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  • 1.
    Adey, Brett N.
    et al.
    Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom.
    Cooper-Knock, Johnathan
    Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom.
    Al Khleifat, Ahmad
    Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom.
    Fogh, Isabella
    Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom.
    van Damme, Philip
    Department of Neurosciences, KU Leuven-University of Leuven, Experimental Neurology, Leuven Brain Institute (LBI), Leuven, Belgium; VIB, Center for Brain and Disease Research, Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
    Corcia, Philippe
    UMR 1253, Université de Tours, Inserm, Tours, France; Centre de référence sur la SLA, CHU de Tours, Tours, France.
    Couratier, Philippe
    Centre de référence sur la SLA, CHRU de Limoges, Limoges, France; UMR 1094, Université de Limoges, Inserm, Limoges, France.
    Hardiman, Orla
    Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
    McLaughlin, Russell
    Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
    Gotkine, Marc
    Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; Agnes Ginges Center for Human Neurogenetics, Department of Neurology, Hadassah Medical Center, Jerusalem, Israel.
    Drory, Vivian
    Department of Neurology, Tel-Aviv Sourasky Medical Centre, Tel-Aviv, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
    Silani, Vincenzo
    Department of Neurology and Laboratory of Neuroscience, Istituto Auxologico Italiano, IRCCS, Milan, Italy; Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano, Milan, Italy.
    Ticozzi, Nicola
    Department of Neurology and Laboratory of Neuroscience, Istituto Auxologico Italiano, IRCCS, Milan, Italy; Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano, Milan, Italy.
    Veldink, Jan H.
    Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands.
    van den Berg, Leonard H.
    Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands.
    de Carvalho, Mamede
    Instituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
    Pinto, Susana
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Instituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
    Mora Pardina, Jesus S.
    ALS Unit, Hospital San Rafael, Madrid, Spain.
    Povedano Panades, Mónica
    Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, Barcelona, L’Hospitalet de Llobregat, Spain.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Weber, Markus
    Neuromuscular Diseases Unit/ALS Clinic, St. Gallen, Switzerland.
    Başak, Nazli A.
    Koc University School of Medicine, Translational Medicine Research Center, NDAL, Istanbul, Turkey.
    Shaw, Christopher E.
    Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom.
    Shaw, Pamela J.
    Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom.
    Morrison, Karen E.
    School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, United Kingdom.
    Landers, John E.
    Department of Neurology, University of Massachusetts Medical School, MA, Worcester, United States.
    Glass, Jonathan D.
    Department of Neurology, Emory University School of Medicine, GA, Atlanta, United States.
    Vourc’h, Patrick
    Department of Neurology, University Hospitals Leuven, Leuven, Belgium; Service de Biochimie et Biologie molécularie, CHU de Tours, Tours, France.
    Dobson, Richard J. B.
    Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London, Maudsley NHS Foundation Trust, King’s College London, London, United Kingdom; Institute of Health Informatics, University College London, London, United Kingdom; NIHR Biomedical Research Centre at University College London Hospitals, NHS Foundation Trust, London, United Kingdom.
    Breen, Gerome
    Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom.
    Al-Chalabi, Ammar
    Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; King’s College Hospital, London, United Kingdom.
    Jones, Ashley R.
    Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom.
    Iacoangeli, Alfredo
    Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London, Maudsley NHS Foundation Trust, King’s College London, London, United Kingdom.
    Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival2023In: Frontiers in Cellular Neuroscience, E-ISSN 1662-5102, Vol. 17, article id 1112405Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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  • 2.
    af Bjerkén, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Flygare, Carolina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Remes, Jussi
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Strandberg, Sara
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Eriksson, Linda
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Bäckström, David C.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Jakobson Mo, Susanna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Reliability and validity of visual analysis of [18F]FE-PE2I PET/CT in early Parkinsonian disease2023In: Nuclear medicine communications, ISSN 0143-3636, E-ISSN 1473-5628, Vol. 44, no 5, p. 397-406Article in journal (Refereed)
    Abstract [en]

    Objective: [18F]FE-PE2I (FE-PE2I) is a new radiotracer for dopamine transporter (DAT) imaging with PET. The aim of this study was to evaluate the visual interpretation of FE-PE2I images for the diagnosis of idiopathic Parkinsonian syndrome (IPS). The inter-rater variability, sensitivity, specificity, and diagnostic accuracy for visual interpretation of striatal FE-PE2I compared to [123I]FP-CIT (FP-CIT) single-photon emission computed tomography (SPECT) was evaluated.

    Methods: Thirty patients with newly onset parkinsonism and 32 healthy controls with both an FE-PE2I and FP-CIT were included in the study. Four patients had normal DAT imaging, of which three did not fulfil the IPS criteria at the clinical reassessment after 2 years. Six raters evaluated the DAT images blinded to the clinical diagnosis, interpreting the image as being ‘normal’ or ‘pathological’, and assessed the degree of DAT-reduction in the caudate and putamen. The inter-rater agreement was assessed with intra-class correlation and Cronbach’s α. For calculation of sensitivity and specificity, DAT images were defined as correctly classified if categorized as normal or pathological by ≥4/6 raters.

    Results: The overall agreement in visual evaluation of the FE-PE2I- and FP-CIT images was high for the IPS patients (α = 0.960 and 0.898, respectively), but lower in healthy controls (FE-PE2I: α = 0.693, FP-CIT: α = 0.657). Visual interpretation gave high sensitivity (both 0.96) but lower specificity (FE-PE2I: 0.86, FP-CIT: 0.63) with an accuracy of 90% for FE-PE2I and 77% for FP-CIT.

    Conclusion: Visual evaluation of FE-PE2I PET imaging demonstrates high reliability and diagnostic accuracy for IPS.

  • 3.
    Ahlenhed, Valdemar
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Risk and predictive factors for poststroke epilepsy - Risk- och prediktiva faktorer för poststroke epilepsi2020Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 4.
    Aineskog, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Johansson, Conny
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Nilsson, Robert
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Koskinen, Lars-Owe D.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Lindvall, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Serum S100B correlates with health-related quality of life and functional outcome in patients at 1 year after aneurysmal subarachnoid haemorrhage2022In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 164, no 8, p. 2209-2218Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Early, objective prognostication after aneurysmal subarachnoid haemorrhage (aSAH) is difficult. A biochemical marker would be desirable. Correlation has been found between levels of the protein S100 beta (S100B) and outcome after aSAH. Timing and clinical usefulness are under investigation.

    METHODS: Eighty-nine patients admitted within 48 h of aSAH were included. Modified ranking scale (mRS), EuroQoL health-related quality of life measure (EQ-5Dindex) and EuroQoL visual analogue scale (EQ-VAS) values were evaluated after 1 year. S100B was measured in blood samples collected at admission and up to day 10.

    RESULTS: S100B correlated significantly with EQ-5Dindex and mRS, but not EQ-VAS at 1 year after aSAH. A receiver operating characteristic analysis for peak S100B values (area under the curve 0.898, 95% confidence interval 0.828-0.968, p < 0.0001), with a cutoff of 0.4 μg/l, yielded 95.3% specificity and 68% sensitivity for predicting unfavourable outcome. Dichotomized S100B (> 0.4 μg/l vs ≤ 0.4 μg/l), age and Hunt and Hess grading scale score (HH) were associated with unfavourable mRS outcome in univariate logistic regression analysis. Dichotomized S100B was the only variable independently correlated with unfavourable mRS outcome in a multivariate logistic regression analysis.

    CONCLUSIONS: For the first time, S100B was shown to correlate with mRS and health-related quality of life at 1 year after aSAH. Peak S100B can be used as a prognostic factor for unfavourable outcome measured as dichotomized mRS after aSAH. A peak value cutoff of 0.4 μg/l is suggested. Ethical approval no: 2013/366-31, 4th of February 2014.

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  • 5.
    Ajobi, Faisal Farhan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Tidig neuroinflammation och prognosen i Parkinsonssjukdom2022Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 6.
    Alonso-Magdalena, Lucía
    et al.
    Department of Neurology, Skåne University Hospital and Department of Clinical Sciences, Lund University, Lund, Sweden.
    Carmona i Codina, Olga
    Department of Neurology, Fundacio Salut Emporda, Figueres and Department of Clinical Sciences, Faculty of Medicine, Girona University, Spain.
    Zia, Elisabet
    Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Pessah-Rasmussen, Hélène
    Department of Rehabilitation medicine, Skåne University Hospital and Department of Clinical Sciences, Lund University, Lund, Sweden.
    Prevalence and disease disability in immigrants with multiple sclerosis in Malmö, southern Sweden2024In: Clinical neurology and neurosurgery, ISSN 0303-8467, E-ISSN 1872-6968, Vol. 240, article id 108255Article in journal (Refereed)
    Abstract [en]

    Background: Multiple sclerosis (MS) is the most common chronic demyelinating disease of the central nervous system and the major non-traumatic cause of permanent disability in young adults. Several migration studies have been performed over the years suggesting a pattern of higher disease disability in certain ethnic groups. To our knowledge, differences in disease progression in immigrants have not been studied in Sweden before. Thus, the aims of our study were to estimate the prevalence of multiple sclerosis among first-generation immigrants in the City of Malmö and to compare differences in disease severity with the native population.

    Methods: All persons with multiple sclerosis living in Malmö on prevalence day 31 Dec 2010 were included. Cases were classified according to the country of birth into Scandinavians, Western and non-Western.

    Results: The crude prevalence was 100/100,000 (95% CI, 80–124) among first-generation immigrants, 154/100,000 (95% CI, 137–173) among individuals with Scandinavian background, 123/100,000 (95% CI, 94–162) in the Western group and 76/100,000 (95% CI, 53–108) in the non-Western group. The mean Multiple Sclerosis Severity Score (MSSS) value among Scandinavians was 4.2 (SD 3.5), whereas the figures in the immigrant group were 4.6 (SD 3.3) and 5.2 (SD 3.7) among Westerns respectively non-Westerns, which differences were not statistically significant. When adjusting for gender, age at onset and initial disease course, the mean MSSS difference between the non-Western and the Scandinavian individuals was 1.7 (95% CI 0.18–3.3, p = 0.030). There were no differences on time to diagnosis or the time from diagnosis to treatment initiation between the three groups.

    Conclusions: We found a lower prevalence among Western and non-Western first-generation immigrants compared to the Scandinavian population and a more severe disease in non-Western immigrants than in Scandinavians.

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  • 7. Alonso-Magdalena, Lucía
    et al.
    Zia, Elisabet
    Carmona I Codina, Olga
    Pessah-Rasmussen, Hélène
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Incidence and prevalence of multiple sclerosis in Malmö, southern Sweden2022In: Multiple Sclerosis International, ISSN 2090-2654, E-ISSN 2090-2662, article id 5464370Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To estimate the incidence and prevalence of multiple sclerosis (MS) in Malmö municipality in southwestern Sweden.

    MATERIALS AND METHODS: Multiple sources were used in the case identification process. Case ascertainment was assessed by medical chart review including examinations such as magnetic resonance imaging, cerebrospinal fluid analyses, and relevant laboratory tests. Cases were classified according to the 2010 McDonald's diagnostic criteria. Onset-adjusted prevalence and a definition of onset symptoms were applied.

    RESULTS: The crude incidence of MS in 2001-2010 in Malmö municipality was 5.3/100,000 (95% confidence interval (CI): 4.5 to 6.2). There was a relapsing onset in 90.5% of cases. The female to male ratio was 1.8. The onset-adjusted prevalence for Dec 2010 was 133/100,000 (95% CI, 120 to 146) with a female to male ratio of 2.1.

    CONCLUSIONS: This is the first population-based epidemiological study in Skåne, the most southwestern part of Sweden showing a high incidence and prevalence. We found a lower incidence than expected according to previous nationwide figures, probably due to methodological differences between the studies. Our findings support the presence of a north-south gradient of MS prevalence in Sweden.

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  • 8. Andelic, Nada
    et al.
    Røe, Cecilie
    Brunborg, Cathrine
    Zeldovich, Marina
    Løvstad, Marianne
    Løke, Daniel
    Borgen, Ida M.
    Voormolen, Daphne C.
    Howe, Emilie I.
    Forslund, Marit V.
    Dahl, Hilde M.
    von Steinbuechel, Nicole
    Koskinen, Lars-Owe (Contributor)
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Frequency of fatigue and its changes in the first 6 months after traumatic brain injury: results from the CENTER-TBI study2021In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 268, no 1, p. 61-73Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Fatigue is one of the most commonly reported subjective symptoms following traumatic brain injury (TBI). The aims were to assess frequency of fatigue over the first 6 months after TBI, and examine whether fatigue changes could be predicted by demographic characteristics, injury severity and comorbidities.

    METHODS: Patients with acute TBI admitted to 65 trauma centers were enrolled in the study Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI). Subjective fatigue was measured by single item on the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), administered at baseline, three and 6 months postinjury. Patients were categorized by clinical care pathway: admitted to an emergency room (ER), a ward (ADM) or an intensive care unit (ICU). Injury severity, preinjury somatic- and psychiatric conditions, depressive and sleep problems were registered at baseline. For prediction of fatigue changes, descriptive statistics and mixed effect logistic regression analysis are reported.

    RESULTS: Fatigue was experienced by 47% of patients at baseline, 48% at 3 months and 46% at 6 months. Patients admitted to ICU had a higher probability of experiencing fatigue than those in ER and ADM strata. Females and individuals with lower age, higher education, more severe intracranial injury, preinjury somatic and psychiatric conditions, sleep disturbance and feeling depressed postinjury had a higher probability of fatigue.

    CONCLUSION: A high and stable frequency of fatigue was found during the first 6 months after TBI. Specific socio-demographic factors, comorbidities and injury severity characteristics were predictors of fatigue in this study.

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  • 9.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Amyotrophic lateral sclerosis and CuZn-superoxide dismutase: a clinical, genetic and enzymatic study1997Doctoral thesis, comprehensive summary (Other academic)
  • 10.
    Andersen, Peter M.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Binzer, M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Nilsson, P.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Ala-Hurula, V.
    Keränen, M.-L.
    Bergmark, L.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Saarinen, A.
    Haltia, T.
    Tarvainen, I.
    Kinnunen, E.
    Udd, B.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation: a clinical and genealogical study of 36 patients1996In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 119, p. 1153-1172Article in journal (Refereed)
  • 11.
    Andersen, Peter M.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Kuźma-Kozakiewicz, Magdalena
    Department of Neurology, Medical University of Warsaw, Warsaw, Poland; Neurodegenerative Diseases Research Group, Medical University of Warsaw, Warsaw, Poland.
    Keller, Jürgen
    Department of Neurology, University of Ulm, Ulm, Germany.
    Maksymowicz-Śliwińska, Anna
    Department of Neurology, Medical University of Warsaw, Warsaw, Poland.
    Barć, Krzysztof
    Department of Neurology, Medical University of Warsaw, Warsaw, Poland.
    Nieporęcki, Krzysztof
    Department of Neurology, Medical University of Warsaw, Warsaw, Poland.
    Finsel, Julia
    Department of Neurology, University of Ulm, Ulm, Germany.
    Vazquez, Cynthia
    Department of Neurology, University of Ulm, Ulm, Germany.
    Helczyk, Olga
    Department of Neurology, University of Ulm, Ulm, Germany.
    Linse, Katharina
    Department of Neurology, Technische Universität Dresden, and German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany.
    Häggström, Ann-Cristin E.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Stenberg, Erica
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Semb, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Professional Development.
    Ciećwierska, Katarzyna
    Department of Neurology, Medical University of Warsaw, Warsaw, Poland.
    Szejko, Natalia
    Department of Neurology, Medical University of Warsaw, Warsaw, Poland.
    Uttner, Ingo
    Department of Neurology, University of Ulm, Ulm, Germany.
    Herrmann, Andreas
    Department of Neurology, Technische Universität Dresden, and German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany.
    Petri, Susanne
    Department of Neurology, Hannover Medical School, Hannover, Germany.
    Meyer, Thomas
    Department of Neurology, Charité CVK, Berlin, Germany.
    Ludolph, Albert C.
    Department of Neurology, University of Ulm, Ulm, Germany; German Center for Neurodegenerative Diseases (DZNE), Ulm, Germany.
    Lulé, Dorothée
    Department of Neurology, University of Ulm, Ulm, Germany.
    Caregivers’ divergent perspectives on patients’ well-being and attitudes towards hastened death in Germany, Poland and Sweden2022In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 23, no 3-4, p. 252-262Article in journal (Refereed)
    Abstract [en]

    Background: During the course of amyotrophic lateral sclerosis (ALS), patients and their families are faced with existential decisions concerning life-prolonging and -shortening measures. Correct anticipation of patient’s well-being and preferences is a prerequisite for patient-centered surrogate decision making.

    Methods: In Germany (N = 84), Poland (N = 77) and Sweden (N = 73) patient-caregiver dyads were interviewed. Standardized questionnaires on well-being (ADI-12 for depressiveness; ACSA for global quality of life) and wish for hastened death (SAHD) were used in ALS patients. Additionally, caregivers were asked to fill out the same questionnaires by anticipating patients’ perspective (surrogate perspective).

    Results: Caregivers significantly underestimated patients’ well-being in Germany and Poland. For Swedish caregivers, there were just as many who underestimated and overestimated well-being. The same was true for wish for hastened death in all three countries. For Swedish and Polish patients, caregivers’ estimation of well-being was not even associated with patients’ responses and the same was true for estimation of wish for hastened death in all three countries. Older caregivers and those with the most frequent encounter with the patient were the closest in their rating of well-being and wish for hastened death to the patients’ actual state, while caregivers with chronic disease him/herself were more likely to underestimate patient’s well-being.

    Discussion: Despite distinct cultural differences, there was a clear discrepancy between patients’ and caregivers’ perspective on patients’ well-being and preferences towards life in all three countries. This possible bias in caregivers’ judgment needs to be taken into account in surrogate decision making.

  • 12.
    Andersen, Peter M.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Nilsson, P.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    CuZn-superoxide dismutase, extracellular superoxide dismutase, and glutathione peroxidase in blood from individuals homozygous for ASP90ALA CuZn-superoxide dismutase mutation1998In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 70, no 2, p. 715-720Article in journal (Refereed)
  • 13.
    Andersen, Peter M.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Nilsson, P.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Keränen, M.-L.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Hägglund, J.
    Karlsborg, M.
    Ronnevi, L.-O.
    Gredal, O.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia1997In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 120, no 10, p. 1723-1737Article in journal (Refereed)
  • 14.
    Andersen, Peter M.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Nilsson, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Ala-Hurula, Veli
    Keränen, Marja-Leena
    Tarvainen, Ilkka
    Haltia, Tuula
    Nilsson, Lotta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Binzer, Michael
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase1995In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 10, p. 61-66Article in journal (Refereed)
  • 15.
    Andersen, Peter Munch
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Extensive heterogeneity in patients with ALS with mutations in SOD1 in France2021In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 92, no 9, p. 914-914Article in journal (Other academic)
  • 16.
    Andersson, Johanna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Idiopathic normal pressure hydrocephalus: epidemiology and diagnostics2021Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Idiopathic normal pressure hydrocephalus (iNPH) is a progressive neurological condition characterized by a deterioration of gait, cognition, and continence. The diagnosis is based on a combination of enlarged ventricles seen in neuroimaging, with typical clinical findings. iNPH often affects elderly individuals (i.e., over the age of 65). Shunt insertion is the only available treatment, with an improvement rate of up to 80%.

    The prevalence has previously been reported to be between 0.5 and 3% among individuals over age 65. However, most previous studies have been conducted on hospital-based materials, and there is a lack of epidemiological studies based on the general population. One of the challenges of diagnosing iNPH is that there are no common, widely accepted diagnostic criteria. There are currently two different diagnostic guidelines: the American-European guidelines and the Japanese ones, which makes it harder to compare different studies.

    The aim of this thesis was to determine the prevalence of iNPH in population-based materials and to evaluate the differences between the diagnostic guidelines. Furthermore, we wanted to assess the quality of life and depressive symptoms among individuals with iNPH compared to those without. In addition, we assessed longitudinal changes in the clinical and radiological findings of iNPH.

    We asked 1,000 individuals aged 65 and older to participate in the study by answering a questionnaire containing typical iNPH symptoms. We invited all participants who had marked at least two symptoms on the questionnaire for further investigation, in addition to a randomly selected group with fewer than two symptoms. A total of 168 participants underwent clinical examinations and computed tomography (CT) of the brain. We followed up with the same cohort two years later with repeated testing, with the addition of questionnaires on depressive symptoms and quality of life. A total of 122 individuals remained in the 2-year follow-up cohort. The clinical examinations included an iNPH-specific grading scale for symptoms and neurological examinations.

    The prevalence of iNPH for those 65 years and older was 3.7% according to the American-European guidelines and 1.5% according to the Japanese guidelines. The prevalence was higher for those over age 80, with no differences between the sexes. Furthermore, participants with iNPH had more depressive symptoms and lower quality of life than those without iNPH. Radiological findings and symptoms progressed slightly over two years, and those with symptom deterioration had an even higher degree of radiological progress compared to those with stationary or improved symptoms.

    This thesis shows that iNPH is fairly common in a normal population of elderly individuals. There is disagreement between the current diagnostic guidelines, which underscores the need for revisions, preferably into one common diagnostic system. In this thesis, individuals with iNPH had a lower functional status, more depressive symptoms, and lower quality of life than those without iNPH.

    Moreover, iNPH progresses slightly in both symptoms and radiological signs over two years, which underlines the value of clinical follow-up for asymptomatic individuals with radiological signs of iNPH. Finally, iNPH is probably underdiagnosed and an important diagnosis to consider in an elderly person with gait and balance impairments.

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  • 17.
    Andersson, Johanna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Rosell, M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Kockum, Karin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Söderström, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Laurell, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Challenges in diagnosing normal pressure hydrocephalus: evaluation of the diagnostic guidelines2017In: eNeurologicalSci, ISSN 2405-6502, Vol. 7, p. 27-31Article in journal (Refereed)
    Abstract [en]

    Purpose: To evaluate the present diagnostic guidelines of idiopathic normal pressure hydrocephalus (iNPH) in a sample from the general population.

    Methods: A total of 168 individuals (93 females, 75 males), mean age 75 years (range 66-92) with and without symptoms of iNPH underwent a CT-scan of the brain, a neurological examination with assessment of the triad symptoms, i.e. gait disturbances, memory impairment and urgency incontinence. The participants were then diagnosed as "unlikely", "possible" and "probable" iNPH according to the American-European and the Japanese guidelines, respectively. Separately, a senior consultant in neurology diagnosed each patient based on the overall clinical picture.

    Results: Obtaining a diagnosis of "probable iNPH" was three times more likely according to the American-European guidelines (n = 35) compared to the Japanese guidelines (n = 11) or the neurologist (n = 11). The concordance was highest (Kappa = 0.69) between the Japanese guidelines and the neurologist.

    Conclusions: Considerable discrepancies were found when diagnosing iNPH according to two international guidelines and a neurologist, respectively. The Japanese guidelines, which include a minimum of two triad symptoms, were most concordant with the neurologist. As a step towards widely accepted, standardized diagnostic criteria, we suggest a revision of the current guidelines, preferably into one common diagnostic system.

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  • 18. Arango-Lasprilla, Juan Carlos
    et al.
    Zeldovich, Marina
    Olabarrieta-Landa, Laiene
    Vindal Forslund, Marit
    Núñez-Fernández, Silvia
    von Steinbuechel, Nicole
    Isager Howe, Emilie
    Røe, Cecilie
    Andelic, Nada
    Koskinen, Lars-Owe D. (Contributor)
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Sundström, Nina (Contributor)
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Early Predictors of Employment Status One Year Post Injury in Individuals with Traumatic Brain Injury in Europe2020In: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 9, no 6, article id 2007Article in journal (Refereed)
    Abstract [en]

    Sustaining a traumatic brain injury (TBI) often affects the individual’s ability to work, reducing employment rates post-injury across all severities of TBI. The objective of this multi-country study was to assess the most relevant early predictors of employment status in individuals after TBI at one-year post-injury in European countries. Using a prospective longitudinal non-randomized observational cohort (The Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) project), data was collected between December 2014–2019 from 63 trauma centers in 18 European countries. The 1015 individuals who took part in this study were potential labor market participants, admitted to a hospital and enrolled within 24 h of injury with a clinical TBI diagnosis and indication for a computed tomography (CT) scan, and followed up at one year. Results from a binomial logistic regression showed that older age, status of part-time employment or unemployment at time of injury, premorbid psychiatric problems, and higher injury severity (as measured with higher Injury severity score (ISS), lower Glasgow Coma Scale (GCS), and longer length of stay (LOS) in hospital) were associated with higher unemployment probability at one-year after injury. The study strengthens evidence for age, employment at time of injury, premorbid psychiatric problems, ISS, GCS, and LOS as important predictors for employment status one-year post-TBI across Europe.

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  • 19.
    Arvidsson, Sandra
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Eriksson, Robert
    Clinical Neurophysiology, Umeå University Hospital, Umeå, Sweden.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Heldestad, Victoria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Enlarged cross-sectional area in peripheral nerves in Swedish patients with hereditary V30M transthyretin amyloidosis2023In: Annals of Medicine, ISSN 0785-3890, E-ISSN 1365-2060, Vol. 55, no 2, article id 2239269Article in journal (Refereed)
    Abstract [en]

    Introduction: In hereditary transthyretin amyloidosis (ATTRv), two different fibrillar forms causing the amyloid deposition, have been identified, displaying substantially cardiac or neuropathic symptoms. Neuropathic symptoms are more frequent in early-onset patients, whereas late-onset patients, besides cardiac symptoms, seem to develop carpal tunnel syndrome, more often. With ultrasonography (US) of peripheral nerves, it is possible to distinguish structural changes, and enlarged cross-sectional area (CSA). The main purpose of this study was, for the first time, to elucidate US of peripheral nerves in Swedish ATTRv patients at an early stage of the disease, and to evaluate possible early enlarged CSA.

    Material and methods: This prospective study included first visit data of 13 patients, aged 30–88 years, of which 11 with late-onset age. All had a positive V30M mutation. Eight men and six women (aged 28–74 years) served as controls.

    Results: Significantly enlarged CSA was seen in ATTRv patients for the tibial nerve at the ankle (p =.001), the sural nerve (p <.001), the peroneal nerve at the popliteal fossa (p =.003), and the ulnar nerve at the middle upper arm (p =.007).

    Conclusion: US of peripheral nerves could be a valuable tool in disease evaluation and could facilitate monitoring of disease progression.

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  • 20.
    Awad, Amar
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Grill, Filip
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Deep brain stimulation does not modulate fMRI resting- state functional connectivity in essential tremorManuscript (preprint) (Other academic)
  • 21.
    Awad, Amar
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Grill, Filip
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Deep brain stimulation does not modulate resting-state functional connectivity in essential tremor2024In: Brain Communications, E-ISSN 2632-1297, Vol. 6, no 2, article id fcae012Article in journal (Refereed)
    Abstract [en]

    While the effectiveness of deep brain stimulation in alleviating essential tremor is well-established, the underlying mechanisms of the treatment are unclear. Essential tremor, as characterized by tremor during action, is proposed to be driven by a dysfunction in the cerebello-thalamo-cerebral circuit that is evident not only during motor actions but also during rest. Stimulation effects on resting-state functional connectivity were investigated by functional MRI in 16 essential tremor patients with fully implanted deep brain stimulation in the caudal zona incerta during On-and-Off therapeutic stimulation, in a counterbalanced design. Functional connectivity was calculated between different constellations of sensorimotor as well as non-sensorimotor regions (as derived from seed-based and data-driven approaches), and compared between On and Off stimulation. We found that deep brain stimulation did not modulate resting-state functional connectivity. The lack of modulation by deep brain stimulation during resting-state, in combination with previously demonstrated effects on the cerebello-thalamo-cerebral circuit during motor tasks, suggests an action-dependent modulation of the stimulation in essential tremor.

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  • 22.
    Baldvinsdóttir, Bryndís
    et al.
    Department of Clinical Sciences, Neurosurgery, Lund University, Lund, Sweden.
    Klurfan, Paula
    Department of Clinical Neuroscience, University of Gothenburg, Gothenburg, Sweden.
    Eneling, Johanna
    Department of Clinical Sciences, Linköping University, Linköping, Sweden.
    Ronne-Engström, Elisabeth
    Department of Neuroscience, Section of Neurosurgery, Uppsala University, Uppsala, Sweden.
    Enblad, Per
    Department of Neuroscience, Section of Neurosurgery, Uppsala University, Uppsala, Sweden.
    Lindvall, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Aineskog, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Friðriksson, Steen
    Department of Clinical Neuroscience, University of Gothenburg, Gothenburg, Sweden.
    Svensson, Mikael
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Alpkvist, Peter
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Hillman, Jan
    Department of Clinical Sciences, Linköping University, Linköping, Sweden.
    Kronvall, Erik
    Department of Clinical Sciences, Neurosurgery, Lund University, Lund, Sweden.
    Nilsson, Ola G.
    Department of Clinical Sciences, Neurosurgery, Lund University, Lund, Sweden.
    Adverse events during endovascular treatment of ruptured aneurysms: a prospective nationwide study on subarachnoid hemorrhage in sweden2023In: Brain and Spine, ISSN 2772-5294, Vol. 3, article id 102708Article in journal (Refereed)
    Abstract [en]

    Introduction: A range of adverse events (AEs) may occur in patients with subarachnoid hemorrhage (SAH). Endovascular treatment is commonly used to prevent aneurysm re-rupture.

    Research question: The aim of this study was to identify AEs related to endovascular treatment, analyze risk factors for AEs and how AEs affect patient outcome.

    Material and methods: Patients with aneurysmal SAH admitted to all neurosurgical centers in Sweden during a 3.5-year period (2014–2018) were prospectively registered. AEs related to endovascular aneurysm treatment were thromboembolic events, aneurysm re-rupture, vessel dissection and puncture site hematoma. Potential risk factors for the AEs were analyzed using multivariate logistic regression. Functional outcome was assessed at one year using the extended Glasgow outcome scale.

    Results: In total, 1037 patients were treated for ruptured aneurysms. Of which, 715 patients were treated with endovascular occlusion. There were 115 AEs reported in 113 patients (16%). Thromboembolic events were noted in 78 patients (11%). Aneurysm re-rupture occurred in 28 (4%), vessel dissection in 4 (0.6%) and puncture site hematoma in 5 (0.7%). Blister type aneurysm, aneurysm smaller than 5 mm and endovascular techniques other than coiling were risk factors for treatment-related AEs. At follow-up, 230 (32%) of the patients had unfavorable outcome. Patients suffering intraprocedural aneurysm re-rupture were more likely to have unfavorable outcome (OR 6.9, 95% CI 2.3–20.9).

    Discussion and conclusion: Adverse events related to endovascular occlusion of a ruptured aneurysm were seen in 16% of patients. Aneurysm re-rupture during endovascular treatment was associated with increased risk of unfavorable functional outcome.

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  • 23.
    Baldvinsdóttir, Bryndís
    et al.
    Department of Clinical Sciences, Neurosurgery, Lund University, Lund, Sweden.
    Kronvall, Erik
    Department of Clinical Sciences, Neurosurgery, Lund University, Lund, Sweden.
    Ronne-Engström, Elisabeth
    Department of Medical Sciences, Neurosurgery, Uppsala University, Uppsala, Sweden.
    Enblad, Per
    Department of Medical Sciences, Neurosurgery, Uppsala University, Uppsala, Sweden.
    Lindvall, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Aineskog, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Friðriksson, Steen
    Department of Clinical Neuroscience, Neurosurgery, University of Gothenburg, Gothenburg, Sweden.
    Klurfan, Paula
    Department of Clinical Neuroscience, Neurosurgery, University of Gothenburg, Gothenburg, Sweden.
    Svensson, Mikael
    Department of Clinical Neuroscience, Neurosurgery, Karolinska Institute, Stockholm, Sweden.
    Alpkvist, Peter
    Department of Clinical Neuroscience, Neurosurgery, Karolinska Institute, Stockholm, Sweden.
    Hillman, Jan
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Eneling, Johanna
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Nilsson, Ola G
    Department of Clinical Sciences, Neurosurgery, Lund University, Lund, Sweden.
    Adverse events associated with microsurgial treatment for ruptured intracerebral aneurysms: A prospective nationwide study on subarachnoid haemorrhage in Sweden2023In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 94, no 7, p. 575-580Article in journal (Refereed)
    Abstract [en]

    Background: Adverse events (AEs) or complications may arise secondary to the treatment of aneurysmal subarachnoid haemorrhage (SAH). The aim of this study was to identify AEs associated with microsurgical occlusion of ruptured aneurysms, as well as to analyse their risk factors and impact on functional outcome.

    Methods: Patients with aneurysmal SAH admitted to the neurosurgical centres in Sweden were prospectively registered during a 3.5-year period (2014-2018). AEs were categorised as intraoperative or postoperative. A range of variables from patient history and SAH characteristics were explored as potential risk factors for an AE. Functional outcome was assessed approximately 1 year after the bleeding using the extended Glasgow Outcome Scale.

    Results: In total, 1037 patients were treated for ruptured aneurysms, of which, 322 patients were treated with microsurgery. There were 105 surgical AEs in 97 patients (30%); 94 were intraoperative AEs in 79 patients (25%). Aneurysm rerupture occurred in 43 patients (13%), temporary occlusion of the parent artery >5 min in 26 patients (8%) and adjacent vessel injury in 25 patients (8%). High Fisher grade and brain oedema on CT were related to increased risk of AEs. At follow-up, 38% of patients had unfavourable outcome. Patients suffering AEs were more likely to have unfavourable outcome (OR 2.3, 95% CI 1.10 to 4.69).

    Conclusion: Intraoperative AEs occurred in 25% of patients treated with microsurgery for ruptured intracerebral aneurysm in this nationwide survey. Although most operated patients had favourable outcome, AEs were associated with increased risk of unfavourable outcome.

  • 24.
    Behzadi, Arvin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Biomarkers for diagnosis and prognosis in amyotrophic lateral sclerosis2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of upper and lower motor neurons, leading to paresis, muscle atrophy, and respiratory failure. ALS can be difficult to diagnose and prognosticate early.

    Aim: To investigate the diagnostic and prognostic characteristics of biomarkers in cerebrospinal fluid (CSF), plasma, and skeletal muscle tissue in patients with ALS.

    Paper I: Neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) were analyzed in CSF using enzyme-linked immunosorbent assay (ELISA), and NFL in plasma was analyzed using single-molecule array (SIMOA). CSF NFL, CSF pNFH, and plasma NFL concentrations can differentiate ALS patients from ALS mimics, and were significantly negatively correlated with the disease duration in ALS patients.

    Paper II: Myosin heavy chain (MyHC) isoforms in extraocular muscles were investigated using immunofluorescence. Control donors had significantly higher proportion of myofibers containing MyHCIIa and significantly lower proportion of myofibers containing MyHCeom in the global layer compared to spinal-onset ALS and bulbar-onset ALS donors. Disease duration in the spinal-onset ALS donors was significantly correlated with the proportion of myofibers containing MyHCIIa in the global layer and MyHCeom in the orbital layer.

    Paper III: The study combined the neurofilament concentrations from Paper I, with cytokines previously analyzed in CSF and plasma using SIMOA, to investigate distinct molecular phenotypes in ALS. Patients with bulbar-onset ALS had significantly higher concentrations of CSF tumor necrosis factor α (TNF-α) compared to ALS mimics. TNF-α and NFL were significantly correlated with each other in both CSF and plasma in ALS patients. Combined analysis of NFL and IL-6 in plasma identified molecular prognostic subgroups in ALS patients.

    Paper IV: Creatine kinase (CK), high-sensitivity cardiac troponin T (hs-cTnT), hs-cTnI, and cystatin C (CysC) were analyzed in plasma in a fully accredited laboratory. CK and hs-cTnT concentrations were significantly elevated in limb-onset ALS compared to controls and bulbar-onset ALS. hs-cTnT concentrations were significantly elevated in truncal-onset ALS compared to controls and bulbar-onset ALS. Multivariable Cox proportional hazards models indicated elevated concentrations of CysC as a significant marker for worse prognosis in ALS.

    Conclusions: The papers report diagnostic and prognostic characteristics of biomarkers in CSF, plasma, and muscle tissue in ALS patients. The significant findings for biomarkers in plasma could be of value since plasma sampling does not involve a lumbar puncture.

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  • 25.
    Behzadi, Arvin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Olesen, Mads Nikolaj
    Pujol-Calderón, Fani
    Tjust, Anton E.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Madsen, Jonna Skov
    Brandslund, Ivan
    Blennow, Kaj
    Zetterberg, Henrik
    Asgari, Nasrin
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Combined analysis of neurofilament light chain and interleukin 6 in plasma reveals distinct molecular phenotypes in ALS and can differentiate ALS patients into prognostic subgroupsManuscript (preprint) (Other academic)
  • 26.
    Behzadi, Arvin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Pujol-Calderón, Fani
    Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.
    Tjust, Anton E.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Höglund, Kina
    Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Portelius, Erik
    Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Blennow, Kaj
    Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Zetterberg, Henrik
    Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom; UK Dementia Research Institute at UCL, London, United Kingdom.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Neurofilaments can differentiate ALS subgroups and ALS from common diagnostic mimics2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 22128Article in journal (Refereed)
    Abstract [en]

    Delayed diagnosis and misdiagnosis are frequent in people with amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease (MND). Neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) are elevated in ALS patients. We retrospectively quantified cerebrospinal fluid (CSF) NFL, CSF pNFH and plasma NFL in stored samples that were collected at the diagnostic work-up of ALS patients (n = 234), ALS mimics (n = 44) and controls (n = 9). We assessed the diagnostic performance, prognostication value and relationship to the site of onset and genotype. CSF NFL, CSF pNFH and plasma NFL levels were significantly increased in ALS patients compared to patients with neuropathies & myelopathies, patients with myopathies and controls. Furthermore, CSF pNFH and plasma NFL levels were significantly higher in ALS patients than in patients with other MNDs. Bulbar onset ALS patients had significantly higher plasma NFL levels than spinal onset ALS patients. ALS patients with C9orf72HRE mutations had significantly higher plasma NFL levels than patients with SOD1 mutations. Survival was negatively correlated with all three biomarkers. Receiver operating characteristics showed the highest area under the curve for CSF pNFH for differentiating ALS from ALS mimics and for plasma NFL for estimating ALS short and long survival. All three biomarkers have diagnostic value in differentiating ALS from clinically relevant ALS mimics. Plasma NFL levels can be used to differentiate between clinical and genetic ALS subgroups.

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  • 27.
    Behzadi, Arvin
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Tjust, Anton Erik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Liu, Jing-Xia
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Andersen, Peter Munch
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. https://orcid.org/0000-0002-4201-8204.
    Pedrosa Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Myofiber type shift in extraocular muscles in amyotrophic lateral sclerosis2023In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 64, no 5, article id 15Article in journal (Refereed)
    Abstract [en]

    Purpose: To investigate changes in myofiber composition in the global layer (GL) and orbital layer (OL) of extraocular muscles (EOMs) from terminal amyotrophic lateral sclerosis (ALS) donors.

    Methods: Medial recti muscles collected postmortem from spinal-onset ALS, bulbar-onset ALS, and healthy control donors were processed for immunofluorescence with antibodies against myosin heavy chain (MyHC) IIa, MyHCI, MyHCeom, laminin, neurofilaments, synaptophysin, acetylcholine receptor γ-subunit, and α-bungarotoxin.

    Results: The proportion of myofibers containing MyHCIIa was significantly smaller and MyHCeom was significantly larger in the GL of spinal-onset ALS and bulbar-onset ALS donors compared to control donors. Changes in the GL were more prominent in the bulbar-onset ALS donors, with a significantly larger proportion of myofibers containing MyHCeom being present compared to spinal-onset ALS donors. There were no significant differences in the myofiber composition in the OL. In the spinal-onset ALS donors, the proportions of myofibers containing MyHCIIa in the GL and MyHCeom in the OL were significantly correlated with the disease duration. Neurofilament and synaptophysin were present at motor endplates of myofibers containing MyHCeom in ALS donors.

    Conclusions: The EOMs of terminal ALS donors displayed changes in the fast-type myofiber composition in the GL, with a more pronounced alteration in bulbar-onset ALS donors. Our results align with the worse prognosis and subclinical changes in eye movement function previously observed in bulbar-onset ALS patients and suggest that the myofibers in the OL might be more resistant to the pathological process in ALS.

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  • 28.
    Behzadi, Arvin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tjust, Anton E.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Weydt, Patrick
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Cardiac troponin T, cystatin C and creatine kinase as biomarkers in clinical phenotypes, genotypes and prognostication in amyotrophic lateral sclerosisManuscript (preprint) (Other academic)
  • 29. Benatar, Michael
    et al.
    Granit, Volkan
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Grignon, Anne-Laure
    McHutchison, Caroline
    Cosentino, Stephanie
    Malaspina, Andrea
    Wuu, Joanne
    Mild motor impairment as prodromal state in amyotrophic lateral sclerosis: a new diagnostic entity2022In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 145, no 10, p. 3500-3508Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis, when viewed as a biological entity rather than a clinical syndrome, probably evolves along a continuum, with the initial clinically silent phase eventually evolving into clinically manifest amyotrophic lateral sclerosis. Since motor neuron degeneration is incremental and cumulative over time, it stands to reason that the clinical syndrome of amyotrophic lateral sclerosis is probably preceded by a prodromal state characterized by minor motor abnormalities that are initially insufficient to permit a diagnosis of amyotrophic lateral sclerosis. This prodromal period, however, is usually missed, given the invariably long delays between symptom onset and diagnostic evaluation. The Pre-Symptomatic Familial ALS Study, a cohort study of pre-symptomatic gene mutation carriers, offers a unique opportunity to observe what is typically unseen. Here we describe the clinical characterization of 20 pre-symptomatic mutation carriers (in SOD1, FUS and C9orf72) whose phenoconversion to clinically manifest disease has been prospectively studied. In so doing, we observed a prodromal phase of mild motor impairment in 11 of 20 phenoconverters. Among the n = 12 SOD1 A4V mutation carriers, phenoconversion was characterized by abrupt onset of weakness, with a short (1-3.5 months) prodromal period observable in a small minority (n = 3); the observable prodrome invariably involved the lower motor neuron axis. By contrast, in all n = 3 SOD1 I113T mutation carriers, diffuse lower motor neuron and upper motor neuron signs evolved insidiously during a prodromal period that extended over a period of many years; prodromal manifestations eventually coalesced into a clinical syndrome that is recognizable as amyotrophic lateral sclerosis. Similarly, in all n = 3 C9orf72 hexanucleotide repeat expansion mutation carriers, focal or multifocal manifestations of disease evolved gradually over a prodromal period of 1-2 years. Clinically manifest ALS also emerged following a prodromal period of mild motor impairment, lasting >4 years and similar to 9 months, respectively, in n = 2 with other gene mutations (SOD1 L106V and FUS c.521del6). On the basis of this empirical evidence, we conclude that mild motor impairment is an observable state that precedes clinically manifest disease in three of the most common genetic forms of amyotrophic lateral sclerosis (SOD1, FUS, C9orf72), and perhaps in all genetic amyotrophic lateral sclerosis; we also propose that this might be true of non-genetic amyotrophic lateral sclerosis. As a diagnostic label, mild motor impairment provides the language to describe the indeterminate (and sometimes intermediate) transition between the unaffected state and clinically manifest amyotrophic lateral sclerosis. Recognizing mild motor impairment as a distinct clinical entity should generate fresh urgency for developing biomarkers reflecting the earliest events in the degenerative cascade, with potential to reduce the diagnostic delay and to permit earlier therapeutic intervention. Having observed ALS phenoconversion in 20 pre-symptomatic gene mutation carriers, Benatar et al. conclude that a prodromal period of mild motor impairment (MMI) precedes many (if not most) forms of ALS. They highlight the implications for reducing diagnostic delay and for early therapeutic intervention.

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  • 30.
    Benatar, Michael
    et al.
    Department of Neurology, University of Miami, FL, Miami, United States.
    Wuu, Joanne
    Department of Neurology, University of Miami, FL, Miami, United States.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Bucelli, Robert C.
    Washington University School of Medicine, MO, St. Louis, United States.
    Andrews, Jinsy A.
    The Neurological Institute, Columbia University Irving Medical Center, NY, New York, United States.
    Otto, Markus
    Department of Neurology, Martin Luther University, Halle-Wittenberg, Halle (Saale), Germany.
    Farahany, Nita A.
    Duke University School of Law, NC, Durham, United States.
    Harrington, Elizabeth A.
    Columbia University Irving Medical Center, NY, New York, United States.
    Chen, Weiping
    Biogen, MA, Cambridge, United States.
    Mitchell, Adele A.
    Biogen, MA, Cambridge, United States.
    Ferguson, Toby
    Biogen, MA, Cambridge, United States.
    Chew, Sheena
    Biogen, MA, Cambridge, United States.
    Gedney, Liz
    Biogen, MA, Cambridge, United States.
    Oakley, Sue
    Biogen, MA, Cambridge, United States.
    Heo, Jeong
    Biogen, MA, Cambridge, United States.
    Chary, Sowmya
    Biogen, MA, Cambridge, United States.
    Fanning, Laura
    Biogen, MA, Cambridge, United States.
    Graham, Danielle
    Biogen, MA, Cambridge, United States.
    Sun, Peng
    Biogen, MA, Cambridge, United States.
    Liu, Yingying
    Biogen, MA, Cambridge, United States.
    Wong, Janice
    Biogen, MA, Cambridge, United States.
    Fradette, Stephanie
    Biogen, MA, Cambridge, United States.
    Design of a randomized, placebo-controlled, phase 3 trial of tofersen initiated in clinically presymptomatic SOD1 variant carriers: the Atlas study2022In: Neurotherapeutics, ISSN 1933-7213, Vol. 19, p. 1248-1258Article in journal (Refereed)
    Abstract [en]

    Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of ALS, with biomarker data from the Pre-Symptomatic Familial ALS (Pre-fALS) study showing that an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease. Tofersen is an investigational antisense oligonucleotide designed to reduce synthesis of superoxide dismutase 1 (SOD1) protein through degradation of SOD1 mRNA. Informed by Pre-fALS and the tofersen clinical development program, the ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease activity (elevated plasma NfL). The ATLAS study will investigate whether tofersen can delay the emergence of clinically manifest ALS. To our knowledge, ATLAS is the first interventional trial in presymptomatic ALS and has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS.

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  • 31.
    Benatar, Michael
    et al.
    Department of Neurology, University of Miami, FL, Miami, United States.
    Wuu, Joanne
    Department of Neurology, University of Miami, FL, Miami, United States.
    McHutchison, Caroline
    Human Cognitive Neuroscience, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom; Euan MacDonald Centre for Mnd Research, University of Edinburgh, Edinburgh, United Kingdom.
    Postuma, Ronald B
    Department of Neurology, Montreal Neurological Institute, McGill University, Montreal, Canada.
    Boeve, Bradley F
    Department of Neurology, Mayo Clinic, MN, Rochester, United States.
    Petersen, Ronald
    Department of Neurology, Mayo Clinic, MN, Rochester, United States.
    Ross, Christopher A
    Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, School of Medicine, MD, Baltimore, United States; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, MD, Baltimore, United States; Department of Pharmacology and Molecular Sciences, Johns Hopkins University, School of Medicine, MD, Baltimore, United States; Department of Neurology, Johns Hopkins University, School of Medicine, MD, Baltimore, United States.
    Rosen, Howard
    Department of Neurology, University of California San Francisco, CA, United States.
    Arias, Jalayne J
    Department of Neurology, University of California San Francisco, CA, United States.
    Fradette, Stephanie
    Biogen, MA, Cambridge, United States.
    McDermott, Michael P
    Department of Biostatistics and Computational Biology, University of Rochester, School of Medicine and Dentistry, NY, Rochester, United States; Department of Neurology, University of Rochester, School of Medicine and Dentistry, NY, Rochester, United States.
    Shefner, Jeremy
    Department of Neurology, Barrow Neurological Institute, AZ, Phoenix, United States.
    Stanislaw, Christine
    Department of Human Genetics, Emory University, GA, Atlanta, United States.
    Abrahams, Sharon
    Human Cognitive Neuroscience, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom; Euan MacDonald Centre for Mnd Research, University of Edinburgh, Edinburgh, United Kingdom.
    Cosentino, Stephanie
    Department of Psychiatry, Columbia University, NY, New York, United States.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Finkel, Richard S
    Department of Pediatric Medicine, Center for Experimental Neurotherapeutics, St. Jude Children's Research Hospital, TN, Memphis, United States.
    Granit, Volkan
    Department of Neurology, University of Miami, FL, Miami, United States.
    Grignon, Anne-Laure
    Department of Neurology, University of Miami, FL, Miami, United States.
    Rohrer, Jonathan D
    Department of Neurodegenerative Disease, Dementia Research Centre, Ucl Institute of Neurology, Queen Square, London, United Kingdom.
    McMillan, Corey T
    Department of Neurology, University of Pennsylvania Perelman, School of Medicine, PA, Philadelphia, United States.
    Grossman, Murray
    Department of Neurology, University of Pennsylvania Perelman, School of Medicine, PA, Philadelphia, United States.
    Al-Chalabi, Ammar
    Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, United Kingdom; Department of Neurology, King's College Hospital, London, United Kingdom.
    Turner, Martin R
    Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
    First International Pre-Symptomatic ALS Workshop,
    Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases2022In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 145, no 1, p. 27-44Article, review/survey (Refereed)
    Abstract [en]

    Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer's disease based on inferred underlying histopathology. Parkinson's disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington's disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned - more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers - we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.

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  • 32.
    Ben-Shabat, Ilan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Darehed, David
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Eriksson, Marie
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Salzer, Jonatan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Characteristics of in-hospital stroke patients in Sweden: a nationwide register-based study2023In: European Stroke Journal, ISSN 2396-9873, E-ISSN 2396-9881, Vol. 8, no 3, p. 777-783Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Few studies have reported the characteristics of patients with in-hospital stroke (IHS) including the reason for hospitalization and invasive procedures before the stroke. We aimed to extend current knowledge.

    PATIENTS AND METHODS: All adult patients with IHS in Sweden during 2010-2019 registered in the Swedish Stroke Register (Riksstroke) were included. The cohort was cross-linked to the National Patient Register and data extracted on background diagnoses, main discharge diagnoses, and procedure codes for the hospitalization when IHS occurred and any hospital-based healthcare contacts within 30 days before IHS.

    RESULTS: 231,402 stroke cases were identified of which 12,551 (5.4%) were in-hospital and had corresponding entries in the National Patient Register. Of the IHS patients, 11,420 (91.0%) had ischemic stroke and 1131 (9.0%) hemorrhagic stroke; 5860 (46.7%) of the IHS patients had at least one invasive procedure prior to ictus. 1696 (13.5%) had a cardiovascular procedure and 560 (4.5%) a neurosurgical procedure. 1319 (10.5%) patients only had minimally invasive procedures such as blood product transfusion, hemodialysis, or central line insertion. Common discharge diagnosis in patients with no invasive procedures were cardiovascular disorders, injuries, and respiratory disorders.

    DISCUSSION AND CONCLUSION: One in every 17 strokes in Sweden occur in a hospital. In this unselected large cohort the previously reported major causes for in-hospital stroke, cardiovascular and neurosurgical procedures, preceded IHS in only 18.0% of cases suggesting that other etiologies are more common than previously reported. Future studies should aim at determining absolute risks of stroke after surgical procedures and ways of risk reduction.

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  • 33.
    Berdynski, Mariusz
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Laboratory of Neurogenetics, Department of Neurodegenerative Disorders, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.
    Miszta, Przemysław
    Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Warsaw, Poland.
    Safranow, Krzysztof
    Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, 72 Powstańców Wlkp. Str., Szczecin, Poland.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Morita, Mitsuya
    Division of Neurology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Japan.
    Filipek, Sławomir
    Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Warsaw, Poland.
    Żekanowski, Cezary
    Laboratory of Neurogenetics, Department of Neurodegenerative Disorders, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.
    Kuźma-Kozakiewicz, Magdalena
    Department of Neurology, Medical University of Warsaw, Warsaw, Poland; Neurodegenerative Diseases Research Group, Medical University of Warsaw, Warsaw, Poland.
    SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity2022In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, no 1, article id 103Article in journal (Refereed)
    Abstract [en]

    Mutations in superoxide dismutase 1 gene (SOD1) are linked to amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder predominantly affecting upper and lower motor neurons. The clinical phenotype of ALS shows inter- and intrafamilial heterogeneity. The aim of the study was to analyze the relations between individual SOD1 mutations and the clinical presentation using in silico methods to assess the SOD1 mutations severity. We identified SOD1 causative variants in a group of 915 prospectively tested consecutive Polish ALS patients from a neuromuscular clinical center, performed molecular modeling of mutated SOD1 proteins and in silico analysis of mutation impact on clinical phenotype and survival analysis of associations between mutations and hazard of clinical end-points. Fifteen SOD1 mutations were identified in 21.1% familial and 2.3% sporadic ALS cases. Their effects on SOD1 protein structure and functioning inferred from molecular modeling and in silico analyses correlate well with the clinical data. Molecular modeling results support the hypothesis that folding intermediates rather than mature SOD1 protein give rise to the source of cytotoxic conformations in ALS. Significant associations between type of mutation and clinical end-points were found.

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  • 34.
    Bergman, Joakim
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Studies of the Biology of Intrathecal Treatment in Progressive MS2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Multiple Sclerosis (MS) is a chronic, inflammatory, autoimmune disease, affecting the central nervous system (CNS). About 85% of afflicted present with a relapsing-remitting form of the disease (RRMS), for which a breakthrough in treatment was made in 2008 with rituximab, an antibody directed towards CD20, a surface antigen on B-cells. These findings also contributed to cementing the importance of the B-cell’s role in MS pathophysiology. However, MS also exist as a progressive phenotype, affecting most MS patients either from onset or after a transition from RRMS, and for progressive MS the same treatment effect of anti-CD20 has not been observed. Still, studies have found follicle-like structures containing B-cells in meninges and subarachnoid space of the cortex in progressive MS brains, supporting the involvement of B-cells. Evidence also support the existence of a chronic, low-grade inflammatory process compartmentalised within the CNS that correlates with the progressive phase of MS, which may present a treatment barrier towards anti-CD20. Peripherally administrated therapeutic antibodies cross the intact blood-brain barrier with low efficiency with only 0.1-0.5% of the plasma concentration occurring in the cerebrospinal fluid (CSF). Intrathecal (IT) administration circumvents the blood-brain barrier, presenting an opportunity to better target the CNS B-cells.

    Aims: To evaluate the safety and feasibility of intrathecal anti-CD20 therapy with rituximab in progressive MS, its effect on disease progression through clinical parameters, and impact on biomarkers in CSF. Furthermore, this thesis aimed to evaluate the effect on biomarkers representative of cell injury related to insertion of a ventricular catheter for drug administration and to examine the interstitial milieu in the brain through microdialysis (MD).

    Methods: The thesis is based on the open-label, phase IIb, multicentre clinical trial Intrathecal Treatment Trial in Progressive Multiple Sclerosis (ITT-PMS; EudraCT 2008-002626-11), in which 23 participants received IT treatment with rituximab, and the extended follow-up study, ITT-PMS extension (EudraCT 2012-000721-53). All participants received a ventricular catheter and an Ommaya reservoir for drug administration through a neurosurgical procedure, and 10 participants received a MD catheter in parallel to the ventricular catheter for 10 days. The treatment effect was evaluated by regular clinical evaluations and analyses of CSF. The clinical outcome was evaluated through walking and upper-limb function tests, and by clinical evaluation scales. Levels of selected CSF biomarkers were analysed from the same time-points as the clinical evaluations.

    Results: After the completion of the extension trial, one clinical parameter (cognitive performance) showed improvement but could most likely be explained by a learning effect. Worsening of walking speed was observed, while the remaining clinical parameters showed no change. Two severe adverse events occurred in the form of low-virulent bacterial meningitis caused by Propionibacterium, but both were treated effectively with antibiotics without residual symptoms. A ‘spike’ was noticed in the level of lumbar CSF neurofilament light (NFL) following surgery but returned to pre-surgery baseline within 6-12 months. No change was observed for any of the other lumbar CSF biomarkers. No meaningful correlation of protein levels was observed when comparing MD samples, ventricular CSF, and lumbar CSF.

    Conclusions: Intrathecal treatment through intraventricular administration was well tolerated but not without risks. A continued progression was observed in gait impairment. The insertion of the ventricular catheter caused white matter injury, measured through an increase in NFL in lumbar CSF, in direct association with the surgical procedure. No impact was observed on other CSF biomarkers. There was a poor correlation between different CNS compartments regarding protein levels, arguing for caution in drawing conclusions about brain pathophysiology from lumbar CSF samples.

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  • 35.
    Bergman, Joakim
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Burman, Joachim
    Bergenheim, A. Tommy
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital, Danderyd Hospital, Stockholm, Sweden.
    Intrathecal treatment trial of rituximab in progressive MS: results after a 2-year extension2021In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 268, no 2, p. 651-657Article in journal (Refereed)
    Abstract [en]

    Objectives: To evaluate the effect of intrathecally (IT) delivered rituximab as a therapeutic intervention for progressive multiple sclerosis (PMS) during a 3-year follow-up period.

    Methods: Participants of a 1-year open-label phase 1b study of IT delivered rituximab to patients with PMS were offered extended treatment with follow-up for an additional 2 years. During the extension phase, treatment with 25 mg rituximab was administered every 6 months via a subcutaneous Ommaya reservoir connected to the right frontal horn with a ventricular catheter.

    Results: Mild to moderate vertigo and nausea occurred in 4 out of 14 participants as temporary adverse events associated with IT rituximab infusion. During the entire 3-year period, two cases of low-virulent bacterial meningitis occurred, which were successfully treated. Walking speed deteriorated significantly during the study.

    Conclusions: IT administration of rituximab via a ventricular catheter was well tolerated. Considering the meningitis cases, the risk of infection was not negligible. The continued loss of walking speed indicates that IT rituximab was not able to stop disease progression.

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  • 36.
    Bergman, Joakim
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden.
    Liv, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Bergenheim, A. Tommy
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Burman, Joachim
    Location matters: highly divergent protein levels in samples from diferent CNS compartments in a clinical trial of rituximab for progressive MS2020In: Fluids and Barriers of the CNS, E-ISSN 2045-8118, no 1, article id 49Article in journal (Refereed)
    Abstract [en]

    Background: The relationship between proteins in different CNS extracellular compartments is unknown. In this study the levels of selected proteins in three compartments in people with progressive multiple sclerosis (PMS) were compared.

    Methods: During an open label, phase 1b study on intraventricular administration of rituximab for PMS, samples were collected from the interstitial space (ISS) of the brain through microdialysis. Samples were also obtained from ventricular and lumbar cerebrospinal fluid (CSF). These samples were analyzed with a multiplexed proximity extension assay, measuring the levels of 180 proteins split equally between two panels, detecting proteins associated with immunology and neurology, respectively.

    Results: Considerable differences in concentrations were observed between the three analyzed compartments. Compared to ventricular CSF, ISS fluid contained statistically significant higher levels of 25 proteins (84% immunology panel and 16% neurology panel). Ventricular CSF contained significantly higher levels of 54 proteins (31% immunology panel and 69% neurology panel) compared to ISS fluid, and 17 proteins (76% immunology panel and 24% neurology panel) compared to lumbar CSF. Lumbar CSF showed significantly higher levels of 115 proteins (32% immunology panel and 68% neurology panel) compared to ventricular CSF. The three compartments displayed poor correlation with a median Spearman’s rho of -0.1 (IQR 0.4) between ISS and ventricular CSF and 0.3 (IQR 0.4) between ventricular and lumbar CSF.

    Conclusion: A substantial heterogeneity in the protein levels of samples obtained from different CNS compartments was seen. Therefore, data obtained from analysis of lumbar CSF should be interpreted with caution when making conclusions about pathophysiological processes in brain tissue.

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  • 37.
    Birnefeld, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Umeå University, Faculty of Medicine, Department of Diagnostics and Intervention.
    Cerebral hemodynamics in stroke, cerebral small vessel disease and pharmacological interventions: a 4D flow MRI study2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background and aim: Current cerebrovascular imaging techniques provide important information on arterial anatomy and structural pathologies, such as stenoses and occlusions, but physicians are left to infer how the blood flow is affected. In addition, the relationship between blood pressure and cerebral blood flow is complex and poorly understood. Increased transmission of cardiac pulsatility to the cerebral microvasculature has been suggested as a causative factor of cerebral small vessel disease (CSVD) but previous research have yielded conflicting results regarding this relationship. 4D flow magnetic resonance imaging (MRI) is a novel and promising technique enabling time-resolved blood flow quantification with whole-brain coverage and relatively short scan times. However, despite its obvious potential, there is not yet an evidence-based application for the use of 4D flow MRI within stroke or CSVD. This dissertation aimed to apply 4D flow MRI to describe blood flow patterns in posterior circulation stroke and cerebral blood flow responses to common pharmacological agents used to alter arterial blood pressure as well as to examine the relationship between cerebral arterial pulsatility and CSVD.

    Methods and Results: This doctoral dissertation consisted of four papers, referred to by roman numerals. 4D flow MRI and computed tomography angiography (CTA) were applied in 25 patients with acute ischemic stroke in the posterior circulation and a reference population of 15 healthy elderly (paper I). Individual flow profiles were created for each stroke patient and hemodynamic disturbances as well as collateral compensation were described. We show that hemodynamic findings were related to structural findings from CTA.

    The cross-sectional relationship between cerebral arterial pulsatility (quantified using 4D flow MRI as pulsatility index [PI] and flow volume pulsatility [FVP]) and features of CSVD were examined using regression analysis in 89 patients with acute ischemic stroke (paper II) and a population-based sample of 862 elderly (paper III). Internal carotid artery FVP was associated with increasing white matter hyperintensity (WMH) volume in patients with stroke and TIA (paper II). In addition, increasing middle cerebral artery FVP and PI were associated with worse cognitive function. In the population sample, high FVP and PI were associated with increasing WMH volume, lower brain volume and the presence of lacunes, but not the composite MRI-CSVD (paper III). Among subjects with MRI-CSVD, displaying symptoms consistent with cerebral small vessel disease was associated with higher WMH volume, lower brain volume and active smoking, but not any measure of pulsatility.

    Eighteen healthy volunteers were administered noradrenaline to increase mean arterial pressure by 20% above baseline, and labetalol to decrease mean arterial pressure to 15% below baseline (paper IV). Cerebral blood flow was measured using phase-contrast MRI at each blood pressure level and compared to baseline. Despite a marked increase in blood pressure, noradrenaline administration caused a reduction in cerebral blood flow and cardiac output. Meanwhile, labetalol administration caused no change in cerebral blood flow but an increased cardiac output.

    Conclusions: 4D flow MRI can detect hemodynamic disturbances and discriminate between hemodynamic disturbances and normal flow in patients with structural vascular pathologies. This additional information compared to structural imaging alone could potentially be used for prognosis and selection for procedures in clinical care. Cerebral arterial pulsatility is modestly associated with several MRI and clinical features of CSVD but not all. Cerebral arterial pulsatility as the main risk factor of CSVD seems unlikely but its involvement in the pathophysiology cannot be ruled out. Raising the blood pressure with noradrenaline decreases cerebral blood flow and cardiac output without any redistribution from peripheral to cerebral flow. This highlights the pitfalls of using blood pressure as a surrogate for cerebral blood flow and questions the validity of our understanding of cerebral autoregulation. Lowering the blood pressure with labetalol does not affect cerebral blood flow, reassuring its use in clinical routine. 4D flow MRI can be integrated into an in-patient work-up in selected cases of acute ischemic stroke and into the workflow of large epidemiological studies.

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  • 38.
    Birnefeld, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Hansson, William
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Larsson, Jenny
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Björnfot, Cecilia
    Qvarlander, Sara
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF). Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Associations of cerebral arterial pulsatility, clinical symptoms and imaging features of cerebral small vessel diseaseManuscript (preprint) (Other academic)
  • 39.
    Birnefeld, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Petersson, Karl
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF). Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Eklund, Anders
    Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Birnefeld, Elin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Qvarlander, Sara
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Haney, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Zarrinkoob, Laleh
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Cerebral blood flow assessed with phase-contrast magnetic resonance imaging during blood pressure changes with noradrenaline and labetalol: a trial in healthy volunteers 2024In: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 140, no 4, p. 669-678Article in journal (Refereed)
    Abstract [en]

    Background: Adequate cerebral perfusion is central during general anesthesia. However, perfusion is not readily measured bedside. Clinicians currently rely mainly on MAP as a surrogate even though the relationship between blood pressure and cerebral blood flow is not well understood. The aim of this study was to apply phase contrast MRI to characterize blood flow responses in healthy volunteers to commonly used pharmacological agents that increase or decrease arterial blood pressure.

    Methods: Eighteen healthy volunteers aged 30-50 years were investigated with phase contrast MRI. Intraarterial blood pressure monitoring was used. First, intravenous noradrenaline was administered to a target MAP of 20% above baseline. After a wash-out period, intravenous labetalol was given to a target MAP of 15% below baseline. Cerebral blood flow was measured using phase contrast MRI and defined as the sum of flow in the internal carotid arteries and vertebral arteries. CO was defined as the flow in the ascending aorta.

    Baseline median cerebral blood flow was 772 ml/min (interquartile range, 674 to 871), and CO was 5,874 ml/min (5,199 to 6,355). The median dose of noradrenaline was 0.17 µg · kg−1 · h−1 (0.14 to 0.22). During noradrenaline infusion, cerebral blood flow decreased to 705 ml/min (606 to 748; P = 0.001), and CO decreased to 4,995 ml/min (4,705 to 5,635; P = 0.01). A median dose of labetalol was 120 mg (118 to 150). After labetalol boluses, cerebral blood flow was unchanged at 769 ml/min (734 to 900; P = 0.68). CO increased to 6,413 ml/min (6,056 to 7,464; P = 0.03).

    Conclusion: In healthy awake subjects, increasing MAP using intravenous noradrenaline decreased cerebral blood flow and CO. This data does not support inducing hypertension with noradrenaline to increase cerebral blood flow. Cerebral blood flow was unchanged when decreasing MAP using labetalol.

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  • 40.
    Birnefeld, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. 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.
    Cerebral arterial pulsatility is associated with features of small vessel disease in patients with acute stroke and TIA: a 4D flow MRI study2020In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 267, no 3, p. 721-730Article in journal (Refereed)
    Abstract [en]

    Cerebral small vessel disease (SVD) is a major cause of stroke and cognitive impairment. However, the underlying mechanisms behind SVD are still poorly understood. High cerebral arterial pulsatility has been suggested as a possible cause of SVD. In population studies, arterial pulsatility has been linked to white matter hyperintensities (WMH), cerebral atrophy, and cognitive impairment, all features of SVD. In stroke, pulsatility data are scarce and contradictory. The aim of this study was to investigate the relationship between arterial pulsatility and SVD in stroke patients. With a cross-sectional design, 89 patients with acute ischemic stroke or TIA were examined with MRI. A neuropsychological assessment was performed 1 year later. Using 4D flow MRI, pulsatile indices (PI) were calculated for the internal carotid artery (ICA) and middle cerebral artery (M1, M3). Flow volume pulsatility (FVP), a measure corresponding to the cyclic expansion of the arterial tree, was calculated for the same locations. These parameters were assessed for associations with WMH volume, brain volume and cognitive function. ICA-FVP was associated with WMH volume (β = 1.67, 95% CI: [0.1, 3.24], p = 0.037). M1-PI and M1-FVP were associated with decreasing cognitive function (β = - 4.4, 95% CI: [- 7.7, - 1.1], p = 0.009 and β = - 13.15, 95% CI: [- 24.26, - 2.04], p = 0.02 respectively). In summary, this supports an association between arterial pulsatility and SVD in stroke patients, and provides a potential target for further research and preventative treatment. FVP may become a useful biomarker for assessing pulsatile stress with PCMRI and 4D flow MRI.

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  • 41.
    Biström, Martin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Environmental risk factors for the occurrence of multiple sclerosis2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background. Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system that typically debuts around age 30. About 2.3 million people are affected in the world today, and besides trauma it is the most common cause of neurological disability among young adults in the western world. The disease likely develops via a complex interplay of genetic vulnerability and environmental risk factors, and adolescence is assumed to be a critical time for disease initiation. The aim of this study was to investigate how MS risk in different age groups is influenced by vitamin D, infections with Epstein-Barr virus and Human herpesviruses 6A and B as well as the metabolic markers leptin and insulin.

    Methods. In this nested case-control study we identified pre-symptomatically drawn blood samples from individuals below age 40, that later developed relapsing remitting MS. This was done through crosslinking of the Swedish MS registry, or a local database, with six Swedish biobanks containing remainders of samples used in microbiological analyses. For each case, one control matched for biobank, sex, date of sampling and age of sampling was selected. These samples were then analysed to determine antibody reactivity against Epstein-Barr virus and Human herpesvirus 6A and B, as well as measure concentrations of leptin, insulin and 25-hydroxyvitamin D. The effect of these variables on MS risk was estimated using conditional logistic regression, both in the entire case-control material as well as stratified into three groups by age at sampling (<20, 20-29 and 30-39) and by sex.

    Results. Human herpesvirus 6A, but not B, was consistently associated with an increased risk of developing MS. In contrast, Epstein-Barr virus demonstrated an age dependent pattern indicating that early infection may be protective against MS while later infection increases the risk. As for the metabolic markers, insulin was not associated with MS while elevated levels of leptin showed an association with increased MS risk both among individuals below 20 years of age and among all men. For women there was instead an inverse association in the oldest group, aged 30-39, when adjusting the leptin analysis for insulin concentrations. Finally, having vitamin D concentrations in the top quintile was associated with decreased MS risk, without evidence of a stronger effect in young subjects.

    Conclusion. These results implicate Human herpesvirus 6A and leptin as risk factors for MS development. They also further support a protective role for vitamin D in MS etiology and provide serological evidence of an age dependency of Epstein-Barr virus infection as it relates to MS risk.

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  • 42.
    Biström, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Oluf
    Alonso-Magdalena, Lucia
    Jons, Daniel
    Gunnarsson, Martin
    Vrethem, Magnus
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Leptin levels are associated with multiple sclerosis risk2021In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 27, no 1, p. 19-27Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Obesity early in life has been linked to increased risk of developing multiple sclerosis (MS). Leptin and insulin are both associated with obesity, making them suitable candidates for investigating this connection.

    OBJECTIVE: To determine if leptin and insulin are risk factors for relapsing-remitting multiple sclerosis (RRMS).

    METHODS: In this nested case-control study using blood samples from Swedish biobanks, we compared concentrations of leptin and insulin in 649 individuals who later developed RRMS with 649 controls matched for biobank, sex, age and date of sampling. Only pre-symptomatically drawn samples from individuals below the age of 40 years were included. Conditional logistic regression was performed on z-scored values to calculate odds ratios (ORs) with 95% confidence intervals (CIs).

    RESULTS: A 1-unit leptin z-score increase was associated with increased risk of MS in individuals younger than 20 years (OR = 1.4, 95% CI = 1.1-1.9) and in all men (OR = 1.4, 95% CI = 1.0-2.0). In contrast, for women aged 30-39 years, there was a lower risk of MS with increased leptin levels (OR = 0.74, 95% CI = 0.54-1.0) when adjusting for insulin levels.

    CONCLUSION: We show that the pro-inflammatory adipokine leptin is a risk factor for MS among young individuals.

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  • 43.
    Biström, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Response to 'Mendelian randomization analysis does not support a role for leptin in multiple sclerosis'2021In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 27, no 1, p. 161-162Article in journal (Refereed)
  • 44.
    Biström, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Jons, Daniel
    Engdahl, Elin
    Gustafsson, Rasmus
    Huang, Jesse
    Brenner, Nicole
    Butt, Julia
    Alonso-Magdalena, Lucia
    Gunnarsson, Martin
    Vrethem, Magnus
    Bender, Noemi
    Waterboer, Tim
    Granåsen, Gabriel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Olsson, Tomas
    Kockum, Ingrid
    Andersen, Oluf
    Fogdell-Hahn, Anna
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Epstein-Barr virus infection after adolescence and Human herpesvirus 6A as risk factors for multiple sclerosis2021In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 28, no 2, p. 579-586Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Infections with human herpesvirus 6A (HHV‐6A) and Epstein–Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV‐6A associated risks of developing MS.

    Methods:  In this nested case–control study, Swedish biobanks were accessed to find pre‐symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead‐based multiplex assay was used to determine serological response against EBV and HHV‐6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals.

    Results: Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20–29 and 30–39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV‐6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6–2.7).

    Conclusions: This study suggests EBV infection after adolescence and age independent HHV‐6A infection as risk factors for MS.

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  • 45.
    Björkblom, Benny
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergenheim, A. Tommy
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Sjöberg, Rickard L.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sandström, Maria
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Distinct metabolic hallmarks of WHO classified adult glioma subtypes2022In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 24, no 9, p. 1454-1468, article id noac042Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Gliomas are complex tumors with several genetic aberrations and diverse metabolic programs contributing to their aggressive phenotypes and poor prognoses. This study defines key metabolic features that can be used to differentiate between glioma subtypes, with potential for improved diagnostics and subtype targeted therapy.

    METHODS: Cross-platform global metabolomic profiling coupled with clinical, genetic, and pathological analysis of glioma tissue from 224 tumors - oligodendroglioma (n=31), astrocytoma (n=31) and glioblastoma (n=162) - were performed. Identified metabolic phenotypes were evaluated in accordance with the WHO classification, IDH-mutation, 1p/19q-codeletion, WHO-grading 2-4, and MGMT promoter methylation.

    RESULTS: Distinct metabolic phenotypes separate all six analyzed glioma subtypes. IDH-mutated subtypes, expressing 2-hydroxyglutaric acid, were clearly distinguished from IDH-wildtype subtypes. Considerable metabolic heterogeneity outside of the mutated IDH pathway were also evident, with key metabolites being high expression of glycerophosphates, inositols, monosaccharides and sugar alcohols and low levels of sphingosine and lysoglycerophospholipids in IDH-mutants. Among the IDH-mutated subtypes, we observed high levels of amino acids, especially glycine and 2-aminoadipic acid, in grade 4 glioma, and N-acetyl aspartic acid in low-grade astrocytoma and oligodendroglioma. Both IDH-wildtype and mutated oligodendroglioma and glioblastoma were characterized by high levels of acylcarnitines, likely driven by rapid cell growth and hypoxic features. We found elevated levels of 5-HIAA in gliosarcoma and a subtype of oligodendroglioma not yet defined as a specific entity, indicating a previously not described role for the serotonin pathway linked to glioma with bimorphic tissue.

    CONCLUSION: Key metabolic differences exist across adult glioma subtypes.

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  • 46.
    Björnebäck, Alexandra
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Kärlreaktivitet vid karotisstenos.2022Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 47.
    Björnfot, Cecilia
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Medicine, Department of Diagnostics and Intervention.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Medicine, Department of Diagnostics and Intervention.
    Larsson, Jenny
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Hansson, William
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Birnefeld, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Garpebring, Anders
    Umeå University, Faculty of Medicine, Department of Diagnostics and Intervention.
    Qvarlander, Sara
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Medicine, Department of Diagnostics and Intervention.
    Koskinen, Lars-Owe D.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Medicine, Department of Diagnostics and Intervention.
    Cerebral arterial stiffness is linked to white matter hyperintensities and perivascular spaces in older adults: a 4D flow MRI study2024In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016Article in journal (Refereed)
    Abstract [en]

    White matter hyperintensities (WMH), perivascular spaces (PVS) and lacunes are common MRI features of small vessel disease (SVD). However, no shared underlying pathological mechanism has been identified. We investigated whether SVD burden, in terms of WMH, PVS and lacune status, was related to changes in the cerebral arterial wall by applying global cerebral pulse wave velocity (gcPWV) measurements, a newly described marker of cerebral vascular stiffness. In a population-based cohort of 190 individuals, 66–85 years old, SVD features were estimated from T1-weighted and FLAIR images while gcPWV was estimated from 4D flow MRI data. Additionally, the gcPWV’s stability to variations in field-of-view was analyzed. The gcPWV was 10.82 (3.94) m/s and displayed a significant correlation to WMH and white matter PVS volume (r = 0.29, p < 0.001; r = 0.21, p = 0.004 respectively from nonparametric tests) that persisted after adjusting for age, blood pressure variables, body mass index, ApoB/A1 ratio, smoking as well as cerebral pulsatility index, a previously suggested early marker of SVD. The gcPWV displayed satisfactory stability to field-of-view variations. Our results suggest that SVD is accompanied by changes in the cerebral arterial wall that can be captured by considering the velocity of the pulse wave transmission through the cerebral arterial network.

  • 48.
    Björnfot, Cecilia
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Garpebring, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Qvarlander, Sara
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Assessing cerebral arterial pulse wave velocity using 4D flow MRI2021In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 41, no 10, p. 2769-2777Article in journal (Refereed)
    Abstract [en]

    Intracranial arterial stiffening is a potential early marker of emerging cerebrovascular dysfunction and could be mechanistically involved in disease processes detrimental to brain function via several pathways. A prominent consequence of arterial wall stiffening is the increased velocity at which the systolic pressure pulse wave propagates through the vasculature. Previous non-invasive measurements of the pulse wave propagation have been performed on the aorta or extracranial arteries with results linking increased pulse wave velocity to brain pathology. However, there is a lack of intracranial “target-organ” measurements. Here we present a 4D flow MRI method to estimate pulse wave velocity in the intracranial vascular tree. The method utilizes the full detectable branching structure of the cerebral vascular tree in an optimization framework that exploits small temporal shifts that exists between waveforms sampled at varying depths in the vasculature. The method is shown to be stable in an internal consistency test, and of sufficient sensitivity to robustly detect age-related increases in intracranial pulse wave velocity.

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  • 49.
    Blomstedt, Yulia
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Stenmark Persson, Rasmus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Awad, Amar
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Hariz, Gun-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Philipson, Johanna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. UCL Institute of Neurology, Queen Square, London, United Kingdom.
    Fytagoridis, Anders
    Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    10 years follow-up of deep brain stimulation in the caudal zona incerta/posterior subthalamic area for essential tremor2023In: Movement Disorders Clinical Practice, E-ISSN 2330-1619, Vol. 10, no 5, p. 783-793Article in journal (Refereed)
    Abstract [en]

    Background: Long-term data on the effects of deep brain stimulation (DBS) for essential tremor (ET) is scarce, especially regarding DBS in the caudal Zona incerta (cZi) and the posterior subthalamic area (PSA). Objectives: The aim of this prospective study was to evaluate the effect of cZi/PSA DBS in ET at 10 years after surgery.

    Methods: Thirty-four patients were included. All patients received cZi/PSA DBS (5 bilateral/29 unilateral) and were evaluated at regular intervals using the essential tremor rating scale (ETRS).

    Results: One year after surgery, there was a 66.4% improvement of total ETRS and 70.7% improvement of tremor (items 1–9) compared with the preoperative baseline. Ten years after surgery, 14 patients had died and 3 were lost to follow-up. In the remaining 17 patients, a significant improvement was maintained (50.8% for total ETRS and 55.8% for tremor items). On the treated side the scores of hand function (items 11–14) had improved by 82.6% at 1 year after surgery, and by 66.1% after 10 years. Since off-stimulation scores did not differ between year 1 and 10, this 20% deterioration of on-DBS scores was interpreted as a habituation. There was no significant increase in stimulation parameters beyond the first year.

    Conclusions: This 10 year follow up study, found cZi/PSA DBS for ET to be a safe procedure with a mostly retained effect on tremor, compared to 1 year after surgery, and in the absence of increase in stimulation parameters. The modest deterioration of effect of DBS on tremor was interpreted as habituation.

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  • 50.
    Bluett, Brent
    et al.
    Central California Movement Disorders, CA, Pismo Beach, United States.
    Ash, Elissa
    Department of Neurology, Faculty of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
    Farheen, Amtul
    Department of Neurology, Lebanon VA Medical Center, PA, Lebanon, United States; Department of Neurology, Penn State Hershey Medical Center, PA, Hershey, United States.
    Fasano, Alfonso
    Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, ON, Toronto, Canada; Krembil Brain Institute, University Health Network, ON, Toronto, Canada; Howard Cohen Normal Pressure Hydrocephalus Program, University Health Network, Toronto Western Hospital, ON, Toronto, Canada; Department of Medicine, Division of Neurology, University of Toronto, ON, Toronto, Canada.
    Krauss, Joachim K.
    Department of Neurosurgery, Medical School Hannover, Hannover, Germany.
    Maranzano, Alessio
    Department of Neurology, Istituto Auxologico Italiano IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
    Passaretti, Massimiliano
    Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.
    Tang-Wai, David F.
    Krembil Brain Institute, University Health Network, ON, Toronto, Canada; Howard Cohen Normal Pressure Hydrocephalus Program, University Health Network, Toronto Western Hospital, ON, Toronto, Canada; Department of Medicine, Division of Neurology, University of Toronto, ON, Toronto, Canada; University Health Network Memory Clinic, Toronto Western Hospital, ON, Toronto, Canada.
    Van Gerpen, Jay
    Department of Neurology, University of Alabama at Birmingham, AL, Huntsville, United States.
    Alonso-Canovas, Araceli
    Movement Disorders Unit. Neurology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.
    Youn, Jinyoung
    Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Martino, Davide
    Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, AB, Calgary, Canada.
    Clinical features of idiopathic normal pressure hydrocephalus: critical review of objective findings2023In: Movement Disorders Clinical Practice, E-ISSN 2330-1619, Vol. 10, no 1, p. 9-16Article, review/survey (Refereed)
    Abstract [en]

    Background: Idiopathic normal pressure hydrocephalus (iNPH) is characterized by the classic clinical triad of gait, cognitive, and urinary dysfunction, albeit incomplete in a relevant proportion of patients. The clinical findings and evolution of these symptoms have been variably defined in the literature.

    Objectives: To evaluate how the phenomenology has been defined, assessed, and reported, we performed a critical review of the existing literature discussing the phenomenology of iNPH. The review also identified the instrumental tests most frequently used and the evolution of clinical and radiologic findings.

    Methods: The review was divided into 3 sections based on gait, cognitive, and urinary dysfunction. Each section performed a literature search using the terms “idiopathic normal pressure hydrocephalus” (iNPH), with additional search terms used by each section separately. The number of articles screened, duplicates, those meeting the inclusion criteria, and the number of articles excluded were recorded. Findings were subsequently tallied and analyzed.

    Results: A total of 1716 articles with the aforementioned search criteria were identified by the 3 groups. A total of 81 full-text articles were reviewed after the elimination of duplicates, articles that did not discuss phenomenological findings or instrumental testing of participants with iNPH prior to surgery, and articles with fewer than 10 participants.

    Conclusions: “Wide-based gait” was the most common gait dysfunction identified. Cognitive testing varied significantly across articles, and ultimately a specific cognitive profile was not identified. Urodynamic testing found detrusor overactivity and “overactive bladder” as the most common symptom of urinary dysfunction.

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