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  • 1. Andersson, Christin
    et al.
    Blennow, Kaj
    Almkvist, Ove
    Andreasen, Niels
    Engfeldt, Peter
    Örebro universitet, Hälsoakademin.
    Johansson, Sven-Erik
    Lindau, Maria
    Eriksdotter-Jönhagen, Maria
    Increasing CSF phospho-tau levels during cognitive decline and progression to dementia2008Inngår i: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 29, nr 10, s. 1466-1473Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Little is known about longitudinal changes of cerebrospinal fluid (CSF) biomarkers during cognitive decline in neurodegenerative disease progression.

    OBJECTIVE: To investigate longitudinal changes in CSF biomarkers--total-tau (T-tau), phospho-tau (P-tau) and beta-amyloid (Abeta42)--during cognitive decline.

    METHODS: Forty memory clinic patients (47.5% females), aged 61.3+/-7.6 (S.D.) years, non-demented at baseline, underwent lumbar puncture and neuropsychological testing at two occasions. Baseline mean MMSE-score was 28.3+/-1.8. Patients were divided into three groups based on baseline memory functioning; severely impaired (SIM), moderately impaired (MIM) and no impairment (NIM).

    RESULTS: There was a significant increase in P-tau in the SIM-group during follow-up, while P-tau in MIM and NIM did not change. Eighty-three percent of the SIM-patients converted to dementia (80% AD), while most MIM- and NIM-patients remained non-demented. T-tau- and Abeta42-levels did not change in any of the memory groups during follow-up.

    CONCLUSION: Increasing P-tau levels during cognitive decline and conversion to dementia suggest that P-tau may be useful as a longitudinal marker of the neurodegenerative process.

  • 2. Andersson, P.
    et al.
    Samrani, G.
    Aging Research Center (ARC), Karolinska Institute and Stockholm University, Stockholm, Sweden; Department of Radiation Sciences, Umeå University, Umeå, Sweden; Department of Integrative Medical Biology, Umeå University, Umeå, Sweden.
    Andersson, M.
    Department of Radiation Sciences, Umeå University, Umeå, Sweden; Department of Integrative Medical Biology, Umeå University, Umeå, Sweden.
    Persson, J.
    Örebro universitet, Institutionen för beteende-, social- och rättsvetenskap. Aging Research Center (ARC), Karolinska Institute and Stockholm University, Stockholm, Sweden.
    Hippocampal subfield volumes contribute to working memory interference control in aging: Evidence from longitudinal associations over 5 years2023Inngår i: Neuroimage: Reports, E-ISSN 2666-9560, Vol. 3, nr 4, artikkel-id 100189Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In memory, familiar but no longer relevant information may disrupt encoding and retrieval of to-be-learned information. While it has been demonstrated that the ability to resolve proactive interference (PI) in working memory (WM) is reduced in aging, the neuroanatomical components of this decline have yet to be determined. Hippocampal (HC) involvement in age-related decline in control of PI is currently not known. In particular, the association between HC subfield volumes and control of PI in WM has not been examined previously. Here we investigate the associations between mean level and 5-year trajectories of gray matter subfield volumes and PI in WM across the adult life span (N = 157). Longitudinal analyses over 5-years across all participants revealed that reduced volume in the subiculum was related to impaired control of PI. Age-stratified analyses showed that this association was most pronounced in older adults. Furthermore, we found that in older adults the effect of age on PI was mediated by GM volume in the HC. The current results show that HC volume is associated with the ability to control PI in WM, and that these associations are modulated by age.

    Fulltekst (pdf)
    Hippocampal subfield volumes contribute to working memory interference control in aging: Evidence from longitudinal associations over 5 years
  • 3.
    Andersson, Pernilla
    et al.
    Örebro universitet, Institutionen för juridik, psykologi och socialt arbete.
    Li, Xin
    Aging Research Center (ARC), Karolinska Institute and Stockholm University, Stockholm, Sweden.
    Persson, Jonas
    Örebro universitet, Institutionen för juridik, psykologi och socialt arbete.
    The association between control of interference and white-matter integrity: A cross-sectional and longitudinal investigation2022Inngår i: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 114, s. 49-60Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Proactive interference (PI) occurs when old information interferes with newly acquired information and has been suggested as a major cause of forgetting in working memory. In this study, we investigate cross-sectional (N = 267) and longitudinal (N = 148) associations between PI and white-matter integrity (WMI) using diffusion-weighted imaging in an adult life-span sample (25-80 years; Mage = 60.15; 138 female). Older age was related to higher PI and lower WMI. Cross-sectional analyses showed associations between PI and WMI spanning several white-matter tracts as well as globally, suggesting that the age-related decline in PI may be driven primarily by global changes in WMI. Furthermore, longitudinal changes in PI were shown to be negatively correlated with concurrent changes in WMI in the fornix. Mediation analyses showed that WMI mediated the relationship between age and PI only in older adults, indicating that WMI becomes increasingly connected to cognitive functioning with increasing age. This is the first demonstration of WMI decline contributing to the age-related decline in PI.

  • 4.
    Andin, Josefine
    et al.
    Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden.
    Elwér, Åsa
    Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden.
    Mäki-Torkko, Elina
    Örebro universitet, Institutionen för medicinska vetenskaper. Audiological Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Arithmetic in the signing brain: Differences and similarities in arithmetic processing between deaf signers and hearing non-signers2023Inngår i: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 101, nr 1, s. 172-195Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Deaf signers and hearing non-signers have previously been shown to recruit partially different brain regions during simple arithmetic. In light of the triple code model, the differences were interpreted as relating to stronger recruitment of the verbal system of numerical processing, that is, left angular and inferior frontal gyrus, in hearing non-signers, and of the quantity system of numerical processing, that is, right horizontal intraparietal sulcus, for deaf signers. The main aim of the present study was to better understand similarities and differences in the neural correlates supporting arithmetic in deaf compared to hearing individuals. Twenty-nine adult deaf signers and 29 hearing non-signers were enrolled in an functional magnetic resonance imaging study of simple and difficult subtraction and multiplication. Brain imaging data were analyzed using whole-brain analysis, region of interest analysis, and functional connectivity analysis. Although the groups were matched on age, gender, and nonverbal intelligence, the deaf group performed generally poorer than the hearing group in arithmetic. Nevertheless, we found generally similar networks to be involved for both groups, the only exception being the involvement of the left inferior frontal gyrus. This region was activated significantly stronger for the hearing compared to the deaf group but showed stronger functional connectivity with the left superior temporal gyrus in the deaf, compared to the hearing, group. These results lend no support to increased recruitment of the quantity system in deaf signers. Perhaps the reason for performance differences is to be found in other brain regions not included in the original triple code model.

  • 5.
    Axelsson, Markus
    et al.
    University of Gothenburg, Gothenburg, Sweden .
    Malmeström, Clas
    University of Gothenburg, Gothenburg, Sweden .
    Gunnarsson, Martin
    Örebro universitet, Institutionen för läkarutbildning. Region Örebro län.
    Zetterberg, Henrik
    University of Gothenburg, Mölndal, Sweden; Institute of Neurology, The University College London (UCL), London, UK.
    Sundstrom, Peter
    Umeå University, Umeå, Sweden .
    Lycke, Jan
    University of Gothenburg, Gothenburg, Sweden .
    Svenningsson, Anders
    Umeå University, Umeå, Sweden .
    Immunosuppressive therapy reduces axonal damage in progressive multiple sclerosis2014Inngår i: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 20, nr 1, s. 43-50Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: In progressive multiple sclerosis (PMS), disease-modifying therapies have not been shown to reduce disability progression.

    Objective: The impact from immunosuppressive therapy in PMS was explored by analyzing cerebrospinal fluid (CSF) biomarkers of axonal damage (neurofilament light protein, NFL), astrogliosis (glial fibrillary acidic protein, GFAP), and B-cell regulation (CXCL13).

    Methods: CSF was obtained from 35 patients with PMS before and after 12-24 months of mitoxantrone (n=30) or rituximab (n=5) treatment, and from 14 age-matched healthy control subjects. The levels of NFL, GFAP, and CXCL13 were determined by immunoassays.

    Results: The mean NFL level decreased by 51% (1781 ng/l, SD 2018 vs. 874 ng/l, SD 694, p=0.007), the mean CXCL13 reduction was 55% (9.71 pg/ml, SD 16.08, vs. 4.37 pg/ml, SD 1.94, p=0.008), while GFAP levels remained unaffected. Subgroup analysis showed that the NFL reduction was confined to previously untreated patients (n=20) and patients with Gd-enhancing lesions on magnetic resonance imaging (n=12) prior to study baseline.

    Conclusions: Our data imply that 12-24 months of immunosuppressive therapy reduces axonal damage in PMS, particularly in patients with ongoing disease activity. Determination of NFL levels in CSF is a potential surrogate marker for treatment efficacy and as endpoint in phase II trials of MS.

  • 6.
    Bazov, Igor
    et al.
    Division of Biological Research on Drug Dependence, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
    Bakalkin, Georgy
    Division of Biological Research on Drug Dependence, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
    Prodynorphin Epialleles2016Inngår i: Epigenetics and Neuroendocrinology: Clinical Focus on Psychiatry, Volume 2 / [ed] Dietmar Spengler, Elisabeth Binder, Springer, 2016, s. 43-76Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Dynorphins, the endogenous ligands for kappa-opioid receptors play an essential role in neuroendocrine regulation, stress response, reward processing, and mood control. These neuropeptides induce strong dysphoric and aversive effects. Polymorphisms in the prodynorphin (PDYN), the dynorphin-encoding gene, are associated with substance addiction and negative craving, while dynorphin mutations cause neurodegeneration in the human brain. Similarly to other neuropeptide genes, PDYN is expressed in selective neural circuits at extremely low tissue levels. A sophisticated epigenetic/transcriptional regulation by cell lineage-specific transcription factors (TFs), insulators, and silencers such as CCCTC-binding factor (CTCF) and RE1-silencing transcription factor (REST) along with mechanisms that control neuronal activity-dependent transcription may define spatial, temporal, and adaptive PDYN expression patterns. Impairment of the epigenetic control of PDYN expression may contribute to human pathological conditions including substance dependence, depression, and chronic pain. Epigenetic and environmental factors may mechanistically converge on the PDYN CpG-SNPs associated with a risk for alcohol dependence, and the resulting methylation signals may be translated into disease predisposition via alterations in PDYN transcription. Understanding the mechanisms that regulate neuropeptide epigenome and transcriptome is essential for understanding of neuropeptide-mediated functional connectivity within neural circuits which activities define cognition and behavior.

  • 7.
    Bazov, Igor
    et al.
    Uppsala University, Uppsala, Sweden.
    Kononenko, Olga
    Uppsala University, Uppsala, Sweden; Bogomoletz Institute of Physiology, Kiev, Ukrain.
    Watanabe, Hiroyuki
    Uppsala University, Uppsala, Sweden.
    Kuntić, Vesna
    University of Belgrade, Belgrade, Serbia.
    Sarkisyan, Daniil
    Financial University under the Government of the Russian Federation, Moscow, Russian Federation.
    Taqi, Malik M.
    Uppsala University, Uppsala, Sweden.
    Hussain, Muhammad Z.
    Uppsala University, Uppsala, Sweden.
    Nyberg, Fred
    Uppsala University, Uppsala, Sweden.
    Yakovleva, Tatjana
    Uppsala University, Uppsala, Sweden.
    Bakalkin, Georgy
    Uppsala University, Uppsala, Sweden.
    The endogenous opioid system in human alcoholics: molecular adaptations in brain areas involved in cognitive control of addiction2013Inngår i: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 18, nr 1, s. 161-169Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The endogenous opioid system (EOS) plays a critical role in addictive processes. Molecular dysregulations in this system may be specific for different stages of addiction cycle and neurocircuitries involved and therefore may differentially contribute to the initiation and maintenance of addiction. Here we evaluated whether the EOS is altered in brain areas involved in cognitive control of addiction including the dorsolateral prefrontal cortex (dl-PFC), orbitofrontal cortex (OFC) and hippocampus in human alcohol-dependent subjects. Levels of EOS mRNAs were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and levels of dynorphins by radioimmunoassay (RIA) in post-mortem specimens obtained from 14 alcoholics and 14 controls. Prodynorphin mRNA and dynorphins in dl-PFC, κ-opioid receptor mRNA in OFC and dynorphins in hippocampus were up-regulated in alcoholics. No significant changes in expression of proenkephalin, and µ- and δ-opioid receptors were evident; pro-opiomelanocortin mRNA levels were below the detection limit. Activation of the κ-opioid receptor by up-regulated dynorphins in alcoholics may underlie in part neurocognitive dysfunctions relevant for addiction and disrupted inhibitory control.

  • 8.
    Bazov, Igor
    et al.
    Uppsala University, Uppsala, Sweden.
    Sarkisyan, Daniil
    Uppsala University, Uppsala, Sweden.
    Kononenko, Olga
    Uppsala University, Uppsala, Sweden.
    Watanabe, Hiroyuki
    Uppsala University, Uppsala, Sweden.
    Karpyak, Victor M
    Mayo Clinic College of Medicine, Rochester, USA.
    Yakovleva, Tatiana
    Uppsala University, Uppsala, Sweden.
    Bakalkin, Georgy
    Uppsala University, Uppsala, Sweden.
    Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics2018Inngår i: Translational Psychiatry, E-ISSN 2158-3188, Vol. 8, nr 1, artikkel-id 122Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Molecular changes in cortical areas of addicted brain may underlie cognitive impairment and loss of control over intake of addictive substances and alcohol. Prodynorphin (PDYN) gives rise to dynorphin (DYNs) opioid peptides which target kappa-opioid receptor (KOR). DYNs mediate alcohol-induced impairment of learning and memory, while KOR antagonists block excessive, compulsive-like drug and alcohol self-administration in animal models. In human brain, the DYN/KOR system may undergo adaptive changes, which along with neuronal loss, may contribute to alcohol-associated cognitive deficit. We addressed this hypothesis by comparing the expression levels and co-expression (transcriptionally coordinated) patterns of PDYN and KOR (OPRK1) genes in dorsolateral prefrontal cortex (dlPFC) between human alcoholics and controls. Postmortem brain specimens of 53 alcoholics and 55 controls were analyzed. PDYN was found to be downregulated in dlPFC of alcoholics, while OPRK1 transcription was not altered. PDYN downregulation was confined to subgroup of subjects carrying C, a high-risk allele of PDYN promoter SNP rs1997794 associated with alcoholism. Changes in PDYN expression did not depend on the decline in neuronal proportion in alcoholics, and thereby may be attributed to transcriptional adaptations in alcoholic brain. Absolute expression levels of PDYN were lower compared to those of OPRK1, suggesting that PDYN expression is a limiting factor in the DYN/KOR signaling, and that the PDYN downregulation diminishes efficacy of DYN/KOR signaling in dlPFC of human alcoholics. The overall outcome of the DYN/KOR downregulation may be disinhibition of neurotransmission, which when overactivated could contribute to formation of alcohol-related behavior.

  • 9.
    Bazov, Igor
    et al.
    Uppsala University, Uppsala, Sweden.
    Sarkisyan, Daniil
    Uppsala University, Uppsala, Sweden.
    Kononenko, Olga
    Uppsala University, Uppsala, Sweden.
    Watanabe, Hiroyuki
    Uppsala University, Uppsala, Sweden.
    Taqi, Mumtaz Malik
    Uppsala University, Uppsala, Sweden; University of Oslo, Oslo, Norway.
    Stålhandske, Lada
    Uppsala University, Uppsala, Sweden.
    Verbeek, Dineke S.
    University of Groningen, Groningen, The Netherlands.
    Mulder, Jan
    Karolinska Institute, Stockholm, Sweden.
    Rajkowska, Grazyna
    University of Mississippi Medical Center, Jackson, USA.
    Sheedy, Donna
    University of Sydney, Sydney, Australia.
    Kril, Jillian
    University of Sydney, Sydney, Australia.
    Sun, Xueguang
    Zymo Research Corporation, Irvine, USA; Cincinnati Children's Hospital Medical Center, Cincinnati, USA.
    Syvänen, Ann-Christine
    Uppsala University, Uppsala, Sweden.
    Yakovleva, Tatiana
    Uppsala University, Uppsala, Sweden.
    Bakalkin, Georgy
    Uppsala University, Uppsala, Sweden.
    Neuronal Expression of Opioid Gene is Controlled by Dual Epigenetic and Transcriptional Mechanism in Human Brain2018Inngår i: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 28, nr 9, s. 3129-3142Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Molecular mechanisms that define patterns of neuropeptide expression are essential for the formation and rewiring of neural circuits. The prodynorphin gene (PDYN) gives rise to dynorphin opioid peptides mediating depression and substance dependence. We here demonstrated that PDYN is expressed in neurons in human dorsolateral prefrontal cortex (dlPFC), and identified neuronal differentially methylated region in PDYN locus framed by CCCTC-binding factor binding sites. A short, nucleosome size human-specific promoter CpG island (CGI), a core of this region may serve as a regulatory module, which is hypomethylated in neurons, enriched in 5-hydroxymethylcytosine, and targeted by USF2, a methylation-sensitive E-box transcription factor (TF). USF2 activates PDYN transcription in model systems, and binds to nonmethylated CGI in dlPFC. USF2 and PDYN expression is correlated, and USF2 and PDYN proteins are co-localized in dlPFC. Segregation of activatory TF and repressive CGI methylation may ensure contrasting PDYN expression in neurons and glia in human brain.

  • 10.
    Bazov, Igor
    et al.
    Uppsala University, Uppsala, Sweden.
    Sarkisyan, Daniil
    Uppsala University, Uppsala, Sweden.
    Kononenko, Olga
    Uppsala University, Uppsala, Sweden.
    Watanabe, Hiroyuki
    Uppsala University, Uppsala, Sweden.
    Yakovleva, Tatiana
    Uppsala University, Uppsala, Sweden.
    Hansson, Anita C.
    Heidelberg University, Mannheim, Germany.
    Sommer, Wolfgang H.
    Heidelberg University, Mannheim, Germany.
    Spanagel, Rainer
    Heidelberg University, Mannheim, Germany.
    Bakalkin, Georgy
    Uppsala University, Uppsala, Sweden.
    Dynorphin and κ-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics2018Inngår i: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, nr 8, s. 7049-7061Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Molecular changes induced by excessive alcohol consumption may underlie formation of dysphoric state during acute and protracted alcohol withdrawal which leads to craving and relapse. A main molecular addiction hypothesis is that the upregulation of the dynorphin (DYN)/κ-opioid receptor (KOR) system in the nucleus accumbens (NAc) of alcohol-dependent individuals causes the imbalance in activity of D1- and D2 dopamine receptor (DR) expressing neural circuits that results in dysphoria. We here analyzed post-mortem NAc samples of human alcoholics to assess changes in prodynorphin (PDYN) and KOR (OPRK1) gene expression and co-expression (transcriptionally coordinated) patterns. To address alterations in D1- and D2-receptor circuits, we studied the regulatory interactions between these pathways and the DYN/KOR system. No significant differences in PDYN and OPRK1 gene expression levels between alcoholics and controls were evident. However, PDYN and OPRK1 showed transcriptionally coordinated pattern that was significantly different between alcoholics and controls. A downregulation of DRD1 but not DRD2 expression was seen in alcoholics. Expression of DRD1 and DRD2 strongly correlated with that of PDYN and OPRK1 suggesting high levels of transcriptional coordination between these gene clusters. The differences in expression and co-expression patterns were not due to the decline in neuronal proportion in alcoholic brain and thereby represent transcriptional phenomena. Dysregulation of DYN/KOR system and dopamine signaling through both alterations in co-expression patterns of opioid genes and decreased DRD1 gene expression may contribute to imbalance in the activity of D1- and D2-containing pathways which may lead to the negative affective state in human alcoholics.

  • 11.
    Becker, Nina
    et al.
    Otto Hahn Group on Associative Memory, Max Planck Institute for Human Development, Berlin, Germany; Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    Kalpouzos, Grégoria
    Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    Persson, Jonas
    Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    Laukka, Erika J.
    Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    Brehmer, Yvonne
    Otto Hahn Group on Associative Memory, Max Planck Institute for Human Development, Berlin, Germany; Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    Differential Effects of Encoding Instructions on Brain Activity Patterns of Item and Associative Memory2017Inngår i: Journal of cognitive neuroscience, ISSN 0898-929X, E-ISSN 1530-8898, Vol. 29, nr 3, s. 545-559Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Evidence from neuroimaging studies suggests a critical role of hippocampus and inferior frontal gyrus (IFG) in associative relative to item encoding. Here, we investigated similarities and differences in functional brain correlates for associative and item memory as a function of encoding instruction. Participants received either incidental (animacy judgments) or intentional encoding instructions while fMRI was employed during the encoding of associations and items. In a subsequent recognition task, memory performance of participants receiving intentional encoding instructions was higher compared with those receiving incidental encoding instructions. Furthermore, participants remembered more items than associations, regardless of encoding instruction. Greater brain activation in the left anterior hippocampus was observed for intentionally compared with incidentally encoded associations, although activity in this region was not modulated by the type of instruction for encoded items. Furthermore, greater activity in the left anterior hippocampus and left IFG was observed during intentional associative compared with item encoding. The same regions were related to subsequent memory of intentionally encoded associations and were thus task relevant. Similarly, connectivity of the anterior hippocampus to the right superior temporal lobe and IFG was uniquely linked to subsequent memory of intentionally encoded associations. Our study demonstrates the differential involvement of anterior hippocampus in intentional relative to incidental associative encoding. This finding likely reflects that the intent to remember triggers a specific binding process accomplished by this region.

  • 12.
    Bendel, Olof
    et al.
    Section of Clinical CNS Research, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
    Alkass, Kanar
    Section of Clinical CNS Research, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
    Bueters, Tjerk
    Section of Clinical CNS Research, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
    von Euler, Mia
    Section of Clinical CNS Research, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
    von Euler, Gabriel
    Section of Clinical CNS Research, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
    Reproducible loss of CA1 neurons following carotid artery occlusion combined with halothane-induced hypotension2005Inngår i: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1033, nr 2, s. 135-142Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The 2-vessel occlusion approach to produce global ischemia in rats requires concomitant reduction of systemic blood pressure. We have utilized the hypotensive effect of halothane administrated by artificial respiration to prevent respiratory arrest and to ensure stable physiological conditions. Systemic blood pressure was reduced to 40-45 mmHg by instant adjustments of the halothane concentration. Bilateral occlusion of the carotid arteries caused a profound and reproducible ischemia, as analyzed by laser-Doppler flowmetry. In the rats exposed to 11, 12, or 13 min of ischemia, 5% died and 5% developed seizures. The extent of neuronal death in CA1 was highly correlated to the duration of ischemia. Following 11 min of ischemia, CA1 neuronal cell death, as analyzed by Fluoro-Jade, was absent 1 day after injury, variable at day 4, and consistent at day 7. The numbers of cresyl violet- and NeuN-positive neurons at day 7 were 8% and 20% of control, respectively. OX42 immunoreactivity was low and variable at day 4, but pronounced at day 7. In conclusion, this rat global ischemia model is relatively simple to perform, has a low mortality, and produces a profound and highly reproducible delayed cell death of hippocampal CA1 neurons.

  • 13.
    Berglund, Annika
    et al.
    Karolinska Institutet Stroke Research Network at Södersjukhuset, Stockholm, Sweden; Center for Gender Medicine, Södersjukhuset, Swede; Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Stockholm, Sweden.
    Svensson, Leif
    Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Stockholm, Sweden.
    Sjöstrand, Christina
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    von Arbin, Magnus
    Department of Clinical Sciences, Karolinska Institutet, Stockholm, Sweden; Department of Internal Medicine, Danderyd Hospital, Danderyd, Sweden.
    von Euler, Mia
    Karolinska Institutet Stroke Research Network at Södersjukhuset, Stockholm, Sweden; Center for Gender Medicine, Södersjukhuset, Swede; Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Stockholm, Sweden; Section of Neurology, Department of Internal Medicine, Södersjukhuset, Stockholm, Sweden; gDepartment of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Wahlgren, Nils
    gDepartment of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Engerström, Lars
    SOS Alarm AB, Emergency Medical Communication Center of Stockholm, Sweden.
    Höjeberg, Bo
    Capio Sankt Göran's Hospital, Stockholm, Sweden.
    Käll, Tor-Björn
    Section of Neurology, Department of Internal Medicine, Södersjukhuset, Stockholm, Sweden.
    Mjörnheim, Susanna
    Department of Internal Medicine, Södertälje Hospital, Södertälje, Sweden.
    Engqvist, Ann
    Department of Internal Medicine, Norrtälje Hospital, Norrtälje, Sweden.
    Higher prehospital priority level of stroke improves thrombolysis frequency and time to stroke unit: the Hyper Acute STroke Alarm (HASTA) study2012Inngår i: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 43, nr 10, s. 2666-2670Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND AND PURPOSE: Early initiated treatment of stroke increases the chances of a good recovery. This randomized controlled study evaluates how an increased priority level for patients with stroke, from level 2 to 1, from the Emergency Medical Communication Center influences thrombolysis frequency, time to stroke unit, and whether other medical emergencies reported negative consequences.

    METHODS: Patients aged 18 to 85 years in Stockholm, Sweden, with symptoms of stroke within 6 hours were randomized from the Emergency Medical Communication Center or emergency medical services to an intervention group, priority level 1, immediate call of an ambulance, or to a control group with standard priority level, that is, priority level 2 (within 30 minutes). Before study start, an educational program on identification of stroke and importance of early initiated treatment was directed to all medical dispatchers and ambulance and emergency department personnel.

    RESULTS: During 2008, 942 patients were randomized of which 53% (n=496) had a final stroke/transient ischemic attack diagnosis. Patients in the Emergency Medical Communication Center randomized intervention group reached the stroke unit 26 minutes earlier than the control group (P<0.001) after the emergency call. Thrombolysis was given to 24% of the patients in the intervention group compared with 10% of the control subjects (P<0.001). The higher priority level showed no negative effect on other critical ill patients requiring priority level 1 prehospital attention.

    CONCLUSIONS: This randomized study shows negligible harm to other medical emergencies, a significant increase in thrombolysis frequency, and a shorter time to the stroke unit for patients with stroke upgraded to priority level 1 from the Emergency Medical Communication Center and through the acute chain of stroke care.

  • 14.
    Bergman, Olle
    et al.
    Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
    Westberg, Lars
    Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Elias
    Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Center of Neurodevelopmental Disorders, Karolinska Institutet, Stockholm, Sweden.
    Study on the possible association of brain-derived neurotrophic factor polymorphism with the developmental course of symptoms of attention deficit and hyperactivity2011Inngår i: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 14, nr 10, s. 1367-1376Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several studies have, with conflicting results, investigated the relationship between the Val⁶⁶Met polymorphism in brain-derived neurotrophic factor (BDNF) and attention deficit hyperactivity disorder (ADHD). We assessed longitudinal, quantitative phenotypes of hyperactivity-impulsivity and inattention in order to determine whether the Val⁶⁶Met polymorphism is associated with age-specific and/or persistent symptoms of hyperactivity-impulsivity and/or inattention in a community-based cohort of 1236 Swedish individuals for which ADHD symptom data were collected when the participants were aged 8-9, 13-14 and 16-17 yr. The Met allele was associated with symptoms of ADHD at ages 8-9 and 13-14 yr. A multivariate regression analysis revealed that the observed effect of the Met allele on ADHD symptoms reflects an influence on persistent hyperactivity-impulsivity symptoms. The present findings support the hypothesis that BDNF is involved in the pathogenesis of ADHD. The results highlight the importance of distinguishing between hyperactivity-impulsivity and inattention, respectively, and demonstrate the value of using a longitudinal approach in genetic studies of ADHD symptoms.

  • 15.
    Bhandage, Amol K.
    et al.
    Uppsala University, Uppsala, Sweden.
    Jin, Zhe
    Uppsala University, Uppsala, Sweden.
    Bazov, Igor
    University of Helsinki, Helsinki, Finland.
    Kononenko, Olga
    University of Helsinki, Helsinki, Finland.
    Bakalkin, Georgy
    University of Helsinki, Helsinki, Finland.
    Korpi, Esa R.
    Uppsala University, Uppsala, Sweden.
    Birnir, Bryndis
    Uppsala University, Uppsala, Sweden.
    GABA-A and NMDA receptor subunit mRNA expression is altered in the caudate but not the putamen of the postmortem brains of alcoholics2014Inngår i: Frontiers in Cellular Neuroscience, E-ISSN 1662-5102, Vol. 8, artikkel-id 415Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chronic consumption of alcohol by humans has been shown to lead to impairment of executive and cognitive functions. Here, we have studied the mRNA expression of ion channel receptors for glutamate and GABA in the dorsal striatum of post-mortem brains from alcoholics (n = 29) and normal controls (n = 29), with the focus on the caudate nucleus that is associated with the frontal cortex executive functions and automatic thinking and on the putamen area that is linked to motor cortices and automatic movements. The results obtained by qPCR assay revealed significant changes in the expression of specific excitatory ionotropic glutamate and inhibitory GABA-A receptor subunit genes in the caudate but not the putamen. Thus, in the caudate we found reduced levels of mRNAs encoding the GluN2A glutamate receptor and the δ, ε, and ρ2 GABA-A receptor subunits, and increased levels of the mRNAs encoding GluD1, GluD2, and GABA-A γ1 subunits in the alcoholics as compared to controls. Interestingly in the controls, 11 glutamate and 5 GABA-A receptor genes were more prominently expressed in the caudate than the putamen (fold-increase varied from 1.24 to 2.91). Differences in gene expression patterns between the striatal regions may underlie differences in associated behavioral outputs. Our results suggest an altered balance between caudate-mediated voluntarily controlled and automatic behaviors in alcoholics, including diminished executive control on goal-directed alcohol-seeking behavior.

  • 16.
    Boberg, Erik
    et al.
    Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Haematology, Karolinska University Hospital, Stockholm, Sweden.
    Iacobaeus, Ellen
    Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Greenfield, Myrto Sklivanioti
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Wang, Yanlu
    Medical Radiation Physics and Nuclear Medicine, Karolinska University Hospital, Stockholm, Sweden; Radiology, Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Msghina, Mussie
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Le Blanc, Katarina
    Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Cellular therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden.
    Reduced prefrontal cortex and sympathetic nervous system activity correlate with fatigue after aHSCT2022Inngår i: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 57, s. 360-369Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Long-term fatigue and cognitive dysfunction affects 35% of allogeneic haematopoietic stem cell transplantation (aHSCT) survivors, suggesting a dysfunctional prefrontal cortex. In this study, we assessed prefrontal cortex and sympathetic nervous system activity in aHSCT patients with fatigue (n = 12), non-fatigued patients (n = 12) and healthy controls (n = 27). Measurement of near-infrared spectroscopy and electrodermal activity was carried out at rest and during cognitive performance (Stroop, verbal fluency and emotion regulation tasks). Prefrontal cortex and sympathetic nervous system activity were also analyzed in response to dopamine and noradrenaline increase after a single dose of methylphenidate. Baseline cognitive performance was similar in the two patient groups. However, after methylphenidate, only non-fatigued patients improved in Stroop accuracy and had better verbal fluency task performance compared to the fatigued group. Task-related activation of prefrontal cortex in fatigued patients was lower compared to non-fatigued patients during all cognitive tests, both before and after methylphenidate administration. During the Stroop task, reaction time, prefrontal cortex activation, and sympathetic nervous system activity were all lower in fatigued patients compared to healthy controls, but similar in non-fatigued patients and healthy controls.Reduced prefrontal cortex activity and sympathetic arousal suggests novel treatment targets to improve fatigue after aHSCT.

  • 17.
    Borg, J.
    et al.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Cervenka, S.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, R
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Matheson, G. J.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Jönsson, E. G.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, Psychiatry Section, University of Oslo, Oslo, Norway.
    Lichtenstein, P.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Henningsson, S.
    Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital, Hvidovre, Denmark.
    Ichimiya, T.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Stenkrona, P.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Halldin, C.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Farde, L.
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden; AstraZeneca Translational Science Center, Karolinska Institutet, Stockholm, Sweden.
    Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain2016Inngår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, nr 8, s. 1077-1084Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about the regulation of receptor and transporter density levels. This lack of knowledge obscures interpretation of differences in protein availability reported in psychiatric patients. In this study, we used positron emission tomography (PET) in a twin design to estimate the relative contribution of genetic and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the serotonin 5-HT1A receptor. Heritability, shared environmental effects and individual-specific non-shared effects were estimated for regional D2/3 and 5-HT1A receptor availability in projection areas. We found a major contribution of genetic factors (0.67) on individual variability in striatal D2/3 receptor binding and a major contribution of environmental factors (pairwise shared and unique individual; 0.70-0.75) on neocortical 5-HT1A receptor binding. Our findings indicate that individual variation in neuroreceptor availability in the adult brain is the end point of a nature-nurture interplay, and call for increased efforts to identify not only the genetic but also the environmental factors that influence neurotransmission in health and disease.

  • 18.
    Brander, Gustaf
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Pérez-Vigil, Ana
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Mataix-Cols, David
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Systematic review of environmental risk factors for Obsessive-Compulsive Disorder: A proposed roadmap from association to causation2016Inngår i: Neuroscience and Biobehavioral Reviews, ISSN 0149-7634, E-ISSN 1873-7528, Vol. 65, s. 36-62Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Objective: To synthesize the current knowledge on possible environmental risk factors for Obsessive-Compulsive Disorder (OCD).

    Method: We conducted a systematic review following PRISMA guidelines. The Embase, PubMed and Scopus databases were searched up until October 6, 2015, employing relevant keywords and MeSH terms.

    Results: 128 studies met inclusion criteria. Potential environmental risk factors for OCD have been identified in the broad areas of perinatal complications, reproductive cycle, and stressful life events. There is limited evidence regarding other potential risk factors, such as parental age, season of birth, socioeconomic status, parental rearing practices, infections, traumatic brain injury, substance use or vitamin deficiency. In general, studies were of limited methodological quality.

    Conclusions: At present, no environmental risk factors have convincingly been associated with OCD. We propose a roadmap for future studies, consisting of longitudinal, population-based research, employing quasi-experimental family and twin designs to identify risk factors that are not only associated with the disorder but also contribute to its causation either directly or moderating the effect of genes.

  • 19.
    Breimer, Lars H.
    et al.
    Fac Med & Hlth, Dept Lab Med, Örebro University Hospital, Örebro, Sweden.
    Nilsson, Torbjorn K.
    Dept Med Biosci, Clin Chem, Umeå Univ, Umeå, Sweden.
    Shedded cell membrane proteins in plasma: Pure waste, or informative biomarkers of pathophysiological processes?2015Inngår i: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 75, nr 6, s. 441-443Artikkel i tidsskrift (Fagfellevurdert)
  • 20.
    Brenner, P.
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Burkill, S.
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Jokinen, J.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Sciences, Umeå University, Umeå, Sweden.
    Hillert, J.
    Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Bahmanyar, S.
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Montgomery, Scott
    Örebro universitet, Institutionen för medicinska vetenskaper. Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, UK.
    Multiple sclerosis and risk of attempted and completed suicide: a cohort study2016Inngår i: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 23, nr 8, s. 1329-1336Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and purpose: Patients with multiple sclerosis (MS) are known to have an elevated suicide risk, but attempted suicide is incompletely investigated. The relation between education level and suicidality has not been investigated in MS patients. Our objective was to estimate attempted suicide and completed suicide risks amongst MS patients.

    Methods: A total of 29 617 Swedish MS patients were identified through the Swedish Patient Register and matched with 296 164 people without MS from the general population. Cox regression analysis estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of MS with attempted and completed suicide, with adjustment for age, sex, education and calendar period.

    Results: The adjusted HR for attempted suicide amongst MS patients is 2.18 (95% CI 1.97-2.43) compared with the general population cohort. For completed suicide the HR is 1.87 (95% CI 1.53-2.30). In both groups women are at higher risk of attempting suicide, whilst men are at higher risk of completing suicide. Education level is inversely associated with completed suicide amongst the non-MS cohort (0.68, 0.51-0.91), but not amongst MS patients (1.10, 0.60-2.04).

    Conclusion: Multiple sclerosis patients are at higher risk of both attempted and completed suicide. No evidence was found of an inverse association between educational level and risk of completed suicide amongst MS patients.

  • 21.
    Bueters, Tjerk
    et al.
    Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    von Euler, Mia
    Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Bendel, Olof
    Section of Clinical CNS Research, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
    von Euler, Gabriel
    Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Degeneration of newly formed CA1 neurons following global ischemia in the rat2008Inngår i: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 209, nr 1, s. 114-124Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The pyramidal neurons of the hippocampal CA1 region are essential for spatial learning and memory and are almost entirely destroyed 7-14 days after transient cerebral ischemia (DAI). Recently, we found that CA1 neurons reappeared at 21-90 DAI, in association with a recovery of ischemia-induced deficits in spatial learning and memory. However, at 125 DAI the number of neurons was fewer than at 90 DAI, suggesting that the new nerve cells undergo neurodegeneration during this time period. We therefore investigated whether neuronal degeneration occurred between 90 and 250 DAI and how this related to learning and memory performance. We found that many of the new CA1 neurons previously seen at 90 DAI had disappeared at 250 DAI. In parallel, large mineralized calcium deposits appeared in the hippocampus and thalamus, in association with neuroinflammatory and astroglial reactions. In spite of the extensive CA1 damage, the ischemic rats showed no deficiencies in spatial learning and memory, as analyzed in the Morris water maze and a complimentary water maze test based on sequential left-right choices. However, ischemia rats showed a general increase in swim length in the Morris water maze suggesting altered search behaviour. Taken together, these results indicate that the CA1 neurons that reappear after transient global ischemia to a large extent degenerate at 125-250 DAI, in parallel with the appearance of a less efficient search strategy.

  • 22.
    Busi, Micol
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. Department of Audiologyl.
    Castiglione, Alessandro
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. Department of Audiology.
    Navigating the Usher Syndrome Genetic Landscape: An Evaluation of the Associations between Specific Genes and Quality Categories of Cochlear Implant Outcomes2024Inngår i: Audiology Research, ISSN 2039-4330, E-ISSN 2039-4349, Vol. 14, nr 2, s. 254-263Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Usher syndrome (US) is a clinically and genetically heterogeneous disorder that involves three main features: sensorineural hearing loss, retinitis pigmentosa (RP), and vestibular impairment. With a prevalence of 4–17/100,000, it is the most common cause of deaf-blindness worldwide. Genetic research has provided crucial insights into the complexity of US. Among nine confirmed causative genes, MYO7A and USH2A are major players in US types 1 and 2, respectively, whereas CRLN1 is the sole confirmed gene associated with type 3. Variants in these genes also contribute to isolated forms of hearing loss and RP, indicating intersecting molecular pathways. While hearing loss can be adequately managed with hearing aids or cochlear implants (CIs), approved RP treatment modalities are lacking. Gene replacement and editing, antisense oligonucleotides, and small-molecule drugs hold promise for halting RP progression and restoring vision, enhancing patients’ quality of life. Massively parallel sequencing has identified gene variants (e.g., in PCDH15) that influence CI results. Accordingly, preoperative genetic examination appears valuable for predicting CI success. To explore genetic mutations in CI recipients and establish correlations between implant outcomes and involved genes, we comprehensively reviewed the literature to gather data covering a broad spectrum of CI outcomes across all known US-causative genes. Implant outcomes were categorized as excellent or very good, good, poor or fair, and very poor. Our review of 95 cochlear-implant patients with US, along with their CI outcomes, revealed the importance of presurgical genetic testing to elucidate potential challenges and provide tailored counseling to improve auditory outcomes. The multifaceted nature of US demands a comprehensive understanding and innovative interventions. Genetic insights drive therapeutic advancements, offering potential remedies for the retinal component of US. The synergy between genetics and therapeutics holds promise for individuals with US and may enhance their sensory experiences through customized interventions.

    Fulltekst (pdf)
    Publisher's fulltext
  • 23.
    Cao, Yang
    et al.
    Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
    Chen, Aimin
    Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, NE, USA.
    Jones, Robert L.
    Organic Analytical Toxicology Branch, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.
    Radcliffe, Jerilynn
    The Children's Hospital of Philadelphia, and University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
    Caldwell, Kathleen L.
    Organic Analytical Toxicology Branch, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.
    Dietrich, Kim N.
    Department of Environmental Health, Division of Epidemiology and Biostatistics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
    Rogan, Walter J.
    Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
    Does background postnatal methyl mercury exposure in toddlers affect cognition and behavior?2010Inngår i: Neurotoxicology, ISSN 0161-813X, E-ISSN 1872-9711, Vol. 31, nr 1, s. 1-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Because the toxicological effects of mercury (Hg) are more serious in the developing central nervous system of children than adults, there are growing concerns about prenatal and early childhood Hg exposure. This study examined postnatal methylmercury (MeHg) exposure and cognition and behavior in 780 children enrolled in the Treatment of Lead (Pb)-exposed Children clinical trial (TLC) with 396 children allocated to the succimer and 384 to the placebo groups. Mercury exposure was determined from analyses of blood drawn 1 week before randomization and 1 week after treatment began when succimer had its maximal effect on blood Pb (PbB). The baseline MeHg concentrations were 0.54 microg/L and 0.52 microg/L and post-treatment concentrations were 0.51 microg/L and 0.48 microg/L for placebo and succimer groups, respectively. Because the baseline characteristics in the two groups were balanced and because succimer had little effect on MeHg concentration and no effect on the cognitive or behavioral test scores, the groups were combined in the analysis of MeHg and neurodevelopment. The children's IQ and neurobehavioral performance were tested at age 2, 5 and 7 years. We saw weak, non-significant but consistently positive associations between blood MeHg and IQ test scores in stratified, spline regression and generalized linear model data analyses. The behavioral problem scores were constant or decreased slightly with increasing MeHg concentration. Additional adjustment for PbB levels in multivariable models did not alter the conclusion for MeHg and IQ scores, but did confirm that concurrent PbB was strongly associated with IQ and behavior in TLC children. The effects of MeHg on neurodevelopmental indices did not substantially differ by PbB strata. We conclude that at the present background postnatal MeHg exposure levels of US children, adverse effects on children's IQ and behavior are not detectable.

  • 24.
    Cheng, Arthur
    et al.
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Chaillou, Thomas
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Gineste, Charlotte
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Schlittler, Maja
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Intracellular Ca(2+) handling and myofibrillar Ca(2+) sensitivity are defective in single muscle fibres of aged humans2015Inngår i: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 593, nr 15, s. 3237-3238Artikkel i tidsskrift (Fagfellevurdert)
  • 25.
    Cronberg, Tobias
    et al.
    Dept Neurol & Rehabil Med, Skåne Univ Hosp, Lund, Sweden; Dept Clin Sci, Lund Univ, Lund, Sweden.
    Lilja, Gisela
    Dept Neurol & Rehabil Med, Skåne Univ Hosp, Lund, Sweden; Dept Clin Sci, Lund Univ, Lund, Sweden.
    Horn, Janneke
    Acad Med Ctr, Dept Intens Care, Univ Amsterdam, Amsterdam, Netherlands.
    Kjaergaard, Jesper
    Ctr Heart, Dept Cardiol, Copenhagen Univ Hosp (Rigshosp), Copenhagen, Denmark.
    Wise, Matt P.
    Adult Crit Care, Univ Wales Hosp, Cardiff, England.
    Pellis, Tommaso
    Intens Care Unit, Santa Maria Angeli, Pordenone, Italy.
    Hovdenes, Jan
    Dept Anesthesiol, Oslo Univ Hosp (Rikshosp), Univ Oslo, Oslo, Norway.
    Gasche, Yvan
    Dept Anesthesiol Pharmacol & Intens Care, Univ Hosp Geneva, Geneva, Switzerland.
    Aneman, Anders
    Dept Intens Care, Liverpool Hosp, Sydney NSW, Australia.
    Stammet, Pascal
    Dept Anesthesiol & Intens Care, Ctr Hosp, Luxembourg, Luxembourg.
    Erlinge, David
    Dept Clin Sci, Lund Univ, Lund, Sweden; Dept Cardiol, Lund Univ, Lund, Sweden.
    Friberg, Hans
    Dept Clin Sci, Lund, Lund Univ, Sweden; Dept Intens & Perioperat Care, Skåne Univ Hosp, Lund, Sweden.
    Hassager, Christian
    Ctr Heart, Dept Cardiol, Copenhagen Univ Hosp (Rigshosp), Copenhagen, Denmark.
    Kuiper, Michael
    Acad Med Ctr, Dept Intens Care, Univ Amsterdam, Amsterdam, Netherlands; Dept Intens Care, Med Ctr Leeuwarden, Leeuwarden, Netherlands.
    Wanscher, Michael
    Ctr Heart, Dept Cardiothorac Anesthesiol, Copenhagen Univ Hosp (Rigshosp), Copenhagen, Denmark.
    Bosch, Frank
    Dept Intens Care, Rijnstaate Hosp, Arnhem, Netherlands.
    Cranshaw, Julius
    Dept Intens Care, Royal Bournemouth Hosp, Bournemouth, England.
    Kleger, Gian-Reto
    Dept Intens Care, Kantonsspital, St Gallen, Switzerland.
    Persson, Stefan
    Dept Anesthesia & Intens Care, Örebro University Hospital, Örebro, Sweden.
    Unden, Johan
    Dept Intens & Perioperat Care, Skåne Univ Hosp, Malmö, Sweden.
    Walden, Andrew
    Dept Intens Care, Royal Berkshire Hosp, Reading, England.
    Winkel, Per
    Ctr Clin Intervent Res, Copenhagen Trial Unit, Copenhagen Univ Hosp R(igshosp), Copenhagen, Denmark.
    Wetterslev, Jorn
    Ctr Clin Intervent Res, Copenhagen Trial Unit, Copenhagen Univ Hosp (Rigshosp), Copenhagen, Denmark.
    Nielsen, Niklas
    Dept Clin Sci, Lund Univ, Lund, Sweden; Anesthesia & Intens Care, Helsingborg Hosp, Helsingborg, Sweden.
    Neurologic Function and Health-Related Quality of Life in Patients Following Targeted Temperature Management at 33 degrees C vs 36 degrees C After Out-of-Hospital Cardiac Arrest A Randomized Clinical Trial2015Inngår i: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 72, nr 6, s. 634-641Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    IMPORTANCE Brain injury affects neurologic function and quality of life in survivors after cardiac arrest. OBJECTIVE To compare the effects of 2 target temperature regimens on long-term cognitive function and quality of life after cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS In this multicenter, international, parallel group, assessor-masked randomized clinical trial performed from November 11, 2010, through January 10, 2013, we enrolled 950 unconscious adults with cardiac arrest of presumed cardiac cause from 36 intensive care units in Europe and Australia. Eleven patients were excluded from analysis for a total sample size of 939. INTERVENTIONS Targeted temperature management at 33 degrees C vs 36 degrees C. MAIN OUTCOMES AND MEASURES Cognitive function was measured by the Mini-Mental State Examination (MMSE) and assessed by observers through the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Patients reported their activities in daily life and mental recovery through Two Simple Questions and their quality of life through the Medical Outcomes Study 36-Item Short Form Health Survey, version 2. RESULTS In the modified intent-to-treat population, including nonsurvivors, the median MMSE score was 14 in the 33 degrees C group (interquartile range [IQR], 0-28) vs 17 in the 36 degrees C group (IQR, 0-29) (P = .77), and the IQCODE score was 115 (IQR, 79-130) vs 115 (IQR, 80-130) (P = .57) in the 33 degrees C and 36 degrees C groups, respectively. The median MMSE score for survivors was within the reference range and similar (33 degrees C group median, 28; IQR, 26-30; vs 36 degrees C group median, 28; IQR, 25-30; P = .61). The median IQCODE score was within the minor deficit range (33 degrees C group median, 79.5; IQR, 78.0-85.9; vs 36 degrees C group median, 80.7; IQR, 78.0-86.9; P = .04). A total of 18.8% vs 17.5% of survivors reported needing help with everyday activities (P = .71), and 66.5% in the 33 degrees C group vs 61.8% in the 36 degrees C group reported that they thought they had made a complete mental recovery (P = .32). The mean (SD) mental component summary score was 49.1 (12.5) vs 49.0 (12.2) (P = .79), and the mean (SD) physical component summary score was 46.8 (13.8) and 47.5 (13.8) (P = .45), comparable to the population norm. CONCLUSIONS AND RELEVANCE Quality of life was good and similar in patients with cardiac arrest receiving targeted temperature management at 33 degrees C or 36 degrees C. Cognitive function was similar in both intervention groups, but many patients and observers reported impairment not detected previously by standard outcome scales.

  • 26.
    Curman, Philip
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden; Dermato-Venereology Clinic, Karolinska University Hospital, Stockholm, Sweden.
    Jebril, William
    Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden; Dermato-Venereology Clinic, Karolinska University Hospital, Stockholm, Sweden.
    Larsson, Henrik
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Bachar-Wikström, Etty
    Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.
    Martin, Cederlöf
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Wikström, Jakob D.
    Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden; Dermato-Venereology Clinic, Karolinska University Hospital, Stockholm, Sweden.
    Increased risk of depression and anxiety in individuals with Darier disease2024Inngår i: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, artikkel-id ljae195Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Patients with Darier disease have an increased risk of depression and anxiety, which agrees with patterns of increased prescription of antidepressants and anxiolytics in people with the disease.

  • 27.
    Diener, Hans-Christoph
    et al.
    Department of Neurology, University Hospital, Essen, Germany.
    Sacco, Ralph L.
    Department of Neurology, University Hospital, Essen, Germany.
    Yusuf, Salim
    Department of Neurology, University Hospital, Essen, Germany.
    Cotton, Daniel
    Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, USA.
    Ounpuu, Stephanie
    Boehringer Ingelheim, Burlington, Canada.
    Lawton, William A.
    Boehringer Ingelheim Ltd, Bracknell, England.
    Palesch, Yuko
    Department of Biostatistics, Bioinformatics and Epidemiology, Medical University of South Carolina, Charleston, South Carolina, USA.
    Martin, Reneé H.
    Department of Biostatistics, Bioinformatics and Epidemiology, Medical University of South Carolina, Charleston, South Carolina, USA.
    Albers, Gregory W.
    Neurology and Neurological Sciences, Stanford University Medical Center, Palo Alto, California, USA.
    Bath, Philip
    Stroke Trials Unit, University of Nottingham, Nottingham, England.
    Bornstein, Natan
    Neurology Department, Ichilov Medical, Center, Tel-Aviv, Israel.
    Chan, Bernard P. L.
    Division of Neurology, Department of Medicine, National University Hospital, Singapore.
    Chen, Sien-Tsong
    Department of Neurology, Chang Gung Memorial Hospital, Taipei, Taiwan.
    Cunha, Luis
    Neurology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal.
    Dahlöf, Björn
    Department of Medicine, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden.
    De Keyser, Jacques
    Department of Neurology, University Medical Center Groningen, Groningen, Netherland.
    Donnan, Geoffrey A.
    National Stroke Research Institute, Austin Health, University of Melbourne, Heidelberg West, Australia.
    Estol, Conrado
    Neurological Center for Treatment and Research, Buenos Aires, Argentina.
    Gorelick, Philip
    Department of Neurology and Rehabilitation, University of Illinois, Chicago, Illinois, USA.
    Gu, Vivian
    Boehringer Ingelheim Shanghai Pharmaceuticals Co Ltd, Shanghai, China.
    Hermansson, Karin
    Boehringer Ingelheim AB, Stockholm, Sweden.
    Hilbrich, Lutz
    Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, USA.
    Kaste, Markku
    Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
    Lu, Chuanzhen
    Neurology Department, Huashan Hospital, Shanghai, China.
    Machnig, Thomas
    Boehringer Ingelheim GmbH, Ingelheim, Germany.
    Pais, Prem
    St John's Medical College, Bangalore, India.
    Roberts, Robin
    Clinical Trials Methodology Group, McMaster University, Hamilton, Ontario, Canada.
    Skvortsova, Veronika
    Neurology & Neurosurgery Clinic, Russian State Medical University, Moscow, Russia.
    Teal, Philip
    Department of Medicine, Neurology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
    Toni, Danilo
    Department of Neurological Sciences, University “La Sapienza”, Rome, Italy.
    VanderMaelen, Cam
    Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, USA.
    Voigt, Thor
    Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, USA.
    Weber, Michael
    Cardiology Department, SUNY Downstate College of Medicine, New York, USA.
    Yoon, Byung-Woo
    Department of Neurology, Seoul National University Hospital, Seoul, Korea.
    Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS), study group
    Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study.2008Inngår i: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 7, nr 10, s. 875-884Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The treatment of ischaemic stroke with neuroprotective drugs has been unsuccessful, and whether these compounds can be used to reduce disability after recurrent stroke is unknown. The putative neuroprotective effects of antiplatelet compounds and the angiotensin II receptor antagonist telmisartan were investigated in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial.

    METHODS: Patients who had had an ischaemic stroke were randomly assigned in a two by two factorial design to receive either 25 mg aspirin (ASA) and 200 mg extended-release dipyridamole (ER-DP) twice a day or 75 mg clopidogrel once a day, and either 80 mg telmisartan or placebo once per day. The predefined endpoints for this substudy were disability after a recurrent stroke, assessed with the modified Rankin scale (mRS) and Barthel index at 3 months, and cognitive function, assessed with the mini-mental state examination (MMSE) score at 4 weeks after randomisation and at the penultimate visit. Analysis was by intention to treat. The study was registered with ClinicalTrials.gov, number NCT00153062.

    FINDINGS: 20,332 patients (mean age 66 years) were randomised and followed-up for a median of 2.4 years. Recurrent strokes occurred in 916 (9%) patients randomly assigned to ASA with ER-DP and 898 (9%) patients randomly assigned to clopidogrel; 880 (9%) patients randomly assigned to telmisartan and 934 (9%) patients given placebo had recurrent strokes. mRS scores were not statistically different in patients with recurrent stroke who were treated with ASA and ER-DP versus clopidogrel (p=0.38), or with telmisartan versus placebo (p=0.61). There was no significant difference in the proportion of patients with recurrent stroke with a good outcome, as measured with the Barthel index, across all treatment groups. Additionally, there was no significant difference in the median MMSE scores, the percentage of patients with an MMSE score of 24 points or less, the percentage of patients with a drop in MMSE score of 3 points or more between 1 month and the penultimate visit, and the number of patients with dementia among the treatment groups. There were no significant differences in the proportion of patients with cognitive impairment or dementia among the treatment groups.

    INTERPRETATION: Disability due to recurrent stroke and cognitive decline in patients with ischaemic stroke were not different between the two antiplatelet regimens and were not affected by the preventive use of telmisartan.

  • 28.
    Edebol Carlman, Hanna M. T.
    et al.
    Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Rode, Julia
    Örebro universitet, Institutionen för medicinska vetenskaper.
    König, Julia
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Repsilber, Dirk
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Hutchinson, Ashley
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Thunberg, Per
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Radiology and Medical Physics.
    Persson, Jonas
    Örebro universitet, Institutionen för juridik, psykologi och socialt arbete.
    Kiselev, Andrey
    Örebro universitet, Institutionen för naturvetenskap och teknik. Center for Applied Autonomous Sensor Systems.
    Pruessner, Jens C.
    Douglas Institute, McGill University, Montréal, QC H4H1R3, Canada; Department of Psychology, University of Konstanz, Konstanz, Germany.
    Brummer, Robert Jan
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Probiotic Mixture Containing Lactobacillus helveticus, Bifidobacterium longum and Lactiplantibacillus plantarum Affects Brain Responses to an Arithmetic Stress Task in Healthy Subjects: A Randomised Clinical Trial and Proof-of-Concept Study2022Inngår i: Nutrients, E-ISSN 2072-6643, Vol. 14, nr 7, artikkel-id 1329Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Probiotics are suggested to impact physiological and psychological stress responses by acting on the gut-brain axis. We investigated if a probiotic product containing Bifidobacterium longum R0175, Lactobacillus helveticus R0052 and Lactiplantibacillus plantarum R1012 affected stress processing in a double-blinded, randomised, placebo-controlled, crossover proof-of-concept study (NCT03615651). Twenty-two healthy subjects (24.2 ± 3.4 years, 6 men/16 women) underwent a probiotic and placebo intervention for 4 weeks each, separated by a 4-week washout period. Subjects were examined by functional magnetic resonance imaging while performing the Montreal Imaging Stress Task (MIST) as well as an autonomic nervous system function assessment during the Stroop task. Reduced activation in regions of the lateral orbital and ventral cingulate gyri was observed after probiotic intervention compared to placebo. Significantly increased functional connectivity was found between the upper limbic region and medioventral area. Interestingly, probiotic intervention seemed to predominantly affect the initial stress response. Salivary cortisol secretion during the task was not altered. Probiotic intervention did not affect cognitive performance and autonomic nervous system function during Stroop. The probiotic intervention was able to subtly alter brain activity and functional connectivity in regions known to regulate emotion and stress responses. These findings support the potential of probiotics as a non-pharmaceutical treatment modality for stress-related disorders.

  • 29.
    Eriksson, Eva Wiman
    et al.
    Dept Dent Sleep Med, Postgrad Dent Educ Ctr, Region Örebro County, Örebro, Sweden.
    Leissner, Lena
    Sleep Unit, Dept Neurol, Örebro University Hospital, Örebro, Sweden.
    Isacsson, Göran
    Dept Orofacial Pain, Västmanland Cty Hosp, Västerås, Sweden.
    Fransson, Anette
    Region Örebro län. Dept Orthodont, Postgrad Dent Educ Ctr, , Region Örebro County, Örebro, Sweden; Dent Sleep Med Clin, Postgrad Dent Educ Ctr, Region Örebro County, Örebro, Sweden.
    A prospective 10-year follow-up polygraphic study of patients treated with a mandibular protruding device2015Inngår i: Sleep and Breathing, ISSN 1520-9512, E-ISSN 1522-1709, Vol. 19, nr 1, s. 393-401Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This 10-year follow-up prospective study aimed to evaluate the effects of treatment with a mandibular protruding device (MPD) on respiratory parameters and subjective symptoms in patients with obstructive sleep apnea (OSA) or snoring. Seventy-seven consecutive patients diagnosed with OSA or snoring were treated with an MPD. At baseline and the 10-year follow-up, a polygraphic examination and questionnaires on sleep quality were administrated and weight, and neck size was measured. At the 10-year follow-up, we examined 64 of the 77 patients and recorded their current treatment (45 MPD, 9 continuous positive airway pressure (CPAP), and 10 no treatment). For MPD patients, 89 % reported MPD use every night and 9 % several nights a week. Compared to baseline, MPD users with OSA had a significantly decreased oxygen desaturation index (ODI) (p = 0.006) and increased lowest arterial oxygen saturation, SaO(2) nadir (p = 0.007) after 10 years. MPD treatment was successful for 70 % of OSA patients, yet 89 % subjectively considered themselves cured, indicating overestimation of the treatment effect. OSA patients who responded to treatment maintained baseline weight and neck size, while these increased for non-responders. Of the baseline snorers still using an MPD, 93 % maintained an ODI value of < 5. All CPAP users had an ODI value of < 5. Both OSA and snorers using an MPD had significantly fewer self- and relative reports of snoring, apnea, daytime tiredness, and poor night sleep quality (p < 0.001). MPD treatment is well tolerated and effective in a long-term, 10-year perspective. Weight gain may jeopardize MPD effects. Both patients and relatives reported significantly less snoring and fewer periods of apnea.

  • 30.
    Fang, Fang
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
    Valdimarsdóttir, Unnur
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; Centre of Public Health Sciences,University of Iceland, Reykjavik, Iceland.
    Fürst, Carl Johan
    Stockholms Sjukhem, Palliative Care Unit, Stockholm.
    Hultman, Christina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; Department of Neuroscience, Psychiatry, Ulleråker,Uppsala University,Uppsala.
    Fall, Katja
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
    Sparén, Pär
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
    Ye, Weimin
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
    Suicide among patients with amyotrophic lateral sclerosis2008Inngår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 131, nr 10, s. 2729-33Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Studies on the suicide risk among patients with amyotrophic lateral sclerosis (ALS) in countries without legalized euthanasia or assisted suicide are important additions to data on the wish to die of these patients. We conducted a population-based cohort study in Sweden between 1965 and 2004, which comprised of 6,642 patients with incident ALS identified from the Swedish Inpatient Register. We calculated the standardized mortality ratios (SMRs) of suicide among the patients using the suicide rates of the general Swedish population as a reference. In total, 21 patients committed suicide during follow-up, compared to the predicted 3.6 suicides. Thus, we noted an almost 6-fold increased risk for suicide among ALS patients [SMR 5.8, 95% confidence interval (CI) 3.6-8.8]. Patients who committed suicide were, on average, around 7 years younger at the time of their first period of hospitalization than patients who did not commit suicide. The highest relative risk for suicide was observed within the first year after the patient's first period of hospitalization (SMR 11.2, 95% CI 5.8-19.6). After that, the relative risks decreased with time after hospitalization (P-value for trend = 0.006), but remained elevated 3 years later. The relative risks of suicide among ALS patients did not show a clear trend over time in contrast to the decreasing trend of relative risks for suicide among patients with cancer during the same period. Patients with ALS are at excess risk of suicide in Sweden and the relative risk is higher during the earlier stage of the disease.

  • 31. Fernell, Elisabeth
    et al.
    Karagiannakis, Aristea
    Örebro universitet, Institutionen för klinisk medicin.
    Edman, Gunnar
    Bjerkenstedt, Lars
    Wiesel, Frits-Axel
    Venizelos, Nikolaos
    Örebro universitet, Institutionen för klinisk medicin.
    Aberrant amino acid transport in fibroblasts from children with autism2007Inngår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 418, nr 1, s. 82-86Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Autism is a developmental, cognitive disorder clinically characterized by impaired social interaction, communication and restricted behaviours. The present study was designed to explore whether an abnormality in transport of tyrosine and/or alanine is present in children with autism. Skin biopsies were obtained from 11 children with autism (9 boys and 2 girls) fulfilling the DSM-IV diagnostic criteria for autistic disorder and 11 healthy male control children. Transport of amino acids tyrosine and alanine across the cell membrane of cultured fibroblasts was studied by the cluster tray method. The maximal transport capacity, Vmax and the affinity constant of the amino acid binding sites, Km, were determined. Significantly increased Vmax for alanine (p = 0.014) and increased Km for tyrosine (p = 0.007) were found in children with autism. The increased transport capacity of alanine across the cell membrane and decreased affinity for transport sites of tyrosine indicates the involvement of two major amino acid transport systems (L- and A-system) in children with autism. This may influence the transport of several other amino acids across the blood–brain-barrier. The significance of the findings has to be further explored. © 2007 Elsevier Ireland Ltd. All rights reserved

  • 32.
    Forsberg, Anette
    et al.
    Division of neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Family Medicine Research Centre, Örebro county council, Örebro, Sweden.
    Press, Rayomand
    Division of neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Widén Holmqvist, Lotta
    Division of neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Division of physiotherapy, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Residual disability 10 years after falling ill in Guillain-Barré syndrome: a prospective follow-up study2012Inngår i: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 317, nr 1-2, s. 74-79Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To describe residual disability 10years after onset of Guillain-Barré syndrome (GBS) and longitudinal changes from 2weeks after onset until 10years afterwards. The Erasmus GBS Outcome score (EGOS) was applied for predicting prognosis at 2 and 10years.

    Methods: Twenty-nine patients, mean age at onset 49years, were followed prospectively from 2weeks to 10years after GBS onset. Measures included; GBS disability score, EGOS, Barthel Index, Frenchay Activity Index, Sickness Impact Profile (SIP), Overall Neuropathy Limitations Scale (ONLS), Walk-12, and Fatigue Severity Scale.

    Results: At 10years, the facial paralysis found in 5 participants at 2years was still present, 11 participants (38%) experienced paresthesia, 6 (21%) had limitations in their arms, and 15 (52%) had limitations in walking. Decreased health-related quality of life on comparison to the general population was seen in the physical dimension of SIP at 10years. The median EGOS at 2weeks was 4.5, which correlated highly only with the Barthel Index at 2years and the ONLS arm scale at 10years.

    Conclusion: The residual disabilities at 1-2years comprised mainly of reduced walking ability, and are still persistent 10years after GBS onset. For some individuals, facial paralysis caused major disability. The EGOS only partly predicted residual disability at 2 and 10years after onset.

  • 33.
    Forslund, Tomas
    et al.
    The Clinical Pharmacology Unit, Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Solna, Sweden; Stockholm County Council, Department of Healthcare Development, Stockholm, Sweden .
    Komen, Joris J.
    Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.
    Andersen, Morten
    Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark .
    Wettermark, Björn
    The Clinical Pharmacology Unit, Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Stockholm County Council, Department of Healthcare Development, Stockholm, Sweden.
    von Euler, Mia
    Clinical Pharmacology Unit, Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Department of Clinical Science and Education, Karolinska Institutet Stroke Research Network at Södersjukhuset, Stockholm, Sweden .
    Mantel-Teeuwisse, Aukje K.
    Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands .
    Braunschweig, Frieder
    Department of Cardiology, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden .
    Hjemdahl, Paul
    Clinical Pharmacology Unit, Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Solna, Sweden .
    Improved Stroke Prevention in Atrial Fibrillation After the Introduction of Non-Vitamin K Antagonist Oral Anticoagulants2018Inngår i: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 49, nr 9, s. 2122-2128Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and Purpose: The purpose of this study was to investigate the impact of improved antithrombotic treatment in atrial fibrillation after the introduction of non-vitamin K antagonist oral anticoagulants on the incidence of stroke and bleeding in a real-life total population, including both primary and secondary care.

    Methods: All resident and alive patients with a recorded diagnosis for atrial fibrillation during the preceding 5 years in the Stockholm County Healthcare database (Vårdanalysdatabasen) were followed for clinical outcomes during 2012 (n=41 008) and 2017 (n=49 510).

    Results: Pharmacy claims for oral anticoagulants increased from 51.6% to 73.8% (78.7% among those with CHA2DS2-VASc ≥2). Non-vitamin K antagonist oral anticoagulant claims increased from 0.4% to 34.4%. Ischemic stroke incidence rates decreased from 2.01 per 100 person-years in 2012 to 1.17 in 2017 (incidence rate ratio, 0.58; 95% CI, 0.52-0.65). The largest increases in oral anticoagulants use and decreases in ischemic strokes were seen in patients aged ≥80 years who had the highest risk of stroke and bleeding. The incidence rates for major bleeding (2.59) remained unchanged (incidence rate ratio, 1.00; 95% CI, 0.92-1.09) even in those with a high bleeding risk. Poisson regression showed that 10% of the absolute ischemic stroke reduction was associated with increased oral anticoagulants treatment, whereas 27% was related to a generally decreased risk for all stroke.

    Conclusions: Increased oral anticoagulants use contributed to a marked reduction of ischemic strokes without increasing bleeding rates between 2012 and 2017. The largest stroke reduction was seen in elderly patients with the highest risks for stroke and bleeding. These findings strongly support the adoption of current guideline recommendations for stroke prevention in atrial fibrillation in both primary and secondary care.

  • 34.
    Fresnais, David
    et al.
    School of Medical Sciences, Örebro University, Örebro, Sweden; Department of Internal Medicine, Central Hospital Karlstad, Region Värmland, Sweden.
    Humble, Mats B.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Bejerot, Susanne
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Meehan, Adrian David
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. Department of Geriatrics.
    Fure, Brynjar
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Apathy as a Predictor for Conversion From Mild Cognitive Impairment to Dementia: A Systematic Review and Meta-Analysis of Longitudinal Studies2023Inngår i: Journal of Geriatric Psychiatry and Neurology, ISSN 0891-9887, E-ISSN 1552-5708, Vol. 36, nr 1, s. 3-17Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Apathy is one of the most prevalent neurobehavioral manifestations in mild cognitive impairment (MCI) and is included among the behavioral and psychological symptoms of dementia (BPSD). Studies suggest that the presence of apathy could be associated with increased dementia risk. The role of apathy in conversion from MCI to dementia, and whether apathy could be a relevant predictor for dementia progression, are still matters of investigation.

    AIM: To study the relationship between apathy and progression to dementia in individuals with MCI.

    METHODS: A systematic literature search in Medline, Embase, Cochrane Library, Epistemonikos, PsychINFO, and CINAHL was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search included longitudinal studies reporting on the association between apathy and dementia.

    RESULTS: The main outcome was pooled unadjusted hazard ratios (HR) of apathy in dementia conversion and included 11 studies with 9504 individuals. There was a significant association between apathy and dementia conversion, HR = 1.54; 95% CI, 1.29, 1.84. Subgroup analysis showed a significant association between apathy and progression to AD.

    CONCLUSION: Apathy was associated with an increased risk of conversion to AD and all-cause dementia in patients with MCI. The role of apathy as a marker for incident dementia needs to be investigated in large, high-quality studies.

  • 35.
    Genove, G.
    et al.
    Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
    Mollick, Tanzina
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Johansson, Kjell
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Photoreceptor degeneration, structural remodeling and glial activation: a morphological study on a genetic mouse model for pericyte deficiency2014Inngår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 279, s. 269-284Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Interaction between pericytes and endothelial cells via platelet-derived growth factor B (PDGF-B) signaling is critical for the development of the retinal microvasculature. The PDGF-B retention motif controls the spatial distribution range of the growth factor in the vicinity of its producing endothelial cells allowing its recognition by PDGF receptor beta-(PDGFR-beta)-carrying pericytes; this promotes recruitment of pericytes to the vascular basement membrane. Impairment of the PDGF-B signaling mechanism causes development of vascular abnormalities, and in the retina this consequently leads to defects in the neurological circuitry. The vascular pathology in the pdgf-b(ret/ret) (PDGF-B retention motif knockout) mouse retina has been previously reported; our study investigates the progressive neuronal defects and changes in the retinal morphology of this pericyte-deficient mouse model. Immunohistochemical analysis revealed retinal injuries to occur as early as postnatal day (P) 10 with substantial damage progressing from P15 and onward. Vascular abnormalities were apparent from P10, however, prominent neuronal defects were mostly observed from P15, beginning with the compromised integrity of the laminated retinal structure characterized by the presence of rosettes and focally distorted regions. Photoreceptor degeneration was observed by loss of both rod and cone cells, including the disassembly and altered structure of their synaptic terminals. Significant shortening of cone outer segments was observed from P10 and later stages; however, decrease in cone density was only observed at P28. Disorganization and dendrite remodeling of rod bipolar cells also added to the diminished neural and synaptic integrity. Moreover, in response to retinal injuries, Muller and microglial cells were observed to be in the reactive phenotype from P15 and onward. Such a sequence of events indicates that the pdgf-b(ret/ret) mouse model displays a short time frame between P10 and P15, during which the retina shifts to a retinopathic phase by the development of prominently altered morphological features.

  • 36. Gustavsson, Anders
    et al.
    Svensson, Mikael
    Örebro universitet, Handelshögskolan vid Örebro universitet.
    Jacobi, Frank
    Allgulander, Christer
    Alonso, Jordi
    Beghi, Ettore
    Dodel, Richard
    Ekman, Mattias
    Faravelli, Carlo
    Fratiglioni, Laura
    Gannon, Brenda
    Jones, David Hilton
    Jennum, Poul
    Jordanova, Albena
    Jonsson, Linus
    Karampampa, Korinna
    Knapp, Martin
    Kobelt, Gisela
    Kurth, Tobias
    Lieb, Roselind
    Linde, Mattias
    Ljungcrantz, Christina
    Maercker, Andreas
    Melin, Beatrice
    Moscarelli, Massimo
    Musayev, Amir
    Norwood, Fiona
    Preisig, Martin
    Pugliatti, Maura
    Rehm, Juergen
    Salvador-Carulla, Luis
    Schlehofer, Brigitte
    Simon, Roland
    Steinhausen, Hans-Christoph
    Stovner, Lars Jacob
    Vallat, Jean-Michel
    Van den Bergh, Peter
    van Os, Jim
    Vos, Pieter
    Xu, Weili
    Wittchen, Hans-Ulrich
    Jonsson, Bengt
    Olesen, Jes
    Cost of disorders of the brain in Europe 20102011Inngår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 21, nr 10, s. 718-779Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Background: The spectrum of disorders of the brain is large, covering hundreds of disorders that are listed in either the mental or neurological disorder chapters of the established international diagnostic classification systems. These disorders have a high prevalence as well as short- and long-term impairments and disabilities. Therefore they are an emotional, financial and social burden to the patients, their families and their social network. In a 2005 landmark study, we estimated for the first time the annual cost of 12 major groups of disorders of the brain in Europe and gave a conservative estimate of 386 billion for the year 2004. This estimate was limited in scope and conservative due to the lack of sufficiently comprehensive epidemiological and/or economic data on several important diagnostic groups. We are now in a position to substantially improve and revise the 2004 estimates. In the present report we cover 19 major groups of disorders, 7 more than previously, of an increased range of age groups and more cost items. We therefore present much improved cost estimates. Our revised estimates also now include the new EU member states, and hence a population of 514 million people. Aims: To estimate the number of persons with defined disorders of the brain in Europe in 2010, the total cost per person related to each disease in terms of direct and indirect costs, and an estimate of the total cost per disorder and country.

    Methods: The best available estimates of the prevalence and cost per person for 19 groups of disorders of the brain (covering well over 100 specific disorders) were identified via a systematic review of the published literature. Together with the twelve disorders included in 2004, the following range of mental and neurologic groups of disorders is covered: addictive disorders, affective disorders, anxiety disorders, brain tumor, childhood and adolescent disorders (developmental disorders), dementia, eating disorders, epilepsy, mental retardation, migraine, multiple sclerosis, neuromuscular disorders, Parkinson's disease, personality disorders, psychotic disorders, sleep disorders, somatoform disorders, stroke, and traumatic brain injury. Epidemiologic panels were charged to complete the literature review for each disorder in order to estimate the 12-month prevalence, and health economic panels were charged to estimate best cost-estimates. A cost model was developed to combine the epidemiologic and economic data and estimate the total cost of each disorder in each of 30 European countries (EU27 + Iceland, Norway and Switzerland). The cost model was populated with national statistics from Eurostat to adjust all costs to 2010 values, converting all local currencies to Euro, imputing costs for countries where no data were available, and aggregating country estimates to purchasing power parity adjusted estimates for the total cost of disorders of the brain in Europe 2010.

    Results: The total cost of disorders of the brain was estimated at (sic)798 billion in 2010. Direct costs constitute the majority of costs (37% direct healthcare costs and 23% direct non-medical costs) whereas the remaining 40% were indirect costs associated with patients production losses. On average, the estimated cost per person with a disorder of the brain in Europe ranged between (sic)285 for headache and (sic)30,000 for neuromuscular disorders. The European per capita cost of disorders of the brain was (sic)1550 on average but varied by country. The cost (in billion (sic)PPP 2010) of the disorders of the brain included in this study was as folows: addiction: (sic)65.7; anxiety disorders: (sic)74.4; brain tumor: (sic)5.2; child/adolescent disorders: (sic)21.3; dementia: (sic)105.2; eating disorders: (sic)0.8; epilepsy: (sic)13.8; headache: (sic)43.5; mental retardation: (sic)43.3; mood disorders: (sic)113.4; multiple sclerosis: (sic)14.6; neuromuscular disorders: (sic)7.7; Parkinson's disease: (sic)13.9; personality disorders: (sic)27.3; psychotic disorders: (sic)93.9; sleep disorders: (sic)35.4; somatoform disorder: (sic)21.2; stroke: (sic)64.1; traumatic brain injury: (sic)33.0. It should be noted that the revised estimate of those disorders included in the previous 2004 report constituted (sic)477 billion, by and large confirming our previous study results after considering the inflation and population increase since 2004. Further, our results were consistent with administrative data on the health care expenditure in Europe, and comparable to previous studies on the cost of specific disorders in Europe. Our estimates were lower than comparable estimates from the US.

    Discussion: This study was based on the best currently available data in Europe and our model enabled extrapolation to countries where no data could be found. Still, the scarcity of data is an important source of uncertainty in our estimates and may imply over- or underestimations in some disorders and countries. Even though this review included many disorders, diagnoses, age groups and cost items that were omitted in 2004, there are still remaining disorders that could not be included due to limitations in the available data. We therefore consider our estimate of the total cost of the disorders of the brain in Europe to be conservative. In terms of the health economic burden outlined in this report, disorders of the brain likely constitute the number one economic challenge for European health care, now and in the future. Data presented in this report should be considered by all stakeholder groups, including policy makers, industry and patient advocacy groups, to reconsider the current science, research and public health agenda and define a coordinated plan of action of various levels to address the associated challenges.

    Recommendations: Political action is required in light of the present high cost of disorders of the brain. Funding of brain research must be increased; care for patients with brain disorders as well as teaching at medical schools and other health related educations must be quantitatively and qualitatively improved, including psychological treatments. The current move of the pharmaceutical industry away from brain related indications must be halted and reversed. Continued research into the cost of the many disorders not included in the present study is warranted. It is essential that not only the EU but also the national governments forcefully support these initiatives.

  • 37.
    Hamre, Charlotta
    et al.
    Department of Physiotherapy, Oslo University Hospital (OUS), Oslo, Norway; Department of Geriatric Medicine, OUS, Oslo, Norway; Institute of Clinical Medicine, University of Oslo (UiO), Oslo, Norway; Department of Neurology, OUS, Oslo, Norway.
    Fure, Brynjar
    Region Örebro län. Örebro universitet, Institutionen för medicinska vetenskaper. Department of Internal Medicine, Central Hospital, Karlstad, Sweden; Department of Neurology, Central Hospital, Karlstad and Örebro, Sweden.
    Helbostad, Jorunn Lægdheim
    Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
    Wyller, Torgeir Bruun
    Department of Geriatric Medicine, OUS, Oslo, Norway; Institute of Clinical Medicine, University of Oslo (UiO), Oslo, Norway.
    Ihle-Hansen, Hege
    Department of Geriatric Medicine, OUS, Oslo, Norway; Department of Neurology, OUS, Oslo, Norway.
    Vlachos, Georgios
    Department of Neurology, OUS, Oslo, Norway.
    Ursin, Marie Helene
    Department of Geriatric Medicine, Bærum Hospital, Vestre Viken Trust, Bærum, Norway.
    Tangen, Gro Gujord
    Department of Geriatric Medicine, OUS, Oslo, Norway; Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tönsberg, Norway; Department of Interdisciplinary Health Sciences, UiO, Oslo, Norway.
    Impairments in spatial navigation during walking in patients 70 years or younger with mild stroke2020Inngår i: Topics in Stroke Rehabilitation, ISSN 1074-9357, E-ISSN 1945-5119, Vol. 27, nr 8, s. 601-609Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Spatial navigation, the ability to determine and maintain a route from one place to another, is needed for independence in everyday life. Knowledge about impairments in spatial navigation in people with mild stroke is scarce.

    Objectives: To explore impairments in spatial navigation in patients ≤70 years after first-ever mild ischemic stroke (NIHSS≤3) and to explore which variables are associated with these impairments 12 months later.

    Methods: Patients were examined in the acute phase, and after 3 and 12 months. To assess impairments in spatial navigation, we used the Floor Maze Test (FMT), with time and FMT-errors as outcomes. Patients' perceived navigational skills were collected using self-report. Logistic regression was used to explore which variables (sociodemographic data, stroke characteristics, cognition, and mobility) were associated with impaired navigation ability.

    Results: Ninety-seven patients (20 females) were included. The mean (SD) age was 55.5 (11.4) years. Timed FMT improved significantly from the acute phase to 12 months (p = <.001). At 12 months, 24 (24.7%) of the participants walked through the maze with errors, and 22 (22.7%) reported spatial navigational problems. The Trail Making Test (TMT)-B was the only variable from the acute phase associated with FMT-errors at 12 months, and being female was the only variable associated with self-reported navigational problems at 12 months.

    Conclusion: Nearly one in four patients experienced spatial navigation problems 12 months after a mild stroke. Executive function (TMT-B), measured in the acute phase, was associated with navigational impairments (FMT-errors) at 12 months, and being female was associated with self-reported navigational problems.

  • 38.
    Hedenius, Martina
    et al.
    Department of Public Health and Caring Sciences, Speech-Language Pathology, Uppsala University, Uppsala, Sweden; Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet and Child and Adolescent Psychiatry, Stockholm Health Care Services, Region Stockholm, Stockholm County Council, BUP-FOU Centrum, Stockholm, Sweden.
    Persson, Jonas
    Örebro universitet, Institutionen för juridik, psykologi och socialt arbete. Aging Research Center (ARC), Karolinska Institutet and Stockholm University, Solna, Sweden.
    Neural correlates of sequence learning in children with developmental dyslexia2022Inngår i: Human Brain Mapping, ISSN 1065-9471, E-ISSN 1097-0193, Vol. 43, nr 11, s. 3559-3576Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Developmental Dyslexia (DD) is a condition in which reading accuracy and/or fluency falls substantially below what is expected based on the individuals age, general level of cognitive ability, and educational opportunities. The procedural circuit deficit hypothesis (PDH) proposes that DD may be largely explained in terms of alterations of the cortico-basal ganglia procedural memory system (in particular of the striatum) whereas the (hippocampus-dependent) declarative memory system is intact, and may serve a compensatory role in the condition. The present study was designed to test this hypothesis. Using Magnetic Resonance Imaging, we examined the functional and structural brain correlates of sequence-specific procedural learning (SL) on the serial reaction time task, in 17 children with DD and 18 typically developing (TD) children. The study was performed over 2 days with a 24-h interval between sessions. In line with the PDH, the DD group showed less activation of the striatum during the processing of sequential statistical regularities. These alterations predicted the amount of SL at day 2, which in turn explained variance in children's reading fluency. Additionally, reduced hippocampal activation predicted larger SL gains between day 1 and day 2 in the TD group, but not in the DD group. At the structural level, caudate nucleus volume predicted the amount of acquired SL at day 2 in the TD group, but not in the DD group. The findings encourage further research into factors that promote learning in children with DD, including through compensatory mechanisms.

  • 39.
    Henriksson, Richard
    et al.
    Integrative Neuroscience Research Branch, Baltimore, USA; Karolinska Institutet, Stockholm, Sweden; Uppsala University, Uppsala, Sweden.
    Bäckman, Cristina M
    Cellular Neurobiology Research Branch, Baltimore, USA.
    Harvey, Brandon K
    Molecular Neuropsychiatry Research Branch, Baltimore, USA.
    Kadyrova, Helena
    Uppsala University, Uppsala, Sweden.
    Bazov, Igor
    Uppsala University, Uppsala, Sweden.
    Shippenberg, Toni S
    Integrative Neuroscience Research Branch, Baltimore, USA.
    Bakalkin, Georgy
    Uppsala University, Uppsala, Sweden.
    PDYN, a gene implicated in brain/mental disorders, is targeted by REST in the adult human brain2014Inngår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1839, nr 11, s. 1226-1232Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The dynorphin κ-opioid receptor system is implicated in mental health and brain/mental disorders. However, despite accumulating evidence that PDYN and/or dynorphin peptide expression is altered in the brain of individuals with brain/mental disorders, little is known about transcriptional control of PDYN in humans. In the present study, we show that PDYN is targeted by the transcription factor REST in human neuroblastoma SH-SY5Y cells and that that interfering with REST activity increases PDYN expression in these cells. We also show that REST binding to PDYN is reduced in the adult human brain compared to SH-SY5Y cells, which coincides with higher PDYN expression. This may be related to MIR-9 mediated down-regulation of REST as suggested by a strong inverse correlation between REST and MIR-9 expression. Our results suggest that REST represses PDYN expression in SH-SY5Y cells and the adult human brain and may have implications for mental health and brain/mental disorders.

  • 40.
    Humble, Mats B.
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Uppsala university.
    Bejerot, Susanne
    Uppsala university.
    Bergqvist, Peter B. F.
    AstraZeneca, Lund, Sweden.
    Reactivity of serotonin in whole blood: response to Mulder et al.2002Inngår i: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 51, nr 3, s. 267-268Artikkel i tidsskrift (Annet vitenskapelig)
  • 41.
    Ingberg, Edvin
    Örebro universitet, Institutionen för medicinska vetenskaper. Avdelningen för neuro- och inflammationsvetenskap, Linköpings universitet, Linköping, Sweden.
    Challenges in experimental stroke research: The 17β-estradiol example2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Ischemic stroke causes millions of deaths around the world each year, and surviving patients often suffer from long-term disability. Hundreds of promising drug candidates have been identified in animal models, but the clinical trials have repeatedly failed. Lack of methodological quality in the animal studies, e.g. low statistical power as a result of small group sizes in combination with high outcome variability and high mortality, has been suggested to in part explain the lack of translational success. In the meta-analytical Papers II and Paper V, we therefore investigated how method parameters impact infarct size variation and mortality in rodent stroke studies. These findings can help researchers to optimize their animal models or to more exactly predict variability and mortality given a certain experimental setup.

    The relation between ischemic stroke and estrogens is complex. Premenopausal women have a lower risk of stroke than men of the same age, suggesting that female sex hormones provide protection against cerebrovascular events. The idea of a beneficial effect on the brain of estrogens was also supported by epidemiological studies showing that estrogens given as postmenopausal hormone replacement therapy decreased the risk of stroke. However, subsequent clinical trials reported the opposite, an increased risk. Interestingly, discrepancies exist also in the animal stroke literature. The majority of the rodent studies on the effects of estrogens have shown protection, but there are also several examples of increased damage. Based on experimental results and a meta-analysis, it was hypothesized that differences in hormone administration methods and their resulting plasma concentrations of estrogens might explain the previous discordant animal findings. Paper I investigated the commonly used methods for 17β-estradiol administration and found that the popular slow-release pellets produced high and unpredictable serum concentrations. A novel method with 17β-estradiol administered orally in Nutella® was also evaluated with promising results. Paper III extracted data regarding methodological choices from all previously published estrogen-stroke studies, and showed through metaanalysis that slow-release pellets are more prone to render estrogens damaging. Finally, Paper IV tested whether estrogens could both exert neuroprotection and promote detrimental effects merely depending on dose and irrespective of the administration route. Surprisingly, and in contrast to the hypothesis, a significant negative correlation was found between 17β-estradiol dose group and infarct size meaning that the higher the dose, the smaller the infarcts.

    In summary, this thesis does not confirm the hypothesis of dose-related neuroprotective vs neurodamaging effects of estrogens on ischemic stroke. If high estrogen doses/plasma concentrations per se can cause increased stroke damage, such a phenomenon is not very robust, and seems to depend on tight dose ranges and/or other experimental circumstances. Although not directly applicable to the clinical situation, hopefully in a long-term perspective these findings may contribute in elucidating when estrogens are beneficial and when they are harmful. Further, it adds to the growing literature on how the quality of experimental stroke research can be increased to try to overcome translational difficulties.

    Delarbeid
    1. Methods for long-term 17β-estradiol administration to mice
    Åpne denne publikasjonen i ny fane eller vindu >>Methods for long-term 17β-estradiol administration to mice
    2012 (engelsk)Inngår i: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 175, nr 1, s. 188-193Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Rodent models constitute a cornerstone in the elucidation of the effects and biological mechanisms of 17β-estradiol. However, a thorough assessment of the methods for long-term administration of 17β-estradiol to mice is lacking. The fact that 17β-estradiol has been demonstrated to exert different effects depending on dose emphasizes the need for validated administration regimens. Therefore, 169 female C57BL/6 mice were ovariectomized and administered 17β-estradiol using one of the two commonly used subcutaneous methods; slow-release pellets (0.18 mg, 60-day release pellets; 0.72 mg, 90-day release pellets) and silastic capsules (with/without convalescence period, silastic laboratory tubing, inner/outer diameter: 1.575/3.175 mm, filled with a 14 mm column of 36 μg 17β-estradiol/mL sesame oil), or a novel peroral method (56 μg 17β-estradiol/day/kg body weight in the hazelnut cream Nutella). Forty animals were used as ovariectomized and intact controls. Serum samples were obtained weekly for five weeks and 17β-estradiol concentrations were measured using radioimmunoassay. The peroral method resulted in steady concentrations within--except on one occasion--the physiological range and the silastic capsules produced predominantly physiological concentrations, although exceeding the range by maximum a factor three during the first three weeks. The 0.18 mg pellet yielded initial concentrations an order of magnitude higher than the physiological range, which then decreased drastically, and the 0.72 mg pellet produced between 18 and 40 times higher concentrations than the physiological range during the entire experiment. The peroral method and silastic capsules described in this article constitute reliable modes of administration of 17β-estradiol, superior to the widely used commercial pellets.

    sted, utgiver, år, opplag, sider
    Maryland Heigths, USA: Elsevier, 2012
    Emneord
    Estradiol, mice, slow-release pellets, silastic capsule, Per os, uterine weight
    HSV kategori
    Identifikatorer
    urn:nbn:se:oru:diva-48106 (URN)10.1016/j.ygcen.2011.11.014 (DOI)000299065800022 ()22137913 (PubMedID)2-s2.0-84855192470 (Scopus ID)
    Tilgjengelig fra: 2016-02-08 Laget: 2016-02-08 Sist oppdatert: 2019-04-05bibliografisk kontrollert
    2. Method parameters' impact on mortality and variability in rat stroke experiments: a meta-analysis
    Åpne denne publikasjonen i ny fane eller vindu >>Method parameters' impact on mortality and variability in rat stroke experiments: a meta-analysis
    2013 (engelsk)Inngår i: BMC Neuroscience, E-ISSN 1471-2202, Vol. 14, artikkel-id 41Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background: Even though more than 600 stroke treatments have been shown effective in preclinical studies, clinically proven treatment alternatives for cerebral infarction remain scarce. Amongst the reasons for the discrepancy may be methodological shortcomings, such as high mortality and outcome variability, in the preclinical studies. A common approach in animal stroke experiments is that A) focal cerebral ischemia is inflicted, B) some type of treatment is administered and C) the infarct sizes are assessed. However, within this paradigm, the researcher has to make numerous methodological decisions, including choosing rat strain and type of surgical procedure. Even though a few studies have attempted to address the questions experimentally, a lack of consensus regarding the optimal methodology remains.

    Methods: We therefore meta-analyzed data from 502 control groups described in 346 articles to find out how rat strain, procedure for causing focal cerebral ischemia and the type of filament coating affected mortality and infarct size variability.

    Results: The Wistar strain and intraluminal filament procedure using a silicone coated filament was found optimal in lowering infarct size variability. The direct and endothelin methods rendered lower mortality rate, whereas the embolus method increased it compared to the filament method.

    CONCLUSIONS: The current article provides means for researchers to adjust their middle cerebral artery occlusion (MCAo) protocols to minimize infarct size variability and mortality.

    sted, utgiver, år, opplag, sider
    London, United Kingdom: BioMed Central (BMC), 2013
    Emneord
    Brain infarction, middle cerebral artery occlusion, rats, methods, mortality, variability
    HSV kategori
    Identifikatorer
    urn:nbn:se:oru:diva-48100 (URN)10.1186/1471-2202-14-41 (DOI)000318616000001 ()23548160 (PubMedID)2-s2.0-84875538383 (Scopus ID)
    Tilgjengelig fra: 2016-02-08 Laget: 2016-02-08 Sist oppdatert: 2024-01-17bibliografisk kontrollert
    3. Impact of methodology on estrogens' effects on cerebral ischemia in rats: an updated meta-analysis
    Åpne denne publikasjonen i ny fane eller vindu >>Impact of methodology on estrogens' effects on cerebral ischemia in rats: an updated meta-analysis
    2014 (engelsk)Inngår i: BMC Neuroscience, E-ISSN 1471-2202, Vol. 15, artikkel-id 22Artikkel, forskningsoversikt (Fagfellevurdert) Published
    Abstract [en]

    Background: Although most animal stroke studies have demonstrated potent neuroprotective effects of estrogens, there are a number of articles reporting the opposite. In 2009, we made the case that this dichotomy was related to administered estrogen dose. Several other suggestions for the discordant results have also been propagated, including the age of the experimental animals and the length of hypoestrogenicity prior to estrogen administration. These two suggestions have gained much popularity, probably because of their kinship with the window of opportunity hypothesis, which is commonly used to explain the analogous dichotomy among human studies. We were therefore encouraged to perform an updated meta-analysis, and to improve it by including all relevant variables in a large multiple regression model, where the impact of confounders could be controlled for.

    Results: The multiple regression model revealed an indisputable impact of estrogen administration mode on the effects of estrogens in ischemic stroke. Subcutaneous slow-release pellets differed from the injection and silastic capsule treatments in terms of impact of estrogens on ischemic stroke, showing that the first mentioned were more prone to render estrogens damaging. Neither the use of elderly animals nor the adoption of longer wash-out periods influenced estrogens' effects on experimental ischemic stroke in rats.

    Conclusions: We conclude that the discordant results regarding estrogens' effects in rat models of ischemic stroke are a consequence of differences in estrogen administration modes. These results are not only of importance for the ongoing debate regarding menopausal hormone therapy, but also have an important bearing on experimental stroke methodology and the apparent translational roadblock for suggested stroke interventions.

    sted, utgiver, år, opplag, sider
    London: BioMed Central (BMC), 2014
    Emneord
    Cerebral ischemia, Estradiol, Estrogens, Meta-analysis, Rats, Stroke
    HSV kategori
    Forskningsprogram
    Neurologi
    Identifikatorer
    urn:nbn:se:oru:diva-35219 (URN)10.1186/1471-2202-15-22 (DOI)000334885400001 ()24495535 (PubMedID)2-s2.0-84893182322 (Scopus ID)
    Merknad

    Funding Agencies:

    County Council of Örebro

    Linköping University, Sweden

    Tilgjengelig fra: 2014-06-02 Laget: 2014-06-02 Sist oppdatert: 2024-01-17bibliografisk kontrollert
    4. Effects of high and low 17β-estradiol doses on focal cerebral ischemia in rats
    Åpne denne publikasjonen i ny fane eller vindu >>Effects of high and low 17β-estradiol doses on focal cerebral ischemia in rats
    2016 (engelsk)Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 6, artikkel-id 20228Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The majority of the numerous animal studies of the effects of estrogens on cerebral ischemia have reported neuroprotective results, but a few have shown increased damage. Differences in hormone administration methods, resulting in highly different 17β-estradiol levels, may explain the discrepancies in previously reported effects. The objective of the present study was to test the hypothesis that it is the delivered dose per se, and not the route and method of administration, that determines the effect, and that high doses are damaging while lower doses are protective. One hundred and twenty ovariectomized female Wistar rats (n = 40 per group) were randomized into three groups, subcutaneously administered different doses of 17β-estradiol and subjected to transient middle cerebral artery occlusion. The modified sticky tape test was performed after 24 h and the rats were subsequently sacrificed for infarct size measurements. In contrast to our hypothesis, a significant negative correlation between 17β-estradiol dose and infarct size was found (p = 0.018). Thus, no support was found for the hypothesis that 17β-estradiol can be both neuroprotective and neurotoxic merely depending on dose. In fact, on the contrary, the findings indicate that the higher the dose of 17β-estradiol, the smaller the infarct.

    sted, utgiver, år, opplag, sider
    London, United Kingdom: Nature Publishing Group, 2016
    HSV kategori
    Identifikatorer
    urn:nbn:se:oru:diva-48094 (URN)10.1038/srep20228 (DOI)000369323500001 ()26839007 (PubMedID)2-s2.0-84957824658 (Scopus ID)
    Merknad

    Funding Agency:

    County Council of Östergötland, Sweden

    Tilgjengelig fra: 2016-02-08 Laget: 2016-02-08 Sist oppdatert: 2022-09-15bibliografisk kontrollert
    5. Method parameters' impact on mortality and variability in mouse stroke experiments: a meta-analysis
    Åpne denne publikasjonen i ny fane eller vindu >>Method parameters' impact on mortality and variability in mouse stroke experiments: a meta-analysis
    Vise andre…
    2016 (engelsk)Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 6, artikkel-id 21086Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Although hundreds of promising substances have been tested in clinical trials, thrombolysis currently remains the only specific pharmacological treatment for ischemic stroke. Poor quality, e.g. low statistical power, in the preclinical studies has been suggested to play an important role in these failures. Therefore, it would be attractive to use animal models optimized to minimize unnecessary mortality and outcome variability, or at least to be able to power studies more exactly by predicting variability and mortality given a certain experimental setup. The possible combinations of methodological parameters are innumerous, and an experimental comparison of them all is therefore not feasible. As an alternative approach, we extracted data from 334 experimental mouse stroke articles and, using a hypothesis-driven meta-analysis, investigated the method parameters' impact on infarct size variability and mortality. The use of Swiss and C57BL6 mice as well as permanent occlusion of the middle cerebral artery rendered the lowest variability of the infarct size while the emboli methods increased variability. The use of Swiss mice increased mortality. Our study offers guidance for researchers striving to optimize mouse stroke models.

    sted, utgiver, år, opplag, sider
    Nature Publishing Group, 2016
    HSV kategori
    Forskningsprogram
    Neurologi
    Identifikatorer
    urn:nbn:se:oru:diva-48937 (URN)10.1038/srep21086 (DOI)000370034300001 ()26876353 (PubMedID)2-s2.0-84958259183 (Scopus ID)
    Merknad

    Funding Agency:

    County Council of Östergötland, Sweden

    Tilgjengelig fra: 2016-03-07 Laget: 2016-03-04 Sist oppdatert: 2023-07-04bibliografisk kontrollert
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  • 42.
    Jin, Zhe
    et al.
    Uppsala University, Uppsala, Sweden.
    Bhandage, Amol K.
    Uppsala University, Uppsala, Sweden.
    Bazov, Igor
    Uppsala University, Uppsala, Sweden.
    Kononenko, Olga
    Uppsala University, Uppsala, Sweden.
    Bakalkin, Georgy
    Uppsala University, Uppsala, Sweden.
    Korpi, Esa R.
    University of Helsinki, Helsinki, Finland.
    Birnir, Bryndis
    Uppsala University, Uppsala, Sweden.
    Expression of specific ionotropic glutamate and GABA-A receptor subunits is decreased in central amygdala of alcoholics2014Inngår i: Frontiers in Cellular Neuroscience, E-ISSN 1662-5102, Vol. 8, artikkel-id 288Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The central amygdala (CeA) has a role for mediating fear and anxiety responses. It is also involved in emotional imbalance caused by alcohol abuse and dependence and in regulating relapse to alcohol abuse. Growing evidences suggest that excitatory glutamatergic and inhibitory γ-aminobutyric acid-ergic (GABAergic) transmissions in the CeA are affected by chronic alcohol exposure. Human post-mortem CeA samples from male alcoholics (n = 9) and matched controls (n = 9) were assayed for the expression level of ionotropic glutamate and GABA-A receptors subunit mRNAs using quantitative real-time reverse transcription-PCR (RT-qPCR). Our data revealed that out of the 16 ionotropic glutamate receptor subunits, mRNAs encoding two AMPA [2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid] receptor subunits GluA1 and GluA4; one kainate receptor subunit GluK2; one NMDA (N-methyl-D-aspartate) receptor subunit GluN2D and one delta receptor subunit GluD2 were significantly decreased in the CeA of alcoholics. In contrast, of the 19 GABA-A receptor subunits, only the mRNA encoding the α2 subunit was significantly down-regulated in the CeA of the alcoholics as compared with control subjects. Our findings imply that the down-regulation of specific ionotropic glutamate and GABA-A receptor subunits in the CeA of alcoholics may represent one of the molecular substrates underlying the new balance between excitatory and inhibitory neurotransmission in alcohol dependence.

  • 43.
    Jin, Zhe
    et al.
    Uppsala University, Uppsala, Sweden.
    Bhandage, Amol K
    Uppsala University, Uppsala, Sweden.
    Bazov, Igor
    Uppsala University, Uppsala, Sweden.
    Kononenko, Olga
    Uppsala University, Uppsala, Sweden.
    Bakalkin, Georgy
    Uppsala University, Uppsala, Sweden.
    Korpi, Esa R
    University of Helsinki, Helsinki, Finland.
    Birnir, Bryndis
    Uppsala University, Uppsala, Sweden.
    Selective increases of AMPA, NMDA, and kainate receptor subunit mRNAs in the hippocampus and orbitofrontal cortex but not in prefrontal cortex of human alcoholics2014Inngår i: Frontiers in Cellular Neuroscience, E-ISSN 1662-5102, Vol. 8, artikkel-id 11Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glutamate is the main excitatory transmitter in the human brain. Drugs that affect the glutamatergic signaling will alter neuronal excitability. Ethanol inhibits glutamate receptors. We examined the expression level of glutamate receptor subunit mRNAs in human post-mortem samples from alcoholics and compared the results to brain samples from control subjects. RNA from hippocampal dentate gyrus (HP-DG), orbitofrontal cortex (OFC), and dorso-lateral prefrontal cortex (DL-PFC) samples from 21 controls and 19 individuals with chronic alcohol dependence were included in the study. Total RNA was assayed using quantitative RT-PCR. Out of the 16 glutamate receptor subunits, mRNAs encoding two AMPA [2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid] receptor subunits GluA2 and GluA3; three kainate receptor subunits GluK2, GluK3 and GluK5 and five NMDA (N-methyl-D-aspartate) receptor subunits GluN1, GluN2A, GluN2C, GluN2D, and GluN3A were significantly increased in the HP-DG region in alcoholics. In the OFC, mRNA encoding the NMDA receptor subunit GluN3A was increased, whereas in the DL-PFC, no differences in mRNA levels were observed. Our laboratory has previously shown that the expression of genes encoding inhibitory GABA-A receptors is altered in the HP-DG and OFC of alcoholics (Jin et al., 2011). Whether the changes in one neurotransmitter system drives changes in the other or if they change independently is currently not known. The results demonstrate that excessive long-term alcohol consumption is associated with altered expression of genes encoding glutamate receptors in a brain region-specific manner. It is an intriguing possibility that genetic predisposition to alcoholism may contribute to these gene expression changes.

  • 44.
    Jons, Daniel
    et al.
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Zetterberg, Henrik
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Dahlgren's Academy, University of Gothenburg, Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute at UCL, London, UK; Hong Kong Centre for Neurodegenerative Diseases, Hong Kong, China.
    Biström, Martin
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Alonso-Magdalena, Lucia
    Department of Neurology, Skåne University Hospital, Lund, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden.
    Gunnarsson, Martin
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. Department of Neurology.
    Vrethem, Magnus
    Department of Neurology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Blennow, Kaj
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Dahlgren's Academy, University of Gothenburg, Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Nilsson, Staffan
    Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Sundström, Peter
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Andersen, Oluf
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Axonal injury in asymptomatic individuals preceding onset of multiple sclerosis2022Inngår i: Annals of Clinical and Translational Neurology, E-ISSN 2328-9503, Vol. 9, nr 6, s. 882-887Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Axonal loss is the main cause of irreversible disability in multiple sclerosis (MS). Serum neurofilament light (sNfL) is a biomarker of axonal disintegration. In this nested case-control study, blood samples from 519 presymptomatic persons (age range 4-39 years) who later received an MS diagnosis showed higher sNfL concentrations than 519 matched controls (p < 0.0001), noticeable at least 10 years before clinical MS onset. Mean values for pre-MS and control groups were 9.6 pg/mL versus 7.4 pg/mL 0-5 years before onset, and 6.4 pg/mL versus 5.8 pg/mL 5-10 years before onset. These results support that axonal injury occurs early in MS pathogenesis.

  • 45.
    Kalpouzos, Grégoria
    et al.
    Aging Research Center (ARC), Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    Garzón, Benjamín
    Aging Research Center (ARC), Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    Sitnikov, Rouslan
    MRI Research Center, Karolinska University Hospital, Stockholm, Sweden.
    Heiland, Carmel
    Aging Research Center (ARC), Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    Salami, Alireza
    Aging Research Center (ARC), Karolinska Institutet and Stockholm University, Stockholm, Sweden Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden Department of Integrative Medical Biology, Physiology Section, Umeå University, Umeå, Sweden.
    Persson, Jonas
    Aging Research Center (ARC), Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    Bäckman, Lars
    Aging Research Center (ARC), Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    Higher Striatal Iron Concentration is Linked to Frontostriatal Underactivation and Poorer Memory in Normal Aging2017Inngår i: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 27, nr 6, s. 3427-3436Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In the brain, intracellular iron is essential for cellular metabolism. However, an overload of free iron is toxic, inducing oxidative stress and cell death. Although an increase of striatal iron has been related to atrophy and impaired cognitive performance, the link between elevated iron and altered brain activity in aging remains unexplored. In a sample of 37 younger and older adults, we examined whether higher striatal iron concentration could underlie age-related differences in frontostriatal activity induced by mental imagery of motor and non-motor scenes, and poorer recall of the scenes. Higher striatal iron concentration was linked to underrecruitment of frontostriatal regions regardless of age and striatal volume, the iron-activity association in right putamen being primarily driven by the older adults. In older age, higher striatal iron was related to poorer memory. Altered astrocytic functions could account for the link between brain iron and brain activity, as astrocytes are involved in iron buffering, neurovascular coupling, and synaptic activity. Our preliminary findings, which need to be replicated in a larger sample, suggest a potential frontostriatal target for intervention to counteract negative effects of iron accumulation on brain function and cognition.

  • 46.
    Karpyak, Victor M.
    et al.
    Mayo Clinic, Rochester, MN, USA.
    Winham, Stacey J.
    Mayo Clinic, Rochester, MN, USA.
    Preuss, Ulrich W.
    Martin-Luther-University of Halle-Wittenberg, Halle/Saale, Germany.
    Zill, Peter
    LMU Munich, Munich, Germany.
    Cunningham, Julie M.
    Mayo Clinic, Rochester, MN, USA.
    Walker, Denise L.
    Mayo Clinic, Rochester, MN, USA.
    Lewis, Kriste A.
    Mayo Clinic, Rochester, MN, USA.
    Geske, Jennifer R.
    Mayo Clinic, Rochester, MN, USA.
    Colby, Colin L.
    Mayo Clinic, Rochester, MN, USA.
    Abulseoud, Osama A.
    Mayo Clinic, Rochester, MN, USA.
    Hall-Flavin, Daniel K.
    Mayo Clinic, Rochester, MN, USA.
    Loukianova, Larissa L.
    Mayo Clinic, Rochester, MN, USA.
    Schneekloth, Terry D.
    Mayo Clinic, Rochester, MN, USA.
    Frye, Mark A.
    Mayo Clinic, Rochester, MN, USA.
    Bazov, Igor
    Uppsala University, Uppsala, Sweden.
    Heit, John A.
    Mayo Clinic, Rochester, MN, USA.
    Bakalkin, Georgy
    Uppsala University, Uppsala, Sweden.
    Mrazek, David A.
    Mayo Clinic, Rochester, MN, USA.
    Biernacka, Joanna M.
    Mayo Clinic, Rochester, MN, USA.
    Association of the PDYN gene with alcohol dependence and the propensity to drink in negative emotional states2013Inngår i: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 16, nr 5, s. 975-985Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Synthetic κ-opioid receptor (KOR) agonists induce dysphoric and pro-depressive effects and variations in the KOR (OPRK1) and prodynorphin (PDYN) genes have been shown to be associated with alcohol dependence. We genotyped 23 single nucleotide polymorphisms (SNPs) in the PDYN and OPRK1 genes in 816 alcohol-dependent subjects and investigated their association with: (1) negative craving measured by a subscale of the Inventory of Drug Taking Situations; (2) a self-reported history of depression; (3) the intensity of depressive symptoms measured by the Beck Depression Inventory-II. In addition, 13 of the 23 PDYN and OPRK1 SNPs, which were previously genotyped in a set of 1248 controls, were used to evaluate association with alcohol dependence. SNP and haplotype tests of association were performed. Analysis of a haplotype spanning the PDYN gene (rs6045784, rs910080, rs2235751, rs2281285) revealed significant association with alcohol dependence (p = 0.00079) and with negative craving (p = 0.0499). A candidate haplotype containing the PDYN rs2281285-rs1997794 SNPs that was previously associated with alcohol dependence was also associated with negative craving (p = 0.024) and alcohol dependence (p = 0.0008) in this study. A trend for association between depression severity and PDYN variation was detected. No associations of OPRK1 gene variation with alcohol dependence or other studied phenotypes were found. These findings support the hypothesis that sequence variation in the PDYN gene contributes to both alcohol dependence and the induction of negative craving in alcohol-dependent subjects.

  • 47.
    Kastrati, G.
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
    Rosén, J.
    Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
    Fredrikson, M.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Chen, X.
    Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands.
    Kuja-Halkola, R.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Jensen, K. B.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Åhs, F.
    Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
    Genetic influences on central and peripheral nervous system activity during fear conditioning2022Inngår i: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, nr 1, artikkel-id 95Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Fear conditioning is an evolutionarily conserved type of learning serving as a model for the acquisition of situationally induced anxiety. Brain function supporting fear conditioning may be genetically influenced, which in part could explain genetic susceptibility for anxiety following stress exposure. Using a classical twin design and functional magnetic resonance imaging, we evaluated genetic influences (h2) on brain activity and standard autonomic measures during fear conditioning. We found an additive genetic influence on mean brain activation (h2 = 0.34) and autonomic responses (h2 = 0.24) during fear learning. The experiment also allowed estimation of the genetic influence on brain activation during safety learning (h2 = 0.55). The mean safety, but not fear, related brain activation was genetically correlated with autonomic responses. We conclude that fear and safety learning processes, both involved in anxiety development, are moderately genetically influenced as expressed both in the brain and the body.

  • 48.
    Kastrati, Gránit
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
    Rosén, Jörgen
    Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
    Thompson, William H.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Chen, Xu
    Department of Biomedical Data Sciences, Leiden University Medical Center, RA, Leiden, the Netherlands.
    Larsson, Henrik
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Nichols, Thomas E.
    Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
    Tracey, Irene
    Wellcome Centre for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
    Fransson, Peter
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Åhs, Fredrik
    Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
    Jensen, Karin B.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Genetic Influence on Nociceptive Processing in the Human Brain: A Twin Study2022Inngår i: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 32, nr 2, s. 266-274Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Nociceptive processing in the human brain is complex and involves several brain structures and varies across individuals. Determining the structures that contribute to interindividual differences in nociceptive processing is likely to improve our understanding of why some individuals feel more pain than others. Here, we found specific parts of the cerebral response to nociception that are under genetic influence by employing a classic twin-design. We found genetic influences on nociceptive processing in the midcingulate cortex and bilateral posterior insula. In addition to brain activations, we found genetic contributions to large-scale functional connectivity (FC) during nociceptive processing. We conclude that additive genetics influence specific brain regions involved in nociceptive processing. The genetic influence on FC during nociceptive processing is not limited to core nociceptive brain regions, such as the dorsal posterior insula and somatosensory areas, but also involves cognitive and affective brain circuitry. These findings improve our understanding of human pain perception and increases chances to find new treatments for clinical pain.

  • 49.
    Kauppi, Karolina
    et al.
    Department of Integrative Medical Biology (Physiology), Umeå University, Umeå, Sweden; Umeå Center for Functional Brain Imaging (UFBI), Umeå, Sweden.
    Nilsson, Lars-Göran
    Department of Psychology, Stockholm University, Stockholm, Sweden; Stockholm Brain Institute, Sweden.
    Persson, Jonas
    Aging Research Center (ARC), Karolinska Institutet, Stockholm, Sweden; Stockholm University, Stockholm, Sweden.
    Nyberg, Lars
    Department of Integrative Medical Biology (Physiology), Umeå University, Umeå, Sweden; Umeå Center for Functional Brain Imaging (UFBI), Umeå, Sweden; Department of Radiation Sciences (Diagnostic Radiology), Umeå University, Umeå, Sweden.
    Additive genetic effect of APOE and BDNF on hippocampus activity2014Inngår i: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 89, nr 1, s. 306-313Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human memory is a highly heritable polygenic trait with complex inheritance patterns. To study the genetics of memory and memory-related diseases, hippocampal functioning has served as an intermediate phenotype. The importance of investigating gene-gene effects on complex phenotypes has been emphasized, but most imaging studies still focus on single polymorphisms. APOE ε4 and BDNF Met, two of the most studied gene variants for variability in memory performance and neuropsychiatric disorders, have both separately been related to poorer episodic memory and altered hippocampal functioning. Here, we investigated the combined effect of APOE and BDNF on hippocampal activation (N=151). No non-additive interaction effects were seen. Instead, the results revealed decreased activation in bilateral hippocampus and parahippocampus as a function of the number of APOE ε4 and BDNF Met alleles present (neither, one, or both). The combined effect was stronger than either of the individual effects, and both gene variables explained significant proportions of variance in BOLD signal change. Thus, there was an additive gene-gene effect of APOE and BDNF on medial temporal lobe (MTL) activation, showing that a larger proportion of variance in brain activation attributed to genetics can be explained by considering more than one gene variant. This effect might be relevant for the understanding of normal variability in memory function as well as memory-related disorders associated with APOE and BDNF.

  • 50.
    Kimland, Elin
    et al.
    Drug Information Center, Division of Clinical Pharmacology, Stockholm, Sweden; Stockholm Regional Pharmacovigilance Center, Stockholm, Sweden.
    Höjeberg, Bo
    Division of Neurology, NEUROTEC, Karolinska University Hospital-Huddinge, Karolinska Institutet, Stockholm, Sweden.
    von Euler, Mia
    Stockholm Regional Pharmacovigilance Center, Stockholm, Sweden; Division of Neurology, NEUROTEC, Karolinska University Hospital-Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Levetiracetam-induced thrombocytopenia2004Inngår i: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 45, nr 7, s. 877-878Artikkel i tidsskrift (Fagfellevurdert)
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