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  • 301.
    Johansson, Elias
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Öhman, K.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Wester, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Symptomatic carotid near-occlusion with full collapse might cause a very high risk of stroke2015Inngår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 277, nr 5, s. 615-623Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BackgroundThe risk of early stroke recurrence amongst patients with symptomatic carotid near-occlusion with and without full collapse is unknown. Therefore, the aim of this study was to analyse the 90-day risk of recurrent ipsilateral ischaemic stroke in patients with symptomatic carotid near-occlusion both with and without full collapse. MethodsThis study was a secondary analysis of the Additional Neurological SYmptoms before Surgery of the Carotid Arteries: a Prospective study (ANSYSCAP). We prospectively analysed 230 consecutive patients with symptomatic 50-99% carotid stenosis or near-occlusion. Based on the combination of several imaging modalities, 205 (89%) patients were classified as having 50-99% carotid stenosis, and 10 (4%) and 15 (7%) as having near-occlusion with and without full collapse, respectively. The 90-day risk of recurrent ipsilateral ischaemic stroke was compared between these three groups. Only events that occurred before carotid endarterectomy were analysed. ResultsThe 90-day risk of recurrent stroke was 18% [95% confidence interval (CI) 12-25%; n=29] for patients with 50-99% carotid stenosis, 0% for patients with near-occlusion without full collapse and 43% (95% CI 25-89%; n=4) for patients with near-occlusion with full collapse (P=0.035, log-rank test). The increased risk of recurrent ipsilateral ischaemic stroke for patients with symptomatic near-occlusion with full collapse remained significant after multivariable adjustment for age, sex and type of presenting event. ConclusionsPatients with symptomatic carotid near-occlusion with full collapse might have a very high risk of stroke recurrence. Carotid endarterectomy could be considered for these patients.

  • 302. Johansson, S.
    et al.
    Forsberg, L.
    Hillert, J.
    Nilsson, P.
    Dahle, C.
    Svenningsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Lycke, J.
    Landtblom, A. -M
    Burman, J.
    Walentin, F.
    Martin, C.
    Piehl, F.
    Olsson, T.
    A Swedish nationwide pharmaco-epidemiological and genetic study of the long-term safety and efficacy of natalizumab2015Inngår i: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 21, s. 285-286Artikkel i tidsskrift (Annet vitenskapelig)
  • 303. Johansson, S.
    et al.
    Forsberg, L.
    Nordin, N.
    Hillert, J.
    Svenningsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Lycke, J.
    Burman, J.
    Landtblom, A. -M
    Walentin, F.
    Martin, C.
    Nilsson, P.
    Dahle, C.
    Piehl, F.
    Olsson, T.
    The IMSE 2 study: a Swedish nationwide pharmaco-epidemiological and genetic study focused on long-term safety and efficacy of fingolimod2015Inngår i: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 21, s. 284-285Artikkel i tidsskrift (Annet vitenskapelig)
  • 304. Johansson, Staffan B.
    et al.
    Eklund, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik.
    Malm, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Stemme, Göran
    Roxhed, Niclas
    A MEMS-based passive hydrocephalus shunt for body position controlled intracranial pressure regulation2014Inngår i: Biomedical microdevices (Print), ISSN 1387-2176, E-ISSN 1572-8781, Vol. 16, nr 4, s. 529-536Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This paper reports a novel micro electro mechanical system (MEMS) valve with posture controlled flow characteristics for improved treatment of hydrocephalus, a disease that is characterized by elevated pressure in the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord. In contrast to conventional differential pressure CSF valves, the CSF valve presented here features a third port which utilizes hydrostatic pressure from a pressure compensating catheter to adapt CSF drainage to optimized levels irrespective of body position. Prototypes have been fabricated using standard MEMS manufacturing processes and the experimental evaluation successfully showed that the flow rate was adjustable with a varying hydrostatic pressure on the third port. Measured data showed that flow rate was at near ideal values at laying body position and that the flow rate can be adjusted to optimal values at standing body position by selecting an appropriate length of the pressure compensating catheter. This is the first pressure balanced CSF valve intended for body position controlled CSF pressure regulation.

  • 305.
    Johansson, Christer
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Fysioterapi.
    Lindström, Britta
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Fysioterapi.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Johansson, Gudrun M.
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Fysioterapi.
    Balance and mobility in patients with newly diagnosed Parkinson's disease - a five-year follow-up of a cohort in northern Sweden2018Inngår i: Disability and Rehabilitation, ISSN 0963-8288, E-ISSN 1464-5165, s. 1-10Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The presence of early balance impairment in patients with Parkinson's disease has not been fully investigated.

    PURPOSE: The purpose of this study was to examine balance and mobility, self-perceived unsteadiness, self-reported falls, and effects of medication on balance among patients at their first visit to a neurological clinic and during the ensuing five years.

    MATERIALS AND METHODS: The participants were collected from a prospective longitudinal study. One hundred and forty-five patients with idiopathic Parkinson's disease and 31 healthy controls were included. The outcome measures were the Berg Balance Scale, the Timed Up and Go, the Postural Stability test and a questionnaire.

    RESULTS: At their first visit to the neurological clinic, the patients performed less well on the Berg Balance Scale (p < 0.001, r = 0.36), the Timed Up and Go (p < 0.001, r = 0.32), and the Postural Stability test (p < 0.001, r = 0.35) compared with the controls. In addition, a higher percentage of the patients reported self-perceived unsteadiness (p < 0.001, phi = 0.47). During the ensuing five years, balance and mobility worsened both with and without medication (p < 0.01, r = 0.24-0.37), although with small median differences.

    CONCLUSIONS: Further studies are needed to confirm that minor balance impairments exist even at the time of diagnosis and worsen during the ensuing five years. IMPLICATIONS FOR REHABILITATION Impairments in balance and mobility may occur early in Parkinson's disease, especially in the elderly patients, and seem to worsen during the first five years. There is a need to use sensitive outcome measures and to ask the patients about unsteadiness and falls to detect balance impairment in this cohort. Parkinsonian medication has a limited effect on balance and may preferably be complemented with balance exercises to target balance impairment early in Parkinson's disease.

  • 306. Jons, D
    et al.
    Sundström, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Andersen, O
    Targeting Epstein-Barr virus infection as an intervention against multiple sclerosis2015Inngår i: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 131, nr 2, s. 69-79Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    We here review contemporary data on genetic and environmental risk factors, particularly Epstein-Barr virus infection, for multiple sclerosis. There is an important immunogenetic etiological factor for multiple sclerosis. However, a general assumption is that immune defense genes are activated by the environment, basically by infections. We contend that the relationship between infectious mononucleosis and multiple sclerosis cannot be completely explained by genetics and inverse causality. Epstein-Barr infection as indicated by positive serology is an obligatory precondition for multiple sclerosis, which is a stronger attribute than a risk factor only. Data on events in the early pathogenesis of multiple sclerosis are cumulating from bio-banks with presymptomatic specimens, but there is only little information from the critical age when Epstein-Barr infection including infectious mononucleosis is acquired, nor on the detailed immunological consequences of this infection in individuals with and without multiple sclerosis. We discuss how focused bio-banking may elaborate a rationale for the development of treatment or vaccination against Epstein-Barr virus infection. A cohort in which intervention against Epstein-Barr infections was performed should be the object of neurological follow-up.

  • 307. Jonsson, L.
    et al.
    Holmen, C.
    Hillert, J.
    Nilsson, P.
    Dahle, C.
    Feltelius, N.
    Sveningsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Lycke, J.
    Landtblom, A-M
    Burman, J.
    Walentin, F.
    Martin, C.
    Piehl, F.
    Olsson, T.
    A Swedish nationwide pharmaco-epidemiological and genetic study (IMSE) of the long-term safety and efficacy of natalizumab2014Inngår i: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 20, s. 166-166Artikkel i tidsskrift (Annet vitenskapelig)
  • 308. Jonsson, L.
    et al.
    Piehl, F.
    Hillert, J.
    Nilsson, P.
    Dahle, C.
    Feltelius, N.
    Svenningsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Lycke, J.
    Fagius, J.
    Wallentin, F.
    Martin, C.
    Olsson, T.
    The immunomodulation and multiple sclerosis epidemiology (IMSE) study; a Swedish nationwide pharmaco-epidemiological and genetic study focussed on long-term safety and efficacy of natalizumab (Tysabri)2013Inngår i: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 19, nr 11, Supplement: S, s. 205-205Artikkel i tidsskrift (Annet vitenskapelig)
  • 309. Kacem, Imen
    et al.
    Funalot, Benoit
    Torny, Frederic
    Lautrette, Geraldine
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Couratier, Philippe
    Early onset Parkinsonism associated with an intronic SOD1 mutation2012Inngår i: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders, ISSN 1466-0822, E-ISSN 1743-4483, Vol. 13, nr 3, s. 315-317Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We report on a patient belonging to a large family with autosomal-dominant amyotrophic lateral sclerosis, who developed asymmetrical akineto-rigid symptoms at 33 years of age. He had no signs of lower motor neuron disease after four years of follow-up. All seven ALS patients from this family harboured a mutation located in the fourth intron of the SOD1 gene. The proband also harboured the same mutation, associated with a 40% decrease in SOD1 erythrocyte activity. This case report suggests that SOD1 mutations might be associated with marked phenotypic variability (ALS or early onset Parkinsonism in this family).

  • 310. Kahlow, H.
    et al.
    Olivecrona, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Surgical and hardware complications to vagal nerve stimulation for drug resistant epilepsy. A longitudinal single centre study of 143 patients2012Inngår i: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 53, nr s5, s. 33-33Artikkel i tidsskrift (Annet vitenskapelig)
  • 311.
    Kahlow, Hannes
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Olivecrona, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Complications of vagal nerve stimulation for drug-resistant epilepsy: A single center longitudinal study of 143 patients2013Inngår i: Seizure, ISSN 1059-1311, E-ISSN 1532-2688, Vol. 22, nr 10, s. 827-833Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To longitudinally study surgical and hardware complications to vagal nerve stimulation (VNS) treatment in patients with drug-resistant epilepsy. Methods: In a longitudinal retrospective study, we analyzed surgical and hardware complications in 143 patients (81 men and 62 women) who between 1994 and 2010 underwent implantation of a VHS-device for drug-resistant epilepsy. The mean follow-up time was 62 +/- 46 months and the total number of patient years 738. Results: 251 procedures were performed on 143 patients. 16.8% of the patients were afflicted by complications related to surgery and 16.8% suffered from hardware malfunctions. Surgical complications were: superficial infection in 3.5%, deep infection needing explantation in 3.5%, vocal cord palsy in 5.6%, which persisted in at least 0.7% for over one year, and other complications in 5.6%. Hardware-related complications were: lead fracture in 11.9% of patients, disconnection in 2.8%, spontaneous turn-off in 1.4% and stimulator malfunction in 1.4%. We noted a tendency to different survival times between the two most commonly used lead models as well as a tendency to increased infection rate with increasing number of stimulator replacements. Conclusion: In this series we report on surgical and hardware complications from our 16 years of experience with VNS treatment. Infection following insertion of the VNS device and vocal cord palsy due to damage to the vagus nerve are the most serious complications related to the surgery. Avoiding unnecessary reoperations in order to reduce the appearances of these complications are of great importance. It is therefore essential to minimize technical malfunctions that will lead to additional surgery. Further studies are needed to evaluate the possible superiority of the modified leads.

  • 312.
    Karlsson, Fredrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Logopedi.
    Blomstedt, Patric
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Olofsson, Katarina
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Linder, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Nordh, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    van Doorn, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Logopedi.
    Control of phonatory onset and offset in Parkinson patients following deep brain stimulation of the subthalamic nucleus and caudal Zona Incerta2012Inngår i: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 18, nr 7, s. 824-827Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Laryngeal hypokinesia is a common symptom in Parkinson’s disease (PD) that affects quality of life. Deep brain stimulation (DBS) is well recognized as a complementary method for treatment of motor symptoms in PD but the outcomes on patients’ control over phonatory alternation have yet not been clearly elucidated. The present study examined the effect of subthalamic nucleus STN-DBS (n=8, aged 51-72 yrs; median=63 yrs) and caudal Zona incerta cZi-DBS (n=8,aged 49-71 yrs; median=61 yrs) on control of onset and offset of phonation in connected speech. The patients were evaluated in a preoperatively (Med ON, 1.5 times the ordinary Levodopa dose) and 12 months postoperatively (Med ON, ordinary Levodopa dose). The results provided evidence of a progressive reduction in the ability to manifest alternations between voicing and voiceless states in a reading task. Mean proportion produced with inappropriate voicing increased from 47.6% to 55.3% and from 62.9% to 68.6% of the total duration for the two groups of patients between Pre-op and Post-op, Stim OFF evaluations. The medial and final parts of the fricative were more affected than the initial part, indicating an increased voicing lead into the following vowel. We propose that this reduction in phonatory control is be due to either progression of the disease, an effect of reduced Levodopa dosage or a microlesional effect. Patients’ proficiency in alternating between voiced and voiceless states in connected speech remained unaffected by both STN-DBS and cZi-DBS.

  • 313.
    Karlsson, Fredrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Logopedi.
    Malinova, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Logopedi.
    Olofsson, Katarina
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Blomstedt, Patric
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Linder, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Nordh, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Voice Tremor Outcomes of Subthalamic Nucleus and Zona Incerta Deep Brain Stimulation in Patients With Parkinson Disease2018Inngår i: Journal of Voice, ISSN 0892-1997, E-ISSN 1873-4588Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ObjectivesWe aimed to study the effect of deep brain stimulation (DBS) in the subthalamic nucleus (STN) and caudal zona incerta (cZi) on level of perceived voice tremor in patients with Parkinson disease (PD).

  • 314.
    Karlsson, Fredrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Logopedi.
    Unger, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Logopedi.
    Wahlgren, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Logopedi.
    Blomstedt, Patric
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Linder, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Nordh, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Zafar, Hamayun
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Klinisk oral fysiologi.
    Doorn, Jan van
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Logopedi.
    Deep brain stimulation of caudal zona incerta and subthalamic nucleus in patients with Parkinson’s disease: effects on diadochokinetic rate2011Inngår i: Parkinson’s Disease, ISSN 2042-0080, Vol. 2011, s. 605607-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The hypokinetic dysarthria observed in Parkinson's disease (PD) affects the range, speed, and accuracy of articulatory gestures in patients, reducing the perceived quality of speech acoustic output in continuous speech. Deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) and of the caudal zona incerta (cZi-DBS) are current surgical treatment options for PD. This study aimed at investigating the outcome of STN-DBS (7 patients) and cZi-DBS (7 patients) in two articulatory diadochokinesis tasks (AMR and SMR) using measurements of articulation rate and quality of the plosive consonants (using the percent measurable VOT metric). The results indicate that patients receiving STN-DBS increased in articulation rate in the Stim-ON condition in the AMR task only, with no effect on production quality. Patients receiving cZi-DBS decreased in articulation rate in the Stim-ON condition and further showed a reduction in production quality. The data therefore suggest that cZi-DBS is more detrimental for extended articulatory movements than STN-DBS.

  • 315.
    Karlsson, Kristin
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Huntington disease- epidemiology and disease severity in Jämtland and Uppsala 20142014Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
  • 316.
    Karlsson, Linnea
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Microembolic occurrences in carotid near-occlusion2018Independent thesis Basic level (professional degree), 20 poäng / 30 hpOppgave
  • 317. Katz, Jonathan S.
    et al.
    Katzberg, Hans D.
    Woolley, Susan C.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Combined fulminant frontotemporal dementia and amyotrophic lateral sclerosis associated with an I113T SOD1 mutation2012Inngår i: AMYOTROPH LATERAL SC, ISSN 1748-2968, Vol. 13, nr 6, s. 567-569Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mutations in the gene for superoxide dismutase type 1 cause amyotrophic lateral sclerosis (ALS), but are not thought to be associated with frontotemporal dementia (FTD). A lack of detailed case reports is one reason, among others, for this skepticism. This case report comments on a patient with familial ALS caused by I113T mutation in the SOD1 gene presenting with progressive cognitive and behavioral decline two years before developing progressive motor degeneration. In conclusion, this case provides evidence that SOD1 mutations can be associated with FTD.

  • 318.
    Kemi Yianoukos, Johannes
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Fatty acids as a risk factor for hip fractures.2014Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
  • 319. Kenna, Kevin P.
    et al.
    van Doormaal, Perry T. C.
    Dekker, Annelot M.
    Ticozzi, Nicola
    Kenna, Brendan J.
    Diekstra, Frank P.
    van Rheenen, Wouter
    van Eijk, Kristel R.
    Jones, Ashley R.
    Keaglel, Pamela
    Shatunov, Aleksey
    Sproviero, William
    Smiths, Bradley N.
    van Es, Michael A.
    Topps, Simon D.
    Kenna, Aoife
    Miller, Jack W.
    Fallini, Claudia
    Tiloca, Cinzia
    McLaughlin, Russell L.
    Vance, Caroline
    Troakes, Claire
    Colombrita, Claudia
    Mora, Gabriele
    Calvo, Andrea
    Verde, Federico
    Al-Sarraj, Safa
    King, Andrew
    Calini, Daniela
    de Belleroche, Jacqueline
    Baas, Frank
    van der Kooi, Anneke J.
    de Visser, Marianne
    ten Asbroek, Anneloor L. M. A.
    Sapp, Peter C.
    McKenna-Yasek, Diane
    Polak, Meraida
    Asress, Seneshaw
    Luis Munoz-Blanco, Jose
    Strom, Tim M.
    Meitinger, Thomas
    Morrison, Karen E.
    Lauria, Giuseppe
    Williams, Kelly L.
    Leigh, P. Nigel
    Nicholson, Garth A.
    Blair, Ian P.
    Leblond, Claire S.
    Dion, Patrick A.
    Rouleau, Guy A.
    Pall, Hardev
    Shaw, Pamela J.
    Turner, Martin R.
    Talbot, Kevin
    Taroni, Franco
    Boylan, Kevin B.
    Van Blitterswijk, Marka
    Rademakers, Rosa
    Esteban-Perez, Jesus
    Garcia-Redondo, Alberto
    Van Damme, Phillip
    Robberecht, Wim
    Chio, Adrian
    Gellera, Cinzia
    Drepper, Carsten
    Sendtner, Michael
    Ratti, Antonia
    Glass, Jonathan D.
    Mora, Jesus S.
    Basak, Nazli A.
    Hardiman, Orla
    Ludolph, Albert C.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Weishaupt, Jochen H.
    Brown, Robert H., Jr.
    Al-Chalabi, Ammar
    Silani, Vincenzo
    Shaw, Christopher E.
    van den Berg, Leonard H.
    Veldink, Jan H.
    Landers, John E.
    D'Alfonso, Sandra
    Mazzini, Letizia
    Comi, Giacomo P.
    Del Bo, Roberto
    Ceroni, Mauro
    Gagliardi, Stella
    Querin, Giorgia
    Bertolin, Cinzia
    Pensato, Viviana
    Castellotti, Barbara
    Corti, Stefania
    Cereda, Cristina
    Corrado, Lucia
    Soraru, Gianni
    NEK1 variants confer susceptibility to amyotrophic lateral sclerosis2016Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, nr 9, s. 1037-1042Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261 His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261 His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.

  • 320.
    Keskin, Isil
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    SOD, ORF and ALS: On the role of SOD1 and C9ORF72 in the pathogenesis of ALS2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is characterized by adult-onset degeneration of upper and lower motor neurons. Symptoms begin focally in one muscle and then spread contiguously, resulting in progressive paralysis and death from respiratory failure. Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause, however, mutations in SOD1 were the first identified and are found in 1-9% of patients. Misfolded SOD1 aggregates in the CNS are hallmarks of ALS associated with SOD1 mutations. However, accumulation of misfolded or aggregated SOD1 protein has also been reported in sporadic and familial ALS without SOD1 mutations, suggesting that wild-type SOD1 could play a role in ALS pathology in general.

    The aims of this thesis are: 1) To describe the resulting disease phenotype and specific characteristics of the SOD1 protein carrying the stable disease- associated mutation L117V. 2) To set up cell-based in vitro models to study the mechanisms of SOD1 misfolding and aggregation under physiologically relevant expression levels. 3) To compare SOD1 activity in patient-derived samples and screen for underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations.

    1) We identified a novel L117V SOD1 mutant in two families of Syrian origin that co-segregated with the disease. This mutation was associated with slow disease progression, reduced penetrance and a uniform phenotype. The L117V mutant protein was indistinguishable from wild-type SOD1 in terms of stability, dismutation activity and misfolding in patient-derived cell lines.

    2) We established patient-derived fibroblast and iPSC-MN lines expressing mutant SOD1 at physiological levels as in vitro models to study misfolding and aggregation of SOD1. We investigated the effects of several cellular pathway disturbances on SOD1 misfolding. Misfolded SOD1 was increased by inhibition of the ubiquitin-proteasome pathway in fibroblasts derived from both patients and controls. An age-related decline in proteasome activity could contribute to the late onset of ALS.

    Next, we studied the effects of low oxygen tension on misfolding and aggregation of SOD1 in patient-derived cells. Low O2 tensions were found to markedly increase C57-C146 disulphide reduction, misfolding and aggregation of SOD1. Importantly, the largest effects were detected in iPSC-MNs. This suggests that motor neurons are specifically vulnerable to misfolding and aggregation of SOD1 under low O2 tension.

    3) We compared the enzymatic activity of SOD1 in blood samples from a large number of ALS patients and controls. We screened for potential underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations. No aberrations in copy number, other large structural changes in introns and exons or intronic mutations in the 30-50 bp flanking the exons were found in the 142 outliers, with either very low or very high SOD1 dismutation activities. However, hemoglobinopathies, including thalassemias and iron deficiency anemia, were associated with high SOD1/mg Hb ratios. Erythrocytes from patients with destabilizing SOD1 mutations showed half the normal activity. There were no significant differences in SOD1 activity between control individuals and ALS patients without a coding SOD1 mutation, or carriers of TBK1 mutations or the hexanucleotide repeat expansion in C9ORF72. Our result suggests that SOD1 enzymatic activity is not associated with the disease in non-SOD1 mutation ALS.

  • 321.
    Keskin, Isil
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Birve, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Berdynski, Mariusz
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap. Polish Academy of Sciences, Warsaw, Poland.
    Hjertkvist, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Rofougaran, Reza
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Nilsson, Torbjörn K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Glass, Jonathan D.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Comprehensive analysis to explain reduced or increased SOD1 enzymatic activity in ALS patients and their relatives2017Inngår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 18, nr 5-6, s. 457-463Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To characterise stabilities in erythrocytes of mutant SOD1 proteins, compare SOD1 enzymatic activities between patients with different genetic causes of ALS and search for underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations.Methods: Blood samples from 4072 individuals, ALS patients with or without a SOD1 mutation, family members and controls were studied. Erythrocyte SOD1 enzymatic activities normalised to haemoglobin content were determined, and effects of haemoglobin disorders on dismutation assessed. Coding SOD1 sequences were analysed by Sanger sequencing, exon copy number variations by fragment length analysis and by TaqMan Assay.Results: Of the 44 SOD1 mutations found, 75% caused severe destabilisation of the mutant protein but in 25% it was physically stable. Mutations producing structural changes caused halved erythrocyte SOD1 activities. There were no differences in SOD1 activities between patients without a SOD1 mutation and control individuals or carriers of TBK1 mutations and C9orf72(HRE). In the low and high SOD1 activity groups no deviations were found in exon copy numbers and intron gross structures. Thalassemias and iron deficiency were associated with increased SOD1 activity/haemoglobin ratios.Conclusion: Adjunct erythrocyte SOD1 activity analysis reliably signals destabilising SOD1 mutations including intronic mutations that are missed by exon sequencing.

  • 322.
    Keskin, Isil
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Birve, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Berdynski, Mariusz
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Hjertkvist, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Rofougaran, Reza
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Nilsson, Torbjörn K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Glass, Jonathan D.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Comprehensive analysis to explain reduced or increased SOD1 enzymatic activity in erythrocytes in ALS patients and their relativesManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Our objective was to in blood samples from 3723 individuals including ALS patients without a coding SOD1 mutation and 372 control individuals characterize stabilities of mutant SOD1s, compare SOD1 enzymatic activities between patients with different genetic causes of ALS, and search for underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations. Erythrocyte SOD1 enzymatic activities normalized to hemoglobin content were determined. Coding SOD1 sequences were analyzed by Sanger sequencing, copy number variations by fragment length analysis and by TaqMan Assay. Hemoglobin disorders were searched for. Of the 46 SOD1 mutations found, ¾ caused severe destabilization of the mutant protein but in ¼ SOD1 was essentially physically stable. Mutations producing structural changes all caused halved SOD activities. There were no differences in SOD1 activities between controls and patients without any detected SOD1 mutations or patients with C9ORF72HRE or TBK1 mutations. In the low and high SOD1 activity groups no deviations were found in exon copy numbers and intron gross structures. Also, no uncommon variants in exon-flanking sequences were detected. Thalassemias and iron deficiency anemia were associated with increased SOD1 activity/hemoglobin ratios. In conclusion, adjunct erythrocyte SOD activity analysis is of value to signal the presence of exon and splice-site-intron mutations that influence the SOD1 structure.

  • 323.
    Keskin, Isil
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Forsgren, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Lange, Dale J.
    Synofzik, Matthis
    Nordström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Zetterström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Gilthorpe, Jonathan D.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Low oxygen tension induces misfolding and aggregation of superoxide dismutase in ALS patient-derived motor neuronsManuskript (preprint) (Annet vitenskapelig)
  • 324.
    Keskin, Isil
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Forsgren, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Lange, Dale J.
    Weber, Markus
    Birve, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Synofzik, Matthis
    Gilthorpe, Jonathan D.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Effects of Cellular Pathway Disturbances on Misfolded Superoxide Dismutase-1 in Fibroblasts Derived from ALS Patients2016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 2, artikkel-id e0150133Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mutations in superoxide dismutase-1 (SOD1) are a common known cause of amyotrophic lateral sclerosis (ALS). The neurotoxicity of mutant SOD1s is most likely caused by misfolded molecular species, but disease pathogenesis is still not understood. Proposed mechanisms include impaired mitochondrial function, induction of endoplasmic reticulum stress, reduction in the activities of the proteasome and autophagy, and the formation of neurotoxic aggregates. Here we examined whether perturbations in these cellular pathways in turn influence levels of misfolded SOD1 species, potentially amplifying neurotoxicity. For the study we used fibroblasts, which express SOD1 at physiological levels under regulation of the native promoter. The cells were derived from ALS patients expressing 9 different SOD1 mutants of widely variable molecular characteristics, as well as from patients carrying the GGGGCC-repeat-expansion in C9orf72 and from non-disease controls. A specific ELISA was used to quantify soluble, misfolded SOD1, and aggregated SOD1 was analysed by western blotting. Misfolded SOD1 was detected in all lines. Levels were found to be much lower in non-disease control and the non-SOD1 C9orf72 ALS lines. This enabled us to validate patient fibroblasts for use in subsequent perturbation studies. Mitochondrial inhibition, endoplasmic reticulum stress or autophagy inhibition did not affect soluble misfolded SOD1 and in most cases, detergent-resistant SOD1 aggregates were not detected. However, proteasome inhibition led to uniformly large increases in misfolded SOD1 levels in all cell lines and an increase in SOD1 aggregation in some. Thus the ubiquitin-proteasome pathway is a principal determinant of misfolded SOD1 levels in cells derived both from patients and controls and a decline in activity with aging could be one of the factors behind the mid-to late-life onset of inherited ALS.

  • 325.
    Keskin, Isil
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Forsgren, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Lehmann, Manuela
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lange, Dale J.
    Synofzik, Matthis
    Nordström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Zetterström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Gilthorpe, Jonathan D.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension2019Inngår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mutations in superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS). Disease pathogenesis is linked to destabilization, disorder and aggregation of the SOD1 protein. However, the non-genetic factors that promote disorder and the subsequent aggregation of SOD1 have not been studied. Mainly located to the reducing cytosol, mature SOD1 contains an oxidized disulfide bond that is important for its stability. Since O2 is required for formation of the bond, we reasoned that low O2 tension might be a risk factor for the pathological changes associated with ALS development. By combining biochemical approaches in an extensive range of genetically distinct patient-derived cell lines, we show that the disulfide bond is an Achilles heel of the SOD1 protein. Culture of patient-derived fibroblasts, astrocytes, and induced pluripotent stem cell-derived mixed motor neuron and astrocyte cultures (MNACs) under low oxygen tensions caused reductive bond cleavage and increases in disordered SOD1. The effects were greatest in cells derived from patients carrying ALS-linked mutations in SOD1. However, significant increases also occurred in wild-type SOD1 in cultures derived from non-disease controls, and patients carrying mutations in other common ALS-linked genes. Compared to fibroblasts, MNACs showed far greater increases in SOD1 disorder and even aggregation of mutant SOD1s, in line with the vulnerability of the motor system to SOD1-mediated neurotoxicity. Our results show for the first time that O2 tension is a principal determinant of SOD1 stability in human patient-derived cells. Furthermore, we provide a mechanism by which non-genetic risk factors for ALS, such as aging and other conditions causing reduced vascular perfusion, could promote disease initiation and progression.

  • 326. Khademi, Mohsen
    et al.
    Dring, Ann
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Gilthorpe, Jonathan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Wuolikainen, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Al Nimer, Faiez
    Harris, Robert
    Andersson, Magnus
    Brundin, Lou
    Piehl, Fredrik
    Olsson, Tomas
    Svenningsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Multivariate analysis of inflammatory and neuronal injury markers in cerebrospinal fluid of multiple sclerosis: higher levels are associated with younger age2012Inngår i: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 253, nr 1-2, s. 100-100Artikkel i tidsskrift (Annet vitenskapelig)
  • 327. Khademi, Mohsen
    et al.
    Dring, Ann M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Gilthorpe, Jonathan D.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Wuolikainen, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Al Nimer, Faiez
    Harris, Robert A.
    Andersson, Magnus
    Brundin, Lou
    Piehl, Fredrik
    Olsson, Tomas
    Svenningsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Intense Inflammation and Nerve Damage in Early Multiple Sclerosis Subsides at Older Age: A Reflection by Cerebrospinal Fluid Biomarkers2013Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 5, s. e63172-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Inflammatory mediators have crucial roles in leukocyte recruitment and subsequent central nervous system (CNS) neuroinflammation. The extent of neuronal injury and axonal loss are associated with the degree of CNS inflammation and determine physical disability in multiple sclerosis (MS). The aim of this study was to explore possible associations between a panel of selected cerebrospinal fluid biomarkers and robust clinical and demographic parameters in a large cohort of patients with MS and controls (n = 1066) using data-driven multivariate analysis. Levels of matrix metalloproteinase 9 (MMP9), chemokine (C-X-C motif) ligand 13 (CXCL13), osteopontin (OPN) and neurofilament-light chain (NFL) were measured by ELISA in 548 subjects comprising different MS subtypes (relapsing-remitting, secondary progressive and primary progressive), clinically isolated syndrome and persons with other neurological diseases with or without signs of inflammation/infection. Principal component analyses and orthogonal partial least squares methods were used for unsupervised and supervised interrogation of the data. Models were validated using data from a further 518 subjects in which one or more of the four selected markers were measured. There was a significant association between increased patient age and lower levels of CXCL13, MMP9 and NFL. CXCL13 levels correlated well with MMP9 in the younger age groups, but less so in older patients, and after approximately 54 years of age the levels of CXCL13 and MMP9 were consistently low. CXCL13 and MMP9 levels also correlated well with both NFL and OPN in younger patients. We demonstrate a strong effect of age on both inflammatory and neurodegenerative biomarkers in a large cohort of MS patients. The findings support an early use of adequate immunomodulatory disease modifying drugs, especially in younger patients, and may provide a biological explanation for the relative inefficacy of such treatments in older patients at later disease stages.

  • 328. Khoo, Sok Kean
    et al.
    Petillo, David
    Kang, Un Jung
    Resau, James H.
    Berryhill, Brian
    Linder, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Neuman, Leslie A.
    Tan, Aik Choon
    Plasma-Based Circulating MicroRNA Biomarkers for Parkinson's Disease2012Inngår i: Journal of Parkinson's Disease, ISSN 1877-7171, Vol. 2, nr 4, s. 321-331Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The current "gold-standard" for Parkinson's disease (PD) diagnosis is based primarily on subjective clinical rating scales related with motor features. Molecular biomarkers that are objective and quantifiable remain attractive as clinical tools to detect PD prior to its motor onsets.

    Objective: Here, we aimed to identify, develop, and validate plasma-based circulating microRNA (miRNAs) as biomarkers for PD.

    Methods: Global miRNA expressions were acquired from a discovery set of 32 PD/32 controls using microarrays. k-Top Scoring Pairs (k-TSP) algorithm and significance analysis of microarrays (SAM) were applied to obtain comprehensive panels of PD-predictive biomarkers. TaqMan miRNA-specific real-time PCR assays were performed to validate the microarray data and to evaluate the biomarker performance using a new replication set of 42 PD/30 controls. Data was analyzed in a paired PD-control fashion. The validation set was composed of 30 PD, 5 progressive supranuclear palsy, and 4 multiple system atrophy samples from a new clinical site.

    Results: We identified 9 pairs of PD-predictive classifiers using k-TSP analysis and 13 most differentially-expressed miRNAs by SAM. A combination of both data sets produced a panel of PD-predictive biomarkers: k-TSP1 (miR-1826/miR-450b-3p), miR-626, and miR-505, and achieved the highest predictive power of 91% sensitivity, 100% specificity, 100% positive predicted value, and 88% negative predicted value in the replication set. However, low predictive values were shown in the validation set.

    Conclusions: This proof-of-concept study demonstrates the feasibility of using plasma-based circulating miRNAs as biomarkers for neurodegenerative disorders such as PD and shows the challenges of molecular biomarker research using samples from multiple clinical sites.

  • 329.
    Koskinen, Lars-Owe D.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Blomstedt, Patric
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Sjöberg, Rickard L.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Predicting improvement after surgery for palmar hyperhidrosis2012Inngår i: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 126, nr 5, s. 324-328Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives Endoscopic transthoracic sympathectomy (ETS) is a surgical procedure used to improve Quality of Life (QoL) in patients with treatment resistant palmar hyperhidrosis (PHH). The aim of this study was to test the hypothesis that low preoperative scores on The Everyday Life Questionnaire (EDLQ) would predict QoL improvement after surgery. Materials and methods Pre- and post-operative QoL scores from a series of 30 consecutive patients who underwent ETS at our institution were analyzed. Results Preoperative QoL scores was a significant predictor of post-operative improvement across all dimensions covered by the questionnaire. Conclusion Preoperative low QoL can be used as a guide in selecting patients with most improved QoL after ETS.

  • 330.
    Koskinen, Lars-Owe D.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Eklund, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Sundström, Nina
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Olivecrona, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Prostacyclin Influences the Pressure Reactivity in Patients with Severe Traumatic Brain Injury Treated with an ICP-Targeted Therapy2015Inngår i: Neurocritical Care, ISSN 1541-6933, E-ISSN 1556-0961, Vol. 22, nr 1, s. 26-33Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This prospective consecutive double-blinded randomized study investigated the effect of prostacyclin on pressure reactivity (PR) in severe traumatic brain injured patients. Other aims were to describe PR over time and its relation to outcome. Blunt head trauma patients, Glasgow coma scale a parts per thousand currency sign8, age 15-70 years were included and randomized to prostacyclin treatment (n = 23) or placebo (n = 25). Outcome was assessed using the extended Glasgow outcome scale (GOSE) at 3 months. PR was calculated as the regression coefficient between the hourly mean values of ICP versus MAP. Pressure active/stable was defined as PR a parts per thousand currency sign0. Mean PR over 96 h (PRtot) was 0.077 +/- A 0.168, in the prostacyclin group 0.030 +/- A 0.153 and in the placebo group 0.120 +/- A 0.173 (p < 0.02). There was a larger portion of pressure-active/stable patients in the prostacyclin group than in the placebo group (p < 0.05). Intra-individual changes over time were common. PRtot correlated negatively with GOSE score (p < 0.04). PRtot was 0.117 +/- A 0.182 in the unfavorable (GOSE 1-4) and 0.029 +/- A 0.140 in the favorable outcome group (GOSE 5-8). Area under the curve for prediction of death (ROC) was 0.742 and for favorable outcome 0.628. Prostacyclin influenced the PR in a direction of increased pressure stability and a lower PRtot was associated with improved outcome. The individual PR varied substantially over time. The predictive value of PRtot for outcome was not solid enough to be used in the clinical situation.

  • 331.
    Koskinen, Lars-Owe D.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Grayson, David
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Olivecrona, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    The complications and the position of the Codman MicroSensor (TM) ICP device: an analysis of 549 patients and 650 Sensors2013Inngår i: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 155, nr 11, s. 2141-2148Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Complications of and insertion depth of the Codman MicroSensor ICP monitoring device (CMS) is not well studied. To study complications and the insertion depth of the CMS in a clinical setting. We identified all patients who had their intracranial pressure (ICP) monitored using a CMS device between 2002 and 2010. The medical records and post implantation computed tomography (CT) scans were analyzed for occurrence of infection, hemorrhage and insertion depth. In all, 549 patients were monitored using 650 CMS. Mean monitoring time was 7.0 +/- 4.9 days. The mean implantation depth was 21.3 +/- 11.1 mm (0-88 mm). In 27 of the patients, a haematoma was identified; 26 of these were less than 1 ml, and one was 8 ml. No clinically significant bleeding was found. There was no statistically significant increase in the number of hemorrhages in presumed coagulopathic patients. The infection rate was 0.6 % and the calculated infection rate per 1,000 catheter days was 0.8. The risk for hemorrhagic and infectious complications when using the CMS for ICP monitoring is low. The depth of insertion varies considerably and should be taken into account if patients are treated with head elevation, since the pressure is measured at the tip of the sensor. To meet the need for ICP monitoring, an intraparenchymal ICP monitoring device should be preferred to the use of an external ventricular drainage (EVD).

  • 332.
    Koskinen, Lars-Owe D.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Malm, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Zakelis, Rolandas
    Bartusis, Laimonas
    Ragauskas, Arminas
    Eklund, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Can intracranial pressure be measured non-invasively bedside using a two-depth Doppler-technique?2017Inngår i: Journal of clinical monitoring and computing, ISSN 1387-1307, E-ISSN 1573-2614, Vol. 31, nr 2, s. 459-467Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Measurement of intracranial pressure (ICP) is necessary in many neurological and neurosurgical diseases. To avoid lumbar puncture or intracranial ICP probes, non-invasive ICP techniques are becoming popular. A recently developed technology uses two-depth Doppler to compare arterial pulsations in the intra- and extra-cranial segments of the ophthalmic artery for non-invasive estimation of ICP. The aim of this study was to investigate how well non-invasively-measured ICP and invasively-measured cerebrospinal fluid (CSF) pressure correlate. We performed multiple measurements over a wide ICP span in eighteen elderly patients with communicating hydrocephalus. As a reference, an automatic CSF infusion apparatus was connected to the lumbar space. Ringer's solution was used to create elevation to pre-defined ICP levels. Bench tests of the infusion apparatus showed a random error (95 % CI) of less than ±0.9 mmHg and a systematic error of less than ±0.5 mmHg. Reliable Doppler signals were obtained in 13 (72 %) patients. An infusion test could not be performed in one patient. Thus, twelve patients and a total of 61 paired data points were studied. The correlation between invasive and non-invasive ICP measurements was good (R = 0.74), and the 95 % limits of agreements were -1.4 ± 8.8 mmHg. The within-patient correlation varied between 0.47 and 1.00. This non-invasive technique is promising, and these results encourage further development and evaluation before the method can be recommended for use in clinical practice.

  • 333.
    Koskinen, Lars-Owe D.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Runnerstam, Magnus
    Koch, Mona
    FOI, Swedish Defence Research Agency, SE-901 82 Umeå, Sweden.
    Karlsson, Britt M.
    FOI, Swedish Defence Research Agency, SE-901 82 Umeå, Sweden.
    Cerebral microvascular effects of nimodipine in combination with soman2012Inngår i: Environmental Toxicology and Pharmacology, ISSN 1382-6689, E-ISSN 1872-7077, Vol. 34, nr 3, s. 905-910Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Nimodipine, a calcium antagonist, has been shown to increase the detoxification of soman. In this study the cerebral microcirculatory effects of nimodipine and the acetylcholinesterase inhibitor soman was studied. Anaesthetised rats were administered nimodipine, 10 mg kg(-1) or vehicle intra-peritoneally, and 1 h later exposed to 45 mu g kg(-1) soman intravenously. The regional blood flows were measured using the microsphere method. Nimodipine and soman markedly increased the cerebral blood flow (CBF) and reduced the vascular resistance. Total CBF increased by 146% after nimodipine and by 105% after soman administration. Combined administration of nimodipine and soman caused additional but not fully additive effects on CBF and vascular resistance, indicating possible different mechanisms of the two agents. A part of the nimodipine induced increased detoxification after AChE-inhibition may be associated with this cerebral vasodilation. (C) 2012 Elsevier B.V. All rights reserved.

  • 334.
    Koskinen, Lars-Owe D.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Sundström, Nina
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Hägglund, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Eklund, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Olivecrona, Magnus
    The relation between brain interstitial clycerol and pressure reactivity in TBI is prostacyclin dependent2018Inngår i: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, nr 16, s. A185-A185Artikkel i tidsskrift (Annet vitenskapelig)
  • 335.
    Koskinen, Lars-owe
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Naredi, Silvana
    Olivecrona, Magnus
    Ten-year follow-up of patients in a double blinded randomized study on prostacyclin treatment in severe traumatic brain injury2017Inngår i: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 31, nr 6-7, s. 770-771Artikkel i tidsskrift (Annet vitenskapelig)
  • 336.
    Koskinen, Lars-Owe
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Olivecrona, Magnus
    Department of Anaesthesia and Intensive Care, University of Örebro, Sweden.
    Grande, P. O.
    Department of Clinical Science in Lund, Anaesthesia and Intensive Care, Lund University, Sweden.
    Severe traumatic brain injury management and clinical outcome using the Lund concept2014Inngår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 283, s. 245-255Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    This review covers the main principles of the Lund concept for treatment of severe traumatic brain injury. This is followed by a description of results of clinical studies in which this therapy or a modified version of the therapy has been used. Unlike other guidelines, which are based on meta-analytical approaches, important components of the Lund concept are based on physiological mechanisms for regulation of brain volume and brain perfusion and to reduce transcapillary plasma leakage and the need for plasma volume expanders. There have been nine non-randomized and two randomized outcome studies with the Lund concept or modified versions of the concept. The non-randomized studies indicated that the Lund concept is beneficial for outcome. The two randomized studies were small but showed better outcome in the groups of patients treated according to the modified principles of the Lund concept than in the groups given a more conventional treatment. This article is part of a Special Issue entitled: Brain compensation. For good?. (C) 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  • 337.
    Kotikawatte, Thivra
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Suppression of Mu waves in the motor cortex during visualisation of right hand movement2016Independent thesis Basic level (professional degree), 20 poäng / 30 hpOppgave
  • 338.
    Kristensen, Bo Traberg
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Stroke in young adults in northern Sweden1998Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Objectives. To study different aspects of cerebral venous and arterial occlusive disease including cerebrospinalfluid hydrodynamics, epidemiology, aetiology, genetics, metabolic and haemostatic disorders, andcognitive function in young adults in Northern Sweden.

    Methods. Cerebrospinal fluid hydrodynamics were investigated with a constant pressure infusion methodin patients with superior sagittal sinus thrombosis. Ten patients were studied with serial examinations, upto 15 years after the onset of the disease.

    Epidemiological data on ischaemic stroke in young adults aged 18 to 44 years were collected to calculateincidence and mortality based on the WHO Northern Sweden MONICA register of acute strokeevents. One hundred and seven consecutive patients aged 18-44 years with ischaemic stroke referred toUmeå university hospital were studied prospectively during a five-year period and were extensively evaluatedaccording to a standardized protocol. During follow-up at least three months after onset 102 and 80patients, respectively, were evaluated for disturbances in the fibrinolytic system and in the metabolism ofhomocysteine. A comprehensive neuropsychological battery was performed in a subset of 20 patients withinfratentorial infarcts.

    Results and conclusions. All patients with superior sagittal sinus thrombosis demonstrated a marked increasein intracranial pressure due to raised pressure in the sagittal sinus. A striking feature was the persistentintracranial pressure increase with only a slow decline over time.

    The incidence rate for ischaemic stroke was higher than previously reported from most countries inWestern Europe. The higher incidence was not explained by a higher prevalence of atherosclerotic vasculopathy. In spite of extensive evaluation, including advanced cardiac imaging, the cause of ischaemic strokein young adults still remains uncertain or unknown in most cases.

    Patients had lowered tissue plasminogen activator activity and increased plasminogen activator inhibitortype 1 activity. Increased fibrinogen levels and tissue plasminogen activator mass concentration wereindependently associated with ischaemic stroke. Metabolic perturbations were closely interrelated with tissueplasminogen activator and plasminogen activator inhibitor type 1 activity. Elevated plasma fibrinogenlevels and abnormalities in the fibrinolytic system in conjunction with metabolic perturbations may be importantcontributors to an increased stroke risk among young adults.

    Stroke patients had an exaggerated increase in total homocysteine levels after methionine loading.Abnormal responsivity to methionine loading was associated with higher tissue plasminogen activatormass concentration, plasminogen activator inhibitor 1 levels and lower tissue plasminogen activator activity. Abnormal homocysteine metabolism may provide an additional thrombogenetic risk, partly mediatedby interactions with the fibrinolytic system.

    Circumscribed infratentorial lesions (mainly cerebellar) impaired central aspects of attention andworking memory, and inflicted damage upon visuospatial skills. In contrast, these patients may not sufferfrom global intellectual impairment and difficulties with respect to memory for previous events. The prognosisis favorable in terms of neurological deficits and handicap, but cognitive disability may be the mostsignificant problem in adapting to their former occupations.Key w ords. Cerebral venous thrombosis, cerebrospinal fluid dynamics, ischaemic stroke, young adults, epidemiology,fibrinolysis, homocysteine, cerebellar infarct, neuropsychology.

  • 339. Kristian, B.
    et al.
    Wachtmeister, K.
    Stefan, F.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Retigabine as add-on treatment of refractory epilepsy a cost-utility study in a Swedish setting2013Inngår i: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 127, nr 6, s. 419-426Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives To calculate comparative incremental cost-effectiveness ratios (cost per quality-adjusted life year, QALY) and net marginal benefits for retigabine as add-on treatment for patients with uncontrolled focal seizures as compared to add-on lacosamide treatment and no add-on treatment, respectively. Materials & Methods Calculations were performed using a validated decision-tree model. The study population consisted of adult patients with focal-onset epilepsy in published randomized placebo-controlled add-on trials of retigabine or lacosamide. Healthcare utilization and QALY for each treatment alternative were calculated. Probabilistic sensitivity analysis was performed using the specification of this model as a basis for Monte Carlo simulations. 2009 prices were used for all costs. Results Results were reported for a 2-year follow-up period. Retigabine add-on treatment was both more effective and less costly than lacosamide add-on treatment, and the cost per additional QALY for the retigabine no add-on (standard) therapy comparison was estimated at 2009Euro 15,753. Using a willingness-to-pay threshold for a QALY of Euro 50,000, the net marginal values were estimated at 2009Euro 605,874 for retigabine vs lacosamide and 2009Euro 2,114,203 for retigabine vs no add-on, per 1,000 patients. The probabilistic analyses showed that the likelihood that retigabine treatment is cost-effective is at least 70%. Conclusions The estimated cost per additional QALY, for the retigabine vs no add-on treatment comparison, is well within the range of newly published estimates of willingness to pay for an additional QALY. Thus, add-on retigabine treatment for people with focal-onset epilepsy with no/limited response to standard antiepileptic treatment appears to be cost-effective.

  • 340. Kurowska, Zuzanna
    et al.
    Jewett, Michael
    Brattås, Per Ludvik
    Jimenez-Ferrer, Itzia
    Kenez, Xuyian
    Björklund, Tomas
    Nordström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Brundin, Patrik
    Swanberg, Maria
    Identification of Multiple QTLs Linked to Neuropathology in the Engrailed-1 Heterozygous Mouse Model of Parkinson's Disease2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 31701Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Motor symptoms in Parkinson's disease are attributed to degeneration of midbrain dopaminergic neurons (DNs). Heterozygosity for Engrailed-1 (En1), one of the key factors for programming and maintenance of DNs, results in a parkinsonian phenotype featuring progressive degeneration of DNs in substantia nigra pars compacta (SNpc), decreased striatal dopamine levels and swellings of nigro-striatal axons in the SwissOF1-En1+/- mouse strain. In contrast, C57Bl/6-En1+/- mice do not display this neurodegenerative phenotype, suggesting that susceptibility to En1 heterozygosity is genetically regulated. Our goal was to identify quantitative trait loci (QTLs) that regulate the susceptibility to PD-like neurodegenerative changes in response to loss of one En1 allele. We intercrossed SwissOF1-En1+/- and C57Bl/6 mice to obtain F2 mice with mixed genomes and analyzed number of DNs in SNpc and striatal axonal swellings in 120 F2-En1+/- 17 week-old male mice. Linkage analyses revealed 8 QTLs linked to number of DNs (p = 2.4e-09, variance explained = 74%), 7 QTLs linked to load of axonal swellings (p = 1.7e-12, variance explained = 80%) and 8 QTLs linked to size of axonal swellings (p = 7.0e-11, variance explained = 74%). These loci should be of prime interest for studies of susceptibility to Parkinson's disease-like damage in rodent disease models and considered in clinical association studies in PD.

  • 341.
    Lagebrant, Marcus
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Choice of treatment of subdural hematomas in shunted hydrocephalus patients2016Independent thesis Basic level (professional degree), 20 poäng / 30 hpOppgave
  • 342.
    Lampa, Ewa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Wänman, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Nordh, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Häggman-Henrikson, Birgitta
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Department of Orofacial pain and Jaw function, Malmö University, Malmö, Sweden.
    Effects on jaw function shortly after whiplash trauma2017Inngår i: Journal of Oral Rehabilitation, ISSN 0305-182X, E-ISSN 1365-2842, Vol. 44, nr 12, s. 941-947Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Normal jaw function involves muscles and joints of both jaw and neck. A whiplash trauma may disturb the integrated jaw-neck sensory-motor function and thereby impair chewing ability; however, it is not known if such impairment is present shortly after a neck trauma or develops over time. The aim was to evaluate jaw function after a recent whiplash trauma. Eighty cases (47 women) were examined within 1 month after a whiplash trauma and compared to 80 controls (47 women) without neck trauma. Participants completed the Jaw disability checklist (JDC) and Neck Disability Index (NDI) questionnaires and performed a 5-minute chewing test. Elicited fatigue and pain during chewing were noted, and group differences were evaluated with Fisher's exact test and Mann-Whitney U-test. Compared to controls, cases had higher JDC (P<.0001) and NDI scores (15% vs 2%, P<.0001), and reported more fatigue (53% vs 31%, P=.006) and pain (30% vs 10%, P=.003) during the chewing test. Cases also had a shorter onset time for fatigue and pain (both P=.001) Furthermore, cases reporting symptoms during chewing had higher JDC and NDI scores compared to cases not reporting symptoms (both P=.01). Symptoms mainly occurred in the trigeminal area for both groups, but also in spinal areas more often for cases than for controls. Taken together, the results indicate that jaw-neck sensory-motor function is impaired already within 1month after a whiplash trauma. The association between neck disability and jaw impairment underlines the close functional relationship between the regions, and stresses the importance of multidisciplinary assessment.

  • 343.
    Lampa, Ewa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Wänman, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Nordh, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Stålnacke, Britt-Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Rehabiliteringsmedicin.
    Häggman-Henrikson, Birgitta
    The Course of Orofacial Pain and Jaw Disability after Whiplash Trauma: A 2-year Prospective StudyManuskript (preprint) (Annet vitenskapelig)
  • 344. Lange, Dale J.
    et al.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Remanan, Rahul
    Marklund, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Benjamin, Daniel
    Pyrimethamine decreases levels of SOD1 in leukocytes and cerebrospinal fluid of ALS patients: A phase I pilot study2013Inngår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, Vol. 14, nr 3, s. 199-204Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mutated SOD1 protein appears to have a gene dose-dependent effect on the severity and progression of ALS. Lowering of SOD1 protein levels might reduce severity and progression of the disease. The antimalarial drug pyrimethamine (PYR) was identified to cause a dose-dependent reduction in SOD1 protein levels in human cells in vitro. To determine if there was a similar effect in humans, we performed a phase I pilot study in 16 ALS patients with SOD1 mutations, 18 weeks in duration. Blood samples were obtained during all visits. The actin normalized leukocyte SOD1 levels were analyzed using Western blot. SOD1 content in the cerebrospinal fluid (CSF) was determined by ELISA and the SOD1 enzymic activity by spectrophotometric analysis using KO2. Clinical assessment of disease severity was assessed using Appel ALS scale and ALSFRS-R. The leukocyte SOD1 levels showed a significant reduction (p < 0.0001) by the third study visit and this reduction was sustained throughout the remainder of the study. CSF also showed a decrease in SOD1 protein content and enzymic activity in the two patients so tested. Thus, PYR use may be associated with a reduction in SOD1 in ALS patients. The significance is uncertain and further detailed study is required.

  • 345. Lange, Dale J.
    et al.
    Shahbazi, Mona
    Silani, Vincenzo
    Ludolph, Albert C.
    Weishaupt, Jochen H.
    Ajroud-Driss, Senda
    Fields, Kara G.
    Remanan, Rahul
    Appel, Stanley H.
    Morelli, Claudia
    Doretti, Alberto
    Maderna, Luca
    Messina, Stefano
    Weiland, Ulrike
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap. Department of Neurology, Ulm University, Ulm, Germany.
    Pyrimethamine Significantly Lowers Cerebrospinal Fluid Cu/Zn Superoxide Dismutase in Amyotrophic Lateral Sclerosis Patients with SOD1 Mutations2017Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 81, nr 6, s. 837-848Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Cu/Zn superoxide dismutase (SOD1) reduction prolongs survival in SOD1-transgenic animal models. Pyrimethamine produces dose-dependent SOD1 reduction in cell culture systems. A previous phase 1 trial showed pyrimethamine lowers SOD1 levels in leukocytes in patients with SOD1 mutations. This study investigated whether pyrimethamine lowered SOD1 levels in the cerebrospinal fluid (CSF) in patients carrying SOD1 mutations linked to familial amyotrophic lateral sclerosis (fALS/SOD1). Methods: A multicenter (5 sites), open-label, 9-month-duration, dose-ranging study was undertaken to determine the safety and efficacy of pyrimethamine to lower SOD1 levels in the CSF in fALS/SOD1. All participants underwent 3 lumbar punctures, blood draw, clinical assessment of strength, motor function, quality of life, and adverse effect assessments. SOD1 levels were measured in erythrocytes and CSF. Pyrimethamine was measured in plasma and CSF. Appel ALS score, ALS Functional Rating Scale-Revised, and McGill Quality of Life Single-Item Scale were measured at screening, visit 6, and visit 9. Results: We enrolled 32 patients; 24 completed 6 visits (18 weeks), and 21 completed all study visits. A linear mixed effects model showed a significant reduction in CSF SOD1 at visit 6 (p<0.001) with a mean reduction of 13.5% (95% confidence interval [CI] 58.4-18.5) and at visit 9 (p<0.001) with a mean reduction of 10.5% (95% CI55.2-15.8). Interpretation: Pyrimethamine is safe and well tolerated in ALS. Pyrimethamine is capable of producing a significant reduction in total CSF SOD1 protein content in patients with ALS caused by different SOD1 mutations. Further long-term studies are warranted to assess clinical efficacy.

  • 346.
    Larsson, Jenny
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Israelsson, Hanna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Eklund, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Malm, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Epilepsy, headache, and abdominal pain after shunt surgery for idiopathic normal pressure hydrocephalus: the INPH-CRasH study2018Inngår i: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 128, nr 6, s. 1674-1683Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE Adverse events related to shunt surgery are common and might have a negative effect on outcome in patients with idiopathic normal pressure hydrocephalus (INPH). The authors' objectives were to establish the frequencies of epilepsy, headache, and abdominal pain and determine their impact on patient quality of life (QOL), in long-term follow-up after shunt surgery for INPH.

    METHODS One hundred seventy-six shunt-treated patients with INPH (mean age 74 years) and 368 age- and sex-matched controls from the population were included. The mean follow-up time after surgery was 21 months (range 6-45 months). Each participant answered a questionnaire regarding present frequency and severity of headache and abdominal pain. Confirmed diagnoses of epilepsy and all prescriptions for antiepileptic drugs (AEDs) before and after shunt surgery for INPH were gathered from national registries. Equivalent presurgical and postsurgical time periods were constructed for the controls based on the date of surgery (the division date for controls is referred to as virtual surgery). All registry data covered a mean period of 6 years (range 3-8 years) before surgery/virtual surgery and 4 years (range 2-6 years) after surgery/virtual surgery. Provoked epileptic seizures were excluded. Patient QOL was assessed with the EuroQoL 5-dimension 5-level instrument.

    RESULTS Epilepsy was more common in shunt-treated patients with INPH than in controls (4.5% vs 1.1%, respectively; p = 0.023), as was treatment with AEDs (14.8% vs 7.3%, respectively; p = 0.010). No difference was found between the populations before surgery/virtual surgery (epilepsy, 2.3% [INPH] vs 1.1% [control], p = 0.280; AED treatment, 8.5% [INPH] vs 5.4% [control], p = 0.235). New-onset epilepsy and new AED treatment after surgery/virtual surgery were more common in INPH (epilepsy, 2.3% [INPH] vs 0.0% [control], p = 0.011; AED, 8.5% [INPH] vs 3.3% [control], p = 0.015). At follow-up, more patients with INPH than controls experienced headache several times per month or more often (36.1% vs 11.6%, respectively; p < 0.001). Patients with INPH and unilateral headache had more right-sided headaches than controls (p = 0.038). Postural headache was experienced by 16% (n = 27 of 169) of the patients with INPH. Twenty percent (n = 35) of the patients with INPH had persistent abdominal pain. Headache was not correlated to lower QOL. The study was underpowered to draw conclusions regarding QOL in patients with INPH who had epilepsy and abdominal pain, but the finding of no net difference in mean QOL indicates that no correlation between them existed.

    CONCLUSIONS Epilepsy, headache, and abdominal pain are common in long-term follow-up in patients after shunt surgery for INPH and are more common among patients with INPH than in the general population. All adverse events, including mild and moderate ones, should be considered during postoperative follow-ups and in the development of new methods for shunt placement.

  • 347.
    Laurell, Katarina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Artto, Ville
    Bendtsen, Lars
    Hagen, Knut
    Häggström, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Linde, Mattias
    Söderström, Lars
    Tronvik, Erling
    Wessman, Maija
    Zwart, John Anker
    Kallela, Mikko
    Premonitory symptoms in migraine: a cross-sectional study in 2714 persons2016Inngår i: Cephalalgia, ISSN 0333-1024, E-ISSN 1468-2982, Vol. 36, nr 10, s. 951-959Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIM: To describe the frequency and number of premonitory symptoms (PS) in migraine, the co-occurrence of different PS, and their association with migraine-related factors.

    METHODS: In this cross-sectional study, a validated questionnaire was sent to Finnish migraine families between 2002 and 2013 to obtain data on 14 predefined PS, migraine diagnoses, demographic factors, and migraine characteristics. The estimated response rate was 80%.

    RESULTS: Out of 2714 persons, 2223 were diagnosed with migraine. Among these, 77% reported PS, with a mean number of 3.0 symptoms compared to 30% (p < 0.001) and 0.5 symptoms (p < 0.001) among 491 persons with non-migraine headaches. Yawning was the most commonly reported symptom (34%) among migraineurs. Females reported PS more frequently than males (81 versus 64%, p < 0.001) and experienced a higher number of different symptoms (mean 3.3 versus 1.8, p < 0.001). All measures of migraine severity were associated with a higher burden of PS. Light and sound sensitivity showed the highest co-occurrence (kappa = 0.51, 95% CI 0.47-0.55). In a generalized linear model, age, gender, higher frequency, duration and intensity of headache, reduced working capacity, most aura symptoms, and associated symptoms of the headache phase were significantly associated with an increased in the number of PS.

    CONCLUSION: PS are experienced by a majority of migraineurs. More severe migraine is associated with a higher burden of PS. Since the material was not entirely representative of the general population of migraineurs, caution should be exercised in generalizing the results.

  • 348. Lawley, Justin S.
    et al.
    Levine, Benjamin D.
    Williams, Michael A.
    Malm, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Eklund, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Polaner, David M.
    Subudhi, Andrew W.
    Hackett, Peter H.
    Roach, Robert C.
    Cerebral spinal fluid dynamics: effect of hypoxia and implications for high-altitude illness2016Inngår i: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 120, nr 2, s. 251-262Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The pathophysiology of acute mountain sickness and high-altitude cerebral edema, the cerebral forms of high-altitude illness, remain uncertain and controversial. Persistently elevated or pathological fluctuations in intracranial pressure are thought to cause symptoms similar to those reported by individuals suffering cerebral forms of high-altitude illness. This review first focuses on the basic physiology of the craniospinal system, including a detailed discussion of the long-term and dynamic regulation of intracranial pressure. Thereafter, we critically examine the available literature, based primarily on invasive pressure monitoring, that suggests intracranial pressure is acutely elevated at altitude due to brain swelling and/or elevated sagittal sinus pressure, but normalizes over time. We hypothesize that fluctuations in intracranial pressure occur around a slightly elevated or normal mean intracranial pressure, in conjunction with oscillations in arterial PO2 and arterial blood pressure. Then these modest fluctuations in intracranial pressure, in concert with direct vascular stretch due to dilatation and/or increased blood pressure transmission, activate the trigeminal vascular system and cause symptoms of acute mountain sickness. Elevated brain water (vasogenic edema) may be due to breakdown of the blood-brain barrier. However, new information suggests cerebral spinal fluid flux into the brain may be an important factor. Regardless of the source (or mechanisms responsible) for the excess brain water, brain swelling occurs, and a "tight fit" brain would be a major risk factor to produce symptoms; activities that produce large changes in brain volume and cause fluctuations in blood pressure are likely contributing factors.

  • 349.
    Leckstroem, Daniel
    et al.
    London, England.
    Salzer, Jonatan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Goldsmith, David
    London, England.
    The trials and tribulations of vitamin D: time for the ‘sunshine’ vitamin to come in out of the cold – or just more broken promises?2014Inngår i: Expert review of Endocrinology & Metabolism, ISSN 1744-6651, Vol. 9, nr 4, s. 327-344Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We are presently faced with the competing notions of modern life being a ‘state of vitamin D depletion’, implying a widespread need to supplement with vitamin D, or, the opposite view, which is that the present evidence can only support at best selective targeted vitamin D intervention. This is important as there is evidence that over the last 40–50 years there were downwards global trends in serum 25(OH)D concentrations, while individual consumption of vitamin D as supplements rose. For this reason and many others, a large population-based interventional study, the VITAL trial, was designed to try to establish the health value of vitamin D supplementation. VITAL is a huge primary prevention trial looking at the effects of vitamin D repletion in preventing cancer and cardiovascular disease in a fundamentally healthy population. This may seem an unusual approach given that what we mostly know about vitamin D is that is has some effects on the skeleton. This review looks to explore current knowledge about vitamin D in health and disease, and at how this is now undergoing significant reappraisal and revision. We will carefully critique the VITAL study design to see if it will allow for the construction of the detailed portfolio of clinical evidence so urgently needed to allow us better to understand role of vitamin D supplementation in health and disease. 

  • 350. Lee, Teresa
    et al.
    Li, Yun R
    Ingre, Caroline
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Weber, Markus
    Grehl, Torsten
    Gredal, Ole
    de Carvalho, Mamede
    Meyer, Thomas
    Tysnes, Ole-Björn
    Auburger, Georg
    Gispert, Suzana
    Bonini, Nancy M
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Gitler, Aaron D
    Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients2011Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 20, nr 9, s. 1697-1700Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease primarily affecting motor neurons. We recently identified intermediate-length polyglutamine (polyQ) expansions (27-33 Qs) in ataxin 2 as a genetic risk factor for sporadic ALS in North American ALS patients. To extend these findings, we assessed the ataxin 2 polyQ repeat length in 1294 European ALS patients and 679 matched healthy controls. We observed a significant association between polyQ expansions and ALS (>30 Qs; P= 6.2 × 10(-3)). Thus, intermediate-length ataxin 2 polyQ repeat expansions are associated with increased risk for ALS also in the European cohort. The specific polyQ length cutoff, however, appears to vary between different populations, with longer repeat lengths showing a clear association. Our findings support the hypothesis that ataxin 2 plays an important role in predisposing to ALS and that polyQ expansions in ataxin 2 are a significant risk factor for the disease.

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