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  • 251.
    Fordell, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Bodin, Kenneth
    Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N).
    Bucht, Gustaf
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    A virtual reality test battery for assessment and screening of spatial neglect2011In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 123, no 3, p. 167-174Article in journal (Refereed)
    Abstract [en]

    Background – There is a need for improved screening methods for spatial neglect.

    Aim – To construct a VR-test battery and evaluate its accuracy and usability in patients with acute stroke.

    Method –  VR-DiSTRO consists of a standard desktop computer, a CRT monitor and eye shutter stereoscopic glasses, a force feedback interface, and software, developed to create an interactive and immersive 3D experience. VR-tests were developed and validated to the conventional Star Cancellation test, Line bisection, Baking Tray Task (BTT), and Visual Extinction test. A construct validation to The Rivermead Behavioral Inattention Test, used as criterion of visuospatial neglect, was made. Usability was assessed according to ISO 9241-11.

    Results –  Thirty-one patients with stroke were included, 9/31 patients had neglect. The sensitivity was 100% and the specificity 82% for the VR-DiSTRO to correctly identify neglect. VR-BTT and VR-Extinction had the highest correlation (r2 = 0.64 and 0.78), as well as high sensitivity and specificity. The kappa values describing the agreement between traditional neglect tests and the corresponding virtual reality test were between 0.47–0.85. Usability was assessed by a questionnaire; 77% reported that the VR-DiSTRO was ‘easy’ to use. Eighty-eight percent reported that they felt ‘focused’, ‘pleased’ or ‘alert’. No patient had adverse symptoms. The test session took 15 min.

    Conclusions –  The VR-DiSTRO quickly and with a high accuracy identified visuospatial neglect in patients with stroke in this construct validation. The usability among elderly patients with stroke was high. This VR-test battery has the potential to become an important screening instrument for neglect and a valuable adjunct to the neuropsychological assessment.

  • 252.
    Fordell, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Bodin, Kenneth
    Umeå University, Faculty of Science and Technology, Department of Computing Science. Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N).
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    RehAtt – scanning training for neglect enhanced by multi-sensory stimulation in Virtual Reality2016In: Topics in Stroke Rehabilitation, ISSN 1074-9357, E-ISSN 1945-5119, Vol. 23, no 3, p. 191-199Article in journal (Refereed)
    Abstract [en]

    Background: There is a lack of effective treatment for neglect. We have developed a new training method, RehAtt (TM). The objective of this study was to determine whether RehAtt (TM) improves spatial attention in chronic neglect after stroke. Methods: RehAtt (TM) consists of a computer with monitor, 3D glasses, and a force feedback interface (Robotic pen) giving sensory motor activation to the contra-lesional arm. The software combines visual scanning training with multi-sensory stimulation in 3D virtual reality (VR) game environment. Fifteen stroke patients with chronic neglect (duration > 6 month) had repeated baseline evaluations to confirm stability of symptoms. There were no test-retest effects for any of the tests. Thereafter, all patients trained 15 h in RehAtt (TM) (3 x 1 h for 5 weeks). A neglect test battery and Catherine Bergego Scale, CBS, were used to assess behavioral outcome after intervention. CBS was also used at a 6-month follow-up. Results: Using repeated measurement analysis improvements due to the training were found for Star cancellation test (p = 0.006), Baking tray task (p < 0.001), and Extinction test (p = 0.05). In the Posner task improvements were seen fewer missed targets (p = 0.024). CBS showed improvements in activities of daily life immediately after training (p < 0.01). After 6 months the patients still reported improvement in CBS. Conclusion: RehAtt (TM) is a new concept for rehabilitation of neglect. Training with the VR-method improved spatial attention and showed transfer to improved spatial attention in activities of daily living in chronic neglect. Our results are promising and merit further studies.

  • 253.
    Fordell, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wahlin, A.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Ekman, U.
    Lenfeldt, Niklas
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Rehabilitation of chronic spatial neglect strengthens functional connectivity between nodes of the dorsal attention network2018In: International Journal of Stroke, ISSN 1747-4930, E-ISSN 1747-4949, Vol. 13, p. 42-42Article in journal (Other academic)
  • 254.
    Fordell, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Ekman, U.
    Lenfeldt, N.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Rehabilitation in chronic neglect using VR strengthens connectivity between nodes of the dorsal attention network2018In: International Journal of Stroke, ISSN 1747-4930, E-ISSN 1747-4949, Vol. 13, p. 50-50Article in journal (Other academic)
    Abstract [en]

    More knowledge is required about the neural mechanisms of functional recovery of spatial neglect in chronic phase after stroke. In this functional magnetic resonance imaging (fMRI) study, we aimed to evaluate changes in resting state functional connectivity (FC) within the dorsal attention network (DAN) in chronic neglect after scanning training in VR that previously shown improvement in left side awareness in behavioral tests and activity of daily living. (Fordell et al 2016)

    Method: Thirteen subjects with chronic spatial neglect (mean duration ¼ 43 months, SD ¼ 29 months) underwent resting state fMRI at baseline and after 15 hours RehAtt training (3x1hr / week for 5 weeks). RehAtt scanning training in 3D includes multi-sensory stimulation and is controlled by their contra-lesional hand using a robotic pen (force-feedback). The analysis specifically examined resting state functional connectivity within the DAN. In addition, using spatial concordance correlation, changes in the spatial topology of the DAN to other networks were analyzed.

    Results: We found an increase in interhemispheric FC between the right FEF and the left IPS following training (pre: 0.33 0.17 [mean SD]; post: 0.45 0.13; p ¼ 0.004). The spatial concordance analyses indicated that training had stronger influence on the DAN compared to other networks.

    Conclusion: VR training that improved left side awareness in chronic stroke patients also increased connectivity within the DAN. Specifically, a region responsible for saccadic eye movement to the left became more integrated with the left posterior parietal cortex. These results highlight a mechanism that can be exploited in the rehabilitation of chronic spatial neglect

  • 255.
    Forsberg, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Graffmo, Karin Sixtensdotter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Pakkenberg, Bente
    Weber, Markus
    Nielsen, Martin
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Munch Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Misfolded SOD1 inclusions in patients with mutations in C9orf72 and other ALS/FTD-associated genes2019In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 90, no 8, p. 861-869Article in journal (Refereed)
    Abstract [en]

    Objective: A hallmark of amyotrophic lateral sclerosis (ALS) caused by mutations in superoxide dismutase-1 (SOD1) are inclusions containing SOD1 in motor neurons. Here, we searched for SOD1-positive inclusions in 29 patients carrying ALS-linked mutations in six other genes.

    Methods: A panel of antibodies that specifically recognise misfolded SOD1 species were used for immunohistochemical investigations of autopsy tissue.

    Results: The 18 patients with hexanucleotide-repeat-expansions in C9orf72 had inclusions of misfolded wild type (WT) SOD1(WT) in spinal motor neurons. Similar inclusions were occasionally observed in medulla oblongata and in the motor cortex and frontal lobe. Patients with mutations in FUS, KIF5A, NEK1, ALSIN or VAPB, carried similar SOD1(WT) inclusions. Minute amounts of misSOD1(WT) inclusions were detected in 2 of 20 patients deceased from non-neurological causes and in 4 of 10 patients with other neurodegenerative diseases. Comparison was made with 17 patients with 9 different SOD1 mutations. Morphologically, the inclusions in patients with mutations in C9orf72HRE, FUS, KIF5A, NEK1, VAPB and ALSIN resembled inclusions in patients carrying the wildtype-like SOD1(D90A) mutation, whereas patients carrying unstable SOD1 mutations (A4V, V5M, D76Y, D83G, D101G, G114A, G127X, L144F) had larger skein-like SOD1-positive inclusions.

    Conclusions and relevance Abundant inclusions containing misfolded SOD1(WT) are found in spinal and cortical motor neurons in patients carrying mutations in six ALS-causing genes other than SOD1. This suggests that misfolding of SOD1(WT) can be part of a common downstream event that may be pathogenic. The new anti-SOD1 therapeutics in development may have applications for a broader range of patients.

  • 256. Forsberg, L.
    et al.
    Johansson, S.
    Nordin, N.
    Hillert, J.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lycke, J.
    Burman, J.
    Landtblom, A. -M
    Walentin, F.
    Martin, C.
    Nilsson, P.
    Dahle, C.
    Piehl, F.
    Olsson, T.
    A Swedish nationwide pharmaco-epidemiological and genetic study (IMSE) of the long-term safety and efficacy of dimethyl fumarate2015In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 21, p. 286-287Article in journal (Other academic)
  • 257. Forsberg, L.
    et al.
    Kågström, S.
    Fält, A.
    Berglund, A.
    Hillert, J.
    Nilsson, P.
    Dahle, C.
    Svenningsson, A.
    Lycke, J.
    Landtblom, A. -M
    Burman, J.
    Martin, C.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gunnarsson, M.
    Piehl, F.
    Olsson, T.
    Clinical effectiveness of dimethyl fumarate with focus on patients treated at least 36 months - a Swedish nationwide study of the long-term effectiveness and safety of dimethyl fumarate (IMSE5)2019In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 25, p. 316-317Article in journal (Other academic)
  • 258. Forsberg, L.
    et al.
    Kågström, S.
    Fält, A.
    Hillert, J.
    Nilsson, P.
    Dahle, C.
    Svenningsson, A.
    Lycke, J.
    Landtblom, A. -M
    Burman, J.
    Martin, C.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gunnarsson, M.
    Piehl, F.
    Olsson, T.
    A Swedish Nationwide study of the long-term effectiveness and safety of teriflunomid based on data from the Swedish "Immunomodulation and Multiple Sclerosis Epidemiology" Study (IMSE 4)2019In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 25, p. 316-316Article in journal (Other academic)
  • 259. Forslund, E B
    et al.
    Granström, A
    Richard, Levi
    Rehab Station Stockholm R & D Unit, Neurotec Department, Karolinska Institutet, Sweden ; Spinalis SCI Research Unit, Neurotec Department, Karolinska Institutet, Sweden.
    Westgren, N
    Hirschfeld, H
    Transfer from table to wheelchair in men and women with spinal cord injury: coordination of body movement and arm forces2007In: Spinal Cord, ISSN 1362-4393, E-ISSN 1476-5624, Vol. 45, no 1, p. 41-48Article in journal (Refereed)
    Abstract [en]

    STUDY DESIGN: A complex set-up was used to investigate kinematics and ground reaction forces.

    SETTING: Motor Control and Physical Therapy Research Laboratory, Neurotec Department, Karolinska Institutet, Huddinge, Sweden.

    OBJECTIVE: To investigate how men and women with spinal cord injury (SCI) perform transfers from table to wheelchair with regard to timing and magnitude of force generation beneath the hands and associated body movements.

    METHODS: A total of 13 subjects (seven men, six women) with thoracic SCI. Kinematics of body movement were recorded (Elite 2000 system) simultaneously with the signals from three force plates (AMTI) placed beneath the buttocks and hands. Temporal and spatial parameters regarding head, trunk and trailing arm displacement, loading amplitudes and loading torque directions of both hands were analyzed for each trial and subject and compared between genders.

    RESULTS: Men and women used similar amplitudes of head bending and forward displacement of the trailing shoulder, while female subjects had significantly larger trunk rotation. Both genders applied significantly more weight on the trailing hand. Differences between genders were seen in direction and timing of peak torque beneath the hands.

    CONCLUSIONS: The forces beneath the trailing hand were larger than those in the leading, if there is weakness or pain in one arm, this arm should be selected as the leading. To avoid excessive load on the arms, technical aids and environmental factors should be very well adapted.

    SPONSORSHIP: This project was funded by the Swedish Research Council and the Health Care Science Committee of Karolinska Institutet.

  • 260.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    The potential of inhibitors of endocannabinoid metabolism as anxiolytic and antidepressive drugs-A practical view2015In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 25, no 6, p. 749-762Article, review/survey (Refereed)
    Abstract [en]

    The endocannabinoid system, comprising cannabinoid CB1 and CB2 receptors, their endogenous ligands anandamide and 2-arachidonoylglyerol, and their synthetic and metabolic enzymes, are involved in many biological processes in the body, ranging from appetite to bone turnover. Compounds inhibiting the breakdown of anandamide and 2-arachidonoylglycerol increase brain levels of these lipids and thus modulate endocannabinoid signalling. In the present review, the preclinical evidence that these enzymes are good targets for development of novel therapies for anxiety and depression are discussed from a practical, rather than mechanistic, point of view. It is concluded that the preclinical data are promising, albeit tempered by problems of tolerance as well as effects upon learning and memory for irreversible monoacylglycerol lipase inhibitors, and limited by a focus upon male rodents alone. Clinical data so far has been restricted to safety studies with inhibitors of anandamide hydrolysis and a hitherto unpublished study on such a compound in elderly patients with major depressive disorders, but under the dose regimes used, they are well tolerated and show no signs of "cannabis-like" behaviours.

  • 261.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Transport of endocannabinoids across the plasma membrane and within the cell2013In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 280, no 9, p. 1895-1904Article, review/survey (Refereed)
    Abstract [en]

    Endocannabinoids are readily accumulated from the extracellular space by cells. Although their uptake properties have the appearance of a process of facilitated diffusion, it is by no means clear as to whether there is a plasma membrane transporter dedicated to this task. Intracellular carrier proteins that shuttle the endocannabinoid anandamide from the plasma membrane to its intracellular targets such as the metabolic enzyme, fatty acid amide hydrolase, have been identified. These include proteins with other primary functions, such as fatty-acid-binding proteins and heat shock protein70, and possibly a fatty acid amide hydrolase-like anandamide transporter protein. Thus, anandamide uptake can be adequately described as a diffusion process across the plasma membrane followed by intracellular carrier-mediated transport to effector molecules, catabolic enzymes and sequestration sites, although it is recognized that different cells are likely to utilize different mechanisms of endocannabinoid transport depending upon the utility of the endocannabinoid for the cell in question.

  • 262. Friberg, Leif
    et al.
    Rosenqvist, Marten
    Lindgren, Arne
    Terent, Andreas
    Norrving, Bo
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    High prevalence of atrial fibrillation among patients with ischemic stroke2014In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 45, no 9, p. 2599-+Article in journal (Refereed)
    Abstract [en]

    Background and Purpose-Atrial fibrillation (AF) is a common cause of devastating but potentially preventable stroke. Estimates of the prevalence of AF among patients with stroke vary considerably because of difficulties in detection of intermittent, silent AF. Better recognition of AF in this patient group may help to identify and offer protection to individuals at risk. Our aim was to determine the nationwide prevalence of AF among patients with ischemic stroke, as well as their use of oral anticoagulation. Methods-Cross-sectional study of unselected patients in cross-linked nationwide Swedish health registers. All 94 083 patients with a diagnosis of ischemic stroke in the nationwide stroke register Riks-Stroke between 2005 and 2010 were studied. Information about previously diagnosed AF, and comorbidity, was obtained from the nationwide Patient Register and cross-referenced with the national Drug Register containing data on all dispensed pharmacological prescriptions in Sweden. Results-Combination of data from Riks-Stroke and from the Patient Register showed that 31 428 (33.4%) patients with ischemic stroke had previously known, or newly diagnosed, AF. Of those, only 16.2% had received warfarin in a pharmacy within 6 months before stroke onset. After hospital discharge, only 35.0% of the survivors received warfarin within the first 3 months after discharge. The likelihood for underlying AF was strongly correlated to the CHA(2)DS(2)-VASC score, which is a point based scheme for assessment of stroke risk in AF but which also predicts likelihood of AF. In this scheme points are given for age, previous stroke or transient ischemic attack, hypertension, heart failure, diabetes, vascular disease and female sex. Conclusions-Access to nationwide register data shows that AF is more common among patients with ischemic stroke than those previously reported. Few patients with stroke and AF had anticoagulant treatment before the event, and few got it after the event. CHA(2)DS(2)-VASc could be a useful monitoring tool to intensify efforts to diagnose AF among patients with cryptogenic stroke.

  • 263.
    Fytagoridis, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Deep brain stimulation of the posterior subthalamic area in the treatment of movement disorders2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: The posterior subthalamic area (PSA) is essentially composed of the caudal Zona incerta and the prelemniscal radiation. Subthalamotomy in the PSA was renowned for its effectiveness in alleviating movement disorders and particularly tremor. The modern literature on DBS of this area is limited, but promising results have been presented for Parkinson’s disease (PD), essential tremor (ET) and other movement disorders.  

    Aim: To evaluate the safety of PSA DBS with emphasis on the panorama of side effects, the distribution of stimulation-induced side effects and the effects of PSA DBS on verbal fluency. To evaluate the therapeutic effect of PSA DBS on less common forms of tremor, tremor-dominant PD, and concerning the long-term results in ET.

    Method: 40 patients were evaluated regarding side effects of the procedure. 28 patients with ET were analyzed for stimulation-induced side effects in a standardized manner. The locations of the contacts that caused stimulation-induced side effects were plotted on atlas slides. A 3-D model of the area was created based on these slides. Verbal fluency was analyzed in 17 patients with ET before surgery, after 3 days and finally after 1 year. Five patients with less common forms of tremor and 18 with ET were evaluated according to the ETRS at baseline and one year or 3-5 years after surgery, respectively. 14 patients with mainly unilateral tremor-dominant PD were evaluated a mean of 18 months after surgery according to the motor part of UPDRS.

    Results: PSA DBS was associated with few serious side-effects, but a transient and mild postoperative dysphasia was found in 22.5% of the patients. There was a slight transient decline in the performance on verbal fluency tests immediately after surgery. Visualization of the contacts causing stimulation-induced side effects showed that identical responses can be elicited from various points in the PSA and its vicinity. The effect on the less common forms of tremor was excellent except for neuropathic tremor where the effect was moderate. A pronounced and sustained microlesional effect was seen for some of the patients. After a mean of 4 years with unilateral PSA DBS the total ETRS score was improved by 52.4%, tremor by 91.8% and hand function by 78.0% in the patients with ET. There was no increase in the stimulation strength over time. In PD, the scores improved 47.7% for contralateral UPDRS III. Contralateral tremor, rigidity, and bradykinesia improved by 82.2%, 34.3%, and 26.7%, respectively.

    Conclusions: PSA DBS generally seem to be a safe procedure, but it may be associated with transient declines of verbal fluency. There was no clear somatotopic pattern with regard to stimulation-induced side effects in the PSA. PSA DBS can alleviate tremor regardless of the etiology. The long-term effects in ET were favorable when compared to our previous results of Vim DBS. The effect on Parkinsonian tremor was satisfying, however, the reductions of rigidity and bradykinesia were less compared to previous studies of PSA DBS for PD.

  • 264.
    Fytagoridis, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Sandvik, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Åström, Mattias
    Bergenheim, Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Long term follow-up of deep brain stimulation of the caudal zona incerta for essential tremor2012In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 83, no 3, p. 258-262Article in journal (Refereed)
    Abstract [en]

    Purpose The ventral intermediate nucleus of thalamus is the standard target for deep brain stimulation (DBS) in essential tremor (ET). However, favourable data have recently highlighted the caudal zona incerta (cZi) as an alternative target. Reports concerning the long-term results are however lacking, and we have therefore evaluated the long-term effects in our patients with ET and cZi DBS.

    Methods 18 patients were evaluated using the Essential Tremor Rating Scale (ETRS) before and on-/off-stimulation at 1 and 3-5 years after surgery (mean 48.5±10.6 months). Two patients were operated on bilaterally but all electrodes were evaluated separately. The stimulation parameters were recorded and the stimulation strength calculated.

    Results A baseline total ETRS mean score of 46.0 decreased to 21.9 (52.4%) at the final evaluation. On the treated side, tremor of the upper extremity (item 5 or 6) improved from 6.1 to 0.5 (91.8%) and hand function (items 11-14) improved from 9.3 to 2.0 (78.0%). Activities of daily living improved by 65.8%. There was no increase in stimulation strength over time.

    Conclusion cZi DBS is a safe and effective treatment for the long term suppression of ET.

  • 265.
    Fytagoridis, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Sjöberg, Richard
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Åström, Mattias
    Fredricks, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Effects of deep brain stimulation in the caudal Zona incerta on verbal fluency2013In: Stereotactic and Functional Neurosurgery, ISSN 1011-6125, E-ISSN 1423-0372, Vol. 91, no 1, p. 24-29Article in journal (Refereed)
    Abstract [en]

    Background: Deep brain stimulation (DBS) of the caudal zona incerta (cZi) is a relatively unexplored and promising treatment in patients with severe essential tremor (ET). Preliminary data further indicate that the ability to produce language may be slightly affected by the treatment.

    Objective: To evaluate the effects on verbal fluency following cZi DBS in patients with ET.

    Method: Seventeen consecutive patients who had undergone DBS of the cZi for ET were tested regarding verbal fluency before surgery, 3 days after surgery and after 1 year. Ten patients were also evaluated by comparing performance on versus off stimulation after 1 year.

    Results: The total verbal fluency score decreased slightly, but significantly, from 22.7 (SD = 10.9) before surgery to 18.1 (SD = 7.5) 3 days after surgery (p = 0.036). After 1 year the score was nonsignificantly decreased to 20.1 (SD = 9.7, p = 0.2678). There was no detectable difference between stimulation on and off after 1 year.

    Conclusion: There was a tendency of an immediate and mostly transient postoperative decline in verbal fluency following cZi DBS for ET. In some of the patients this reduction was, however, more pronounced and also sustained over time.

  • 266.
    Fytagoridis, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery. Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden.
    Åström, M.
    Wårdell, K.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Stimulation-induced side effects in the posterior subthalamic area: distribution, characteristics and visualization2013In: Clinical neurology and neurosurgery (Dutch-Flemish ed. Print), ISSN 0303-8467, E-ISSN 1872-6968, Vol. 115, no 1, p. 65-71Article in journal (Refereed)
    Abstract [en]

    Objective: The posterior subthalamic area (PSA) is an emerging but relatively unexplored target for DBS treatment of tremor. The aim of the study was to explore the area further by evaluating the spatial distribution and the characteristics of stimulation-induced side effects in this area.

    Methods: Twenty-eight patients with essential tremor (ET) implanted with 33 DBS electrodes were evaluated concerning stimulation-induced side effects by testing each contact separately one year after surgery. The location of the side effects were plotted on axial slides of the Morel Stereotactic Atlas and a 3-dimensional model of the area for visualization was created.

    Results: Visualization of the contacts eliciting stimulation-induced side effects demonstrated that identical responses can be elicited from various points in the PSA and its vicinity. The majority of contacts inducing muscular affection and cerebellar symptoms, including dysarthria, could not be attributed to an effect on the internal capsule. Paresthesias, affecting various body parts were elicited throughout the area without a clear somatotopic pattern.

    Conclusion: Stimulation-induced side effects in the PSA and its vicinity were difficult to attribute to certain anatomical areas as the same response was induced from various locations. Therefore, this study could not provide a meaningful somatotopic map with regard to stimulation-induced side effects in the PSA.

  • 267.
    Fytagoridis, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Clinical Neuroscience, Neurosurgery, Karolinska Institutet, Stockholm.
    Åström, Mattias
    Samuelsson, Jennifer
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Deep Brain Stimulation of the Caudal Zona Incerta: Tremor Control in Relation to the Location of Stimulation Fields2016In: Stereotactic and Functional Neurosurgery, ISSN 1011-6125, E-ISSN 1423-0372, Vol. 94, no 6, p. 363-370Article in journal (Refereed)
    Abstract [en]

    Background: The caudal zona incerta (cZi) and posterior subthalamic area (PSA) are an emerging deep brain stimulation (DBS) target for essential tremor (ET). Objectives: To evaluate the efficacy of tremor control in relation to the anatomical locations of stimulation fields in 50 patients with ET and DBS of the cZi. Methods: A total of 240 contacts were evaluated separately with monopolar stimulation, and amplitudes were optimized for improvement of tremor and hand function. Stimulation fields, i.e., volumes of neural activation, were simulated for each optimized setting and assembled into probabilistic stimulation maps (PSMs). Results: There were differences in the anatomical distribution of PSMs associated with good versus poor tremor control. The location of PSMs which achieved good and excellent tremor control corresponded well with the PSM for the clinically used settings, and they were located within the superior part of the PSA. Conclusions: PSMs may serve as a useful tool for defining the most efficacious anatomical location of stimulation. The best tremor control in this series of cZi DBS was achieved with stimulation of the superior part of the PSA, which corresponds to the final part of the cerebellothalamic projections before they reach the ventral lateral thalamus.

  • 268. Fält, A.
    et al.
    Kågström, S.
    Forsberg, L.
    Hillert, J.
    Nilsson, P.
    Dahle, C.
    Svenningsson, A.
    Lycke, J.
    Landtblom, A. -M
    Burman, J.
    Martin, C.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gunnarsson, M.
    Piehl, F.
    Olsson, T.
    A swedish post-market surveillance study of the long-term effectiveness and safety of alemtuzumab (IMSE 3) for patients treated at least 24 months2019In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 25, p. 327-328Article in journal (Other academic)
  • 269. Fält, A.
    et al.
    Kågström, S.
    Forsberg, L.
    Hillert, J.
    Nilsson, P.
    Dahle, C.
    Svenningsson, A.
    Lycke, J.
    Landtblom, A. -M
    Burman, J.
    Martin, C.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gunnarsson, M.
    Piehl, F.
    Olsson, T.
    A Swedish real word study of the long-term effectiveness and safety of fingolimod (IMSE 2) with focus on patients treated at least 48 months2019In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 25, p. 536-537Article in journal (Other academic)
  • 270. Gallo, Valentina
    et al.
    Brayne, Carol
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Barker, Roger A
    Petersson, Jesper
    Hansson, Oskar
    Lindqvist, Daniel
    Ruffmann, Claudio
    Ishihara, Lianna
    Luben, Robert
    Arriola, Larraitz
    Bergareche, Alberto
    Gavrila, Diana
    Erro, Maria Elena
    Vanacore, Nicola
    Sacerdote, Carlotta
    Bueno-De-Mesquita, Bas
    Vermeulen, Roel
    Seelen, Meinie
    Sieri, Sabina
    Masala, Giovanna
    Ramat, Silvia
    Kyrozis, Andreas
    Thricopolou, Antonia
    Panico, Salvatore
    Mattiello, Amalia
    Kaaks, Rudolf
    Teucher, Birgit
    Katzke, Verena
    Kloss, Manja
    Curry, Lisa
    Calboli, Federico
    Riboli, Elio
    Vineis, Paolo
    Middleton, Lefkos
    Parkinson's Disease Case Ascertainment in the EPIC Cohort: The NeuroEPIC4PD Study2015In: Neurodegenerative Diseases, ISSN 1660-2854, E-ISSN 1660-2862, Vol. 15, no 6, p. 331-338Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Large epidemiological prospective studies represent an important opportunity for investigating risk factors for rare diseases such as Parkinson's disease (PD). Here we describe the procedures we used for ascertaining PD cases in the EPIC (European Prospective Investigation into Cancer and Nutrition) study. Methods: The following three-phase procedure was used: (1) elaboration of a NeuroEPIC4PD template for clinical data collection, (2) identification of all potential PD cases via record linkage and (3) validation of the diagnosis through clinical record revision, in a population of 220,494 subjects recruited in 7 European countries. All cases were labelled with the NeuroEPIC4PD diagnoses of 'definite', 'very likely', 'probable', or 'possible' PD. Results: A total of 881 PD cases were identified, with over 2,741,780 person-years of follow-up (199 definite, 275 very likely, 146 probable, and 261 possible). Of these, 734 were incident cases. The mean age at diagnosis was 67.9 years (SD 9.2) and 458 patients (52.0%) were men. Bradykinesia was the most frequent presenting motor sign (76.5%). Tremor-dominant and akinetic rigid forms of PD were the most common types of PD. A total of 289 patients (32.8%) were dead at the time of the last follow-up. Conclusions: This exercise proved that it is feasible to ascertain PD in large population-based cohort studies and offers a potential framework to be replicated in similar studies.

  • 271. Gallo, Valentina
    et al.
    Bueno-De-Mesquita, H Bas
    Vermeulen, Roel
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Kyrozis, Andreas
    Linseisen, Jakob
    Kaaks, Rudolph
    Allen, Naomi E
    Roddam, Andrew W
    Boshuizen, Hendriek C
    Peeters, Petra H
    Palli, Domenico
    Mattiello, Amalia
    Sieri, Sabina
    Tumino, Rosario
    Jiménez-Martín, Juan-Manuel
    Díaz, María José Tormo
    Suarez, Laudina Rodriguez
    Trichopoulou, Antonia
    Agudo, Antonio
    Arriola, Larraitz
    Barricante-Gurrea, Aurelio
    Bingham, Sheila
    Khaw, Kay-Tee
    Manjer, Jonas
    Lindkvist, Björn
    Overvad, Kim
    Bach, Flemming W
    Tjønneland, Anne
    Olsen, Anja
    Bergmann, Manuela M
    Boeing, Heiner
    Clavel-Chapelon, Francoise
    Lund, Eiliv
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Middleton, Lefkos
    Vineis, Paolo
    Riboli, Elio
    Smoking and risk for amyotrophic lateral sclerosis: analysis of the EPIC cohort2009In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 65, no 4, p. 378-385Article in journal (Refereed)
    Abstract [en]

    Objective: Cigarette smoking has been reported as "probable" risk factor for Amyotrophic Lateral Sclerosis (ALS), a poorly understood disease in terms of aetiology. The extensive longitudinal data of the European Prospective Investigation into Cancer and Nutrition (EPIC) were used to evaluate age-specific mortality rates from ALS and the role of cigarette smoking on the risk of dying from ALS.

    Methods: A total of 517,890 healthy subjects were included, resulting in 4,591,325 person-years. ALS cases were ascertained through death certificates. Cox hazard models were built to investigate the role of smoking on the risk of ALS, using packs/years and smoking duration to study dose-response.

    Results: A total of 118 subjects died from ALS, resulting in a crude mortality rate of 2.69 per 100,000/year. Current smokers at recruitment had an almost two-fold increased risk of dying from ALS compared to never smokers (HR = 1.89, 95% C.I. 1.14-3.14), while former smokers at the time of enrollment had a 50% increased risk (HR = 1.48, 95% C.I. 0.94-2.32). The number of years spent smoking increased the risk of ALS (p for trend = 0.002). Those who smoked more than 33 years had more than a two-fold increased risk of ALS compared with never smokers (HR = 2.16, 95% C.I. 1.33-3.53). Conversely, the number of years since quitting smoking was associated with a decreased risk of ALS compared with continuing smoking.

    Interpretation: These results strongly support the hypothesis of a role of cigarette smoking in aetiology of ALS. We hypothesize that this could occur through lipid peroxidation via formaldehyde exposure.

  • 272. Gallo, Valentina
    et al.
    Vineis, Paolo
    Cancellieri, Mariagrazia
    Chiodini, Paolo
    Barker, Roger A.
    Brayne, Carol
    Pearce, Neil
    Vermeulen, Roel
    Panico, Salvatore
    Bueno-de-Mesquita, Bas
    Vanacore, Nicola
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Ramat, Silvia
    Ardanaz, Eva
    Arriola, Larraitz
    Peterson, Jesper
    Hansson, Oskar
    Gavrila, Diana
    Sacerdote, Carlotta
    Sieri, Sabina
    Kühn, Tilman
    Katzke, Verena A.
    van der Schouw, Yvonne T.
    Kyrozis, Andreas
    Masala, Giovanna
    Mattiello, Amalia
    Perneczky, Robert
    Middleton, Lefkos
    Saracci, Rodolfo
    Riboli, Elio
    Exploring causality of the association between smoking and Parkinson's disease2019In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 48, no 3, p. 912-925Article in journal (Refereed)
    Abstract [en]

    Background: The aim of this paper is to investigate the causality of the inverse association between cigarette smoking and Parkinson's disease (PD). The main suggested alternatives include a delaying effect of smoking, reverse causality or an unmeasured confounding related to a low-risk-taking personality trait.

    Methods: A total of 715 incident PD cases were ascertained in a cohort of 220 494 individuals from NeuroEPIC4PD, a prospective European population-based cohort study including 13 centres in eight countries. Smoking habits were recorded at recruitment. We analysed smoking status, duration, and intensity and exposure to passive smoking in relation to PD onset.

    Results: Former smokers had a 20% decreased risk and current smokers a halved risk of developing PD compared with never smokers. Strong dose-response relationships with smoking intensity and duration were found. Hazard ratios (HRs) for smoking <20 years were 0.84 [95% confidence interval (CI) 0.67-1.07], 20-29 years 0.73 (95% CI 0.56-0.96) and >30 years 0.54 (95% CI 0.43-0.36) compared with never smokers. The proportional hazard assumption was verified, showing no change of risk over time, arguing against a delaying effect. Reverse causality was disproved by the consistency of dose-response relationships among former and current smokers. The inverse association between passive smoking and PD, HR 0.70 (95% CI 0.49-0.99) ruled out the effect of unmeasured confounding.

    Conclusions: These results are highly suggestive of a true causal link between smoking and PD, although it is not clear which is the chemical compound in cigarette smoking responsible for the biological effect.

  • 273. Gallo, Valentina
    et al.
    Wark, Petra A.
    Jenab, Mazda
    Pearce, Neil
    Brayne, Carol
    Vermeulen, Roel
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hallmans, Goran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Kyrozis, Andreas
    Vanacore, Nicola
    Vahdaninia, Mariam
    Grote, Verena
    Kaaks, Rudolf
    Mattiello, Amalia
    Bueno-de-Mesquita, H. Bas
    Peeters, Petra H.
    Travis, Ruth C.
    Petersson, Jesper
    Hansson, Oskar
    Arriola, Larraitz
    Jimenez-Martin, Juan-Manuel
    Tjonneland, Anne
    Halkjaer, Jytte
    Agnoli, Claudia
    Sacerdote, Carlotta
    Bonet, Catalina
    Trichopoulou, Antonia
    Gavrila, Diana
    Overvad, Kim
    Weiderpass, Elisabete
    Palli, Domenico
    Ramon Quiros, J.
    Tumino, Rosario
    Khaw, Kay-Tee
    Wareham, Nicholas
    Barricante-Gurrea, Aurelio
    Fedirko, Veronika
    Ferrari, Pietro
    Clavel-Chapelon, Francoise
    Boutron-Ruault, Marie-Christine
    Boeing, Heiner
    Vigl, Matthaeus
    Middleton, Lefkos
    Riboli, Elio
    Vineis, Paolo
    Prediagnostic body fat and risk of death from amyotrophic lateral sclerosis The EPIC cohort2013In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 80, no 9, p. 829-838Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of this study was to investigate for the first time the association between body fat and risk of amyotrophic lateral sclerosis (ALS) with an appropriate prospective study design. Methods: The EPIC (European Prospective Investigation into Cancer and Nutrition) study included 518,108 individuals recruited from the general population across 10 Western European countries. At recruitment, information on lifestyle was collected and anthropometric characteristics were measured. Cox hazard models were fitted to investigate the associations between anthropometric measures and ALS mortality. Results: Two hundred twenty-two ALS deaths (79 men and 143 women) occurred during the follow-up period (mean follow-up = 13 years). There was a statistically significant interaction between categories of body mass index and sex regarding ALS risk (p = 0.009): in men, a significant linear decrease of risk per unit of body mass index was observed (hazard ratio = 0.93, 95% confidence interval 0.86-0.99 per kg/m(2)); among women, the risk was more than 3-fold increased for underweight compared with normal-weight women. Among women, a significant risk reduction increasing the waist/hip ratio was also evident: women in the top quartile had less than half the risk of ALS compared with those in the bottom quartile (hazard ratio = 0.48, 95% confidence interval 0.25-0.93) with a borderline significant p value for trend across quartiles (p = 0.056). Conclusion: Increased prediagnostic body fat is associated with a decreased risk of ALS mortality. Neurology (R) 2013; 80: 829-838

  • 274. Ganesalingam, Jeban
    et al.
    An, Jiyan
    Bowser, Robert
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Shaw, Christopher E.
    pNfH is a promising biomarker for ALS2013In: Amytrophic Lateral Sclerosis and Frontotemporal degeneration, ISSN 2167-8421, Vol. 14, no 2, p. 146-149Article in journal (Refereed)
    Abstract [en]

    A diagnostic biomarker for ALS would permit early intervention with disease-modifying therapies while a biomarker for disease activity could accelerate the pace of drug discovery by facilitating shorter, and less costly, drug trials to be conducted with a smaller number of patients. Neurofilaments are the most abundant neuronal cytoskeletal protein. We set out to determine whether pNfH was a credible biomarker for ALS. pNfH levels were determined using an ELISA for 150 ALS subjects and 140 controls. We demonstrated a seven-fold elevation in the cerebrospinal fluid (CSF) levels of phosphorylated neurofilament heavy subunit (pNfH) in ALS (median n = 2787 pg/ml, n = 150), compared to headache and other benign controls (3 (4 pg/ml, n = 100, p = < 0.05). There was a 10-fold elevation of pNfH compared to ALS mimics (266 pg/ml, n = 20) and other neurodegenerative and inflammatory conditions (27 (pg/ml for n = 20) which was also highly significant (p = < 0.05). pNfH achieved a diagnostic sensitivity of 90% and specificity of 87% in distinguishing ALS from all controls. We also detected an inverse correlation between CSF pNfH levels and disease duration (time from symptom onset to death, r(2) = 0.1247, p = 0.001). In conclusion, pNfH represents a promising candidate for inclusion in a panel of diagnostic and prognostic biomarkers.

  • 275. Garrett, Douglas D.
    et al.
    Nagel, Irene E.
    Preuschhof, Claudia
    Burzynska, Agnieszka Z.
    Marchner, Janina
    Wiegert, Steffen
    Jungehuelsing, Gerhard J.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Villringer, Arno
    Li, Shu-Chen
    Heekeren, Hauke R.
    Baeckman, Lars
    Lindenberger, Ulman
    Amphetamine modulates brain signal variability and working memory in younger and older adults2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 24, p. 7593-7598Article in journal (Refereed)
    Abstract [en]

    Better-performing younger adults typically express greater brain signal variability relative to older, poorer performers. Mechanisms for age and performance-graded differences in brain dynamics have, however, not yet been uncovered. Given the age-related decline of the dopamine (DA) system in normal cognitive aging, DA neuromodulation is one plausible mechanism. Hence, agents that boost systemic DA [such as d-amphetamine (AMPH)] may help to restore deficient signal variability levels. Furthermore, despite the standard practice of counterbalancing drug session order (AMPH first vs. placebo first), it remains understudied how AMPH may interact with practice effects, possibly influencing whether DA up-regulation is functional. We examined the effects of AMPH on functional-MRI-based blood oxygen level-dependent (BOLD) signal variability (SDBOLD) in younger and older adults during a working memory task (letter n-back). Older adults expressed lower brain signal variability at placebo, but met or exceeded young adult SDBOLD levels in the presence of AMPH. Drug session order greatly moderated change-change relations between AMPH-driven SDBOLD and reaction time means (RTmean) and SDs (RTSD). Older adults who received AMPH in the first session tended to improve in RTmean and RTSD when SDBOLD was boosted on AMPH, whereas younger and older adults who received AMPH in the second session showed either a performance improvement when SDBOLD decreased (for RTmean) or no effect at all (for RTSD). The present findings support the hypothesis that age differences in brain signal variability reflect aging-induced changes in dopaminergic neuromodulation. The observed interactions among AMPH, age, and session order highlight the state-and practice-dependent neurochemical basis of human brain dynamics.

  • 276.
    Gasslander, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience. Departments of Cardiology and Health, Medicine and Caring Services, Linkoping University, Vrinnevi General Hospital Norrköping.
    Sundström, Nina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Koskinen, Lars-Owe D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Risk factors for developing subdural hematoma: a registry-based study in 1457 patients with shunted idiopathic normal pressure hydrocephalus2020In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, p. 1-10Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Subdural hematomas and hygromas (SDHs) are common complications in idiopathic normal pressure hydrocephalus (iNPH) patients with shunts. In this registry-based study, patients with shunted iNPH were screened nationwide to identify perioperative variables that may increase the risk of SDH.

    METHODS: The Swedish Hydrocephalus Quality Registry was reviewed for iNPH patients who had undergone shunt surgery in Sweden in 2004-2014. Potential risk factors for SDH were recorded preoperatively and 3 months after surgery. Drug prescriptions were identified from a national pharmacy database. Patients who developed SDHs were compared with those without SDHs.

    RESULTS: The study population consisted of 1457 patients, 152 (10.4%) of whom developed an SDH. Men developed an SDH more often than women (OR 2.084, 95% CI 1.421-3.058, p < 0.001). Patients on platelet aggregation inhibitors developed an SDH more often than those who were not (OR 1.733, 95% CI 1.236-2.431, p = 0.001). At surgery, shunt opening pressures had been set 5.9 mm H2O lower in the SDH group than in the no-SDH group (109.6 ± 24.1 vs 115.5 ± 25.4 mm H2O, respectively, p = 0.009). Antisiphoning devices (ASDs) were used in 892 patients but did not prevent SDH. Mean opening pressures at surgery and the follow-up were lower with shunts with an ASD, without causing more SDHs. No other differences were seen between the groups.

    CONCLUSIONS: iNPH patients in this study were diagnosed and operated on in routine practice; thus, the results represent everyday care. Male sex, antiplatelet medication, and a lower opening pressure at surgery were risk factors for SDH. Physical status and comorbidity were not. ASD did not prevent SDH, but a shunt with an ASD allowed a lower opening pressure without causing more SDHs.

  • 277.
    Georgiev, Dejan
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Occupational Therapy. Department of Neurology, University Clinical Centre Ljubljana, Ljubljana, Slovenia; Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK.
    Hamberg, Katarina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hariz, Gun-Marie
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Gender differences in Parkinson's disease: a clinical perspective2017In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 136, no 6, p. 570-584Article in journal (Refereed)
    Abstract [en]

    Available data indicate that there are gender differences in many features of Parkinson's disease (PD). Precise identification of the gender differences is important to tailor treatment, predict outcomes, and meet other individual and social needs in women and men with PD. The aim of this study was to review the available clinical data on gender differences in PD. Original articles and meta-analyses published between 1990 and 2016 systematically exploring gender differences in PD were reviewed. There is slight male preponderance in incidence and prevalence of PD. PD starts earlier in men. Women tend to be more prone to develop tremor-dominant PD but are less rigid than men. Motor improvement after deep brain stimulation is equal in both sexes, but women tend to show better improvement in activities of daily living. Furthermore, women with PD show better results on tests for general cognitive abilities, outperform men in verbal cognitive tasks, show more pain symptoms, and score higher on depression scales. It seems, however, that the differences in cognition, mood, and pain perception are not disease specific as similar gender differences can be found in healthy subjects and in other neurological conditions. Despite PD being the most frequently studied movement disorder, studies investigating gender differences in PD are still scarce with most of the studies being cross-sectional. Good-quality, prospective, longitudinal studies analyzing gender differences in PD and comparing them to matched healthy controls are needed in order to properly address the issues of gender differences in PD.

  • 278.
    Ghasimi, Soma
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Dahlin, Anna M.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma2016In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 127, no 3, p. 483-492Article in journal (Refereed)
    Abstract [en]

    During the last years, genome wide association studies have discovered common germline genetic variants associated with specific glioma subtypes. We aimed to study the association between these germline risk variants and tumor phenotypes, including copy number aberrations and protein expression. A total of 91 glioma patients were included. Thirteen well known genetic risk variants in TERT, EGFR, CCDC26, CDKN2A, CDKN2B, PHLDB1, TP53, and RTEL1 were selected for investigation of possible correlations with the glioma somatic markers: EGFR amplification, 1p/19q codeletion and protein expression of p53, Ki-67, and mutated IDH1. The CDKN2A/B risk variant, rs4977756, and the CDKN2B risk variant, rs1412829 were inversely associated (p = 0.049 and p = 0.002, respectively) with absence of a mutated IDH1, i.e., the majority of patients homozygous for the risk allele showed no or low expression of mutated IDH1. The RTEL1 risk variant, rs6010620 was associated (p = 0.013) with not having 1p/19q codeletion, i.e., the majority of patients homozygous for the risk allele did not show 1p/19q codeletion. In addition, the EGFR risk variant rs17172430 and the CDKN2B risk variant rs1412829, both showed a trend for association (p = 0.055 and p = 0.051, respectively) with increased EGFR copy number, i.e., the majority of patients homozygote for the risk alleles showed chromosomal gain or amplification of EGFR. Our findings indicate that CDKN2A/B risk genotypes are associated with primary glioblastoma without IDH mutation, and that there is an inverse association between RTEL1 risk genotypes and 1p/19q codeletion, suggesting that these genetic variants have a molecular impact on the genesis of high graded brain tumors. Further experimental studies are needed to delineate the functional mechanism of the association between genotype and somatic genetic aberrations.

  • 279. Gispert, Suzana
    et al.
    Kurz, Alexander
    Waibel, Stefan
    Bauer, Peter
    Liepelt, Inga
    Geisen, Christof
    Gitler, Aaron D.
    Becker, Tim
    Weber, Markus
    Berg, Daniela
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Krueger, Rejko
    Riess, Olaf
    Ludolph, Albert C.
    Auburger, Georg
    The modulation of Amyotrophic Lateral Sclerosis risk by Ataxin-2 intermediate polyglutamine expansions is a specific effect2012In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 45, no 1, p. 356-361Article in journal (Refereed)
    Abstract [en]

    Full expansions of the polyglutamine domain (polyQ >= 34) within the polysome-associated protein ataxin-2 (ATXN2) are the cause of a multi-system neurodegenerative disorder, which usually presents as a Spino-Cerebellar Ataxia and is therefore known as SCA2, but may rarely manifest as Levodopa-responsive Parkinson syndrome or as motor neuron disease. Intermediate expansions (27 <= polyQ <= 33) were reported to modify the risk of Amyotrophic Lateral Sclerosis (ALS). We have now tested the reproducibility and the specificity of this observation. In 559 independent ALS patients from Central Europe, the association of ATXN2 expansions (30 <= polyQ <= 35) with ALS was highly significant. The study of 1490 patients with Parkinson's disease (PD) showed an enrichment of ATXN2 alleles 27/28 in a subgroup with familial cases, but the overall risk of sporadic PD was unchanged. No association was found between polyQ expansions in Ataxin-3 (ATXN3) and ALS risk. These data indicate a specific interaction between ATXN2 expansions and the causes of ALS, possibly through altered RNA-processing as a common pathogenic factor. (C) 2011 Elsevier Inc. All rights reserved.

  • 280.
    Glader, Eva-Lotta
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Edlund, Hilda
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Sukhova, M
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Norrving, B
    Eriksson, Marie
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    More equal stroke unit care over time. A 15-year follow up of socioeconomic disparities in stroke unit care in Sweden2013In: Cerebrovascular Diseases, ISSN 1015-9770, E-ISSN 1421-9786, Vol. 35, no Suppl. 3, p. 702-702Article in journal (Other academic)
  • 281.
    Glader, Eva-Lotta
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Edlund, Hilda
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Sukhova, Maria
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Norrving, Bo
    Department of Clinical Sciences, Section of Neurology, Lund University, Sweden.
    Eriksson, Marie
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Reduced inequality in access to stroke unit care over time: a 15-year follow-up of socioeconomic disparities in Sweden2013In: Cerebrovascular Diseases, ISSN 1015-9770, E-ISSN 1421-9786, Vol. 36, no 5-6, p. 407-411Article in journal (Refereed)
    Abstract [en]

    Background: Despite the compelling scientific evidence on the superiority of stroke unit care, far from all acute stroke patients have access to stroke unit care. In congruence with what has been observed when other new methods are introduced in health care, we hypothesized that there has been an inequality in the buildup phase of stroke units but that the gradients between patient groups have decreased as the total capacity of stroke unit care has increased. The purpose of this study was to explore if patients in a national sample who were socioeconomically disadvantaged (low education or low income) had reduced access to stroke unit care and if differences varied over time.

    Methods: All patients 18-74 years of age registered between 1995 and 2009 in Riks-Stroke, the Swedish stroke register, were included. The Stroke Unit Trialists' definition of a stroke unit has been adopted by Riks-Stroke and hospitals participating in the registry. Basic patient characteristics, stroke risk factors, process and outcome variables are recorded in Riks-Stroke. Socioeconomic data were accessed from Statistics Sweden. Multiple logistic regression analyses were used to calculate odds ratios (ORs) for stroke unit care between prespecified patient subgroups.

    Results: A total of 319,240 stroke patients were included in Riks-Stroke during the years 1995-2009, and 124,173 were aged between 18 and 74 years; they were included in the final analyses. After adjustment for confounders in a multiple regression model, women were treated in stroke units slightly less often [OR 0.97, 95% confidence interval (CI) 0.95-0.99]. There were no statistically significant associations between stroke unit care and age or between stroke unit care and cohabiting or living alone. The highest level of education predicted access to stroke unit care (secondary vs. primary school: OR 1.04, 95% CI 1.01-1.07; university vs. primary school: OR 1.06, 95% CI 1.02-1.10). Differences according to level of education diminished over time (p = 0.001). Income was not independently associated with stroke unit care, and over time the proportion of patients treated in stroke units increased at a similar rate in all income groups (p = 0.12).

    Conclusions: Even in a country with modest socioeconomic differences in the general population and public financing of all acute hospital care, socioeconomic inequalities in access to stroke unit care were evident during the early years, but they diminished as the total capacity for stroke unit care increased.

    © 2013 S. Karger AG, Basel.

  • 282. Godbolt, Alison K
    et al.
    Lindgren, Marie
    Stenberg, Maud
    Norrlands universitetssjukhus.
    Cronberg, Tobias
    Tengvar, Christer
    Sörbo, Ann
    Långvarig svår medvetandestörning efter hjärnskada hos vuxna: nya rekommendationer ger underlag för utredning och rehabilitering2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 49-50, p. 2230-2234Article in journal (Refereed)
    Abstract [en]

    After severe acquired brain injury some patients develop a prolonged disorder of consciousness (vegetative state or minimally conscious state), and as such cannot actively participate in neurorehabilitation. However, international opinion and recent research developments emphasize the need for involvement of rehabilitation medicine units in the care of these patients. The article presents recommendations for the care of adult patients with prolonged disorders of consciousness, which have been developed by a multidisciplinary working party, in order to promote good care, and identify areas for further improvements.

  • 283. Godbolt, Alison K.
    et al.
    Stenberg, Maud
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine.
    Jakobsson, Jan
    Sorjonen, Kimmo
    Krakau, Karolina
    Stålnacke, Britt-Marie
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine.
    DeBoussard, Catharina Nygren
    Subacute complications during recovery from severe traumatic brain injury: frequency and associations with outcome2015In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 5, no 4, article id e007208Article in journal (Refereed)
    Abstract [en]

    Background: Medical complications after severe traumatic brain injury (S-TBI) may delay or prevent transfer to rehabilitation units and impact on long-term outcome.

    Objective: Mapping of medical complications in the subacute period after S-TBI and the impact of these complications on 1-year outcome to inform healthcare planning and discussion of prognosis with relatives.

    Setting: Prospective multicentre observational study. Recruitment from 6 neurosurgical centres in Sweden and Iceland.

    Participants and assessments: Patients aged 18-65 years with S-TBI and acute Glasgow Coma Scale 3-8, who were admitted to neurointensive care. Assessment of medical complications 3 weeks and 3 months after injury. Follow-up to 1 year. 114 patients recruited with follow-up at 1 year as follows: 100 assessed, 7 dead and 7 dropped out.

    Outcome measure: Glasgow Outcome Scale Extended.

    Results: 68 patients had >= 1 complication 3 weeks after injury. 3 weeks after injury, factors associated with unfavourable outcome at 1 year were: tracheostomy, assisted ventilation, on-going infection, epilepsy and nutrition via nasogastric tube or percutaneous endoscopic gastroscopy (PEG) tube (univariate logistic regression analyses). Multivariate analysis demonstrated that tracheostomy and epilepsy retained significance even after incorporating acute injury severity into the model. 3 months after injury, factors associated with unfavourable outcome were tracheostomy and heterotopic ossification (Fisher's test), infection, hydrocephalus, autonomic instability, PEG feeding and weight loss (univariate logistic regression). PEG feeding and weight loss at 3 months were retained in a multivariate model.

    Conclusions: Subacute complications occurred in two-thirds of patients. Presence of a tracheostomy or epilepsy at 3 weeks, and of PEG feeding and weight loss at 3 months, had robust associations with unfavourable outcome that were incompletely explained by acute injury severity.

  • 284. Gonzalez, Henrik
    et al.
    Olsson, Tomas
    Borg, Kristian
    Management of postpolio syndrome2010In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 9, no 6, p. 634-642Article in journal (Refereed)
    Abstract [en]

    Postpolio syndrome is characterised by the exacerbation of existing or new health problems, most often muscle weakness and fatigability, general fatigue, and pain, after a period of stability subsequent to acute polio infection. Diagnosis is based on the presence of a lower motor neuron disorder that is supported by neurophysiological findings, with exclusion of other disorders as causes of the new symptoms. The muscle-related effects of postpolio syndrome are possibly associated with an ongoing process of denervation and reinnervation, reaching a point at which denervation is no longer compensated for by reinnervation. The cause of this denervation is unknown, but an inflammatory process is possible. Rehabilitation in patients with postpolio syndrome should take a multiprofessional and multidisciplinary approach, with an emphasis on physiotherapy, including enhanced or individually modified physical activity, and muscle training. Patients with postpolio syndrome should be advised to avoid both inactivity and overuse of weak muscles. Evaluation of the need for orthoses and assistive devices is often required.

  • 285. Gonzalez-Duarte, Alejandra
    et al.
    Adams, David
    O'Riordan, William
    Yang, Chih-Chao
    Yamashita, Taro
    Kristen, Arnt
    Tournev, Ivaylo
    Schmidt, Hartmut
    Coelho, Teresa
    Berk, John
    Ghandi, Pritesh
    Chen, Jihong
    Gollob, Jared
    Goyal, Sunita
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Changes in neuropathy stage in patients with hATTR amyloidosis following patisiran treatment: Analysis from APOLLO2018In: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 23, no 4, p. 400-400Article in journal (Other academic)
  • 286. Gorram, Farida
    et al.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Alarcon, Flora
    Hebrard, Berenice
    Funalot, Benoit
    Nuel, Gregory
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Plante-Bordeneuve, Violaine
    Variation of Penetrance estimates in a wide spectrum of TTR-FAP families: implication for management of carriers2018In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 90Article in journal (Other academic)
    Abstract [en]

    Objective: Refine estimation of penetrance in TTR-FAP families, unravelling the role of covariates. Background: TTR-FAP is an autosomal dominant neuropathy caused by mutations in the TTR gene. Recently, therapeutic advances including gene modifying approaches proved effective to halt disease progression. Val30Met, the most common variant in Portugal and Latin America is associated to age at onset (AO) below 50 y-o. In Western Europe, US, Japan, heterogeneity of TTR variants is associated to AO above 50 y-o, a mixed polyneuropathy and cardiomyopathy. Determining the risk of being affected (penetrance) is essential to guide gene carrier management.

    Design/Methods: NPSE is a non-parametric method developed to estimate penetrance, taking into account covariates. Genealogical data from 227 kindreds were collected. There were 92 Val30Met families from Sweden, 64 Val30Met from Portugal and 73 from France including 37 Val30Met and 36 families carrying other TTR variants frequently identified: Ser77Tyr (15), Ile107Val (12), Ser77Phe (9).

    Results: We found highly significant differences of penetrance between Val30Met families from various origins. Risk estimates also differed between the TTR variants (French Val30Met, Ser77Tyr, Ile107Val, Ser77Phe) (p < 0.004). In the French and Swedish Val30Met families, the disease risk remained below 10% until age 40 years then increased to 72% and 63% at 80 years, respectively. In Portuguese families, the risk was above 20% from age 30 years then up to 92% at 80 y-o. In Ile107Val, Ser77Tyr and Ser77Phe families the risk was virtually null until 50 years of age and raised to 54%, 70%, and 86% at age 80 years, respectively. A higher risk is observed when the disease is maternally inherited in Portuguese and Swedish kindreds (p <0.001).

    Conclusions: Important variation of penetrance is observed in TTR-FAP families according covariates. Such data will help for management of gene carriers, allowing early diagnosis and therapeutic initiation timely.

  • 287.
    Graipe, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Söderström, Lars
    Mooe, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Increased Use of Ticagrelor After Myocardial Infarction Is Not Associated With Intracranial Hemorrhage: Results From a Nationwide Swedish Registry2018In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 49, no 12, p. 2877-2882Article in journal (Refereed)
    Abstract [en]

    Background and Purpose: Guidelines recommend dual antiplatelet treatment with ticagrelor instead of clopidogrel after acute myocardial infarction. Ticagrelor increases major and minor noncoronary artery bypass graft bleeding compared with clopidogrel, but whether the risk of intracranial hemorrhage (ICH) increases is unknown. We aimed to examine any association between ticagrelor and ICH and to identify predictors of ICH among unselected patients after acute myocardial infarction.

    Methods: Patients with acute myocardial infarction were identified using the Register of Information and Knowledge About Swedish Heart Intensive Care Admissions, and the data were combined with the Swedish National Patient Registry to identify ICH occurrence. To avoid obvious selection bias related to the choice of dual antiplatelet treatment, we divided the study cohorts into 2 time periods of similar length using the first prescription of ticagrelor as a cutoff point (December 20, 2011). The risk of ICH during the first period (100% clopidogrel treatment) versus the second period (52.1% ticagrelor and 47.8% clopidogrel treatment) was assessed using Kaplan-Meier analysis. Cox proportional-hazards regression analyses, with assessment of interactions between all significant variables, were used to identify predictors of ICH.

    Results: The analysis included 47 674 patients with acute myocardial infarction. The cumulative incidence of ICH during the first period was 0.59% (91 cases [95% CI, 0.49-0.69]) versus 0.52% (97 cases [95% CI, 0.43-0.61]) during the second period (P=0.83). In multivariable Cox analysis, study period (second versus first period) was not predictive of ICH. Interaction analyses showed that age and prior cardiovascular morbidities were of importance in predicting the risk of ICH.

    Conclusions: The increased use of ticagrelor was not associated with ICH, whereas age and prior cardiovascular morbidities were related to the risk of ICH and interacted significantly.

  • 288.
    Granberg Sandlund, M.
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Diamant, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Granåsen, Gabriel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Salzer, Jonatan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Quality of care in acute dizziness presentations2019In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 26, no S1, p. 926-926Article in journal (Other academic)
    Abstract [en]

    Background and aims: Dizziness is a common symptom at emergency departments. Studies have shown poor quality of care in acute dizziness presentations, including the overuse of computed tomography (CT) and failure to detect benign causes. This study aims to evaluate whether a management algorithm has improved the quality of care for dizzy patients at Umeå University Hospital, Sweden.

    Methods: This was an interventional study using medical records to collect data for acute dizziness presentations before (period 1, 2012–2014) and after (period 2, 2016-2017) the implementation of a management algorithm (see figure). Outcomes were changes in a set of pre-defined quality markers and health economic effects.

    Results: Total n=2126 and n=1487 acute dizziness presentations were identified in period 1 and 2, respectively. Baseline characteristics were similar. The proportion of patients undergoing Dix-Hallpike testing increased, 20.8% vs. 37.7%, (p<0.01), as did BPPV diagnoses, 7.6% vs. 15.3%, (p<0.01). Hospitalization became less common, 61.5% vs. 47.6% (p<0.01). The proportion undergoing any neuroradiological investigation decreased, 44.8% vs. 36.3% (p<0.01) with a shift from CT to MRI, with unchanged sensitivity for diagnosing cerebrovascular causes. The average cost for the care of one dizzy patient decreased from $2561 during period 1 to $1808 during period 2.

    Conclusion: This study shows how the implementation of a management algorithm for dizzy patients can improve the quality of care and lower the expenses, without an increased number of missed stroke cases.

  • 289.
    Granlund Sandlund, Mikael
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Managing dizzy patients – a matter of quality - A follow-up study after implementing a management algorithm for dizzy patients at the Emergency Department2018Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 290.
    Granqvist, Mathias
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Boremalm, Malin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Poorghobad, Amyar
    Svenningsson, Anders
    Salzer, Jonatan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Frisell, Thomas
    Piehl, Fredrik
    Comparative Effectiveness of Rituximab and Other Initial Treatment Choices for Multiple Sclerosis2018In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 75, no 3, p. 320-327Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Comparative real-world effectiveness studies of initial disease-modifying treatment (DMT) choices for relapsing-remitting multiple sclerosis (RRMS) that include rituximab are lacking.

    OBJECTIVE To assess the effectiveness and drug discontinuation rates of rituximab among patients with newly diagnosed RRMS compared with injectable DMTs, dimethyl fumarate, fingolimod, or natalizumab.

    DESIGN, SETTING, AND PATIENTS This retrospective cohort study used prospectively collected data to examine specialized care of 2 Swedish county-based community samples of patients with RRMS. Patients with RRMS who received diagnoses from January 1, 2012, to October 31, 2015, who resided in Stockholm or Vasterbotten Counties were identified from a Swedish multiple sclerosis registry.

    MAIN OUTCOMES AND MEASURES All reasons for drug discontinuation of initial treatment choice (main outcome) and specific reasons for switching (secondary outcomes) were analyzed with multivariable Cox regression, including propensity scores.

    RESULTS Among 494 patients (median [interquartile range] age, 34.4 [27.4-43.4] years; 158 men [32.0%]), 215 received an injectable DMT (43.5%); 86 (17.4%), dimethyl fumarate; 17 (3.4%), fingolimod; 50 (10.1%), natalizumab; 120 (24.3%), rituximab; and 6 (1.2%), other DMT. Regional preferences were pronounced, with 42 of 52 (81%) and 78 of 442 (18%) receiving rituximab in Vasterbotten and Stockholm, respectively. The annual discontinuation rate for rituximab, injectable DMTs, dimethyl fumarate, fingolimod, and natalizumab were 0.03, 0.53, 0.32, 0.38, and 0.29, respectively. Continued disease activity was the main reason for discontinuation of injectable DMTs, dimethyl fumarate, and fingolimod; positive John Cunningham virus serology results were the main reason for discontinuation of natalizumab. Rate of clinical relapses and/or neuroradiologic disease activity were significantly lower for rituximab compared with injectable DMTs and dimethyl fumarate, with a tendency for lower relapse rates also compared with natalizumab and fingolimod. The annual discontinuation rate of initial treatment choice was significantly lower in Vasterbotten compared with Stockholm (0.09 and 0.37, respectively).

    CONCLUSIONS AND RELEVANCE Rituximab was superior to all other DMT in terms of drug discontinuation and displayed better clinical efficacy compared with injectable DMTs and dimethyl fumarate with borderline significance compared with natalizumab and fingolimod. The county where rituximab constituted the main initial treatment choice displayed better outcomes in most measured variables. Collectively, our findings suggest that rituximab performs better than other commonly used DMTs in patients with newly diagnosed RRMS.

  • 291. Granqvist, Mathias
    et al.
    Burman, Joachim
    Gunnarsson, Martin
    Lycke, Jan
    Nilsson, Petra
    Olsson, Tomas
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Svenningsson, Anders
    Vrethem, Magnus
    Frisell, Thomas
    Piehl, Fredrik
    Comparative effectiveness of dimethyl fumarate as the initial and secondary treatment for MS2019In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970Article in journal (Refereed)
    Abstract [en]

    Background: Population-based real-world evidence studies of the effectiveness and tolerability of dimethyl fumarate in relation to common treatment alternatives are still limited. Objective: To evaluate the clinical effectiveness and tolerability of dimethyl fumarate (DMF) as the initial and secondary treatment for relapsing-remitting multiple sclerosis (RRMS) patients compared with common treatment alternatives in Sweden. Methods: We conducted a nationwide retrospective observational cohort study of all RRMS patients identified through the Swedish MS registry initiating DMF (n = 641) or interferons/glatiramer acetate (IFN/GA; n = 555) as the initial therapy, or DMF (n = 703) or fingolimod (FGL; n = 194) after switch from IFN/GA between 1 January 2014 and 31 December 2016. Results: The discontinuation rate was lower with DMF as the initial treatment than IFN/GA (adjusted hazard rate (HR): 0.46, 95% confidence interval (CI): 0.37-0.58, p < 0.001), but higher than FGL as the secondary treatment (HR: 1.51, CI: 1.08-2.09, p < 0.05). Annualized relapse rate (ARR) was lower with DMF compared to IFN/GA (0.04, CI: 0.03-0.06 vs 0.10, CI: 0.07-0.13; p < 0.05), but not FGL (0.03, CI: 0.02-0.05 vs 0.02, CI: 0.01-0.04; p = 0.41). Finally, time to first relapse (TTFR) was longer with DMF as the initial, but not secondary, therapy (p < 0.05 and p = 0.20, respectively). Conclusion: Our findings indicate that DMF performs better than IFN/GA as the initial treatment for RRMS. Compared to FGL, DMF displayed a lower tolerability, but largely similar effectiveness outcomes.

  • 292. Gravesteijn, B. Y.
    et al.
    Sewalt, C. A.
    Ercole, A.
    Lecky, F.
    Menon, D.
    Steyerberg, E. W.
    Maas, A. I. R.
    Lingsma, H. F.
    Klimek, M.
    Variation in the practice of tracheal intubation in Europe after traumatic brain injury: a prospective cohort study2020In: Anaesthesia, ISSN 0003-2409, E-ISSN 1365-2044, Vol. 75, no 1, p. 45-53Article in journal (Refereed)
    Abstract [en]

    Traumatic brain injury patients frequently undergo tracheal intubation. We aimed to assess current intubation practice in Europe and identify variation in practice. We analysed data from patients with traumatic brain injury included in the prospective cohort study collaborative European neurotrauma effectiveness research in traumatic brain injury (CENTER-TBI) in 45 centres in 16 European countries. We included patients who were transported to hospital by emergency medical services. We used mixed-effects multinomial regression to quantify the effects on pre-hospital or in-hospital tracheal intubation of the following: patient characteristics; injury characteristics; centre; and trauma system characteristics. A total of 3843 patients were included. Of these, 1322 (34%) had their tracheas intubated; 839 (22%) pre-hospital and 483 (13%) in-hospital. The fit of the model with only patient characteristics predicting intubation was good (Nagelkerke R2 64%). The probability of tracheal intubation increased with the following: younger age; lower pre-hospital or emergency department GCS; higher abbreviated injury scale scores (head and neck, thorax and chest, face or abdomen abbreviated injury score); and one or more unreactive pupils. The adjusted median odds ratio for intubation between two randomly chosen centres was 3.1 (95%CI 2.1-4.3) for pre-hospital intubation, and 2.7 (95%CI 1.9-3.5) for in-hospital intubation. Furthermore, the presence of an anaesthetist was independently associated with more pre-hospital intubation (OR 2.9, 95%CI 1.3-6.6), in contrast to the presence of ambulance personnel who are allowed to intubate (OR 0.5, 95%CI 0.3-0.8). In conclusion, patient and injury characteristics are key drivers of tracheal intubation. Between-centre differences were also substantial. Further studies are needed to improve the evidence base supporting recommendations for tracheal intubation.

  • 293. Grenander, A.
    et al.
    Bredbacka, S.
    Rydvall, A.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Aroch, R.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Edner, G.
    Koskinen, Lars-Owe D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Olivecrona, M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Antithrombin treatment in patients with traumatic brain injury: a pilot study2001In: J Neurosurg Anesthesiol, Vol. 13, no 1, p. 49-56Article in journal (Refereed)
    Abstract [en]

    This study will determine if early administration of antithrombin concentrate to patients with traumatic brain injury (TBI) can inhibit or significantly shorten the time of coagulopathy. The progress of brain injury monitored by computed tomographic scan (CT) was also assessed, as was the time needed for intensive care and outcome related to Glasgow outcome scale (GOS). Twenty-eight patients with isolated brain trauma verified with CT were included in either of two parallel groups. The Glasgow coma score (GCS) was mean 7.5, and median 7.0; signifying a moderate to severe traumatic brain injury but with a mortality of only 3.5%. The patients randomized to antithrombin treatment received a total of 100 U/kg BW during 24 hours. To measure hypercoagulability, soluble fibrin (SF), D-dimer (D-d), and thrombin-antithrombin complex (TAT) were assessed together with antithrombin (AT) and routine coagulation tests. Before treatment, SF, D-d, and TAT were markedly increased in both groups. Soluble fibrin and D-dimer (measured after treatment began) appeared to decrease faster in the AT group, and there was a statistically significant difference between the groups at 36 hours for SF and at 36 hours, 48 hours, and at Day 3 for D-d. Thrombin-antithrombin complex levels were very high in both groups but, surprisingly, showed no significant difference between the groups. The authors conclude that antithrombin concentrate administered to patients with severe TBI resulted in a marginal reduction of hypercoagulation. We could not detect any obvious influence by antithrombin on brain injury progress, on CT, or on outcome or time needed for intensive care.

  • 294.
    Gromicho, Marta
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Pinto, Susana
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Instituto de Medicina Molecular and Institute of Physiology, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, Lisbon, Portugal.
    Gisca, Eugeniu
    Pronto-Laborinho, Ana Catarina
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    de Carvalho, Mamede
    Frequency of C9orf72 hexanucleotide repeat expansion and SOD1 mutations in Portuguese patients with amyotrophic lateral sclerosis2018In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 70, article id 325.e7Article in journal (Refereed)
    Abstract [en]

    Mutation frequency of the 2 main amyotrophic lateral sclerosis (ALS) erelated genes, C9orf72 and SOD1, varies considerably across the world. We analyzed those genes in a large population of Portuguese ALS patients (n = 371) and recorded demographic and clinical features. Familial ALS (FALS) was disclosed in 11.6% of patients. Mutations in either SOD1 or C9orf72 were found in 9.2% of patients and accounted for 40% of FALS and 5.2% of sporadic ALS. SOD1 mutations were rare (0.83%), but a novel and probably disease-causing mutation was identified: p. Ala152Pro (c. 457G>C). The C9orf72 hexanucleotide repeat expansion was the commonest abnormality, accounting for 4.6% of sporadic ALS and 37.5% of FALS; in these patients, Frontotemporal Dementia was prevalent. This first report on the frequency of C9orf72 hexanucleotide repeat expansion and SOD1 mutations in Portuguese ALS patients reiterate that the genetic architecture of ALS varies among different geographic regions. The mutations incidence in ALS patients (w10%) and associated phenotypes suggest that genetic tests should be offered to more patients, and other genes should be investigated in our population. 

  • 295. Gros-Louis, Francois
    et al.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Dupre, Nicolas
    Urushitani, Makoto
    Dion, Patrick
    Souchon, Frederique
    D'Amour, Monique
    Camu, William
    Meininger, Vincent
    Bouchard, Jean-Pierre
    Rouleau, Guy A
    Julien, Jean-Pierre
    Chromogranin B P413L variant as risk factor and modifier of disease onset for amyotrophic lateral sclerosis2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 51, p. 21777-21782Article in journal (Refereed)
    Abstract [en]

    Recently, chromogranins were reported to interact specifically with mutant forms of superoxide dismutase that are linked to amyotrophic lateral sclerosis (ALS). This interaction led us to analyze the frequencies of sequence variants of the CHGB gene in ALS patients and matched controls from three different countries. Of particular interest was the finding of the P413L CHGB variant present in 10% of ALS patients (n = 705) as compared to 4.5% in controls (n = 751), conferring a 2.2-fold greater relative risk to develop the disease (P < 0.0001). This effect was mainly contributed by the samples of French origin that yielded a frequency of the P413L variation at 17% in ALS (n = 289) and 5% in controls (n = 448), conferring a 3.3-fold greater risk to develop ALS. Furthermore, the P413L CHGB variant is associated with an earlier age of onset by almost a decade in both sporadic ALS and familial ALS cases. Genetic variation influencing age of onset in ALS had not previously been reported. Expression of fusion CHGB-EGFP constructs in SHSY-5Y cells revealed that the P413L variation can cause defective sorting of CHGB into secretory granules. The finding that CHGB may act as a susceptibility gene and modifier of onset in ALS is consistent with the emerging view that dysfunction of the secretory pathway may contribute to increased vulnerability of motor neurons.

  • 296. Gruden, Marina A
    et al.
    Davydova, Tatiana V
    Narkevich, Victor B
    Fomina, Valentina G
    Wang, Chao
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kudrin, Vladimir S
    Morozova-Roche, Ludmilla A
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sewell, Robert DE
    Intranasal administration of alpha-synuclein aggregates: a Parkinson's disease model with behavioral and neurochemical correlates2014In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 263, p. 158-168Article in journal (Refereed)
    Abstract [en]

    Parkinson's disease (PD) is a neurodegenerative disorder in which both alpha-synuclein (alpha-syn) and dopamine (DA) have a critical role. Our previous studies instigated a novel PD model based on nasal inoculation with alpha-syn aggregates which expressed parkinsonian-like behavioral and immunological features. The current study in mice substantiated the robustness of the amyloid nasal vector model by examining behavioral consequences with respect to DA-ergic neurochemical corollaries. In vitro generated alpha-syn oligomers and fibrils were characterized using atomic force microscopy and the thioflavin T binding assay. These toxic oligomers or fibrils administered alone (0.48 mg/kg) or their 50:50 combination (total dose of 0.48 mg/kg) were given intranasally for 14 days and "open-field" behavior was tested on days 0, 15 and 28 of the protocol. Behavioral deficits at the end of the 14-day dosing regime and on day 28 (i.e., 14 days after treatment completion) induced rigidity, hypokinesia and immobility. This was accompanied by elevated nigral but not striatal DA, DOPAC and HVA concentrations in response to dual administration of alpha-syn oligomers plus fibrils but not the oligomers by themselves. alpha-Syn fibrils intensified not only the hypokinesia and immobility 14 days post treatment, but also reduced vertical rearing and enhanced DA levels in the substantia nigra. Only nigral DA turnover (DOPAC/DA but not HVA/DA ratio) was augmented in response to fibril treatment but there were no changes in the striatum. Compilation of these novel behavioral and neurochemical findings substantiate the validity of the alpha-syn nasal vector model for investigating parkinsonian-like symptoms.

    (C) 2014 Elsevier B.V. All rights reserved.

  • 297. Gruden, Marina A.
    et al.
    Yanamandra, Kiran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kucheryanu, Valery G.
    Bocharova, Olga R.
    Sherstnev, Vladimir V.
    Morozova-Roche, Ludmilla A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sewell, Robert D. E.
    Correlation between Protective Immunity to alpha-Synuclein Aggregates, Oxidative Stress and Inflammation2012In: Neuroimmunomodulation, ISSN 1021-7401, E-ISSN 1423-0216, Vol. 19, no 6, p. 334-342Article in journal (Refereed)
    Abstract [en]

    Objective: Protein aggregation leading to central amyloid deposition is implicated in Parkinson's disease (PD). During disease progression, inflammation and oxidative stress may well invoke humoral immunity against pathological aggregates of PD-associated alpha-synuclein. The aim was to investigate any possible concurrence between autoimnnune responses to alpha-synuclein monomers, oligomers or fibrils with oxidative stress and inflammation.

    Methods: The formation of alpha-synuclein amyloid species was assessed by thioflavin-T assay and atomic force microscopy was employed to confirm their morphology. Serum autoantibody titers to alpha-synuclein conformations were determined by ELISA. Enzyme activity and concentrations of oxidative stress/inflammatory indicators were evaluated by enzyme and ELISA protocols.

    Results: In PD patient sera, a differential increase in autoantibody titers to alpha-synuclein monomers, toxic oligomers or fibrils was associated with boosted levels of the pro-inflammatory cytokine interleukin-6 and tumour necrosis factor-alpha, but a decrease in interferon-gamma concentration. In addition, levels of malondialdehyde were elevated whilst those of glutathione were reduced along with decrements in the activity of the antioxidants: superoxide dismutase, catalase and glutathione transferase.

    Conclusions: It is hypothesized that the generation of alpha-synuclein amyloid aggregates allied with oxidative stress and inflammatory reactions may invoke humoral immunity protecting against dopaminergic neuronal death. Hence, humoral immunity is a common integrative factor throughout PD progression which is directed towards prevention of further neurodegeneration, so potential treatment strategies should attempt to maintain PD patient immune status. Copyright (c) 2012 S. Karger AG, Basel

  • 298.
    Gu, Thomas
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Johansson, Elias
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Konferensrapport ESOC 20172017In: Vaskulär medicin, ISSN 2000-3188, Vol. 33, no 3, p. 4-4Article in journal (Other academic)
  • 299.
    Gu, Weigang
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Thrombectomy versus intravenous thrombolysis for treating acute anterior and posterior circulation stroke2016In: Cerebrovascular Diseases, ISSN 1015-9770, E-ISSN 1421-9786, Vol. 41, p. 145-145Article in journal (Other academic)
  • 300.
    Gu, Weigang
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Norrlands universitetssjukhus, Umeå.
    Jonasson, Per
    Avdelningen för diagnostisk radiologi, Norrlands universitetssjukhus, Umeå.
    Trombektomi gav gott resultat vid basilaris­trombos: Förlängt tidsfönster för ingreppet föreslås2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 27-28, p. 1188-1190Article in journal (Refereed)
    Abstract [en]

    [Thrombectomy gave good results in basilar thrombosis. Prolonged time window for the intervention is proposed].

    Basilar stroke is one of the most devastating acute cerebral vascular events. Intravascular thrombectomy may be performed beyond the 4.5 hours intravenous thrombolysis time window. However, the time window for thrombectomy in basilar stroke remains unclear. In our clinics, two cases of coma of unknown origin were diagnosed through CT angiography as distal basilar occlusion and treated with thromb­ectomy. Recanalization was achieved at 10 hours after stroke onset in case 1 and at 13 hours in case 2. The first patient regained consciousness shortly after operation and walked unlimited at 2 months after stroke. The second patient woke up slowly with cortical blindness, cerebellar ataxia, and unilateral weakness. At 10 months post stroke, he moved unlimited with mRS 2. Therefore, acute brain CT scan should always be accompanied with CT angiography in cases of coma of unknown origin for the differential diagnosis of basilar stroke where thrombectomy may be considered up to 13 hours after stroke onset.

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