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  • 1. Akram, Harith
    et al.
    Miller, Sarah
    Lagrata, Susie
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Ashburner, John
    Behrens, Tim
    Matharu, Manjit
    Zrinzo, Ludvic
    Optimal deep brain stimulation site and target connectivity for chronic cluster headache2017In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 89, no 20, p. 2083-2091Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the mechanism of action of deep brain stimulation for refractory chronic cluster headache and the optimal target within the ventral tegmental area. Methods: Seven patients with refractory chronic cluster headache underwent high spatial and angular resolution diffusion MRI preoperatively. MRI-guided and MRI-verified electrode implantation was performed unilaterally in 5 patients and bilaterally in 2. Volumes of tissue activation were generated around active lead contacts with a finite-element model. Twelve months after surgery, voxel-based morphometry was used to identify voxels associated with higher reduction in headache load. Probabilistic tractography was used to identify the brain connectivity of the activation volumes in responders, defined as patients with a reduction of >= 30% in headache load. Results: There was no surgical morbidity. Average follow-up was 34 +/- 14 months. Patients showed reductions of 76 +/- 33% in headache load, 46 +/- 41% in attack severity, 58 +/- 41% in headache frequency, and 51 +/- 46% in attack duration at the last follow-up. Six patients responded to treatment. Greatest reduction in headache load was associated with activation in an area cantered at 6 mm lateral, 2 mm posterior, and 1 mm inferior to the midcommissural point of the third ventricle. Average responders' activation volume lay on the trigeminohypothalamic tract, connecting the trigeminal system and other brainstem nuclei associated with nociception and pain modulation with the hypothalamus, and the prefrontal and mesial temporal areas. Conclusions: We identify the optimal stimulation site and structural connectivity of the deep brain stimulation target for cluster headache, explicating possible mechanisms of action and disease pathophysiology.

  • 2.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Is all ALS genetic?2017In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 89, no 3, p. 220-221Article in journal (Other academic)
  • 3. Aronsson, Mattias
    et al.
    Persson, Josefine
    Blomstrand, Christian
    Wester, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Sweden.
    Levin, Lars-Ake
    Cost-effectiveness of endovascular thrombectomy in patients with acute ischemic stroke2016In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 86, no 11, p. 1053-1059Article in journal (Refereed)
    Abstract [en]

    Objective:To evaluate the cost-effectiveness of adding endovascular thrombectomy to standard care in patients with acute ischemic stroke.Methods:The cost-effectiveness analysis of endovascular thrombectomy in patients with acute ischemic stroke was based on a decision-analytic Markov model. Primary outcomes from ESCAPE, Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial (EXTEND-IA), Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN), Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours (REVASCAT), and Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke (SWIFT PRIME) along with data from published studies and registries were used in this analysis. We used a health care payer perspective and a lifelong time horizon to estimate costs and effects.Results:The model showed that adding thrombectomy with stent retrievers to guideline-based care (including IV thrombolysis) resulted in a gain of 0.40 life-years and 0.99 quality-adjusted life-years along with a cost savings of approximately $221 per patient. The sensitivity analysis showed that the results were not sensitive to changes in uncertain parameters or assumptions.Conclusions:Adding endovascular treatment to standard care resulted in substantial clinical benefits at low costs. The results were consistent throughout irrespective of whether data from ESCAPE, EXTEND-IA, MR CLEAN, REVASCAT, or SWIFT PRIME were used in this model.

  • 4. Aziz, Tipu Z.
    et al.
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. UCL Institute of Neurology, Unit of Functional Neurosurgery, London, England.
    To sleep or not to sleep during deep brain stimulation surgery for Parkinson disease?2017In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 89, no 19, p. 1938-1939Article in journal (Other academic)
  • 5. Benatar, Michael
    et al.
    Stanislaw, Christine
    Reyes, Eliana
    Hussain, Sumaira
    Cooley, Anne
    Fernandez, Maria Catalina
    Dauphin, Danielle D.
    Michon, Sara-Claude
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wuu, Joanne
    Presymptomatic ALS genetic counseling and testing: Experience and recommendations2016In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 86, no 24, p. 2295-2302Article, review/survey (Refereed)
    Abstract [en]

    Remarkable advances in our understanding of the genetic contributions to amyotrophic lateral sclerosis (ALS) have sparked discussion and debate about whether clinical genetic testing should routinely be offered to patients with ALS. A related, but distinct, question is whether presymptomatic genetic testing should be offered to family members who may be at risk for developing ALS. Existing guidelines for presymptomatic counseling and testing are mostly based on small number of individuals, clinical judgment, and experience from other neurodegenerative disorders. Over the course of the last 8 years, we have provided testing and 317 genetic counseling sessions (including predecision, pretest, posttest, and ad hoc counseling) to 161 first-degree family members participating in the Pre-Symptomatic Familial ALS Study (Pre-fALS), as well as testing and 75 posttest counseling sessions to 63 individuals with familial ALS. Based on this experience, and the real-world challenges we have had to overcome in the process, we recommend an updated set of guidelines for providing presymptomatic genetic counseling and testing to people at high genetic risk for developing ALS. These recommendations are especially timely and relevant given the growing interest in studying presymptomatic ALS.

  • 6. Benatar, Michael
    et al.
    Wuu, Joanne
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Atassi, Nazem
    David, William
    Cudkowicz, Merit
    Schoenfeld, David
    Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS2018In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 90, no 7, p. E565-E574Article in journal (Refereed)
    Abstract [en]

    ObjectiveTo examine the safety and tolerability as well as the preliminary efficacy of arimoclomol, a heat shock protein co-inducer that promotes nascent protein folding, in patients with rapidly progressive SOD1 amyotrophic lateral sclerosis (ALS).

    MethodsThis was a double-blind, placebo-controlled trial in which patients with rapidly progressive SOD1-mutant ALS were randomized 1:1 to receive arimoclomol 200 mg tid or matching placebo for up to 12 months. Study procedures were performed using a mix of in-person and remote assessments. Primary outcome was safety and tolerability. Secondary outcome was efficacy, with survival as the principal measure. Additional efficacy measures were the rates of decline of the Revised ALS Functional Rating Scale (ALSFRS-R) and percent predicted forced expiratory volume in 6 seconds (FEV6), and the Combined Assessment of Function and Survival (CAFS).

    ResultsThirty-eight participants were randomized. Thirty-six (19 placebo, 17 arimoclomol) were included in the prespecified intent-to-treat analysis. Apart from respiratory function, groups were generally well-balanced at baseline. Adverse events occurred infrequently, and were usually mild and deemed unlikely or not related to study drug. Adjusting for riluzole and baseline ALSFRS-R, survival favored arimoclomol with a hazard ratio of 0.77 (95% confidence interval [CI] 0.32-1.80). ALSFRS-R and FEV6 declined more slowly in the arimoclomol group, with treatment differences of 0.5 point/month (95% CI -0.63 to 1.63) and 1.24 percent predicted/month (95% CI -2.77 to 5.25), respectively, and the CAFS similarly favored arimoclomol.

    ConclusionsThis study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. Although not powered for therapeutic effect, the consistency of results across the range of prespecified efficacy outcome measures suggests a possible therapeutic benefit of arimoclomol.

    Clinicaltrials.gov identifierNCT00706147.

    Classification of evidenceThis study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. The study lacked the precision to conclude, or to exclude, an important therapeutic benefit of arimoclomol.

  • 7. Carew, J. D.
    et al.
    Nair, G.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Wuu, J.
    Gronka, S.
    Hu, X.
    Benatar, M.
    Presymptomatic spinal cord neurometabolic findings in SOD1-positive people at risk for familial ALS2011In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 77, no 14, p. 1370-1375Article in journal (Refereed)
    Abstract [en]

    Objectives: It has been speculated that amyotrophic lateral sclerosis (ALS) is characterized by a premanifest period during which neurodegeneration precedes the appearance of clinical manifestations. Magnetic resonance spectroscopy (MRS) was used to measure rations of neurometabolites in the cervical spine of asymptomatic individuals with a mutation in the SOD1 gene (SOD1+) and compare their neurometabolic ratios to patients with ALS and healthy controls.

    Methods: A cross-sectional study of (1)H-MRS of the cervical spine was performed on 24 presymptomatic SOD1+ volunteers, 29 healthy controls, and 23 patients with ALS. All presymptomatic subjects had no symptoms of disease, normal forced vital capacity, and normal electromyographic examination. Relative concentrations of choline (Cho), creatine (Cr), myo-inositol (Myo), and N-acetylasparate (NAA) were determined.

    Results: NAA/Cr and NAA/Myo rations are reduced in both SOD1+ subjects (39.7%, p = 0.001 and 18.0%, p = 0.02) and patients with ALS (41.2%, p < 0.001 and 24.0%, p = 0.01) compared to controls. Myo/Cr is reduced (10.3%, p = 0.02) in SOD1+ subjects compared to controls, but no difference was found between patients with ALS and controls. By contrast, NAA/Cho is reduced in patients with ALS (24.0%, p = 0.002), but not in presymptomatic SOD1+ subjects compared to controls.

    Conclusions: Changes in neurometabolite ratios in the cervical spinal cord are evident in presymptomatic SOD1+ individuals in advance of symptoms and clinical or electromyographic changes in this population resemble changes observed in patients with clinically apparent ALS. This suggest that neurometabolic changed occur early in the course of the disease process.

  • 8.
    Carlsson, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Nylander, P-O
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Forsman-Semb, Kristina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmgren, Gösta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Molecular Biology.
    Identification of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1.2002In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 59, no 11, p. 1804-1807Article in journal (Refereed)
  • 9. Coelho, Teresa
    et al.
    Maia, Luis F.
    da Silva, Ana Martins
    Cruz, Marcia Waddington
    Plante-Bordeneuve, Violaine
    Lozeron, Pierre
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Campistol, Josep M.
    Conceicao, Isabel Maria
    Schmidt, Hartmut H. -J.
    Trigo, Pedro
    Kelly, Jeffery W.
    Labaudinie, Richard
    Chan, Jason
    Packman, Jeff
    Wilson, Amy
    Grogan, Donna R.
    Tafamidis for transthyretin familial amyloid polyneuropathy: A randomized, controlled trial2012In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 79, no 8, p. 785-792Article in journal (Refereed)
    Abstract [en]

    Objectives: To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP). Methods: In this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score-Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population. Results: There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups. Conclusions: Although the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment. Classification of evidence: This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months. Neurology (R) 2012;79:785-792

  • 10.
    de Flon, Pierre
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gunnarsson, Martin
    Laurell, Katarina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Söderström, Lars
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Lindqvist, Thomas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Krauss, Wolfgang
    Dring, Ann
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Bergman, Joakim
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Reduced inflammation in relapsing-remitting multiple sclerosis after therapy switch to rituximab2016In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 87, no 2, p. 141-147Article in journal (Refereed)
    Abstract [en]

    Objective: To describe the effects of switching treatment from ongoing first-line injectable therapies to rituximab on inflammatory activity measured by MRI and levels of CSF neurofilament light chain (CSF-NFL) in a cohort of patients with clinically stable relapsing-remitting multiple sclerosis (RRMS).

    Method: Seventy-five patients with clinically stable RRMS treated with the first-line injectables interferon-β (IFN-β) and glatiramer acetate (GA) at 3 Swedish centers were switched to rituximab in this open-label phase II multicenter study. After a run-in period of 3 months, 2 IV doses of 1,000 mg rituximab were given 2 weeks apart followed by repeated clinical assessment, MRI, and CSF-NFL for 24 months.

    Results: The mean cumulated number of gadolinium-enhancing lesions per patient at months 3 and 6 after treatment shift to rituximab was reduced compared to the run-in period (0.028 vs 0.36, p = 0.029). During the first year after treatment shift, the mean number of new or enlarged T2 lesions per patient was reduced (0.01 vs 0.28, p = 0.004) and mean CSF-NFL levels were reduced by 21% (p = 0.01).

    Conclusions: For patients with RRMS, a treatment switch from IFN or GA to rituximab is associated with reduced inflammatory activity measured by MRI and CSF-NFL.

    Classification of evidence: This study provides Class IV evidence that rituximab has an equal or superior effect in reducing inflammatory activity in RRMS measured by MRI and CSF-NFL compared to first-line injectables during the first year after treatment shift.

  • 11. Ekblad, Laura L.
    et al.
    Johansson, Jarkko
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Turku PET Centre, University of Turku, Finland.
    Helin, Semi
    Viitanen, Matti
    Laine, Hanna
    Puukka, Pauli
    Jula, Antti
    Rinne, Juha O.
    Midlife insulin resistance, APOE genotype, and late-life brain amyloid accumulation2018In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 90, no 13, p. e1150-e1157Article in journal (Refereed)
    Abstract [en]

    Objective To examine whether midlife insulin resistance is an independent risk factor for brain amyloid accumulation in vivo after 15 years, and whether this risk is modulated by APOE epsilon 4 genotype. Methods This observational study examined 60 elderly volunteers without dementia (mean age at baseline 55.4 and at follow-up 70.9 years, 55.5% women) from the Finnish population-based, nationwide Health2000 study with [C-11]Pittsburgh compound B-PET imaging in 2014-2016. The participants were recruited according to their homeostatic model assessment of insulin resistance (HOMA-IR) values in the year 2000, and their APOE epsilon 4 genotype. The exposure group (IR+, n = 30) consisted of individuals with HOMA-IR > 2.17 at baseline (highest tertile of the Health2000 study population), and the control group (IR-, n = 30) consisted of individuals with HOMA-IR < 1.25 at baseline (lowest tertile). The groups were enriched for APOE epsilon 4 carriers, resulting in 50% (n = 15) APOE epsilon 4 carriers in both groups. Analyses were performed with multivariate logistic and linear regression. Results An amyloid-positive PET scan was found in 33.3% of the IR-group and 60.0% of the IR+ group (odds ratio 3.0, 95% confidence interval 1.1-8.9, p = 0.04). The increased risk was seen in carriers and noncarriers of APOE epsilon 4 genotype. Higher midlife, but not late-life continuous HOMA-IR was associated with a greater brain amyloid burden at follow-up after multivariate adjustments for other cognitive and metabolic risk factors (ss = 0.11, 95% confidence interval 0.002-0.22, p = 0.04). Conclusions These results indicate that midlife insulin resistance is an independent risk factor for brain amyloid accumulation in elderly individuals without dementia.

  • 12.
    Eriksson, Marie
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Glader, Eva-Lotta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Norrving, Bo
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Poststroke suicide attempts and completed suicides: a socioeconomic and nationwide perspective2015In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 84, no 17, p. 1732-1738Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: We examined attempted and completed suicides after stroke to determine whether they were associated with socioeconomic status, other patient characteristics, or time after stroke.

    METHODS: This nationwide cohort study included stroke patients from Riksstroke (the Swedish Stroke Register) from 2001 to 2012. We used personal identification numbers to link the Riksstroke data with other national registers. Suicide attempts were identified by a record of hospital admission for intentional self-harm (ICD-10: X60-X84), and completed suicides were identified in the national Cause of Death Register. We used multiple Cox regression to analyze time from stroke onset to first suicide attempt.

    RESULTS: We observed 220,336 stroke patients with a total follow-up time of 860,713 person-years. During follow-up, there were 1,217 suicide attempts, of which 260 were fatal. This was approximately double the rate of the general Swedish population. Patients with lower education or income (hazard ratio [HR] 1.37, 95% confidence interval [CI] 1.11-1.68) for primary vs university and patients living alone (HR 1.73, 95% CI 1.52-1.97) had an increased risk of attempted suicide, and patients born outside of Europe had a lower risk compared to patients of European origin. Male sex, young age, severe stroke, and poststroke depression were other factors associated with an increased risk of attempted suicide after stroke. The risk was highest during the first 2 years after stroke.

    CONCLUSIONS: Both clinical and socioeconomic factors increase the risk of poststroke suicide attempts. This suggests a need for psychosocial support and suicide preventive interventions in high-risk groups of stroke patients.

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

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

  • 14.
    Gustafsson, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Aasly, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Stråhle, Stefan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine.
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Nordstrom, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Low muscle strength in late adolescence and Parkinson disease later in life2015In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 84, no 18, p. 1862-1869Article in journal (Refereed)
    Abstract [en]

    Objective:To evaluate maximal isometric muscle force at 18 years of age in relation to Parkinson disease (PD) later in life.Methods:The cohort consisted of 1,317,713 men who had their muscle strength measured during conscription (1969-1996). Associations between participants' muscle strength at conscription and PD diagnoses, also in their parents, were examined using multivariate statistical models.Results:After adjustment for confounders, the lowest compared to the highest fifth of handgrip strength (hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.06-1.79), elbow flexion strength (HR 1.34, 95% CI 1.02-1.76), but not knee extension strength (HR 1.24, 95% CI 0.94-1.62) was associated with an increased risk of PD during follow-up. Furthermore, men whose parents were diagnosed with PD had reduced handgrip (fathers: mean difference [MD] -5.7 N [95% CI -7.3 to -4.0]; mothers: MD -5.0 N [95% CI -7.0 to -2.9]) and elbow flexion (fathers: MD -4.3 N [95% CI -5.7 to -2.9]; mothers: MD -3.9 N [95% CI -5.7 to -2.2]) strength, but not knee extension strength (fathers: MD -1.1 N [95% CI -2.9 to 0.8]; mothers: MD -0.7 N [95% CI -3.1 to 1.6]), than those with no such familial history.Conclusions:Maximal upper extremity voluntary muscle force was reduced in late adolescence in men diagnosed with PD 30 years later. The findings suggest the presence of subclinical motor deficits 3 decades before the clinical onset of PD.

  • 15.
    Gustafsson, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Depression and subsequent risk of Parkinson disease: A nationwide cohort study2015In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 84, no 24, p. 2422-2429Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the long-term risk of Parkinson disease (PD) after depression and evaluate potential confounding by shared susceptibility to the 2 diagnoses.

    METHODS: The nationwide study cohort included 140,688 cases of depression, matched 1:3 using a nested case-control design to evaluate temporal aspects of study parameters (total, n = 562,631). Potential familial coaggregation of the 2 diagnoses was investigated in a subcohort of 540,811 sibling pairs. Associations were investigated using multivariable adjusted statistical models.

    RESULTS: During a median follow-up period of 6.8 (range, 0-26.0) years, 3,260 individuals in the cohort were diagnosed with PD. The multivariable adjusted odds ratio (OR) for PD was 3.2 (95% confidence interval [CI], 2.5-4.1) within the first year of depression, decreasing to 1.5 (95% CI, 1.1-2.0) after 15 to 25 years. Among participants with depression, recurrent hospitalization was an independent risk factor for PD (OR, 1.4; 95% CI, 1.1-1.9 for ≥5 vs 1 hospitalization). In family analyses, siblings' depression was not significantly associated with PD risk in index persons (OR, 1.1; 95% CI, 0.9-1.4).

    CONCLUSIONS: The time-dependent effect, dose-response pattern for recurrent depression, and lack of evidence for coaggregation among siblings all indicate a direct association between depression and subsequent PD. Given that the association was significant for a follow-up period of more than 2 decades, depression may be a very early prodromal symptom of PD, or a causal risk factor.

  • 16. Hansson, Oskar
    et al.
    Janelidze, Shorena
    Hall, Sara
    Magdalinou, Nadia
    Lees, Andrew J.
    Andreasson, Ulf
    Norgren, Niklas
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Constantinescu, Radu
    Zetterberg, Henrik
    Blennow, Kaj
    Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder2017In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 88, no 10, p. 930-937Article in journal (Refereed)
    Abstract [en]

    Objective: To determine if blood neurofilament light chain (NfL) protein can discriminate between Parkinson disease (PD) and atypical parkinsonian disorders (APD) with equally high diagnostic accuracy as CSF NfL, and can therefore improve the diagnostic workup of parkinsonian disorders. Methods: The study included 3 independent prospective cohorts: the Lund (n 5 278) and London (n 5 117) cohorts, comprising healthy controls and patients with PD, progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), as well as an early disease cohort (n 5 109) of patients with PD, PSP, MSA, or CBS with disease duration <= 3 years. Blood NfL concentration was measured using an ultrasensitive single molecule array (Simoa) method, and the diagnostic accuracy to distinguish PD from APD was investigated. Results: We found strong correlations between blood and CSF concentrations of NfL (p >= 0.73-0.84, p <= 0.001). Blood NfL was increased in patients with MSA, PSP, and CBS (i.e., all APD groups) when compared to patients with PD as well as healthy controls in all cohorts (p, 0.001). Furthermore, in the Lund cohort, blood NfL could accurately distinguish PD from APD (area under the curve [AUC] 0.91) with similar results in both the London cohort (AUC 0.85) and the early disease cohort (AUC 0.81). Conclusions: Quantification of blood NfL concentration can be used to distinguish PD from APD. Blood-based NfL might consequently be included in the diagnostic workup of patients with parkinsonian symptoms in both primary care and specialized clinics.

  • 17.
    Israelsson, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wikkelsö, Carsten
    Laurell, Katarina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Kahlon, Babar
    Leijon, Göran
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Vascular risk factors in INPH A prospective case- control study (the INPH-CRasH study)2017In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 88, no 6, p. 577-585Article in journal (Refereed)
    Abstract [en]

    Objective: To assess the complete vascular risk factor (VRF) profile of idiopathic normal pressure hydrocephalus (INPH) using a large sample of representative patients with INPH and populationbased controls to determine the extent to which vascular disease influences INPH pathophysiology. Methods: All patients with INPH who underwent shunting in Sweden in 2008-2010 were compared to age-and sex-matched population-based controls. Inclusion criteria were age 60-85 years and no dementia. The 10 most important VRFs and cerebrovascular and peripheral vascular disease were prospectively assessed using blood samples, clinical examinations, and standardized questionnaires. Assessed VRFs were hypertension, hyperlipidemia, diabetes, obesity, psychosocial factors, smoking habits, diet, alcohol intake, cardiac disease, and physical activity. Results: In total, 176 patients with INPH and 368 controls participated. Multivariable logistic regression analysis indicated that hyperlipidemia (odds ratio [OR] 2.380; 95% confidence interval [CI] 1.434-3.950), diabetes (OR 2.169; 95% CI 1.195-3.938), obesity (OR 5.428; 95% CI 2.502-11.772), and psychosocial factors (OR 5.343; 95% CI 3.219-8.868) were independently associated with INPH. Hypertension, physical inactivity, and cerebrovascular and peripheral vascular disease were also overrepresented in INPH. Moderate alcohol intake and physical activity were overrepresented among the controls. The population-attributable risk percentage was 24%. Conclusions: Our findings confirm that patients with INPH have more VRFs and lack the protective factors present in the general population. Almost 25% of cases of INPH may be explained by VRFs. This suggests that INPH may be a subtype of vascular dementia. Targeted interventions against modifiable VRFs are likely to have beneficial effects on INPH.

  • 18.
    Janunger, Tomas
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Nilsson-Ardnor, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Wiklund, Per-Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lindgren, P
    Escher, S A
    Lackovic, K
    Nilsson, A K
    Stegmayr, Birgitta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    A novel stroke locus identified in a northern Sweden pedigree: linkage to chromosome 9q31-33.2009In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 73, no 21, p. 1767-1773Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The population of northern Sweden is characterized by reduced genetic diversity and a high incidence of stroke. We sought to reduce genetic variation further, using genealogic analysis in a set of nuclear families affected by stroke, and we subsequently performed a genome-wide scan to identify novel stroke susceptibility loci. METHODS: Through genealogy, 7 nuclear families with a common ancestor, connected over 8 generations, were identified. A genome-wide scan using 449 microsatellite markers was performed with subsequent haplotype analyses. RESULTS: A maximum allele-sharing lod score of 4.81 on chromosome 9q31-q33 was detected. Haplotype analysis identified a common 2.2-megabase interval in the chromosomal region in 4 of the nuclear families, where an overrepresentation of intracerebral hemorrhage was observed. CONCLUSIONS: We have identified a novel susceptibility locus for stroke. Haplotype analysis suggests that a shared genetic factor is of particular importance for intracerebral hemorrhage.

  • 19.
    Johansson, Elias
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Cuadrado-Godia, Elisa
    Hayden, Derek
    Bjellerup, Jakob
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ois, Angel
    Roquer, Jaume
    Wester, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Kelly, Peter J.
    Recurrent stroke in symptomatic carotid stenosis awaiting revascularization: A pooled analysis2016In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 86, no 6, p. 498-504Article in journal (Refereed)
    Abstract [en]

    Objective: We aimed to quantify the risk and predictors of ipsilateral ischemic stroke in patients with symptomatic carotid stenosis awaiting revascularization (carotid endarterectomy [CEA] or carotid artery stenting) by pooling individual patient data from recent prospective studies with high rates of treatment with modern stroke prevention medications.

    Methods: Data were included from 2 prospective hospital-based registries (Umea, Barcelona) and one prospective population-based study (Dublin). Patients with symptomatic 50%-99% carotid stenosis eligible for carotid revascularization were included and followed for early recurrent ipsilateral stroke or retinal artery occlusion (RAO).

    Results: Of 607 patients with symptomatic 50%-99% carotid stenosis, 377 met prespecified inclusion criteria. Ipsilateral recurrent ischemic stroke/RAO risk pre-revascularization was 2.7% (1 day), 5.3% (3 days), 11.5% (14 days), and 18.8% (90 days). On bivariate analysis, presentation with a cerebral vs ocular event was associated with higher recurrent stroke risk (log-rank p = 0.04). On multivariable Cox regression, recurrence was associated with older age (adjusted hazard ratio [HR] per 10-year increase 1.5, p = 0.02) with a strong trend for association with cerebral (stroke/TIA) vs ocular symptoms (adjusted HR 2.7, p = 0.06), but not degree of stenosis, smoking, vascular risk factors, or medications.

    Conclusions: We found high risk of recurrent ipsilateral ischemic events within the 14-day time period currently recommended for CEA. Randomized trials are needed to determine the benefits and safety of urgent vs subacute carotid revascularization within 14 days after symptom onset.

  • 20. Kariuki, Symon M.
    et al.
    Kakooza-Mwesige, Angelina
    Wagner, Ryan G.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Chengo, Eddie
    White, Steven
    Kamuyu, Gathoni
    Ngugi, Anthony K.
    Sander, Josemir W.
    Neville, Brian G. R.
    Newton, Charles R. J.
    Prevalence and factors associated with convulsive status epilepticus in Africans with epilepsy2015In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 84, no 18, p. 1838-1845Article in journal (Refereed)
    Abstract [en]

    Objective:We conducted a community survey to estimate the prevalence and describe the features, risk factors, and consequences of convulsive status epilepticus (CSE) among people with active convulsive epilepsy (ACE) identified in a multisite survey in Africa.Methods:We obtained clinical histories of CSE and neurologic examination data among 1,196 people with ACE identified from a population of 379,166 people in 3 sites: Agincourt, South Africa; Iganga-Mayuge, Uganda; and Kilifi, Kenya. We performed serologic assessment for the presence of antibodies to parasitic infections and HIV and determined adherence to antiepileptic drugs. Consequences of CSE were assessed using a questionnaire. Logistic regression was used to identify risk factors.Results:The adjusted prevalence of CSE in ACE among the general population across the 3 sites was 2.3 per 1,000, and differed with site (p < 0.0001). Over half (55%) of CSE occurred in febrile illnesses and focal seizures were present in 61%. Risk factors for CSE in ACE were neurologic impairments, acute encephalopathy, previous hospitalization, and presence of antibody titers to falciparum malaria and HIV; these differed across sites. Burns (15%), lack of education (49%), being single (77%), and unemployment (78%) were common in CSE; these differed across the 3 sites. Nine percent with and 10% without CSE died.Conclusions:CSE is common in people with ACE in Africa; most occurs with febrile illnesses, is untreated, and has focal features suggesting preventable risk factors. Effective prevention and the management of infections and neurologic impairments may reduce the burden of CSE in ACE.

  • 21. Kaufmann, Horacio
    et al.
    Maurer, Mathew
    Coelho, Teresa
    Plante-Bordeneuve, Violaine
    Rapezzi, Claudio
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Comparison of US and Non-US Patients with Familial Amyloid Polyneuropathy (FAP) and Familial Amyloid Cardiomyopathy (FAC) in THAOS - The Transthyretin Amyloidosis Outcomes Survey2012In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 78, no Suppl 1, p. P01114-Article in journal (Other academic)
  • 22. Khalil, Michael
    et al.
    Salzer, Jonatan
    CSF neurofilament light: A universal risk biomarker in multiple sclerosis?2016In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 87, no 11, p. 1068-1069Article in journal (Refereed)
  • 23.
    Lenfeldt, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hansson, William
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Three-day CSF drainage barely reduces ventricular size in normal pressure hydrocephalus2012In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 79, no 3, p. 237-242Article in journal (Refereed)
    Abstract [en]

    Objective: External lumbar drainage (ELD) of CSF is a test to determine the suitability of a shunt for patients with normal pressure hydrocephalus (NPH), but its effect on ventricular volume is not known. This study investigates the effect of 3-day ELD of 500 mL on ventricular size and clinical features in patients with idiopathic NPH.

    Methods: Fifteen patients were investigated in a 1.5-T MRI scanner before and after ELD. Ventricular volume was measured manually. Clinical features involved motor and cognitive functions, testing primarily gait and attention. Reduction in ventricular volume was correlated to total drain volume and clinical parameters. Statistical tests were nonparametric, and p < 0.05 was required for significance.

    Results: Drain volume was 415 mL (median 470 mL, range 160-510 mL). Ventricular size was reduced in all patients, averaging 3.7 mL (SD 2.2 mL, p < 0.001), which corresponded to a 4.2% contraction. The ratio of volume contraction to drain volume was only 0.9%. Seven patients improved in gait and 6 in attention. Ventricular reduction and total drain volume correlated neither with improvement nor with each other. The 7 patients with the largest drain volumes (close to 500 mL), had ventricular changes varying from 1.3 to 7.5 mL.

    Conclusions: Clinical improvement occurs in patients with NPH after ELD despite unaltered ventricles, suggesting that ventricular size is of little relevance for postshunt improvement or determining shunt function. The clinical effect provided by ELD, mimicking shunting, is probably related to the recurring CSF extractions rather than to the cumulative effect of the drainage on ventricular volume. Neurology(R) 2012;79:237-242

  • 24.
    Lenfeldt, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Koskinen, L-O D
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Bergenheim, A Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    CSF pressure assessed by lumbar puncture agrees with intracranial pressure.2007In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 68, no 2, p. 155-158Article in journal (Refereed)
  • 25. Malm, J
    et al.
    Kristensen, B
    Karlsson, T
    Carlberg, B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Fagerlund, M
    Olsson, T
    Cognitive impairment in young adults with infratentorial infarcts.1998In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 51, no 2, p. 433-40Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To describe cognitive functions and functional outcome in young patients with isolated infratentorial infarcts.

    BACKGROUND: Contemporary knowledge implies a cerebellar contribution to cognitive behavior. Neuropsychological examination of patients with selective cerebellar lesions provides an opportunity to document the existence and nature of clinically relevant cognitive manifestations from lesions of the cerebellum.

    METHODS: Prospective case series. The patients were assessed acutely and at 4 and 12 months after onset. Twenty-four patients from a consecutive series of 105 patients aged 18 to 44 years with cerebral infarction had a brain stem or cerebellar infarction. Fourteen age-matched controls were used for neuropsychological comparisons. Evaluation included MRI, angiography, and transesophageal echocardiography. Disability and neurologic dysfunction were assessed by the modified Rankin scale, NIH stroke scale, and maximal working capacity. A comprehensive neuropsychological battery was performed at baseline in 20 of the 24 patients.

    RESULTS: Eighteen patients had a cerebellar infarct. Two patients had lateral medullary infarcts, and two isolated pontine infarcts. Twenty-two patients had a favorable outcome according to the modified Rankin scale (grade 0-2) and the NIH scale. In contrast, 12 patients were granted full or partial sick leave at the 4 months follow-up, and 10 patients at 12 months. Patients generally performed worse than controls in various aspects of cognitive function, especially in tasks concerning working memory, the temporary storage of complex information, and cognitive flexibility. Measures of verbal IQ (r = -0.74) and performance IQ (r = -0.78) were related to the size of the infarct. The block design task performance in the early poststroke period predicted maximal working capacity at 12 months.

    CONCLUSIONS: Cerebellar damage impairs central aspects of attention and visuospatial skills. In contrast, intelligence and episodic memory remain unchanged. When the lesion involves large portions of the cerebellar hemispheres, changes concerning broad areas of intelligence may occur. The prognosis is favorable for neurologic dysfunction, but cognitive deficits may prevent return to work.

  • 26.
    Malm, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Jacobsson, Johan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Reference values for CSF outflow resistance and intracranial pressure in healthy elderly2011In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 76, no 10, p. 903-909Article in journal (Refereed)
    Abstract [en]

    This study reports reference values for ICP and R(out) and should be used for comparison when investigating disorders with suspected CSF dynamic disturbances in the elderly. ICP was in the same range as that reported in the young and middle-aged. The upper limit of R(out) was higher than previously believed to be the upper limit of normal for this age group.

  • 27.
    Norgren, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Rosengren, Lars
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Gunnarsson, Martin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Neurofilament light and glial fibrillary acidic protein in multiple sclerosis2004In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 63, no 9, p. 1586-1590Article in journal (Refereed)
    Abstract [en]

    Objective: To evaluate levels of neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) in CSF from patients with multiple sclerosis (MS) in relation to clinical progress of the disease.

    Methods: CSF levels of NFL and GFAP were determined by sensitive ELISAs in 99 patients with different subtypes of MS, classified in terms of “ongoing relapse” or “clinically stable disease,” and 25 control subjects. Levels were compared with paraclinical data such as immunoglobulin G index and inflammatory cell count in the CSF, and the levels were related to Expanded Disability Status Scale score and progression index at clinical follow-up evaluations later in the disease course.

    Results: NFL and GFAP levels were elevated in MS patients as compared with control subjects (p < 0.001). The NFL levels were higher at relapses, whereas GFAP levels were unaffected. High NFL levels correlated with progression in patients with an active relapse (r = 0.49; p < 0.01) and in clinically stable patients (r = 0.29; p < 0.05). GFAP correlated to progression in the total patient cohort (r = 0.24; p < 0.05). Moreover, a strong correlation between NFL levels and inflammatory cell counts was evident in the group of patients with an ongoing relapse (r = 0.52; p = 0.001).

    Conclusions: CSF levels of neurofilament light and glial fibrillary acidic protein may have prognostic value in multiple sclerosis.

  • 28. Novakova, Lenka
    et al.
    Zetterberg, Henrik
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Axelsson, Markus
    Khademi, Mohsen
    Gunnarsson, Martin
    Malmestrom, Clas
    Svenningsson, Anders
    Olsson, Tomas
    Piehl, Fredrik
    Blennow, Kaj
    Lycke, Jan
    Monitoring disease activity in multiple sclerosis using serum neurofilament light protein2017In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 89, no 22, p. 2230-2237Article in journal (Refereed)
    Abstract [en]

    Objective: To examine the effects of disease activity, disability, and disease-modifying therapies (DMTs) on serum neurofilament light (NFL) and the correlation between NFL concentrations in serum and CSF in multiple sclerosis (MS). Methods: NFL concentrations were measured in paired serum and CSF samples (n = 521) from 373 participants: 286 had MS, 45 had other neurologic conditions, and 42 were healthy controls (HCs). In 138 patients with MS, the serum and CSF samples were obtained before and after DMT treatment with a median interval of 12 months. The CSF NFL concentration was measured with the Uman Diagnostics NF-light enzyme-linked immunosorbent assay. The serum NFL concentration was measured with an in-house ultrasensitive single-molecule array assay. Results: In MS, the correlation between serum and CSF NFL was r = 0.62 (p< 0.001). Serum concentrations were significantly higher in patients with relapsing-remitting MS (16.9 ng/L) and in patients with progressive MS (23 ng/L) than in HCs (10.5 ng/L, p< 0.001 and p< 0.001, respectively). Treatment with DMT reduced median serum NFL levels from 18.6 (interquartile range [IQR] 12.6-32.7) ng/L to 15.7 (IQR 9.6-22.7) ng/L (p< 0.001). Patients with relapse or with radiologic activity had significantly higher serum NFL levels than those in remission (p< 0.001) or those without new lesions on MRI (p< 0.001). Conclusions: Serum and CSF NFL levels were highly correlated, indicating that blood sampling can replace CSF taps for this particular marker. Disease activity and DMT had similar effects on serum and CSF NFL concentrations. Repeated NFL determinations in peripheral blood for detecting axonal damage may represent new possibilities in MS monitoring.

  • 29. Saeed, M
    et al.
    Yang, Y
    Deng, H-X
    Hung, W-Y
    Siddique, N
    Dellefave, L
    Gellera, C
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Siddique, T
    Age and founder effect of SOD1 A4V mutation causing ALS.2009In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 72, no 19, p. 1634-1639Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The alanine to valine mutation at codon 4 (A4V) of SOD1 causes a rapidly progressive dominant form of amyotrophic lateral sclerosis (ALS) with exclusively lower motor neuron disease and is responsible for 50% of SOD1 mutations associated with familial ALS in North America. This mutation is rare in Europe. The authors investigated the origin (geographic and time) of the A4V mutation. METHODS: Several cohorts were genotyped: North American patients with confirmed A4V mutation (n = 54), Swedish (n = 3) and Italian (n = 6) A4V patients, patients with ALS with SOD1 non-A4V mutations (n = 66) and patients with sporadic ALS (n = 96), healthy white (n = 96), African American (n = 17), Chinese (n = 53), Amerindian (n = 11), and Hispanic (n = 12) subjects. High-throughput SNP genotyping was performed using Taqman assay in 384-well format. A novel biallelic CA repeat in exon 5 of SOD1, tightly linked to A4V, was genotyped on sequencing gels. Association statistics were estimated using Haploview. p Values less than 0.05 were considered significant. Age of A4V was estimated using a novel method based on r(2) degeneration with genetic distance and a Bayesian method incorporated in DMLE+. RESULTS: A single haplotype of 10 polymorphisms across a 5.86-cM region was associated with A4V (p = 3.0e-11) when white controls were used, suggesting a founder effect. The strength of association of this haplotype progressively decreased when African American, Chinese, Hispanic, and Amerindian subjects were used as controls. The associated European haplotype was different from the North American haplotype, indicating two founder effects for A4V (Amerindian and European). The estimated age of A4V with the r(2) degeneration method was 458 +/- 59 years (range 398-569) and in agreement with the Bayesian method (554-734 years with 80-90% posterior probability). CONCLUSIONS: North American SOD1 alanine to valine mutation at codon 4 descended from two founders (Amerindian and European) 400-500 years ago.

  • 30.
    Sailer, Alexandra
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Cunic, DI
    Paradiso, GO
    Gunraj, CA
    Wagle-Shukla, A
    Moro, E
    Lozano, AM
    Lang, AE
    Chen, R
    Subthalamic nucleus stimulation modulates afferent inhibition in Parkinson disease2007In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 68, no 5, p. 356-363Article in journal (Refereed)
    Abstract [en]

    Background: Peripheral sensory stimulation at the wrist inhibits the motor cortex as measured by transcranial magnetic stimulation at interstimulus intervals of approximately 20 ms (short latency afferent inhibition [SAI]) and 200 ms ( long latency afferent inhibition [LAI]). Previous studies suggested that reduced SAI in Parkinson disease (PD) reflects adverse effect of dopaminergic medications and reduced LAI may be related to nondopaminergic manifestations of PD. We hypothesize that subthalamic nucleus (STN) deep brain stimulation (DBS) may correct these deficiencies.

    Methods: We studied the effects of STN DBS on SAI and LAI in seven PD patients and age-matched controls. PD patients were studied in an off medication followed by an on medication session, with the stimulator switched on or off in random order in each session.

    Results: In the on medication session, SAI was reduced in the stimulator off condition and was restored by STN DBS. LAI was partially normalized by STN DBS in the medication on condition.

    Conclusions: Subthalamic nucleus (STN) stimulation improves short latency afferent inhibition, suggesting that it could normalize pathways that are adversely affected by dopaminergic medications. The effect of STN stimulation on long latency afferent inhibition suggests that it may influence nondopaminergic pathways involved in sensorimotor integration.

  • 31.
    Salzer, Jonatan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Nyström, Maria
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Vitamin D as a protective factor in multiple sclerosis2012In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 79, no 21, p. 2140-2145Article in journal (Refereed)
    Abstract [en]

    Objective: To examine the association between 25-hydroxyvitamin D (25[OH]D) levels and the risk of multiple sclerosis (MS) in blood samples collected prospectively and during gestation.

    Methods: In this nested case-control study, 2 population-based biobanks with 291,500 samples from164,000 persons collected since 1975 in the northern half of Sweden were used. We identified prospectively collected blood samples from MS cases (n = 192, controls matched 2:1) and gestational samples from pregnant mothers where the offspring had later developed MS (n = 37, control mothers matched 5:1). 25(OH)D levels were measured using an ELISA, and the risk of MS was analyzed using matched logistic regression.

    Results: Levels of 25(OH)D ≥75 (vs <75) nmol/L in prospectively collected blood samples were associated with a decreased risk of MS (odds ratio [OR] 0.39, 95% confidence interval [CI] 0.16- 0.98). No decrease in MS risk was found in the offspring exposed to gestational 25(OH)D levels ≥75 (vs <75) nmol/L (OR 1.8, 95%CI 0.53-5.8). The prevalence of 25(OH)D levels ≥75 nmol/L in female controls decreased gradually during 1976-2005 (p trend = 0.005).

    Conclusion: This study supports the presence of an association between high 25(OH)D levels during the years preceding disease onset and a decreased risk of MS. In the very limited material with samples drawn in early pregnancy, where month-of-birth effects were controlled for, we found no association between gestational 25(OH)D levels and MS risk in the offspring. Decreasing 25(OH) D levels in the population may contribute to explain the increasing MS incidence that is suggested from epidemiologic studies.

  • 32.
    Salzer, Jonatan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Svenningsson, Rasmus
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Clinical Neuroscience, Danderyd Hospital, Karolinska Institutet, Stockholm.
    Alping, Peter
    Novakova, Lenka
    Björck, Anna
    Fink, Katharina
    Islam-Jakobsson, Protik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Malmeström, Clas
    Axelsson, Markus
    Vågberg, Mattias
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lycke, Jan
    Piehl, Fredrik
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm.
    Rituximab in multiple sclerosis: a retrospective observational study on safety and efficacy2016In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 87, no 20, p. 2074-2081Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the safety and efficacy of rituximab in multiple sclerosis (MS). Methods: In this retrospective uncontrolled observational multicenter study, off-label rituximab-treated patients with MS were identified through the Swedish MS register. Outcome data were collected from the MS register and medical charts. Adverse events (AEs) grades 2-5 according to the Common Terminology Criteria for Adverse Events were recorded. Results: A total of 822 rituximab-treated patients with MS were identified: 557 relapsing-remitting MS (RRMS), 198 secondary progressive MS (SPMS), and 67 primary progressive MS (PPMS). At baseline, 26.2% had contrast-enhancing lesions (CELs). Patients were treated with 500 or 1,000 mg rituximab IV every 6-12 months, during a mean 21.8 (SD 14.3) months. During treatment, the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of patients displayed CELs. Median Expanded Disability Status Scale remained unchanged in RRMS (p = 0.42) and increased by 0.5 and 1.0 in SPMS and PPMS, respectively (p = 0.10 and 0.25). Infusion-related AEs occurred during 7.8% of infusions and most were mild. A total of 89 AEs grades >= 2 (of which 76 infections) were recorded in 72 patients. No case of progressive multifocal leukoencephalopathy was detected. Conclusions: This is the largest cohort of patients with MS treated with rituximab reported so far. The safety, clinical, and MRI findings in this heterogeneous real-world cohort treated with different doses of rituximab were similar to those reported in previous randomized controlled trials on B-cell depletion therapy in MS. Classification of evidence: This study provides Class IV evidence that for patients with MS, rituximab is safe and effective.

  • 33. Simon, KC
    et al.
    van der Mei, IAF
    Munger, KL
    Ponsonby, A
    Dickinson, J
    Dwyer, T
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Ascherio, A
    Combined effects of smoking, anti-EBNA antibodies, and HLA-DRB1*1501 on multiple sclerosis risk2010In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 74, no 17, p. 1365-1371Article in journal (Refereed)
    Abstract [en]

    Objective: To examine the interplay between smoking, serum antibody titers to the Epstein-Barr virus nuclear antigens (anti-EBNA), and HLA-DR15 on multiple sclerosis (MS) risk. Methods: Individual and pooled analyses were conducted among 442 cases and 865 controls from 3 MS case-control studies-a nested case-control study in the Nurses' Health Study/Nurses' Health Study II, the Tasmanian MS Study, and a Swedish MS Study. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% CIs for the association between smoking, anti-EBNA titers, HLA-DR15, and MS risk. Study estimates were pooled using inverse variance weights to determine a combined effect and p value. Results: Among MS cases, anti-EBNA titers were significantly higher in ever smokers compared to never smokers. The increased risk of MS associated with high anti-EBNA Ab titers was stronger among ever smokers (OR = 3.9, 95% CI = 2.7-5.7) compared to never smokers (OR = 1.8, 95% CI = 1.4-2.3; p for interaction = 0.001). The increased risk of MS associated with a history of smoking was no longer evident after adjustment for anti-EBNA Ab titers. No modification or confounding by HLA-DR15 was observed. The increased risk of MS associated with ever smoking was only observed among those who had high anti-EBNA titers (OR = 1.7, 95% CI = 1.1-2.6). Conclusions: Smoking appears to enhance the association between high anti-EBNA titer and increased multiple sclerosis (MS) risk. The association between HLA-DR15 and MS risk is independent of smoking. Further work is necessary to elucidate possible biologic mechanisms to explain this finding

  • 34. Sundqvist, Emilie
    et al.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Linden, Magdalena
    Hedstrom, Anna Karin
    Aloisi, Francesca
    Hillert, Jan
    Kockum, Ingrid
    Alfredsson, Lars
    Olsson, Tomas
    Lack of replication of interaction between EBNA1 IgG and smoking in risk for multiple sclerosis2012In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 79, no 13, p. 1363-1368Article in journal (Refereed)
    Abstract [en]

    Background: Epstein-Barr virus infection, smoking, HLA-A*02, and DRB1*15 have all been proposed as risk factors for multiple sclerosis (MS). In 2010, Simon et al. described an interaction on the multiplicative scale between EBNA1 immunoglobulin G (IgG) and smoking regarding risk of MS, a finding that we attempted to replicate. Methods: This Swedish case-control study consisted of patients with newly diagnosed MS and matched controls. Using logistic regression, we analyzed association to MS risk and interactions between EBNA1 IgG and smoking, HLA-DRB1*15, and A*02, respectively, on the multiplicative scale. In addition, we analyzed interactions on the additive scale using attributable proportion due to interaction (AP). Results: We did not observe any interaction on the multiplicative scale between EBNA1 IgG and any of the 3 risk factors, smoking, DRB1*15, or absence of A*02, although in a conditional analysis the interaction with absence of A*02 becomes significant. However, we observed interactions on the additive scale between EBNA1 IgG and DRB1*15 (AP = 0.34, 95% confidence interval 0.11-0.57, p = 5 x 10(-3)) and between EBNA1 IgG and absence of A*02 (AP = 0.36, 0.13-0.59, p = 2 x 10(-3)) but not between smoking and DRB1*15 and EBNA1 IgG. The interaction between EBNA1 IgG and DRB1*15 was not significant in the conditional analysis. Conclusion: We did not observe any interaction between EBNA1 IgG and smoking, regardless of scale used, and thus did not replicate the observations from Simon et al. Neurology (R) 2012;79:1363-1368

  • 35.
    Sundström, Anna
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Marklund, Petter
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Nilsson, Lars-Göran
    Department of Psychology, Stockholm University.
    Cruts, M.
    Depatrment of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Belgium.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Van Broeckhoven, C.
    Depatrment of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Belgium.
    Nyberg, Lars
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    APOE influences on neurosychological function after mild head injury: within-person comparisons2004In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 62, no 11, p. 1963-1966Article in journal (Refereed)
    Abstract [en]

    Objective: To examine the relationship between neuropsychological outcome following mild head injury (MHI) and APOE genotype.

    Methods: Data from a population-based longitudinal study (n = 3,500) were used to identify 34 adults who experienced MHI during the course of the study. Their pre- and postinjury performances on a battery of nine neuropsychological tests were compared within person, and the postinjury performance was compared with that of age- and gender-matched control subjects.

    Results: The within-person comparisons showed that participants with at least oneAPOE ε4 allele (n = 11) had a significantly decreased postinjury performance on three of the tests, whereas the postinjury performance for APOE ε4-negative participants (n = 23) was unchanged. There was no significant difference in postinjury performance between participants with/without the ε4 allele, and neither group was impaired relative to controls.

    Conclusions: APOE genotype may influence the outcome following an MHI. Pre/postinjury within-person comparisons seem more sensitive than control group comparisons for detecting injury-related effects.

  • 36.
    Sundström, Anna
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    APOE influences in neuropsychological function after mild head injury: Within-person comparisons - Reply2004In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 63, p. 2460-Article in journal (Refereed)
  • 37.
    Svenningsson, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Celius, Elisabeth
    Schreiber, Karen
    Fuchs, Siegrid
    Falk, Eva
    Berko, Sara
    Moller, Christian Max
    Penner, Iris Katharina
    Natalizumab Reduces Fatigue as Measured by the Fatigue Scale for Motor and Cognitive Functions (FSMC) - First Results from the TYNERGY Trial2012In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 78, no Suppl 1, p. P07081-Article in journal (Other academic)
  • 38.
    Svenningsson, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Dring, Ann Marie
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Fogdell-Hahn, Anna
    Jones, Iwan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Engdahl, Elin
    Lundkvist, Malin
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gilthorpe, Jonathan D
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Fatal neuroinflammation in a case of multiple sclerosis with anti-natalizumab antibodies2013In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 80, no 10, p. 965-967Article in journal (Other academic)
  • 39.
    Svenningsson, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Salzer, Jonatan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Vågberg, Mattias
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study2014In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 83, no 22, p. 2099-2100Article in journal (Refereed)
  • 40. Taes, I
    et al.
    Goris, A
    Lemmens, R
    van Es, M A
    van den Berg, L H
    Chio, A
    Traynor, B J
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Slowik, A
    Tomik, B
    Brown, R H
    Shaw, C E
    Al-Chalabi, A
    Boonen, S
    Van Den Bosch, L
    Dubois, B
    Van Damme, P
    Robberecht, W
    Tau levels do not influence human ALS or motor neuron degeneration in the SOD1G93A mouse2010In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 74, no 21, p. 1687-1693Article in journal (Refereed)
    Abstract [en]

    Background: The microtubule-associated protein tau is thought to play a pivotal role in neurodegeneration. Mutations in the tau coding gene MAPT are a cause of frontotemporal dementia, and the H1/H1 genotype of MAPT, giving rise to higher tau expression levels, is associated with progressive supranuclear palsy, corticobasal degeneration, and Parkinson disease (PD). Furthermore, tau hyperphosphorylation and aggregation is a hallmark of Alzheimer disease (AD), and reducing endogenous tau has been reported to ameliorate cognitive impairment in a mouse model for AD. Tau hyperphosphorylation and aggregation have also been described in amyotrophic lateral sclerosis (ALS), both in human patients and in the mutant SOD1 mouse model for this disease. However, the precise role of tau in motor neuron degeneration remains uncertain.

    Methods: The possible association between ALS and the MAPT H1/H2 polymorphism was studied in 3,540 patients with ALS and 8,753 controls. Furthermore, the role of tau in the SOD1G93A mouse model for ALS was studied by deleting Mapt in this model.

    Results: The MAPT genotype of the H1/H2 polymorphism did not influence ALS susceptibility (odds ratio = 1.08 [95% confidence interval 0.99–1.18], p = 0.08) and did not affect the clinical phenotype. Lowering tau levels in the SOD1G93A mouse failed to delay disease onset (p = 0.302) or to increase survival (p = 0.557).

    Conclusion: These findings suggest that the H1/H2 polymorphism in MAPT is not associated with human amyotrophic lateral sclerosis, and that lowering tau levels in the mutant SOD1 mouse does not affect the motor neuron degeneration in these animals.

  • 41. Tajsharghi, H
    et al.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Darin, N
    Martinsson, T
    Kyllerman, M
    Wahlström, J
    Oldfors, A
    Myosin heavy chain IIa gene mutation E706K is pathogenic and its expression increases with age2002In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 58, no 5, p. 780-786Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The authors recently described a new autosomal dominant myopathy (OMIM 605637 inclusion body myopathy 3) associated with a missense mutation in the myosin heavy chain (MyHC) IIa gene (MyHC IIa, Human Gene Map [HGM] locus MYH2). Young patients showed minor changes in their muscle biopsies, although dystrophic alterations and rimmed vacuoles with 15- to 20-nm tubulofilaments identical to those in sporadic inclusion body myositis (s-IBM) were observed in some of the adult (especially older) patients. The current study was undertaken to investigate the relation between expression of the mutant MyHC IIa and pathologic changes in muscle.

    METHODS: The expression of MyHC IIa in nine muscle specimens from six individuals carrying the mutation was analyzed by immunohistochemistry, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and a new reverse transcriptase--PCR method to measure the relative abundance of the various MyHC transcripts.

    RESULTS: Young patients with muscle weakness and minor pathologic changes in muscle expressed MyHC IIa at undetectable levels. MyHC IIa was expressed at high levels in adults with a progressive clinical course and dystrophic muscle changes. In these cases, a large number of muscle fibers were hybrids with expression of more than one MyHC isoform. Both MyHC IIa alleles were equally expressed. The relative level of MyHC IIa transcripts exceeded that of the corresponding protein, indicating an increased turnover of mutated protein. MyHC IIa expression was a consistent finding in muscle fibers with rimmed vacuoles.

    CONCLUSIONS: The clear correlation between pathologic changes and expression of MyHC IIa indicates that defects in MyHC may lead not only to muscle weakness but also to muscle degeneration. The consistent expression of MyHC IIa in muscle fibers with rimmed vacuoles indicates that the breakdown of sarcomeric proteins is a key element in the pathogenesis of rimmed vacuoles of s-IBM type.

  • 42. Valdmanis, P N
    et al.
    Kabashi, E
    Dyck, A
    Hince, P
    Lee, J
    Dion, P
    D'Amour, M
    Souchon, F
    Bouchard, J-P
    Salachas, F
    Meininger, V
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Camu, W
    Dupré, N
    Rouleau, G A
    Association of paraoxonase gene cluster polymorphisms with ALS in France, Quebec, and Sweden2008In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 71, no 7, p. 514-520Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The paraoxonase gene cluster on chromosome 7 comprising the PON1-3 genes is an attractive candidate for association in amyotrophic lateral sclerosis (ALS) given the role of paraoxonase genes during the response to oxidative stress and their contribution to the enzymatic break down of nerve toxins. Oxidative stress is considered one of the mechanisms involved in ALS pathogenesis. Evidence for this includes the fact that mutations of SOD1, which normally reduce the production of toxic superoxide anion, account for 12% to 23% of familial cases in ALS. In addition, PON variants were shown to be associated with susceptibility to ALS in several North American and European populations. METHODS: We extended this analysis to examine 20 single nucleotide polymorphisms (SNPs) across the PON gene cluster in a set of patients from France (480 cases, 475 controls), Quebec (159 cases, 95 controls), and Sweden (558 cases, 506 controls). RESULTS: Although individual SNPs were not considered associated on their own, a haplotype of SNPs at the C-terminal portion of PON2 that includes the PON2 C311S amino acid change was significant in the French (p value 0.0075) and Quebec (p value 0.026) populations as well as all three populations combined (p value 1.69 x 10(-6)). Stratification of the samples showed that this variation was pertinent to ALS susceptibility as a whole, and not to a particular subset of patients. CONCLUSIONS: These findings contribute to the increasing weight of evidence that genetic variants in the paraoxonase gene cluster are associated with amyotrophic lateral sclerosis.

  • 43. Wills, A-M
    et al.
    Cronin, S
    Slowik, A
    Kasperaviciute, D
    Van Es, M A
    Morahan, J M
    Valdmanis, P N
    Meininger, V
    Melki, J
    Shaw, C E
    Rouleau, G A
    Fisher, E M C
    Shaw, P J
    Morrison, K E
    Pamphlett, R
    Van den Berg, L H
    Figlewicz, D A
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Al-Chalabi, A
    Hardiman, O
    Purcell, S
    Landers, J E
    Brown, R H
    A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS.2009In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 73, no 1, p. 16-24Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Six candidate gene studies report a genetic association of DNA variants within the paraoxonase locus with sporadic amyotrophic lateral sclerosis (ALS). However, several other large studies, including five genome-wide association studies, have not duplicated this finding. METHODS: We conducted a meta-analysis of 10 published studies and one unpublished study of the paraoxonase locus, encompassing 4,037 ALS cases and 4,609 controls, including genome-wide association data from 2,018 ALS cases and 2,425 controls. RESULTS: The combined fixed effects odds ratio (OR) for rs662 (PON1 Q192R) was 1.09 (95% confidence interval [CI], 1.02-1.16, p = 0.01); the genotypic OR for RR homozygotes at Q192R was 1.25 (95% CI, 1.07-1.45, p = 0.0004); the combined OR for rs854560 (PON1 L55M) was 0.97 (95% CI, 0.86-1.10, p = 0.62); the OR for rs10487132 (PON2) was 1.08 (95% CI, 0.92-1.27, p = 0.35). Although the rs662 polymorphism reached a nominal level of significance, no polymorphism was significant after multiple testing correction. In the subanalysis of samples with genome-wide data from which population outliers were removed, rs662 had an OR of 1.06 (95% CI, 0.97-1.16, p = 0.22). CONCLUSIONS: In contrast to previous positive smaller studies, our genetic meta-analysis showed no significant association of amyotrophic lateral sclerosis (ALS) with the PON locus. This is the largest meta-analysis of a candidate gene in ALS to date and the first ALS meta-analysis to include data from whole genome association studies. The findings reinforce the need for much larger and more collaborative investigations of the genetic determinants of ALS.

  • 44. Witjas, Tatiana
    et al.
    Carron, Romain
    Krack, Paul
    Eusebio, Alexandre
    Vaugoyeau, Marianne
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Azulay, Jean Philippe
    Régis, Jean
    A prospective single-blind study of Gamma Knife thalamotomy for tremor2015In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 85, no 18, p. 1562-1568Article in journal (Refereed)
    Abstract [en]

    Objective: To evaluate the safety and efficacy of unilateral Gamma Knife thalamotomy (GKT) for treatment of severe tremor with a prospective blinded assessment. Methods: Fifty patients (mean age: 74.5 years; 32 men) with severe refractory tremor (36 essential, 14 parkinsonian) were treated with unilateral GKT. Targeting of the ventral intermediate nucleus (Vim) was achieved with Leksell Gamma Knife with a single shot through a 4-mm collimator helmet. The prescription dose was 130 Gy. Neurologic and neuropsychological assessments including a single-blinded video assessment of the tremor severity performed by a movement disorders neurologist from another center were performed before and 12 months after treatment. MRI follow-up occurred at 3, 6, and 12 months. Results: The upper limb tremor score improved by 54.2% on the blinded assessment (p < 0.0001). All tremor components (rest, postural, and intention) were improved. Activities of daily living were improved by 72.2%. Cognitive functions remained unchanged. Following GKT, the median delay of improvement was 5.3 months (range 1-12 months). The only side effect was a transient hemiparesis associated with excessive edema around the thalamotomy in one patient. Conclusion: This blinded prospective assessment demonstrates that unilateral GKT is a safe and efficient procedure for severe medically refractory tremor. Side effects were rare and transient in this study.

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