut Sci, Irvine, CA 92697 USA.
    Uhlén, Mathias
    Karolinska Inst, Dept Neurosci, Sci Life Lab, S-17165 Stockholm, Sweden; Royal Inst Technol, Albanova Univ Ctr, Sci Life Lab, S-17165 Stockholm, Sweden.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Bagdy, György
    Semmelweis Univ, Dept Pharmacodynam, Nagyvarad Ter 4, H-1089 Budapest, Hungary; Hungarian Acad Sci, Neuropsychopharmacol & Neurochem Res Grp, Nagyvarad Ter 4, H-1089 Budapest, Hungary.
    Hökfelt, Tomas
    Karolinska Inst, Dept Neurosci, Retzius Lab, Retzius Vag 8, S-17177 Stockholm, Sweden.
    Exploring the role of neuropeptide S in the regulation of arousal: a functional anatomical study.2016In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 221, no 7, p. 3521-3546Article in journal (Refereed)
    Abstract [en]

    Neuropeptide S (NPS) is a regulatory peptide expressed by limited number of neurons in the brainstem. The simultaneous anxiolytic and arousal-promoting effect of NPS suggests an involvement in mood control and vigilance, making the NPS-NPS receptor system an interesting potential drug target. Here we examined, in detail, the distribution of NPS-immunoreactive (IR) fiber arborizations in brain regions of rat known to be involved in the regulation of sleep and arousal. Such nerve terminals were frequently apposed to GABAergic/galaninergic neurons in the ventro-lateral preoptic area (VLPO) and to tyrosine hydroxylase-IR neurons in all hypothalamic/thalamic dopamine cell groups. Then we applied the single platform-on-water (mainly REM) sleep deprivation method to study the functional role of NPS in the regulation of arousal. Of the three pontine NPS cell clusters, the NPS transcript levels were increased only in the peri-coerulear group in sleep-deprived animals, but not in stress controls. The density of NPS-IR fibers was significantly decreased in the median preoptic nucleus-VLPO region after the sleep deprivation, while radioimmunoassay and mass spectrometry measurements showed a parallel increase of NPS in the anterior hypothalamus. The expression of the NPS receptor was, however, not altered in the VLPO-region. The present results suggest a selective activation of one of the three NPS-expressing neuron clusters as well as release of NPS in distinct forebrain regions after sleep deprivation. Taken together, our results emphasize a role of the peri-coerulear cluster in the modulation of arousal, and the importance of preoptic area for the action of NPS on arousal and sleep.

  • 29. Adori, Csaba
    et al.
    Glueck, Laura
    Barde, Swapnali
    Yoshitake, Takashi
    Kovacs, Gabor G.
    Mulder, Jan
    Magloczky, Zsofia
    Havas, Laszlo
    Boelcskei, Kata
    Mitsios, Nicholas
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Szolcsanyi, Janos
    Kehr, Jan
    Ronnback, Annica
    Schwartz, Thue
    Rehfeld, Jens F.
    Harkany, Tibor
    Palkovits, Miklos
    Schulz, Stefan
    Hokfelt, Tomas
    Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer's disease2015In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 129, no 4, p. 541-563Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites. This is noteworthy since cortical and hypothalamic somatostatin content is reduced in neurodegenerative pathologies. Yet a possible role of a somatostatin signal deficit in the maintenance of noradrenergic projections remains unknown. Here, we deployed tissue microarrays, immunohistochemistry, quantitative morphometry and mRNA profiling in a cohort of Alzheimer's and age-matched control brains in combination with genetic models of somatostatin receptor deficiency to establish causality between defunct somatostatin signalling and noradrenergic neurodegeneration. In Alzheimer's disease, we found significantly reduced somatostatin protein expression in the temporal cortex, with aberrant clustering and bulging of tyrosine hydroxylase-immunoreactive afferents. As such, somatostatin receptor 2 (SSTR2) mRNA was highly expressed in the human LC, with its levels significantly decreasing from Braak stages III/IV and onwards, i.e., a process preceding advanced Alzheimer's pathology. The loss of SSTR2 transcripts in the LC neurons appeared selective, since tyrosine hydroxylase, dopamine beta-hydroxylase, galanin or galanin receptor 3 mRNAs remained unchanged. We modeled these pathogenic changes in Sstr2 (-/-) mice and, unlike in Sstr1 (-/-) or Sstr4 (-/-) genotypes, they showed selective, global and progressive degeneration of their central noradrenergic projections. However, neuronal perikarya in the LC were found intact until late adulthood (< 8 months) in Sstr2 (-/-) mice. In contrast, the noradrenergic neurons in the superior cervical ganglion lacked SSTR2 and, as expected, the sympathetic innervation of the head region did not show any signs of degeneration. Our results indicate that SSTR2-mediated signaling is integral to the maintenance of central noradrenergic projections at the system level, and that early loss of somatostatin receptor 2 function may be associated with the selective vulnerability of the noradrenergic system in Alzheimer's disease.

  • 30.
    Aeinehband, Shahin
    et al.
    Karolinska Institutet.
    Lindblom, Rickard P. F.
    Karolinska Institutet.
    Al Nimer, Faiez
    Karolinska Institutet.
    Vijayaraghavan, Swetha
    Karolinska Institutet.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Khademi, Mohsen
    Karolinska Institutet.
    Olsson, Tomas
    Karolinska Institutet.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Darreh-Shori, Taher
    Karolinska Institutet.
    Piehl, Fredrik
    Karolinska Institutet.
    Complement Component C3 and Butyrylcholinesterase Activity Are Associated with Neurodegeneration and Clinical Disability in Multiple Sclerosis2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 4, article id e0122048Article in journal (Refereed)
    Abstract [en]

    Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genomewide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects. We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with >= 9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability. Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation. These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.

  • 31.
    af Bjerkén, Sara
    Umeå University, Faculty of Medicine, Integrative Medical Biology.
    On dopamine neurons: nerve fiber outgrowth and L-DOPA effects2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Parkinson’s disease is a disorder mainly characterized by progressive degeneration of dopamine producing neurons in the substantia nigra of the midbrain. The most commonly used treatment strategy is to pharmacologically restore the lost function by the administration of the dopaminergic precursor L-DOPA. Another treatment strategy is to replace the degenerated neurons with immature fetal ventral mesencephalic tissue, or ultimately stem cell-derived tissue. Grafting trials have, however, revealed poor reinnervation capacity of the grafts, leaving much of the striata dopamine-denervated. An additional drawback is the upcoming of dyskinesia (involuntary movements), a phenomenon also observed during L-DOPA treatment of Parkinson’s disease patients. Attempts to characterize nerve fiber formation from dopamine neurons have demonstrated that the nerve fibers are formed in two morphologically diverse outgrowth patterns, one early outgrowth seen in the absence of astrocytes and one later appearing outgrowth seen in co-existence with astrocytes.

    The overall objective of this thesis has been to study the dopaminergic outgrowth including guidance of nerve fiber formation, and to look into the mechanisms of L-DOPA-induced dyskinesia. The first paper in this thesis characterizes the different outgrowth patterns described above and their relation to different glial cells. The study demonstrated the two different outgrowth patterns to be a general phenomenon, applying not only to dopamine neurons. Attempts of characterization revealed no difference of origin in terms of dopaminergic subpopulations, i.e. A9 or A10, between the outgrowth patterns. Furthermore, the “roller-drum” technique was found optimal for studying the dual outgrowth sequences.

    The second and the third paper also utilized the “roller-drum” technique in order to promote both patterns of neuronal fiber formation. The effects of glial cell line-derived neurotrophic factor (GDNF) on the formation of dopamine nerve fibers, was investigated. Cultures prepared from gdnf knockout mice revealed that dopaminergic neurons survive and form nerve fiber outgrowth in the absence of GDNF. The dopaminergic nerve fibers exhibited an outgrowth pattern consistent with that previous observed in rat. GDNF was found to exert effect on the glial-associated outgrowth whereas the non-glial-associated was not affected. Astrocytic proliferation was inhibited using cytosine β-D-arabinofuranoside, resulting in reduced glial-associated outgrowth. The non-glial-associated dopaminergic outgrowth was on the other hand promoted, and was retained over longer time in culture. Furthermore, the non-glial-associated nerve fibers were found to target the fetal frontal cortex. Different developmental stages were shown to promote and affect the outgrowths differently. Taken together, these data indicate and state the importance of astrocytes and growth factors for neuronal nerve fiber formation and guidance. It also stresses the importance of fetal donor age at the time for transplantation.

    The fourth and fifth studies focus on L-DOPA dynamics and utilize in vivo chronoamperometry. In study four, 6-OHDA dopamine-depleted rats were exposed to chronic L-DOPA treatment and then rated as dyskinetic or non-dyskinetic. The electrochemical recordings demonstrated reduced KCl-evoked release in the intact striatum after chronic L-DOPA treatment. Time for maximal dopamine concentration after L-DOPA administration was found to be shorter in dyskinetic animals than in non-dyskinetic animals. The serotonergic nerve fiber content in the striatum was evaluated and brains from dyskinetic animals were found to exhibit significantly higher nerve fiber density compared to non-dyskinetic animals. Furthermore, the mechanisms behind the conversion of L-DOPA to dopamine in 6-OHDA dopamine-depleted rats were studied. Local administration of L-DOPA in the striatum increased the KCl-evoked dopamine release in the intact striatum. Acute application of L-DOPA resulted sometimes in a rapid conversion to dopamine, probably without vesicle packaging. This type of direct conversion is presumably occurring in non-neuronal tissue. Furthermore, KCl-evoked dopamine releases were present upon local application of L-DOPA in the dopamine-depleted striatum, suggesting that the conversion to dopamine took place elsewhere, than in dopaminergic nerve fibers. In conclusion, these studies state the importance of astrocytes for neuronal nerve fiber formation and elucidate the complexity of L-DOPA conversion in the brain.

    Download full text (pdf)
    FULLTEXT01
  • 32.
    af Bjerkén, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Stenmark Persson, Rasmus
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Barkander, Anna
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Karalija, Nina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Pelegrina-Hidalgo, Noelia
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Gerhardt, Greg A
    Virel, Ana
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Noradrenaline is crucial for the substantia nigra dopaminergic cell maintenance2019In: Neurochemistry International, ISSN 0197-0186, E-ISSN 1872-9754, Vol. 131, article id 104551Article in journal (Refereed)
    Abstract [en]

    In Parkinson's disease, degeneration of substantia nigra dopaminergic neurons is accompanied by damage on other neuronal systems. A severe denervation is for example seen in the locus coerulean noradrenergic system. Little is known about the relation between noradrenergic and dopaminergic degeneration, and the effects of noradrenergic denervation on the function of the dopaminergic neurons of substantia nigra are not fully understood. In this study, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) was injected in rats, whereafter behavior, striatal KCl-evoked dopamine and glutamate releases, and immunohistochemistry were monitored at 3 days, 3 months, and 6 months. Quantification of dopamine-beta-hydroxylase-immunoreactive nerve fiber density in the cortex revealed a tendency towards nerve fiber regeneration at 6 months. To sustain a stable noradrenergic denervation throughout the experimental timeline, the animals in the 6-month time point received an additional DSP4 injection (2 months after the first injection). Behavioral examinations utilizing rotarod revealed that DSP4 reduced the time spent on the rotarod at 3 but not at 6 months. KCl-evoked dopamine release was significantly increased at 3 days and 3 months, while the concentrations were normalized at 6 months. DSP4 treatment prolonged both time for onset and reuptake of dopamine release over time. The dopamine degeneration was confirmed by unbiased stereology, demonstrating significant loss of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra. Furthermore, striatal glutamate release was decreased after DSP4. In regards of neuroinflammation, reactive microglia were found over the substantia nigra after DSP4 treatment. In conclusion, long-term noradrenergic denervation reduces the number of dopaminergic neurons in the substantia nigra and affects the functionality of the nigrostriatal system. Thus, locus coeruleus is important for maintenance of nigral dopaminergic neurons.

  • 33.
    af Klinteberg, Britt
    et al.
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS). Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden.
    Johansson, Sven-Erik
    Levander, Maria
    Alm, Per Olof
    Oreland, Lars
    Smoking habits – Associations with personality/behavior, platelet monoamine oxidase activity and plasma thyroid hormone levels2017In: Personality and Individual Differences, ISSN 0191-8869, E-ISSN 1873-3549, Vol. 118, p. 71-76Article in journal (Refereed)
    Abstract [en]

    The objective was to outline results from our scientific studies on the associations among childhood behavior, adult personality, and biochemical factors in smoking habits. The studies consisted of: (1) follow-up of young criminals and controls, subdivided into risk for antisocial behavior groups, based on childhood rating levels of a projective test; and adult smoking habit groups; and (2) a large group of young adults examined on the same inventories. Personality in terms of KSP and EPQ-I scale scores, controlled for intelligence, indicated that the high and very high risk groups displayed significantly higher self-rated impulsiveness, anxiety, and nonconformity, as compared to the low risk group. Further, the very high risk group subjects, found to be overrepresented among subjects with heavy smoking habits, displayed lower mean platelet MAO-B activity and higher thyroid hormone levels than the low risk group. Thus, the higher the childhood risk for antisocial behavior, the clearer the adult personality pattern making subjects more disposed for smoking appeared; and the higher smoking habits, the stronger the relationships with biochemical measures. Results are discussed in terms of possible underlying mechanisms influencing personality and smoking habits.

  • 34. Afdile, Mamdooh
    et al.
    Jääskeläinen, Iiro P.
    Post-Movie Subliminal Measurement (PMSM), for Investigating Implicit Social Bias2020In: Journal of Visualized Experiments, E-ISSN 1940-087X, no 156Article in journal (Refereed)
    Abstract [en]

    This protocol describes the use of movies to investigate brain mechanisms underlying implicit social biases during functional magnetic resonance imaging. When the face of a protagonist is presented after a movie subliminally, it evokes an implicit response based on knowledge of the protagonist gained during the movie.

  • 35.
    Afdile, Mamdooh
    et al.
    Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland;Department of Media, School of Arts Design and Architecture, Aalto University, Espoo, Finland.
    Jääskeläinen, Iiro P
    Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland;Advanced Magnetic Imaging Centre, Aalto NeuroImaging, Aalto University, Espoo, Finland.
    Glerean, Enrico
    Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland;Department of Computer Science, School of Science, Aalto University, Espoo, Finland;Turku PET Centre, University of Turku, Turku, Finland;Helsinki Institute for Information Technology, Aalto University, Espoo, Finland.
    Smirnov, Dmitry
    Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland.
    Alho, Jussi
    Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland;Department of Psychology and Logopedics, Medicum, Faculty of Medicine, Helsinki University, Helsinki, Finland.
    Äimälä, Anna
    Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland.
    Sams, Mikko
    Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland;Department of Computer Science, School of Science, Aalto University, Espoo, Finland;Advanced Magnetic Imaging Centre, Aalto NeuroImaging, Aalto University, Espoo, Finland.
    Contextual knowledge provided by a movie biases implicit perception of the protagonist2019In: Social Cognitive & Affective Neuroscience, ISSN 1749-5016, E-ISSN 1749-5024, Vol. 14, no 5, p. 519-527Article in journal (Refereed)
    Abstract [en]

    We are constantly categorizing other people as belonging to our in-group (‘one of us’) or out-group (‘one of them’). Such grouping occurs fast and automatically and can be based on others’ visible characteristics such as skin color or clothing style. Here we studied neural underpinnings of implicit social grouping not often visible on the face, male sexual orientation. A total of 14 homosexuals and 15 heterosexual males were scanned in functional magnetic resonance imaging while watching a movie about a homosexual man, whose face was also presented subliminally before (subjects did not know about the character’s sexual orientation) and after the movie. We discovered significantly stronger activation to the man’s face after seeing the movie in homosexual but not heterosexual subjects in medial prefrontal cortex, frontal pole, anterior cingulate cortex, right temporal parietal junction and bilateral superior frontal gyrus. In previous research, these brain areas have been connected to social perception, self-referential thinking, empathy, theory of mind and in-group perception. In line with previous studies showing biased perception of in-/out-group faces to be context dependent, our novel approach further demonstrates how complex contextual knowledge gained under naturalistic viewing can bias implicit social perception.

  • 36.
    Affatato, Oreste
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Beating of hammers2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    I've been investigating the connection between migraine and depression—two debilitating disorders with high comorbidity. My overarching goal is to unravel their pathophysiology and pinpoint associated risk factors to pave the way for more effective therapeutic interventions. The fruits of my labor is discussed in the introductory part of the thesis and comprises four first-author publications in international peer-reviewed journals.

    In the first two projects, I worked mostly on the comorbid aspects of migraine and depression. I conducted a meta-analysis on the efficacy of onabotulinumtoxinA injections as a treatment for those grappling with both migraine and depression. The findings were promising, showing not only the treatment's safety and effectiveness but also hinting at a shared pathophysiology between the two conditions. The second project delved into the structural brain anatomy, utilizing voxel-based magnetic resonance imaging measures to explore subcortical volumes in migraine and depression patients. The distinct patterns observed suggest a nuanced relationship at the subcortical level.

    Expanding beyond comorbidity, my research ventured into the occupational determinants of migraine, scrutinizing the impact of job-related factors on migraine prevalence. Leveraging data from the UK Biobank, the third project identified strong associations between migraine and specific job categories, setting the stage for future interventions and policies to enhance workers' well-being. Additionally, my exploration into the role of the cerebellum and brainstem in migraine pathophysiology, using the UK Biobank data, unveiled larger gray matter volumes in multiple cerebellar regions in individuals with migraines. This sheds light on potential mechanisms underlying migraine attacks, contributing significantly to our understanding and potential treatments for these challenging disorders.

    Download full text (pdf)
    UUThesis_Affatato,O-2024
    Download (jpg)
    presentationsbild
  • 37.
    Affatato, Oreste
    et al.
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Dahlén, Amelia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Mwinyi, Jessica
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Assessing volumetric brain differences in migraine and depression patients: a UK Biobank study2023In: BMC Neurology, E-ISSN 1471-2377, Vol. 23, no 1, article id 284Article in journal (Refereed)
    Abstract [en]

    Background: Migraine and depression are two of the most common and debilitating conditions. From a clinical perspective, they are mostly prevalent in women and manifest a partial overlapping symptomatology. Despite the high level of comorbidity, previous studies hardly investigated possible common patterns in brain volumetric differences compared to healthy subjects. Therefore, the current study investigates and compares the volumetric difference patterns in sub-cortical regions between participants with migraine or depression in comparison to healthy controls.

    Methods: The study included data from 43 930 participants of the large UK Biobank cohort. Using official ICD10 diagnosis, we selected 712 participants with migraine, 1 853 with depression and 23 942 healthy controls. We estimated mean volumetric difference between the groups for the different sub-cortical brain regions using generalized linear regression models, conditioning the model within the levels of BMI, age, sex, ethnical background, diastolic blood pressure, current tobacco smoking, alcohol intake frequency, Assessment Centre, Indices of Multiple Deprivation, comorbidities and total brain volume.

    Results: We detected larger overall volume of the caudate (mean difference: 66, 95% CI [-3, 135]) and of the thalamus (mean difference: 103 mm(3), 95% CI [-2, 208]) in migraineurs than healthy controls. We also observed that individuals with depression appear to have also larger overall (mean difference: 47 mm(3), 95% CI [-7, 100]) and gray matter (mean difference: 49 mm(3), 95% CI [2, 95]) putamen volumes than healthy controls, as well as larger amygdala volume (mean difference: 17 mm(3), 95% CI [-7, 40]).

    Conclusion: Migraineurs manifested larger overall volumes at the level of the nucleus caudate and of the thalamus, which might imply abnormal pain modulation and increased migraine susceptibility. Larger amygdala and putamen volumes in participants with depression than controls might be due to increased neuronal activity in these regions.

    Download full text (pdf)
    FULLTEXT01
  • 38.
    Affatato, Oreste
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan).
    Miguet, Maud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biothechnol, Moscow, Russia..
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan).
    Major sex differences in migraine prevalence among occupational categories: a cross-sectional study using UK Biobank2021In: Journal of Headache and Pain, ISSN 1129-2369, E-ISSN 1129-2377, Vol. 22, no 1, article id 145Article in journal (Refereed)
    Abstract [en]

    Background Migraine represents one of the most prevalent neurological conditions worldwide. It is a disabling condition with high impact on the working situation of migraineurs. Interestingly, gender-related differences regarding an association of migraine with important occupational characteristics has been hardly studied. Methods The current study scrutinizes gender-specific differences in the prevalence of migraine across a broad spectrum of occupational categories, shedding also light on associations with important job-related features such as shift work, job satisfaction, and physical activity. The study included data from 415 712 participants from the UK Biobank cohort, using the official ICD10 diagnosis of migraine and other health conditions as selection criteria. Prevalence ratios of migraineurs compared to healthy controls among different occupational categories and job-related variables were estimated using log-binomial regression analyses. Statistical models were adjusted for important sociodemographic features such as age, BMI, ethnicity, education and neuroticism. To better highlight specific differences between men and women we stratified by sex. Results We detected a differential prevalence pattern of migraine in relation to different job categories between men and women. Especially in men, migraine appears to be more prevalent in highly physically demanding occupations (PR 1.38, 95% CI [0.93, 2.04]). Furthermore, migraine is also more prevalent in jobs that frequently involve shift or night shift work compared to healthy controls. Interestingly, this prevalence is especially high in women (shift work PR 1.45, 95% CI [1.14, 1.83], night shift work PR 1.46, 95% CI [0.93, 2.31]). Conclusion Our results show that migraine is genderdependently associated with physically demanding jobs and shift working.

    Download full text (pdf)
    FULLTEXT01
  • 39.
    Affatato, Oreste
    et al.
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Mwinyi, Jessica
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Volumetric Differences in Cerebellum and Brainstem in Patients with Migraine: A UK Biobank Study2023In: Biomedicines, E-ISSN 2227-9059, Vol. 11, no 9, article id 2528Article in journal (Refereed)
    Abstract [en]

    Background: The cerebellum and the brainstem are two brain structures involved in pain processing and modulation that have also been associated with migraine pathophysiology. The aim of this study was to investigate possible associations between the morphology of the cerebellum and brainstem and migraine, focusing on gray matter differences in these brain areas.

    Methods: The analyses were based on data from 712 individuals with migraine and 45,681 healthy controls from the UK Biobank study. Generalized linear models were used to estimate the mean gray matter volumetric differences in the brainstem and the cerebellum. The models were adjusted for important biological covariates such as BMI, age, sex, total brain volume, diastolic blood pressure, alcohol intake frequency, current tobacco smoking, assessment center, material deprivation, ethnic background, and a wide variety of health conditions. Secondary analyses investigated volumetric correlation between cerebellar sub-regions.

    Results: We found larger gray matter volumes in the cerebellar sub-regions V (mean difference: 72 mm3, 95% CI [13, 132]), crus I (mean difference: 259 mm3, 95% CI [9, 510]), VIIIa (mean difference: 120 mm3, 95% CI [0.9, 238]), and X (mean difference: 14 mm3, 95% CI [1, 27]).

    Conclusions: Individuals with migraine show larger gray matter volumes in several cerebellar sub-regions than controls. These findings support the hypothesis that the cerebellum plays a role in the pathophysiology of migraine.

    Download full text (pdf)
    FULLTEXT01
  • 40.
    Agalave, Nilesh M
    et al.
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Max
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Abdelmoaty, Sally
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Su, Jie
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Baharpoor, Azar
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Lundbäck, Peter
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Palmblad, Karin
    Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Andersson, Ulf
    Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Harris, Helena
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Svensson, Camilla I
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis.2014In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 155, no 9, p. 1802-1813Article in journal (Refereed)
    Abstract [en]

    Extracellular high mobility group box-1 protein (HMGB1) plays important roles in the pathogenesis of nerve injury- and cancer-induced pain. However, the involvement of spinal HMGB1 in arthritis-induced pain has not been examined previously and is the focus of this study. Immunohistochemistry showed that HMGB1 is expressed in neurons and glial cells in the spinal cord. Subsequent to induction of collagen antibody-induced arthritis (CAIA), Hmgb1 mRNA and extranuclear protein levels were significantly increased in the lumbar spinal cord. Intrathecal (i.t.) injection of a neutralizing anti-HMGB1 monoclonal antibody or recombinant HMGB1 box A peptide (Abox), which each prevent extracellular HMGB1 activities, reversed CAIA-induced mechanical hypersensitivity. This occurred during ongoing joint inflammation as well as during the postinflammatory phase, indicating that spinal HMGB1 has an important function in nociception persisting beyond episodes of joint inflammation. Importantly, only HMGB1 in its partially oxidized isoform (disulfide HMGB1), which activates toll-like receptor 4 (TLR4), but not in its fully reduced or fully oxidized isoforms, evoked mechanical hypersensitivity upon i.t. injection. Interestingly, although both male and female mice developed mechanical hypersensitivity in response to i.t. HMGB1, female mice recovered faster. Furthermore, the pro-nociceptive effect of i.t. injection of HMGB1 persisted in Tlr2- and Rage-, but was absent in Tlr4-deficient mice. The same pattern was observed for HMGB1-induced spinal microglia and astrocyte activation and cytokine induction. These results demonstrate that spinal HMGB1 contributes to nociceptive signal transmission via activation of TLR4 and point to disulfide HMGB1 inhibition as a potential therapeutic strategy in treatment of chronic inflammatory pain.

  • 41.
    Agalave, Nilesh M.
    et al.
    Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden.;Univ Texas Dallas, Sch Behav & Brain Sci, Dept Neurosci, Neuroimmunol & Behav Grp, Richardson, TX 75083 USA..
    Rudjito, Resti
    Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Farinotti, Alex Bersellini
    Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Emami Khoonsari, Payam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Sandor, Katalin
    Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Nomura, Yuki
    Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Szabo-Pardi, Thomas A.
    Univ Texas Dallas, Sch Behav & Brain Sci, Dept Neurosci, Neuroimmunol & Behav Grp, Richardson, TX 75083 USA..
    Urbina, Carlos Morado
    Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Palada, Vinko
    Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Price, Theodore J.
    Univ Texas Dallas, Sch Behav & Brain Sci, Dept Neurosci, Pain Neurobiol Res Grp, Richardson, TX 75083 USA..
    Harris, Helena Erlandsson
    Karolinska Inst, Ctr Mol Med, Dept Med, Stockholm, Sweden..
    Burton, Michael D.
    Univ Texas Dallas, Sch Behav & Brain Sci, Dept Neurosci, Neuroimmunol & Behav Grp, Richardson, TX 75083 USA..
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Svensson, Camilla, I
    Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Sex-dependent role of microglia in disulfide high mobility group box 1 protein-mediated mechanical hypersensitivity2021In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 162, no 2, p. 446-458Article in journal (Refereed)
    Abstract [en]

    High mobility group box 1 protein (HMGB1) is increasingly regarded as an important player in the spinal regulation of chronic pain. Although it has been reported that HMGB1 induces spinal glial activation in a Toll-like receptor (TLR)4-dependent fashion, the aspect of sexual dimorphisms has not been thoroughly addressed. Here, we examined whether the action of TLR4-activating, partially reduced disulfide HMGB1 on microglia induces nociceptive behaviors in a sex-dependent manner. We found disulfide HMGB1 to equally increase microglial Iba1 immunoreactivity in lumbar spinal dorsal horn in male and female mice, but evoke higher cytokine and chemokine expression in primary microglial culture derived from males compared to females. Interestingly, TLR4 ablation in myeloid-derived cells, which include microglia, only protected male mice from developing HMGB1-induced mechanical hypersensitivity. Spinal administration of the glial inhibitor, minocycline, with disulfide HMGB1 also prevented pain-like behavior in male mice. To further explore sex difference, we examined the global spinal protein expression using liquid chromatography-mass spectrometry and found several antinociceptive and anti-inflammatory proteins to be upregulated in only male mice subjected to minocycline. One of the proteins elevated, alpha-1-antitrypsin, partially protected males but not females from developing HMGB1-induced pain. Targeting downstream proteins of alpha-1-antitrypsin failed to produce robust sex differences in pain-like behavior, suggesting that several proteins identified by liquid chromatography-mass spectrometry are required to modulate the effects. Taken together, the current study highlights the importance of mapping sex dimorphisms in pain mechanisms and point to processes potentially involved in the spinal antinociceptive effect of microglial inhibition in male mice.

  • 42.
    Agelii, Anna
    University of Skövde, School of Humanities and Informatics.
    TREATING HORROR WITH ECSTASY: Neurobiological Rationale for Treating Post- Traumatic Stress Disorder with 3,4- methylenedioxymethylamphetamine2013Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Post-traumatic stress disorder (PTSD) is a disabling condition that afflicts 1-10% of the general population, with twice as high lifetime prevalence for women than men. Treatments exist, but none have proven reliable and consistent efficacy. A large minority of patients remain treatment-resistant despite undergoing several different types of treatment over extended periods of time. Recently completed studies in the U.S. and in Switzerland have demonstrated the potential of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment-resistant PTSD. One of the major problems of treating PTSD is the patients’ fear state and inability to form a therapeutic alliance. Both these issues can be facilitated through administration of MDMA; the psychological effects - such as heightened empathy, increased openness and diminished anxiety – seem well-suited for therapeutic purposes. The rationale behind treating PTSD with MDMA has been indicated in neuroimaging studies; MDMA affects some of the neural structures altered in patients with PTSD, most notably the amygdala and the ventromedial prefrontal cortex. Using the Schedule 1 substance MDMA for this purpose is however controversial; animal studies have indicated that MDMA is neurotoxic, although no adverse effects on humans related to incidental use of MDMA in a controlled setting have been found. In conclusion, the data support that MDMA may be an efficient tool for treating PTSD, as well as safe and effective to use in a clinical context.

    Download full text (pdf)
    fulltext
  • 43.
    Aggarwal, Tanya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hoeber, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Ivert, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Vasylovska, Svitlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Kozlova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Boundary Cap Neural Crest Stem Cells Promote Survival of Mutant SOD1 Motor Neurons2017In: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, ISSN 1878-7479, Vol. 14, no 3, p. 773-783Article in journal (Refereed)
    Abstract [en]

    ALS is a devastating disease resulting in degeneration of motor neurons (MNs) in the brain and spinal cord. The survival of MNs strongly depends on surrounding glial cells and neurotrophic support from muscles. We previously demonstrated that boundary cap neural crest stem cells (bNCSCs) can give rise to neurons and glial cells in vitro and in vivo and have multiple beneficial effects on co-cultured and co-implanted cells, including neural cells. In this paper, we investigate if bNCSCs may improve survival of MNs harboring a mutant form of human SOD1 (SOD1(G93A)) in vitro under normal conditions and oxidative stress and in vivo after implantation to the spinal cord. We found that survival of SOD1(G93A) MNs in vitro was increased in the presence of bNCSCs under normal conditions as well as under oxidative stress. In addition, when SOD1(G93A) MN precursors were implanted to the spinal cord of adult mice, their survival was increased when they were co-implanted with bNCSCs. These findings show that bNCSCs support survival of SOD1(G93A) MNs in normal conditions and under oxidative stress in vitro and improve their survival in vivo, suggesting that bNCSCs have a potential for the development of novel stem cell-based therapeutic approaches in ALS models.

    Download full text (pdf)
    fulltext
  • 44.
    Aghanoori, Mohamad-Reza
    et al.
    St Boniface Gen Hosp, Albrechtsen Res Ctr, Div Neurodegenerat Disorders, Winnipeg, MB, Canada.;Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada.;Univ Calgary, Cumming Sch Med, Dept Med Genet, 3330 Hosp Dr NW, Calgary, AB T2N 4N2, Canada..
    Agarwal, Prasoon
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada.;Univ Manitoba, Childrens Hosp Res Inst Manitoba, Winnipeg, MB, Canada..
    Gauvin, Evan
    St Boniface Gen Hosp, Albrechtsen Res Ctr, Div Neurodegenerat Disorders, Winnipeg, MB, Canada..
    Nagalingam, Raghu S.
    Univ Manitoba, Rady Fac Hlth Sci, Dept Physiol & Pathophysiol, Winnipeg, MB, Canada.;St Boniface Gen Hosp, Inst Cardiovasc Sci, Albrechtsen Res Ctr, Winnipeg, MB, Canada..
    Bonomo, Raiza
    Loyola Univ, Cellular & Mol Dept, Stritch Sch Med, Chicago, IL 60611 USA..
    Yathindranath, Vinith
    Univ Manitoba, Kleysen Inst Adv Med, Winnipeg, MB, Canada..
    Smith, Darrell R.
    St Boniface Gen Hosp, Albrechtsen Res Ctr, Div Neurodegenerat Disorders, Winnipeg, MB, Canada..
    Hai, Yan
    Univ Manitoba, Rady Fac Hlth Sci, Dept Biochem & Med Genet, Winnipeg, MB, Canada..
    Lee, Samantha
    Univ Manitoba, Rady Fac Hlth Sci, Dept Biochem & Med Genet, Winnipeg, MB, Canada..
    Jolivalt, Corinne G.
    Univ Calif San Diego, Dept Pathol, San Diego, CA USA..
    Calcutt, Nigel A.
    Univ Calif San Diego, Dept Pathol, San Diego, CA USA..
    Jones, Meaghan J.
    Univ Manitoba, Rady Fac Hlth Sci, Dept Biochem & Med Genet, Winnipeg, MB, Canada..
    Czubryt, Michael P.
    Univ Manitoba, Rady Fac Hlth Sci, Dept Physiol & Pathophysiol, Winnipeg, MB, Canada.;St Boniface Gen Hosp, Inst Cardiovasc Sci, Albrechtsen Res Ctr, Winnipeg, MB, Canada..
    Miller, Donald W.
    Univ Manitoba, Kleysen Inst Adv Med, Winnipeg, MB, Canada..
    Dolinsky, Vernon W.
    Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada.;Univ Manitoba, Childrens Hosp Res Inst Manitoba, Winnipeg, MB, Canada..
    Mansuy-Aubert, Virginie
    Loyola Univ, Cellular & Mol Dept, Stritch Sch Med, Chicago, IL 60611 USA..
    Fernyhough, Paul
    St Boniface Gen Hosp, Albrechtsen Res Ctr, Div Neurodegenerat Disorders, Winnipeg, MB, Canada.;Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada..
    CEBP beta regulation of endogenous IGF-1 in adult sensory neurons can be mobilized to overcome diabetes-induced deficits in bioenergetics and axonal outgrowth2022In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 79, no 4, article id 193Article in journal (Refereed)
    Abstract [en]

    Aberrant insulin-like growth factor 1 (IGF-1) signaling has been proposed as a contributing factor to the development of neurodegenerative disorders including diabetic neuropathy, and delivery of exogenous IGF-1 has been explored as a treatment for Alzheimer's disease and amyotrophic lateral sclerosis. However, the role of autocrine/paracrine IGF-1 in neuroprotection has not been well established. We therefore used in vitro cell culture systems and animal models of diabetic neuropathy to characterize endogenous IGF-1 in sensory neurons and determine the factors regulating IGF-1 expression and/or affecting neuronal health. Single-cell RNA sequencing (scRNA-Seq) and in situ hybridization analyses revealed high expression of endogenous IGF-1 in non-peptidergic neurons and satellite glial cells (SGCs) of dorsal root ganglia (DRG). Brain cortex and DRG had higher IGF-1 gene expression than sciatic nerve. Bidirectional transport of IGF-1 along sensory nerves was observed. Despite no difference in IGF-1 receptor levels, IGF-1 gene expression was significantly (P < 0.05) reduced in liver and DRG from streptozotocin (STZ)-induced type 1 diabetic rats, Zucker diabetic fatty (ZDF) rats, mice on a high-fat/ high-sugar diet and db/db type 2 diabetic mice. Hyperglycemia suppressed IGF-1 gene expression in cultured DRG neurons and this was reversed by exogenous IGF-1 or the aldose reductase inhibitor sorbinil. Transcription factors, such as NFAT1 and CEBP beta, were also less enriched at the IGF-1 promoter in DRG from diabetic rats vs control rats. CEBP beta overexpression promoted neurite outgrowth and mitochondrial respiration, both of which were blunted by knocking down or blocking IGF-1. Suppression of endogenous IGF-1 in diabetes may contribute to neuropathy and its upregulation at the transcriptional level by CEBP beta can be a promising therapeutic approach.

  • 45.
    Agnvall, Anne
    et al.
    University of Skövde, School of Bioscience.
    Unessi, Reza
    University of Skövde, School of Bioscience.
    The Neural Correlates of Emotional Intelligence: A Systematic Review2023Independent thesis Basic level (degree of Bachelor), 15 credits / 22,5 HE creditsStudent thesis
    Abstract [en]

    Emotional intelligence (EI) lies at the intersection of emotion and cognition and is seen as beneficial to our relationships and well-being. Yet, there is a gap in knowledge regarding the neural correlates of EI. There are three prevailing models defining the psychological construct of EI, the trait model, the ability model, and the mixed model. According to the ability model, EI consists of two facets - experiential and strategic EI. Experiential EI refers to abilities of perceiving and using emotions to facilitate thoughts, whereas strategic EI refers to abilities of understanding and managing emotions. This systematic review aims to investigate whether, and to what extent, the neural correlates of experiential and strategic EI rely on similar or different neural substrates. Five peer-reviewed studies met the inclusion criteria and were included. All the studies used Mayer-Salovey-Caruso Emotional Intelligence Test to measure EI. The brain imaging techniques used included structural and functional magnetic resonance imaging and diffusion tensor imaging. The findings of the review suggest that experiential and strategic EI rely partly on distinct and partly on common neural circuitry. Neural correlates associated primarily with strategic EI were gray matter volumes of ventromedial and ventrolateral prefrontal cortex and anterior and posterior insula. Both strategic and experiential EI were found to correlate with the rostral anterior cingulate cortex gray matter activation, and the effective connectivity of the anterior prefrontal cortex. Further research and development of measurement methodology are needed to deepen the understanding of strategic and experiential EI and their neural correlates.

    Download full text (pdf)
    fulltext
  • 46.
    Agnvall, Beatrix
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Bélteky, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Brain size is reduced by selectionfor tameness in Red Junglefowl–correlated effects in vital organs2017In: Scientific Reports, E-ISSN 2045-2322, Vol. 7, article id 3306Article in journal (Refereed)
    Abstract [en]

    During domestication animals have undergone changes in size of brain and other vital organs. We hypothesize that this could be a correlated effect to increased tameness. Red Junglefowl (ancestors of domestic chickens) were selected for divergent levels of fear of humans for five generations. The parental (P0) and the fifth selected generation (S5) were culled when 48–54 weeks old and the brains were weighed before being divided into telencephalon, cerebellum, mid brain and optic lobes. Each single brain part as well as the liver, spleen, heart and testicles were also weighed. Brains of S5 birds with high fear scores (S5 high) were heavier both in absolute terms and when corrected for body weight. The relative weight of telencephalon (% of brain weight) was significantly higher in S5 high and relative weight of cerebellum was lower. Heart, liver, testes and spleen were all relatively heavier (% of body weight) in S5 high. Hence, selection for tameness has changed the size of the brain and other vital organs in this population and may have driven the domesticated phenotype as a correlated response.

    Download full text (pdf)
    fulltext
  • 47. Agostinelli, Emilio
    et al.
    Gonzalez-Velandia, Kevin Y.
    Hernandez-Clavijo, Andres
    Maurya, Devendra Kumar
    Neurobiology Group, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy.
    Xerxa, Elena
    Lewin, Gary R.
    Dibattista, Michele
    Menini, Anna
    Pifferi, Simone
    A Role for STOML3 in Olfactory Sensory Transduction2021In: eNeuro, E-ISSN 2373-2822, Vol. 8, no 2, article id ENEURO.0565-20.2021Article in journal (Refereed)
    Abstract [en]

    Stomatin-like protein-3 (STOML3) is an integral membrane protein expressed in the cilia of olfactory sensory neurons (OSNs), but its functional role in this cell type has never been addressed. STOML3 is also expressed in dorsal root ganglia neurons, where it has been shown to be required for normal touch sensation. Here, we extended previous results indicating that STOML3 is mainly expressed in the knob and proximal cilia of OSNs. We additionally showed that mice lacking STOML3 have a morphologically normal olfactory epithelium. Because of its presence in the cilia, together with known olfactory transduction components, we hypothesized that STOML3 could be involved in modulating odorant responses in OSNs. To investigate the functional role of STOML3, we performed loose patch recordings from wild-type (WT) and Stoml3 knock-out (KO) OSNs. We found that spontaneous mean firing activity was lower with additional shift in interspike intervals (ISIs) distributions in Stoml3 KOs compared with WT neurons. Moreover, the firing activity in response to stimuli was reduced both in spike number and duration in neurons lacking STOML3 compared with WT neurons. Control experiments suggested that the primary deficit in neurons lacking STOML3 was at the level of transduction and not at the level of action potential generation. We conclude that STOML3 has a physiological role in olfaction, being required for normal sensory encoding by OSNs.

    Download full text (pdf)
    fulltext
  • 48. Aguila, Julio
    et al.
    Cheng, Shangli
    Kee, Nigel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Karolinska Institutet, Sweden.
    Cao, Ming
    Wang, Menghan
    Deng, Qiaolin
    Hedlund, Eva
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Karolinska Institutet, Sweden.
    Spatial RNA Sequencing Identifies Robust Markers of Vulnerable and Resistant Human Midbrain Dopamine Neurons and Their Expression in Parkinson's Disease2021In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 14, article id 699562Article in journal (Refereed)
    Abstract [en]

    Defining transcriptional profiles of substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) dopamine neurons is critical to understanding their differential vulnerability in Parkinson's Disease (PD). Here, we determine transcriptomes of human SNc and VTA dopamine neurons using LCM-seq on a large sample cohort. We apply a bootstrapping strategy as sample input to DESeq2 and identify 33 stably differentially expressed genes (DEGs) between these two subpopulations. We also compute a minimal sample size for identification of stable DEGs, which highlights why previous reported profiles from small sample sizes display extensive variability. Network analysis reveal gene interactions unique to each subpopulation and highlight differences in regulation of mitochondrial stability, apoptosis, neuronal survival, cytoskeleton regulation, extracellular matrix modulation as well as synapse integrity, which could explain the relative resilience of VTA dopamine neurons. Analysis of PD tissues showed that while identified stable DEGs can distinguish the subpopulations also in disease, the SNc markers SLIT1 and ATP2A3 were down-regulated and thus appears to be biomarkers of disease. In summary, our study identifies human SNc and VTA marker profiles, which will be instrumental for studies aiming to modulate dopamine neuron resilience and to validate cell identity of stem cell-derived dopamine neurons.

  • 49.
    Aguila, Monica
    et al.
    UCL Inst Ophthalmol, England.
    Bellingham, James
    UCL Inst Ophthalmol, England.
    Athanasiou, Dimitra
    UCL Inst Ophthalmol, England.
    Bevilacqua, Dalila
    UCL Inst Ophthalmol, England.
    Duran, Yanai
    UCL Inst Ophthalmol, England.
    Maswood, Ryea
    UCL Inst Ophthalmol, England.
    Parfitt, David A.
    UCL Inst Ophthalmol, England.
    Iwawaki, Takao
    Kanazawa Med Univ, Japan.
    Spyrou, Ioannis
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences.
    Smith, Alexander J.
    UCL Inst Ophthalmol, England.
    Ali, Robin R.
    UCL Inst Ophthalmol, England.
    Cheetham, Michael E.
    UCL Inst Ophthalmol, England.
    AAV-mediated ERdj5 overexpression protects against P23H rhodopsin toxicity2020In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 29, no 8, p. 1310-1318Article in journal (Refereed)
    Abstract [en]

    Rhodopsin misfolding caused by the P23H mutation is a major cause of autosomal dominant retinitis pigmentosa (adRP). To date, there are no effective treatments for adRP. The BiP co-chaperone and reductase ERdj5 (DNAJC10) is part of the endoplasmic reticulum (ER) quality control machinery, and previous studies have shown that overexpression of ERdj5 in vitro enhanced the degradation of P23H rhodopsin, whereas knockdown of ERdj5 increased P23H rhodopsin ER retention and aggregation. Here, we investigated the role of ERdj5 in photoreceptor homeostasis in vivo by using an Erdj5 knockout mouse crossed with the P23H knock-in mouse and by adeno-associated viral (AAV) vector-mediated gene augmentation of ERdj5 in P23H-3 rats. Electroretinogram (ERG) and optical coherence tomography of Erdj5(-/-) and P23H(+/-):Erdj5(-/-) mice showed no effect of ERdj5 ablation on retinal function or photoreceptor survival. Rhodopsin levels and localization were similar to those of control animals at a range of time points. By contrast, when AAV2/8-ERdj5-HA was subretinally injected into P23H-3 rats, analysis of the full-field ERG suggested that overexpression of ERdj5 reduced visual function loss 10 weeks post-injection (PI). This correlated with a significant preservation of photoreceptor cells at 4 and 10 weeks PI. Assessment of the outer nuclear layer (ONL) morphology showed preserved ONL thickness and reduced rhodopsin retention in the ONL in the injected superior retina. Overall, these data suggest that manipulation of the ER quality control and ER-associated degradation factors to promote mutant protein degradation could be beneficial for the treatment of adRP caused by mutant rhodopsin.

    Download full text (pdf)
    fulltext
  • 50.
    Aguilar-Calvo, Patricia
    et al.
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Bett, Cyrus
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Sevillano, Alejandro M.
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Kurt, Timothy D.
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Lawrence, Jessica
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Soldau, Katrin
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Sigurdson, Christina J.
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA; Univ Calif Davis, CA USA.
    Generation of novel neuroinvasive prions following intravenous challenge2018In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 28, no 6, p. 999-1011Article in journal (Refereed)
    Abstract [en]

    Prions typically spread into the central nervous system (CNS), likely via peripheral nerves. Yet prion conformers differ in their capacity to penetrate the CNS; certain fibrillar prions replicate persistently in lymphoid tissues with no CNS entry, leading to chronic silent carriers. Subclinical carriers of variant Creutzfeldt-Jakob (vCJD) prions in the United Kingdom have been estimated at 1:2000, and vCJD prions have been transmitted through blood transfusion, however, the circulating prion conformers that neuroinvade remain unclear. Here we investigate how prion conformation impacts brain entry of transfused prions by challenging mice intravenously to subfibrillar and fibrillar strains. We show that most strains infiltrated the brain and caused terminal disease, however, the fibrillar prions showed reduced CNS entry in a strain-dependent manner. Strikingly, the highly fibrillar mCWD prion strain replicated in the spleen and emerged in the brain as a novel strain, indicating that a new neuroinvasive prion had been generated from a previously non-neuroinvasive strain. The new strain showed altered plaque morphology, brain regions targeted and biochemical properties and these properties were maintained upon intracerebral passage. Intracerebral passage of prion-infected spleen re-created the new strain. Splenic prions resembled the new strain biochemically and intracerebral passage of prion-infected spleen re-created the new strain, collectively suggesting splenic prion replication as a potential source. Taken together, these results indicate that intravenous exposure to prion-contaminated blood or blood products may generate novel neuroinvasive prion conformers and disease phenotypes, potentially arising from prion replication in non-neural tissues or from conformer selection.

1234567 1 - 50 of 5414
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf