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  • 1. Abel, Olubunmi
    et al.
    Shatunov, Aleksey
    Jones, Ashley R.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Powell, John F.
    Al-Chalabi, Ammar
    Development of a Smartphone App for a Genetics Website: The Amyotrophic Lateral Sclerosis Online Genetics Database (ALSoD)2013In: JMIR mhealth and uhealth, E-ISSN 2291-5222, Vol. 1, no 2, article id e18Article in journal (Refereed)
    Abstract [en]

    Background: The ALS Online Genetics Database (ALSoD) website holds mutation, geographical, and phenotype data on genes implicated in amyotrophic lateral sclerosis (ALS) and links to bioinformatics resources, publications, and tools for analysis. On average, there are 300 unique visits per day, suggesting a high demand from the research community. To enable wider access, we developed a mobile-friendly version of the website and a smartphone app. Objective: We sought to compare data traffic before and after implementation of a mobile version of the website to assess utility. Methods: We identified the most frequently viewed pages using Google Analytics and our in-house analytic monitoring. For these, we optimized the content layout of the screen, reduced image sizes, and summarized available information. We used the Microsoft. NET framework mobile detection property (HttpRequest. IsMobileDevice in the Request. Browser object in conjunction with HttpRequest. UserAgent), which returns a true value if the browser is a recognized mobile device. For app development, we used the Eclipse integrated development environment with Android plug-ins. We wrapped the mobile website version with the WebView object in Android. Simulators were downloaded to test and debug the applications. Results: The website automatically detects access from a mobile phone and redirects pages to fit the smaller screen. Because the amount of data stored on ALSoD is very large, the available information for display using smartphone access is deliberately restricted to improve usability. Visits to the website increased from 2231 to 2820, yielding a 26% increase from the pre-mobile to post-mobile period and an increase from 103 to 340 visits (230%) using mobile devices (including tablets). The smartphone app is currently available on BlackBerry and Android devices and will be available shortly on iOS as well. Conclusions: Further development of the ALSoD website has allowed access through smartphones and tablets, either through the website or directly through a mobile app, making genetic data stored on the database readily accessible to researchers and patients across multiple devices.

  • 2.
    Ahmadi, Mahboobah
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Liu, Jing-Xia
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Stål, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Human extraocular muscles in ALS2010In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 51, no 7, p. 3494-3501Article in journal (Refereed)
    Abstract [en]

    PURPOSE. To investigate the general morphology, fiber type content, and myosin heavy chain (MyHC) composition of extraocular muscles (EOMs) from postmortem donors with amyotrophic lateral sclerosis (ALS) and to evaluate whether EOMs are affected or truly spared in this disease. METHODS. EOM and limb muscle samples obtained at autopsy from ALS donors and EOM samples from four control donors were processed for immunohistochemistry with monoclonal antibodies against distinct MyHC isoforms and analyzed by SDS-PAGE. In addition, hematoxylin and eosin staining and nicotinamide tetrazolium reductase (NADH-TR) activity were studied. RESULTS. Wide heterogeneity was observed in the appearance of the different EOMs from each single donor and between donors, irrespective of ALS type or onset. Pathologic morphologic findings in ALS EOMs included presence of atrophic and hypertrophic fibers, either clustered in groups or scattered; increased amounts of connective tissue; and areas of fatty replacement. The population of fibers stained with anti-MyHCslow tonic was smaller than that of MyHCIpositive fibers and was mostly located in the orbital layer in most of the ALS EOM samples, whereas an identical staining pattern for both fiber populations was observed in the control specimens. MyHCembryonic was notably absent from the ALS EOMs. CONCLUSIONS. The EOMs showed signs of involvement with altered fiber type composition, contractile protein content, and cellular architecture. However, when compared to the limb muscles, the EOMs were remarkably preserved. EOMs are a useful model for the study of the pathophysiology of ALS.

  • 3.
    Ambarki, Khalid
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Israelsson, Hanna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Brain ventricular size in healthy elderly: comparison between evans index and volume measurement.2010In: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 67, no 1, p. 94-99Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A precise definition of ventricular enlargement is important in the diagnosis of hydrocephalus as well as in assessing central atrophy. The Evans index (EI), a linear ratio between the maximal frontal horn width and the cranium diameter, has been extensively used as an indirect marker of ventricular volume (VV). With modern imaging techniques, brain volume can be directly measured. OBJECTIVE: To determine reference values of intracranial volumes in healthy elderly individuals and to correlate volumes with the EI. METHODS: Magnetic resonance imaging (3 T) was performed in 46 healthy white elderly subjects (mean age +/- standard deviation, 71 +/- 6 years) and in 20 patients (74 +/- 7 years) with large ventricles according to visual inspection. VV, relative VV (RVV), and EI were assessed. Ventricular dilation was defined using VV and EI by a value above the 95th percentile range for healthy elderly individuals. RESULTS: In healthy elderly subjects, we found VV = 37 +/- 18 mL, RVV = 2.47 +/- 1.17%, and EI = 0.281 +/- 0.027. Including the patients, there was a strong correlation between EI and VV (R = 0.94) as well as between EI and RVV (R = 0.95). However, because of a wide 95% prediction interval (VV: +/-45 mL; RVV: +/- 2.54%), EI did not give a sufficiently good estimate of VV and RVV. CONCLUSION: VV (or RVV) and the EI reflect different properties. The exclusive use of EI in clinical studies as a marker of enlarged ventricles should be questioned. We suggest that the definition of dilated ventricles in white elderly individuals be defined as VV >77 mL or RVV >4.96 %. Future studies should compare intracranial volumes with clinical characteristics and prognosis.

  • 4.
    Andersen, Peter
    et al.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Borasio, G D
    Dengler, R
    Hardiman, O
    Kollewe, K
    Leigh, P N
    Pradat, P-F
    Silani, V
    Tomik, B
    EFNS task force on management of amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients and relatives.2005In: European journal of neurology, ISSN 1351-5101, Vol. 12, no 12, p. 921-38Article in journal (Refereed)
  • 5.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene.2006In: Current neurology and neuroscience reports, ISSN 1528-4042, Vol. 6, no 1, p. 37-46Article in journal (Other academic)
  • 6.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Amyotrophic lateral sclerosis genetics with Mendelian inheritance2006In: Amyotrophic Lateral Sclerosis, Martin Dunitz Publishers Ltd, London , 2006, p. 187-208Chapter in book (Other (popular science, discussion, etc.))
  • 7.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    The genetics of amyotrophic lateral sclerosis (ALS)2004In: Advances in Clinical Neurophysiology: Proceedings of the 27th International Congress of Clinical Neurophysiology, AAEM 50th Anniversary and 57th Annual Meeting of the ACNS Joint Meeting, San Francisco, CA, USA, 15-20 September 2003, Elsevier, Amsterdam , 2004, p. 211-224Chapter in book (Other (popular science, discussion, etc.))
  • 8.
    Andersen, Peter M
    et al.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Restagno, Gabriella
    Stewart, Heather G
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Chiò, Adriano
    Disease penetrance in amyotrophic lateral sclerosis associated with mutations in the SOD1 gene.2004In: Ann Neurol, ISSN 0364-5134, Vol. 55, no 2, p. 298-9; author reply 299Article in journal (Refereed)
  • 9.
    Andersen, Peter Munch
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    The genetics of amyotrophic lateral sclerosis (ALS).2004In: Suppl Clin Neurophysiol, ISSN 1567-424X, Vol. 57, p. 211-27Article in journal (Refereed)
  • 10.
    Andersen, Peter Munch
    et al.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Borasio, Gian Domenico
    Dengler, Reinhard
    Hardiman, Orla
    Kollewe, Katja
    Leigh, Peter Nigel
    Pradat, Pierre-Francois
    Silani, Vincenzo
    Tomik, Barbara
    Good practice in the management of amyotrophic lateral sclerosis: clinical guidelines. An evidence-based review with good practice points. EALSC Working Group.2007In: Amyotrophic lateral sclerosis, ISSN 1748-2968, Vol. 8, no 4, p. 195-213Article in journal (Other academic)
  • 11.
    Andersson, Kennet
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Manchester, Ian R
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Andersson, Nina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Shiriaev, Anton
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Assessment of cerebrospinal fluid outflow conductance using an adaptive observer-experimental and clinical evaluation2007In: Physiological Measurement, ISSN 0967-3334, E-ISSN 1361-6579, Vol. 28, no 11, p. 1355-1368Article in journal (Refereed)
    Abstract [en]

    Idiopathic normal pressure hydrocephalus (INPH) patients have a disturbance in the dynamics of the cerebrospinal fluid (CSF) system. The outflow conductance, C, of the CSF system has been suggested to be prognostic for positive outcome after treatment with a CSF shunt. All current methods for estimation of C have drawbacks; these include lack of information on the accuracy and relatively long investigation times. Thus, there is a need for improved methods. To accomplish this, the theoretical framework for a new adaptive observer (OBS) was developed which provides real-time estimation of C. The aim of this study was to evaluate the OBS method and to compare it with the constant pressure infusion (CPI) method. The OBS method was applied to data from infusion investigations performed with the CPI method. These consisted of repeated measurements on an experimental set-up and 30 patients with suspected INPH. There was no significant difference in C between the CPI and the OBS method for the experimental set-up. For the patients there was a significant difference, −0.84 ± 1.25 µl (s kPa)−1, mean ± SD (paired sample t-test, p < 0.05). However, such a difference is within clinically acceptable limits. This encourages further development of this new real-time approach for estimation of the outflow conductance.

  • 12.
    Andersson, Kennet
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Manchester, Ian R
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    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, Radiation Physics.
    Real-time estimation of cerebrospinal fluid system parameters via oscillating pressure infusion2010In: Medical and Biological Engineering and Computing, ISSN 0140-0118, E-ISSN 1741-0444, Vol. 48, no 11, p. 1123-1131Article in journal (Refereed)
    Abstract [en]

    Hydrocephalus is related to a disturbed cerebrospinal fluid (CSF) system. For diagnosis, lumbar infusion test are performed to estimate outflow conductance, C (out), and pressure volume index, PVI, of the CSF system. Infusion patterns and analysis methods used in current clinical practice are not optimized. Minimizing the investigation time with sufficient accuracy is of major clinical relevance. The aim of this study was to propose and experimentally evaluate a new method, the oscillating pressure infusion (OPI). The non-linear model of the CSF system was transformed into a linear time invariant system. Using an oscillating pressure pattern and linear system identification methods, C (out) and PVI with confidence intervals, were estimated in real-time. Forty-two OPI and constant pressure infusion (CPI) investigations were performed on an experimental CSF system, designed with PVI = 25.5 ml and variable C (out). The ARX model robustly estimated C (out) (mean C (out,OPI) - C (out,CPI) = 0.08 μl/(s kPa), n = 42, P = 0.68). The Box-Jenkins model proved most reliable for PVI (23.7 ± 2.0 ml, n = 42). The OPI method, with its oscillating pressure pattern and new parameter estimation methods, efficiently estimated C (out) and PVI as well as their confidence intervals in real-time. The results from this experimental study show potential for the OPI method and supports further evaluation in a clinical setting.

  • 13.
    Andersson, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology. Neurologi.
    Bäcklund, Tomas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Assessment of cerebrospinal fluid outflow conductance using constant-pressure infusion - a method with real time estimation of reliability2005In: Physiological Measurement, ISSN 0967-3334, E-ISSN 1361-6579, Vol. 26, no 6, p. 1137-1148Article in journal (Refereed)
  • 14.
    Andersson, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Department of Biomedical Engineering and Informatics, Umeå University Hospital.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Department of Biomedical Engineering and Informatics, Umeå University Hospital.
    Dependency of cerebrospinal fluid outflow resistance on intracranial pressure2008In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 109, no 5, p. 918-922Article in journal (Refereed)
    Abstract [en]

    OBJECT: The outflow resistance (Rout) of the cerebrospinal fluid (CSF) system has generally been accepted by most investigators as independent of intracranial pressure (ICP), but there are also those claiming that it is not. The general belief is that this question has been investigated numerous times in the past, but few studies have actually been specifically aimed at looking at this relationship, and no study has been able to provide scientific evidence to elucidate fully this fundamental and important issue. The objective of this study was to investigate the relationship between ICP and CSF outflow in 30 patients investigated for idiopathic normal-pressure hydrocephalus. METHODS: Lumbar infusion tests with constant pressure levels were performed, and ICP and corresponding flow were measured on 6 pressure levels for each patient. All data were standardized for comparison. RESULTS: In the range of moderate increases from baseline pressure (approximately 5-12 mm Hg, mean baseline pressure 11.7 mm Hg), the assumption of a pressure-independent Rout was confirmed (p = 0.5). However, when the pressure increment from baseline pressure was larger (approximately 15-22 mm Hg), the relationship had a nonlinear tendency (p < 0.05). CONCLUSIONS: The results of this study support the classic textbook theory of a pressure-independent Rout in the normal ICP range, where the CSF system is commonly operating. However, the theory might have to be questioned in regions where ICP exceeds baseline pressure by too much.

  • 15.
    Andersson, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Adaptive method for assessment of cerebrospinal fluid outflow conductance.2007In: Medical and Biological Engineering and Computing, ISSN 0140-0118, E-ISSN 1741-0444, Vol. 45, no 4, p. 337-343Article in journal (Refereed)
    Abstract [en]

    Outflow conductance (C out) is important for predicting shunt responsiveness in patients with suspected idiopathic adult hydrocephalus syndrome (IAHS). C out is determined by performing an infusion test into the cerebrospinal fluid system, and the reliability of the test is dependent on the measurement time. The objective of this study was to develop an adaptive signal analysis method to reduce the investigation time, by taking the individual intracranial pressure variations of the patient into consideration. The method was evaluated on 28 patients with suspected IAHS. The results from full time investigations (60 min) were compared to the results of the new algorithm. Applying the new adaptive method resulted in a reduction of mean investigation time by 14.3 ± 5.9 min (mean ± SD), p < 0.01. The reduction of reliability in the C out estimation was found clinically negligible. We thus recommend this adaptive method to be used when performing constant pressure infusion tests.

  • 16.
    Arnell, Kai
    et al.
    Department of Paediatric Surgery, University Hospital, Uppsala.
    Koskinen, Lars-Owe D
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Eklund, Anders
    Evaluation of Strata NSC and Codman Hakim adjustable cerebrospinal fluid shunts and their corresponding antisiphon devices: laboratory investigation2009In: Journal of Neurosurgery: Pediatrics, ISSN 1933-0707, E-ISSN 1933-0715, Vol. 3, no 3, p. 166-172Article in journal (Refereed)
    Abstract [en]

    OBJECT: The authors investigated and compared the in vitro characteristics of 2 CSF shunts, the Strata NSC and the Codman Hakim, and their corresponding antisiphon devices (ASDs).

    METHODS: Six new CSF shunts and the corresponding ASDs for each model were tested in an automated, computerized experimental setup based on pressure regulation. Opening pressure accuracy, resistance, sensitivity to abdominal pressure, antisiphon effect, and the influence of different ASD positions were determined.

    RESULTS: In general the shunts performed according to the manufacturers' specifications. However, at the lowest setting, the opening pressure of the Strata NSC was close to 0, and in the Codman Hakim shunt, it was higher than specified. The resistance in the Codman Hakim shunt (5.4 mm Hg/ml/min) was much higher than that in the Strata NSC (3.6 mm Hg/ml/min). Abdominal pressure affected opening pressure in both valves. Positioning the Strata ASD above or below the ventricular catheter tip resulted in higher and lower opening pressures, respectively, than when it was placed in line with the catheter. The positioning of the Codman Hakim ASD did not influence the opening pressure.

    CONCLUSIONS: Both CSF shunts work properly, but at the lowest setting the opening pressure of the Strata NSC was near 0 and in the Codman Hakim it was twice the manufacturer's specifications. The resistance in the Strata NSC was below the normal physiological range, and in the Codman Hakim device it was in the lower range of normal. The ASD did not change the shunt characteristics in the lying position and therefore might not do so in children. If this is the case, then a shunt system with an integrated ASD could be implanted at the first shunt insertion, thus avoiding a second operation and the possibility of infection.

  • 17. Beghi, Ettore
    et al.
    Berg, Anne
    Carpio, Arturo
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Hesdorffer, Dale C
    Hauser, W Allen
    Malmgren, Kristina
    Shinnar, Shlomo
    Temkin, Nancy
    Thurman, David
    Tomson, Torbjörn
    Comment on epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE).2005In: Epilepsia, ISSN 0013-9580, Vol. 46, no 10, p. 1698-9; author reply 1701Article in journal (Other academic)
  • 18. Beghi, Ettore
    et al.
    Carpio, Arturo
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Hesdorffer, Dale C
    Malmgren, Kristina
    Sander, Josemir W
    Tomson, Torbjorn
    Hauser, W Allen
    Recommendation for a definition of acute symptomatic seizure2010In: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 51, no 4, p. 671-675Article in journal (Refereed)
    Abstract [en]

    Acute symptomatic seizures must be distinguished from unprovoked seizures and separately categorized for epidemiologic purposes. These recommendations are based upon the best available data at the time of this report. Systematic studies should be undertaken to better define the associations in question, with special reference to metabolic and toxic insults, for which the time window for the occurrence of an acute symptomatic seizure and the absolute values for toxic and metabolic dysfunction still require a clear identification.

  • 19.
    Behrens, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Lenfeldt, Niklas
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Ambarki, Khalid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Koskinen, Lars-Owe
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Transcranial Doppler pulsatility index: not an accurate method to assess intracranial pressure.2010In: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 66, no 6, p. 1050-1057Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Transcranial Doppler sonography (TCD) assessment of intracranial blood flow velocity has been suggested to accurately determine intracranial pressure (ICP). OBJECTIVE: We attempted to validate this method in patients with communicating cerebrospinal fluid systems using predetermined pressure levels. METHODS: Ten patients underwent a lumbar infusion test, applying 4 to 5 preset ICP levels. On each level, the pulsatility index (PI) in the middle cerebral artery was determined by measuring the blood flow velocity using TCD. ICP was simultaneously measured with an intraparenchymal sensor. ICP and PI were compared using correlation analysis. For further understanding of the ICP-PI relationship, a mathematical model of the intracranial dynamics was simulated using a computer. RESULTS: The ICP-PI regression equation was based on data from 8 patients. For 2 patients, no audible Doppler signal was obtained. The equation was ICP = 23*PI + 14 (R = 0.22, P < .01, N = 35). The 95% confidence interval for a mean ICP of 20 mm Hg was -3.8 to 43.8 mm Hg. Individually, the regression coefficients varied from 42 to 90 and the offsets from -32 to +3. The mathematical simulations suggest that variations in vessel compliance, autoregulation, and arterial pressure have a serious effect on the ICP-PI relationship. CONCLUSIONS: The in vivo results show that PI is not a reliable predictor of ICP. Mathematical simulations indicate that this is caused by variations in physiological parameters.

  • 20.
    Bergemalm, Daniel
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Srivastava, Vaibhav
    Sveriges lantbruksuniversitet.
    Graffmo, Karin S.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Wingsle, Gunnar
    Sveriges lantbruksuniversitet.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Superoxide dismutase-1 and other proteins in inclusions from transgenic amyotrophic lateral sclerosis model miceManuscript (preprint) (Other academic)
    Abstract [en]

    Mutant superoxide dismutase-1 (SOD1) causes amyotrophic lateral sclerosis (ALS) through a cytotoxic mechanism of unknown nature. A hallmark in ALS patients and transgenic mouse models carrying human SOD1 (hSOD1) mutations are hSOD1-immunoreactive inclusions in spinal cord ventral horns. The hSOD1 inclusions may block essential cellular functions or cause toxicity through sequestering of other proteins. Inclusions from 4 different transgenic mouse models were examined after density gradient ultracentrifugation. The inclusions are complex structures with heterogeneous densities and are disrupted by detergents. The aggregated hSOD1 was mainly composed of subunits that lacked the native stabilizing intrasubunit disulfide bond. A proportion of subunits formed hSOD1 oligomers or was bound to other proteins through disulfide bonds. Dense inclusions could be isolated and the protein composition was analyzed using proteomic techniques. Mutant hSOD1 accounted for half of the protein. Ten other proteins were identified. Two were cytoplasmic chaperones, 4 were cytoskeletal proteins, and 4 were proteins that normally reside in the endoplasmic reticulum (ER). The presence of ER proteins in inclusions containing the primarily cytosolic hSOD1 further supports the notion that ER stress is involved in ALS.

  • 21.
    Bergemalm, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Srivastava, Vaibhav
    Graffmo, Karin S
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wingsle, Gunnar
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Superoxide dismutase-1 and other proteins in inclusions from transgenic amyotrophic lateral sclerosis model mice2010In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 114, no 2, p. 408-418Article in journal (Refereed)
    Abstract [en]

    Mutant superoxide dismutase-1 (SOD1) causes amyotrophic lateral sclerosis (ALS) through a cytotoxic mechanism of unknown nature. A hallmark in ALS patients and transgenic mouse models carrying human SOD1 (hSOD1) mutations are hSOD1-immunoreactive inclusions in spinal cord ventral horns. The hSOD1 inclusions may block essential cellular functions or cause toxicity through sequestering of other proteins. Inclusions from four different transgenic mouse models were examined after density gradient ultracentrifugation. The inclusions are complex structures with heterogeneous densities and are disrupted by detergents. The aggregated hSOD1 was mainly composed of subunits that lacked the native stabilizing intra-subunit disulfide bond. A proportion of subunits formed hSOD1 oligomers or was bound to other proteins through disulfide bonds. Dense inclusions could be isolated and the protein composition was analyzed using proteomic techniques. Mutant hSOD1 accounted for half of the protein. Ten other proteins were identified. Two were cytoplasmic chaperones, four were cytoskeletal proteins, and 4 were proteins that normally reside in the endoplasmic reticulum (ER). The presence of ER proteins in inclusions containing the primarily cytosolic hSOD1 further supports the notion that ER stress is involved in ALS.

  • 22.
    Bergemalm, Daniel
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Jonsson, P Andreas
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Graffmo, Karin S
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Rehnmark, Anna
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Overloading of stable and exclusion of unstable human superoxide dismutase-1 variants in mitochondria of murine amyotrophic lateral sclerosis models2006In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 26, no 16, p. 4147-4154Article in journal (Refereed)
  • 23.
    Birve, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Neuwirth, Christoph
    Weber, Markus
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Nilsson, Ann-Charloth
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Jonsson, Per Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    A novel SOD1 splice site mutation associated with familial ALS revealed by SOD activity analysis2010In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, no 21, p. 4201-4206Article in journal (Refereed)
    Abstract [en]

    More than 145 mutations have been found in the gene CuZn-Superoxide dismutase (SOD1) in patients with amyotrophic lateral sclerosis (ALS). The vast majority are easily detected nucleotide mutations in the coding region. In a patient from a Swiss ALS family with half-normal erythrocyte SOD1 activity, exon flanking sequence analysis revealed a novel thymine to guanine mutation 7 bp upstream of exon 4 (c.240-7T>G). The results of splicing algorithm analyses were ambiguous, but five out of seven analysis tools suggested a potential novel splice site that would add six new base pairs to the mRNA. If translated, this mRNA would insert Ser and Ile between Glu78 and Arg79 in the SOD1 protein. In fibroblasts from the patient, the predicted mutant transcript and the mutant protein were both highly expressed, and despite the location of the insertion into the metal ion-binding loop IV, the SOD1 activity appeared high. In erythrocytes, which lack protein synthesis and are old compared with cultured fibroblasts, both SOD1 protein and enzymic activity was 50% of controls. Thus, the usage of the novel splice site is near 100%, and the mutant SOD1 shows the reduced stability typical of ALS-associated mutant SOD1s. The findings suggests that this novel intronic mutation is causing the disease and highlights the importance of wide exon-flanking sequencing and transcript analysis combined with erythrocyte SOD1 activity analysis in comprehensive search for SOD1 mutations in ALS. We find that there are potentially more SOD1 mutations than previously reported.

  • 24. Blauw, Hylke M
    et al.
    Al-Chalabi, Ammar
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    van Vught, Paul W J
    Diekstra, Frank P
    van Es, Michael A
    Saris, Christiaan G J
    Groen, Ewout J N
    van Rheenen, Wouter
    Koppers, Max
    Van't Slot, Ruben
    Strengman, Eric
    Estrada, Karol
    Rivadeneira, Fernando
    Hofman, Albert
    Uitterlinden, Andre G
    Kiemeney, Lambertus A
    Vermeulen, Sita H M
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Waibel, Stefan
    Meyer, Thomas
    Cronin, Simon
    McLaughlin, Russell L
    Hardiman, Orla
    Sapp, Peter C
    Tobin, Martin D
    Wain, Louise V
    Tomik, Barbara
    Slowik, Agnieszka
    Lemmens, Robin
    Rujescu, Dan
    Schulte, Claudia
    Gasser, Thomas
    Brown, Robert H
    Landers, John E
    Robberecht, Wim
    Ludolph, Albert C
    Ophoff, Roel A
    Veldink, Jan H
    van den Berg, Leonard H
    A large genome scan for rare CNVs in amyotrophic lateral sclerosis2010In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, no 20, p. 4091-4099Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 × 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 × 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 × 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 × 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.

  • 25.
    Blomstedt, Patric
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Hariz, Marwan I
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Tisch, Stephen
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Bergenheim, Tommy A
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    A family with a hereditary form of torsion dystonia from northern Sweden treated with bilateral pallidal deep brain stimulation2009In: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 24, no 16, p. 2415-2419Article in journal (Refereed)
    Abstract [en]

    To evaluate pallidal DBS in a non-DYT1 form of hereditary dystonia. We present the results of pallidal DBS in a family with non-DYT1 dystonia where DYT5 to 17 was excluded. The dystonia is following an autosomal dominant pattern. Ten members had definite dystonia and five had dystonia with minor symptoms. Four patients received bilateral pallidal DBS. Mean age was 47 years. The patients were evaluated before surgery, and "on" stimulation after a mean of 2.5 years (range 1-3) using the Burke-Fahn-Marsden scale (BFM). Mean BFM score decreased by 79 % on stimulation, from 42.5 +/- 24 to 9 +/- 6.5 at the last evaluation. Cervical involvement improved by 89%. The 2 patients with oromandibular dystonia and blepharospasm demonstrated a reduction of 95% regarding these symptoms. The present study confirms the effectiveness of pallidal DBS in a new family with hereditary primary segmental and generalized dystonia.

  • 26.
    Blomstedt, Patric
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Sandvik, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Fredricks, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Deep brain stimulation of the subthalamic nucleus versus the zona incerta in the treatment of essential tremor2011In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 153, no 12, p. 2329-2335Article in journal (Refereed)
    Abstract [en]

    Background: Deep brain stimulation (DBS) is an effective treatment for essential tremor (ET). Currently the ventrolateral thalamus is the target of choice, but the posterior subthalamic area (PSA), including the caudal zona incerta (cZi), has demonstrated promising results, and the subthalamic nucleus (STN) has been suggested as a third alternative. The objective of the current study was to evaluate the effect of STN DBS in ET and to compare this to cZi DBS.

    Methods: Four patients with ET were implanted with two ipsilateral electrodes, one in the STN and one in the cZi. All contacts were evaluated concerning the acute effect on tremor, and the effect of chronic DBS in either target was analyzed.

    Results: STN and cZi both proved to be potent targets for DBS in ET. DBS in the cZi was more efficient, since the same degree of tremor reduction could here be achieved at lower energy consumption. Three patients became tremor-free in the treated hand with either STN or cZi DBS, while the fourth had a minor residual tremor after stimulation in either target.

    Conclusion: In this limited material, STN DBS was demonstrated to be an efficient treatment for ET, even though cZi DBS was more efficient. The STN may be an alternative target in the treatment of ET, pending further investigations to decide on the relative merits of the different targets.

  • 27. Blumen, Sergiu C
    et al.
    Inzelberg, Rivka
    Nisipeanu, Puiu
    Carasso, Ralph L
    Oved, Daniel
    Aizenstein, Orna
    Drory, Vivian E
    Bergstrom, Christina
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Aggressive familial ALS with unusual brain MRI and a SOD1 gene mutation.2010In: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders, ISSN 1466-0822, E-ISSN 1743-4483, Vol. 11, no 1-2, p. 228-231Article in journal (Refereed)
    Abstract [en]

    We studied two sisters with rapidly progressing ALS starting at the ages of 46 and 48 years and leading to death after 14 months. Both fulfilled the El Escorial criteria for definite ALS and had marked upper motor neuron (UMN) predominance. Brain MRI, on fluid attenuation recovery (FLAIR) mode, showed outstanding hyperintensities of the precentral gyrus, centrum semiovale, corona radiata and along the corticospinal pathways in the brainstem. Screening for the SOD1 gene disclosed, at codon 140, a base substitution of adenine for thymine (GGT>CCA) known as the A140A 'silent' mutation since it does not change the amino acid (alanine) encoded for at that position. The severe UMN involvement and the fast progression of the disease may correlate with the MRI findings. It is also possible that the A140A mutation is not incidental; the mutated mRNA might be cytotoxic.

  • 28. Bolin, Kristian
    et al.
    Berggren, F
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Lacosamide as treatment of epileptic seizures: cost utility results for Sweden2010In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 121, no 6, p. 406-412Article in journal (Refereed)
    Abstract [en]

    The estimated cost per QALY gained falls within the range of reported estimates of the willingness-to-pay for an additional QALY. The results imply that lacosamide is cost-effective in the treatment of uncontrolled partial-onset seizures (1 euro approximately 9.6 SEK).

  • 29. Broom, W J
    et al.
    Parton, M J
    Vance, C A
    Russ, C
    Andersen, P M
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Hansen, V
    Leigh, P N
    Powell, J F
    Al-Chalabi, A
    Shaw, C E
    No association of the SOD1 locus and disease susceptibility or phenotype in sporadic ALS.2004In: Neurology, ISSN 1526-632X, Vol. 63, no 12, p. 2419-22Article in journal (Refereed)
  • 30. Broom, Wendy J
    et al.
    Johnson, Daniel V
    Garber, Manuel
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Lennon, Niall
    Landers, John
    Nusbaum, Chad
    Russ, Carsten
    Brown, Robert H
    DNA sequence analysis of the conserved region around the SOD1 gene locus in recessively inherited ALS2009In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 463, no 1, p. 64-69Article in journal (Refereed)
    Abstract [en]

    Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS cases; 12-23% are associated with mutations in the Cu/Zn superoxide dismutase gene (SOD1). All ALS-linked SOD1 mutations present with a dominant pattern of inheritance apart from the aspartate to alanine mutation in exon 4 (D90A). This mutation has been observed in dominant, recessive and apparently sporadically cases. SOD1(D90A/D90A) ALS cases have a very slow disease progression (>10 years), raising the hypothesis that modifier genes linked to SOD1 ameliorate the phenotype of recessively inherited SOD1(D90A/D90A) mutations. Previous sequence analysis of a conserved haplotype region around the SOD1 gene did not reveal any functional polymorphisms within known coding or putative regulatory regions. In the current study we expanded the previous analyses by sequencing the entire SOD1 conserved haplotypic region. Although many polymorphisms were identified, none of these variants explain the slowly progressive phenotype observed in patients with recessive SOD1(D90A) mutations. This study disproves the hypothesis that there is a tightly linked genetic protective factor specifically located close to the SOD1 gene in SOD1(D90A) mediated ALS.

  • 31. Broom, Wendy J
    et al.
    Russ, Carsten
    Sapp, Peter C
    McKenna-Yasek, Diane
    Hosler, Betsy A
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Brown, Robert H
    Variants in candidate ALS modifier genes linked to Cu/Zn superoxide dismutase do not explain divergent survival phenotypes.2006In: Neurosci Lett, ISSN 0304-3940, Vol. 392, no 1-2, p. 52-7Article in journal (Refereed)
  • 32. Brotherton, Terrell
    et al.
    Polak, Meraida
    Kelly, Crystal
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Glass, Jonathan D
    A novel ALS SOD1 C6S mutation with implications for aggregation related toxicity and genetic counseling2011In: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders, ISSN 1466-0822, E-ISSN 1743-4483, Vol. 12, no 3, p. 215-219Article in journal (Refereed)
    Abstract [en]

    In this report we describe an ALS family with a novel missense SOD1 mutation with substitution of serine for cysteine at the sixth amino acid (C6S). This mutation has interesting implications for the role of disulfides in causing disease. After identification of the ALS proband, we examined 17 members of an extended family and performed DNA mutation analysis on 21 family members. The level and activity of SOD1 in C6S carriers and wild-type family members was analyzed in erythrocytes. We found that the C6S mutation results in disease with an autosomal dominant mode of inheritance and markedly reduced penetrance. The S6 mutated protein demonstrates high stability relative to the C6 wild-type protein. The specific dismutation activity of S6 SOD1 is normal. In conclusion, C6S is a novel FALS associated mutation with reduced disease penetrance, long survival time and a phenotype very different from the other SOD1 mutations reported in codon C6. This mutation may provide insight into the role of SOD1 structural changes in disease.

  • 33.
    Byström, Roberth
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Gröbner, Gerhard
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Oliveberg, Mikael
    Stockholms universitet.
    SOD1 mutations targeting surface hydrogen bonds promote ALS without reducing apo-state stability2010In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 25, p. 19544-52Article in journal (Refereed)
    Abstract [en]

    In good accord with the protein-aggregation hypothesis for neurodegenerative diseases, ALS-associated SOD1 mutations are found to reduce structural stability or net repulsive charge. Moreover there are weak indications that the ALS disease progression rate is correlated with the degree of mutational impact on the apo-SOD1 structure. A bottleneck for obtaining more conclusive information about these structure-disease relationships, however, is the large intrinsic variability in patient survival times and insufficient disease statistics for the majority of ALS-provoking mutations. As an alternative test of the structure-disease relationship we focus here on the SOD1 mutations that appear to be outliers in the data set. The results identify several ALS-provoking mutations whose only effect on apo SOD1 is the elimination or introduction of a single charge, i.e., D76V/Y, D101N and N139D/K. The thermodynamic stability and folding behaviour of these mutants are indistinguishable from the wildtype control. Moreover, D101N is an outlier in the plot of stability loss vs. patient survival time by having rapid disease progression. Common to the identified mutations is that they truncate conserved salt-links and/or H-bond networks in the functional loops IV or VII. The results show that the local impact of ALS-associated mutations on the SOD1 molecule can sometimes overrun their global effects on apo-state stability and net repulsive charge, and point at the analysis of property outliers as an efficient strategy for mapping out new ALS-provoking features.

  • 34.
    Byström, Roberth
    et al.
    Umeå University, Faculty of Science and Technology, Chemistry.
    Andersen, Peter Munch
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Gröbner, Gerhard
    Umeå University, Faculty of Science and Technology, Chemistry.
    Oliveberg, Mikael
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
    Identification of property outliers among ALS-associated SOD1 mutations: Common effect on surface hydrogen bondsManuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    In good accord with the protein-aggregation hypothesis for neurodegenerative diseaseALS-associated SOD1 mutations are found to reduce structural stability or netrepulsive charge. Moreover there are weak indications that the ALS diseaseprogression is correlated with the degree of mutational impact on the SOD1 structure.A bottleneck for obtaining more conclusive information about these structure-diseaserelationships, however, is the large intrinsic variability in patient survival times andinsufficient disease statistics for the majority of ALS-provoking mutations. As analternative test of the structure-disease relationship we focus here on the SOD1 amutation that appears to be outliers in the data set. The results identify several ALSprovokingmutations whose only effect on apo SOD1 is the elimination orintroduction of a single charge, i.e., D76V/Y, D101N and N139D/K. Thethermodynamic stability and folding behaviour of these mutants are indistinguishablefrom the wildtype control, showing that structurally benign replacements of individualsurface charges are sufficient to trigger ALS. Moreover, D101N is a clear outlier inthe plot of stability loss vs. patient survival time by having too rapid diseaseprogression. Common to the identified mutations is that they truncate conserved saltlinksand/or H-bond networks in the functional loops IV or VII. The results show thatthe local impact of ALS-associated mutations on the SOD1 molecule can sometimesoverrun their global effects on stability and net repulsive charge, and point at theanalysis of property outliers as an efficient strategy for mapping out new ALSprovokingfeatures.

  • 35.
    Carlsson, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Nylander, P-O
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Forsman-Semb, Kristina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmgren, Gösta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Molecular Biology.
    Identification of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1.2002In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 59, no 11, p. 1804-1807Article in journal (Refereed)
  • 36. Couthouis, Julien
    et al.
    Hart, Michael P
    Shorter, James
    DeJesus-Hernandez, Mariely
    Erion, Renske
    Oristano, Rachel
    Liu, Annie X
    Ramos, Daniel
    Jethava, Niti
    Hosangadi, Divya
    Epstein, James
    Chiang, Ashley
    Diaz, Zamia
    Nakaya, Tadashi
    Ibrahim, Fadia
    Kim, Hyung-Jun
    Solski, Jennifer A
    Williams, Kelly L
    Mojsilovic-Petrovic, Jelena
    Ingre, Caroline
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Boylan, Kevin
    Graff-Radford, Neill R
    Dickson, Dennis W
    Clay-Falcone, Dana
    Elman, Lauren
    McCluskey, Leo
    Greene, Robert
    Kalb, Robert G
    Lee, Virginia M-Y
    Trojanowski, John Q
    Ludolph, Albert
    Robberecht, Wim
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Nicholson, Garth A
    Blair, Ian P
    King, Oliver D
    Bonini, Nancy M
    Van Deerlin, Vivianna
    Rademakers, Rosa
    Mourelatos, Zissimos
    Gitler, Aaron D
    A yeast functional screen predicts new candidate ALS disease genes2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 52, p. 20881-20890Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of the segenes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having amore severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.

  • 37. Cronin, Simon
    et al.
    Greenway, Matthew J
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Hardiman, Orla
    Screening of hypoxia-inducible genes in sporadic ALS2008In: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders, ISSN 1466-0822, E-ISSN 1743-4483, Vol. 9, no 5, p. 299-305Article in journal (Refereed)
    Abstract [en]

    Genetic variations in two hypoxia-inducible angiogenic genes, VEGF and ANG, have been linked with sporadic amyotrophic lateral sclerosis (SALS). Common variations in these genes may reduce the levels or functioning of their products. VEGF and ANG belong to a larger group of angiogenic genes that are up-regulated under hypoxic conditions. We hypothesized that common genetic variation across other members of this group may also predispose to sporadic ALS. To screen other hypoxia-inducible angiogenic genes for association with SALS, we selected 112 tagging single nucleotide polymorphisms (tgSNPs) that captured the common genetic variation across 16 VEGF-like and eight ANG-like hypoxia-inducible genes. Screening for association was performed in 270 Irish individuals with typical SALS and 272 ethnically matched unrelated controls. SNPs showing association in the Irish phase were genotyped in a replication sample of 281 Swedish sporadic ALS patients and 286 Swedish controls. Seven markers showed association in the Irish. The one modest replication signal observed in the Swedish replication sample, at rs3801158 in the gene inhibin beta A, was for the opposite allele vs. the Irish cohort. We failed to detect association of common variation across 24 candidate hypoxia-inducible angiogenic genes with SALS.

  • 38. Czaplinski, A
    et al.
    Steck, A J
    Andersen, P M
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Weber, M
    Flail arm syndrome: a clinical variant of amyotrophic lateral sclerosis.2004In: Eur J Neurol, ISSN 1351-5101, Vol. 11, no 8, p. 567-8Article in journal (Refereed)
  • 39. Devil, M
    et al.
    Andersen, PM
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Van Den Bosch, L
    Robberecht, W
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Genetics of amyotrophic lateral sclerosis2004Chapter in book (Other (popular science, discussion, etc.))
  • 40.
    Edman, Anne-Christine
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Myofibrillens finstruktur i tvärstrimmig skelettmuskulatur1988Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The detailed structure of the myofibrillar material in fibres from different muscles has been studied. Specimens have been obtained from human muscles and from different muscles frequently examined in experimental studies. Both light- and electron microscopical techniques have been used. Of central importance has been the method, which makes it possible to prepare ultrathin sections of frozen tissue, i.e. cryo-ult- ramicrotomy. A number of techniques for image analysis have been applied in order to obtain objektive data from the micrographs.

    In Paper I the present knowledge about muscle fibre structure, cryo-- sectioning and image analysis is summarized and relevant methodological problems are discussed. Paper II describes the detailed structure of the C-zone of the A-band and shows, above all, that structures occur with different repeats along the long axis of the myofibril. Paper III describes the subcellular organization of different fibres in a homogeneous (based on enzyme histochemical mATPase) population, and shows that different structural characteristies can vary independently of each other. Paper IV describes the structural diversity of the myofibrillar M-band, and paper V the diversity of the myofilament fine structure in different fibres. The results show that there is a most sophisticated, and previosly unrealized, structural specialization both within the myofibrils and between myofibrils from different fibres and muscles, even if the fibres are of the same fibre type. The findings suggest that generally used models, showing the structural organization within myofibrils and myofilaments, are oversimplifications. The fibre population is more heterogeneously built up than the common systems for fibre type classification makes one to belive.

  • 41. Eisen, Andrew
    et al.
    Mezei, Michelle M
    Stewart, Heather G
    Fabros, Marife
    Gibson, Gillan
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    SOD1 gene mutations in ALS patients from British Columbia, Canada: clinical features, neurophysiology and ethical issues in management2008In: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders, ISSN 1466-0822, E-ISSN 1743-4483, Vol. 9, no 2, p. 108-119Article in journal (Refereed)
    Abstract [en]

    Two hundred and fifty-four ALS patients from British Columbia, Canada were screened for mutations in the gene encoding the enzyme superoxide dismutase type 1 (SOD1). Thirteen patients (5.1%) carried one of six missense mutations (A4V, G72C, D76Y, D90A, C111Y, I113T). Mutations were found both in sporadic and familial ALS cases. Atypical clinical features delayed diagnosis in some cases. The demographic and clinical features of the mutation carrying index cases are summarized, and compared with those of screened patients without mutations. The phenotypic variability between SOD1 mutation carrying patients in this study is dramatic, even among patients with the same mutation This underlines the hypothesis that ALS is a biologically heterogeneous disorder in which genetics, environment and ageing all interrelate to form the final clinical phenotype.

  • 42.
    Eklund, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Koskinen, L-O D
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Malm, J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Features of the Sinushunt and its influence on the cerebrospinal fluid system2004In: J Neurol Neurosurg Psychiatry, ISSN 0022-3050, Vol. 75, no 8, p. 1156-1159Article in journal (Refereed)
    Abstract
  • 43.
    Eklund, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Lundkvist, B
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Koskinen, L-O D
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Malm, J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Infusion technique can be used to distinguish between dysfunction of a hydrocephalus shunt system and a progressive dementia.2004In: Med Biol Eng Comput, ISSN 0140-0118, Vol. 42, no 5, p. 644-649Article in journal (Refereed)
    Abstract
  • 44.
    Eklund, Anders
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences.
    Smielewski, Peter
    Chambers, Iain
    Alperin, Noam
    Malm, Jan
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Czosnyka, Marek
    Marmarou, Anthony
    Assessment of cerebrospinal fluid outflow resistance.2007In: Medical and Biological Engineering and Computing, ISSN 0140-0118, E-ISSN 1741-0444, Vol. 45, no 8, p. 719-735Article in journal (Refereed)
  • 45. Ekman, Mattias
    et al.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Economic evidence in epilepsy: a review.2004In: Eur J Health Econ, ISSN 1618-7598, Vol. 5 Suppl 1, p. S36-42Article in journal (Other academic)
  • 46.
    Engström, Birgitta
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Information to the patient: an attempt to satisfy the patient's need for information1986Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Dissatisfaction with medical information is a common problem among patients. There is also evidence that patients lack information that physicians believe they have given to the patient. The aims of this study were to 1) survey patients' subjective need for, and satisfaction with, the information that they received during their hospital stay 2) develop and evaluate systematic routines for giving information to the patients and also communication and collaboration between the medical and nursing staff concerning the satisfaction of the patients' need for information.

    The study was an intervention project and the research perspective was organizational psychology.

    Survey study. The patients experienced a considerable need for medical information, especially about the examination results and prognosis. The patients' need for information regarding prognosis was the least satisfied.

    Intervention 1. A general improvement of the information to the patients occurred when the systematic routines were established. The patients' subjective need for information was unchanged throughout two years. Their satisfaction with information, after an initial improvement, did not increase throughout these two years. There was low correlation between the patients' and their physicians' estimations concerning the patients' need for information on diagnosis, prognosis and examination results. Likewise, concerning the adequacy of that information.

    Intervention 2. Communication and collaboration between the medical and nursing staff included a system for assessment and solution of the patients' information problems. Problem-solving took place at a multidisciplinary team conference (MTC). Medical problems were better elucidated than the patients' psychological problems. After training of registered nurses (RN) as conference chairpersons, the patients need for information was better understood. The staff reported 42 information problems after training compared to two before. For half of the information problems decisions were discussed on steps to be taken in order to satisfy the patients' need for information. A year after the system for assessment and solution of information problems was established, the patients were more satisfied with information about examinations and their results and on information about medication (p< 0.05). Further, new norms for the patients' need for information were established and a change was initiated.

    The results are discussed with regard to how and why patients' shall have information, by whom and to whom information shall be given, when and where information shall be given and which content it shall have.

  • 47. Feigin, V
    et al.
    Brainin, M
    Breteler, M M B
    Martyn, C
    Wolfe, C
    Bornstein, N
    Fieschi, C
    Sevcik, P
    Lima, M L
    Boysen, G
    Beghi, E
    Tzourio, C
    Demarin, V
    Gusev, E
    López-Pousa, S
    Forsgren, L
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Teaching of neuroepidemiology in Europe: time for action.2004In: Eur J Neurol, ISSN 1351-5101, Vol. 11, no 12, p. 795-9Article in journal (Other academic)
  • 48. Felbecker, Ansgar
    et al.
    Camu, William
    Valdmanis, Paul N
    Sperfeld, Anne-Dorte
    Waibel, Stefan
    Steinbach, Peter
    Rouleau, Guy A
    Ludolph, Albert C
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Four familial ALS pedigrees discordant for two SOD1 mutations: are all SOD1 mutations pathogenic?2010In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 81, no 5, p. 572-577Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: 153 mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been claimed to be associated with amyotrophic lateral sclerosis (ALS) in familial and sporadic ALS in an autosomal dominant or autosomal recessive pattern with complete or reduced penetrance. The authors now report four ALS pedigrees from Finland, France, Germany and Sweden with either the D90A or E100K SOD1 mutations in some but not all affected members. After re-collecting DNA, the non-segregation of the SOD1 mutations with disease was confirmed by three independent laboratories using different PCR primers: while some of the affected patients carry SOD1 mutations, other affected family members have two wildtype/normal SOD1 genes. In addition, some unaffected members within the same families are carriers of SOD1 gene mutations. To exclude other known genetic causes, the authors ruled out mutations within the genes coding for VAPB, ANG, TDP43, FUS and DCTN1 in affected individuals in the four pedigrees.

    CONCLUSIONS: The authors find that the D90A and E100K SOD1 gene mutations found in some patients are not the exclusive cause of ALS in these pedigrees. Whether this is also the case for the other 151 SOD1 mutations reported in ALS pedigrees is unknown. The findings have consequences for genetic testing in clinical practice when diagnosing ALS and for genetic counselling in ALS. Some SOD1 mutations may be part of an oligo- or epigentic pattern of inheritance. Such a pattern of inheritance may model other oligo- or polygenetic traits responsible for other forms of ALS.

  • 49. Fogh, Isabella
    et al.
    Rijsdijk, Fruhling
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Sham, Pak C
    Knight, Joanne
    Neale, Benjamin
    McKenna-Yasek, Diane
    Silani, Vincenzo
    Brown, Robert H
    Powell, John F
    Al-Chalabi, Ammar
    Age at onset in sod1-mediated amyotrophic lateral sclerosis shows familiality2007In: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753, Vol. 8, no 3, p. 235-236Article in journal (Other academic)
  • 50.
    Forsberg, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Glial nuclear aggregates of superoxide dismutase-1 are regularly present in patients with amyotrophic lateral sclerosis2011In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 121, no 5, p. 623-634Article in journal (Refereed)
    Abstract [en]

    The most common cause of amyotrophic lateral sclerosis (ALS) is mutations in superoxide dismutase-1 (SOD1). Since there is evidence for the involvement of non-neuronal cells in ALS we searched for signs of SOD1 abnormalities focusing on glia. Spinal cords from 9 ALS patients carrying SOD1 mutations, 51 patients with sporadic or familial ALS who lacked such mutations, and 46 controls were examined by immunohistochemistry. A set of anti-peptide antibodies with specificity for misfolded SOD1 species was used. Misfolded SOD1 in the form of granular aggregates was regularly detected in the nuclei of ventral horn astrocytes, microglia and oligodendrocytes in ALS patients carrying and as well as lacking SOD1 mutations. There was negligible staining in neurodegenerative and non-neurological controls. Misfolded SOD1 appeared occasionally also in nuclei of motoneurons of ALS patients. The results suggest that misfolded SOD1 present in glial and motoneuron nuclei may generally be involved in ALS pathogenesis.

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