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  • 51.
    Bergdahl, Jan
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Nilsson, Lars-Göran
    Riklund Åhlström, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Nyberg, Lars
    Umeå University, Faculty of Social Sciences, Department of Psychology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Treatment of chronic stress in employees: subjective, cognitive and neural correlates2005In: Scandinavian Journal of Psychology, ISSN 0036-5564, E-ISSN 1467-9450, Vol. 46, no 5, p. 395-402Article in journal (Refereed)
    Abstract [en]

    This study reports the effect of an affect-focused intervention program, the Affect School, on stress, psychological symptoms, cognitive functioning and neural activity. Fifty employees in social service and education, with high levels of chronic stress, were randomly divided into a treatment (N= 27) and control (N= 23) group. Complete sets of data were available in 20 participants in the treatment group and 17 in the control group. The Perceived Stress Questionnaire assessed stress and the Symptom Check List-90 psychological symptoms before and after treatment. Episodic-memory functioning under focused and divided attention conditions was also assessed. Prior and after the Affect School, seven participants in the treatment group were studied with functional magnetic resonance imaging (fMRI) during episodic memory processing. After the Affect School there was a reduction in stress and psychological symptoms for the treatment group but not in the control group. The controls showed a reduction in episodic memory functioning whereas the performance of the treatment group remained intact. The fMRI scanning indicated a qualitative change in the neural network subserving episodic memory. These preliminary results suggest that the Affect School is effective on individuals with high stress.

  • 52.
    Bergh, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Structural investigation of SOD1 aggregates in ALS: identification of prion strains using anti-peptide antibodies2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative syndrome characterized by progressive degeneration of motor neurons that result in muscle wasting. The symptoms advance gradually to paralysis and eventually death. Most patients suffer from sporadic ALS (sALS) but 10% report a familial predisposition. Mutations in the gene encoding super­oxide dismutase-1 (SOD1) were the first identified cause of ALS. The disease mecha­nism is debated but there is a consensus that mutations in this protein confer a cytotoxic gain of function. SOD1 aggregates in motor neurons are hallmarks of ALS both in patients and in transgenic mouse models expressing a mutated form of human SOD1 (hSOD1). Recently, our group showed that SOD1 aggregates are present also in sALS patients, thus indicating a broader involvement of this protein in ALS. Misfolding and aggregation of SOD1 are dif­ficult to study in vivo since aggregate concentration in the central nervous system (CNS) is exceedingly low. The aim of this thesis was to find a method circumventing this problem to investigate the hSOD1 aggregate structure, distribution and spread in ALS disease.

    Many studies provide circumstantial evidence that the wild-type hSOD1 protein can be neurotoxic. We developed the first homozygous mouse model that highly overexpresses the wild-type enzyme. These mice developed an ALS-like syndrome and become terminally ill after around 370 days. Motor neuron loss and SOD1 aggregate accumulation in the CNS were observed. This lends further support to the hypothesis of a more general involve­ment of SOD1 in human disease.

    A panel of polyclonal antibodies covering 90% of the SOD1 protein was developed by our laboratory. These antibodies were shown to be highly specific for misfolded SOD1. Aggre­gated hSOD1 was purified from the CNS of terminally ill hSOD1 mice. Disordered segments in aggregated hSOD1 could be identified with these antibodies. Two aggregate strains with different structural architectures, molecular properties, and growth kinetics, were found using this novel method. The strains, denoted A and B, were also associated with different disease progression. Aggregates formed in vitro were structurally different from these strains. The results gave rise to questions about aggregate development and possible prion-like spread. To investigate this, inoculations of purified strain A and B hSOD1 seeds was performed in lumbar spinal cords of 100-day old mice carrying a hSOD1G85R mutation. Mice seeded with A or B aggregates developed premature signs of ALS and became terminally ill 200 days earlier than mice inoculated with control preparation. Interestingly, a tem­plated spread of aggregates along the neuraxis was concomitantly observed, with strain A and B provoking the buildup of their respective hSOD1 aggregate structure. The phenotypes initiated by the A and B strains differed regarding progression rates, distribution, end-stage aggregate levels, and histopathology. To further establish the importance of hSOD1 aggregates in human disease, purification and inoculation of aggregate seeds from spinal cords of ALS patients and mice carrying the hSOD1G127X mutation were performed. Inoculation of both human and mouse seeds as described above, induced strain A aggregation and premature fatal ALS-like disease.

    In conclusion, the data presented in this thesis provide a new, straightforward method for characterization of aggregate strains in ALS, and plausibly also in other neurodegen­erative diseases. Two different prion strains of hSOD1 aggregates were identified in mice that resulted in ALS-like disease. Emerging data suggest that prion-like growth and spread of hSOD1 aggregation could be the primary pathogenic mechanism not only in hSOD1 transgenic models, but also in human ALS.

  • 53.
    Berghard, Anna
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Hägglund, Anna-Carin
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lhx2-dependent specification of olfactory sensory neurons is required for successful integration of olfactory, vomeronasal, and GnRH neurons2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 8, p. 3464-3472Article in journal (Refereed)
    Abstract [en]

    Inactivation of the LIM-homeodomain 2 gene (Lhx2) results in a severe defect in specification of olfactory sensory neurons (OSNs). However, the ramifications of lack of Lhx2-dependent OSN specification for formation of the primary olfactory pathway have not been addressed, since mutant mice die in utero. We have analyzed prenatal and postnatal consequences of conditionally inactivating Lhx2 selectively in OSNs. A cell-autonomous effect is that OSN axons cannot innervate their target, the olfactory bulb. Moreover, the lack of Lhx2 in OSNs causes unpredicted, non-cell-autonomous phenotypes. First, the olfactory bulb shows pronounced hypoplasia in adults, and the data suggest that innervation by correctly specified OSNs is necessary for adult bulb size and organization. Second, absence of an olfactory nerve in the conditional mutant reveals that the vomeronasal nerve is dependent on olfactory nerve formation. Third, the lack of a proper vomeronasal nerve prevents migration of gonadotropin-releasing hormone (GnRH) cells the whole distance to their final positions in the hypothalamus during embryo development. As adults, the conditional mutants do not pass puberty, and these findings support the view of an exclusive nasal origin of GnRH neurons in the mouse. Thus, Lhx2 in OSNs is required for functional development of three separate systems.—Berghard, A., Hägglund, A.-C., Bohm, S., and Carlsson, L. Lhx2-dependent specification of olfactory sensory neurons is required for successful integration of olfactory, vomeronasal, and GnRH neurons.

  • 54.
    Berginström, Nils
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. School of Sport Sciences, The Arctic University of Norway, Tromsø, Norway Medicine.
    Ekman, Urban
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health. School of Sport Sciences, The Arctic University of Norway, Tromsø, Norway.
    Pharmaco-fMRI in Patients With Traumatic Brain Injury: A Randomized Controlled Trial With the Monoaminergic Stabilizer (-)-OSU61622019In: The journal of head trauma rehabilitation, ISSN 0885-9701, E-ISSN 1550-509X, Vol. 34, no 3, p. 189-198Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To examine the effects of monoaminergic stabilizer (-)-OSU6162 on brain activity, as measured by blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI), in patients in the chronic phase of traumatic brain injury suffering from fatigue.

    SETTING: Neurorehabilitation clinic.

    PARTICIPANTS: Patients with traumatic brain injury received either placebo (n = 24) or active treatment (n = 28). Healthy controls (n = 27) went through fMRI examination at one point and were used in sensitivity analysis on normalization of BOLD response.

    DESIGN: Randomized, double-blinded, placebo-controlled design.

    MAIN MEASURES: Effects on BOLD signal changes from before to after treatment during performance of a fatiguing attention task.

    RESULTS: The fMRI results revealed treatment effects within the right occipitotemporal cortex and the right orbitofrontal cortex. In these regions, the BOLD response was normalized relative to healthy controls at the postintervention fMRI session. No effects were seen in regions in which we previously observed activity differences between patients and healthy controls while performing this fMRI task, such as the striatum.

    CONCLUSION: (-)-OSU6162 treatment had influences on functional brain activity, although the normalized regional BOLD response was observed in regions that were not a priori hypothesized to be sensitive to this particular treatment, and was not accompanied by any effects on in-scanner test performance or on fatigue.

  • 55.
    Bergman, J.
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Dring, Ann
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wuolikainen, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Bergenheim, Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Cytokine levels in interstitial brain fluid in progressive multiple sclerosis measured via intracerebral microdialysis2016In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 22, p. 511-511Article in journal (Refereed)
  • 56.
    Bergström, Fredrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    The neural substrates of non-conscious working memory2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Despite our distinct impression to the contrary, we are only conscious of a fraction of all the neural activity underlying our thoughts and behavior. Most neural processes occur non-consciously, and in parallel with our conscious experience. However, it is still unclear what the limits of non-conscious processes are in terms of higher cognitive functions. Many recent studies have shown that increasingly more advanced functions can operate non-consciously, but non-conscious information is still thought to be fleeting and undetectable within 500 milliseconds. Here we used various techniques to render information non-conscious, together with functional magnetic resonance imaging (fMRI), to investigate if non-consciously presented information can be retained for several seconds, what the neural substrates of such retention are, and if it is consistent with working memory maintenance.

    Results: In Study I we used an attentional blink paradigm to render stimuli (single letters) non-conscious, and a variable delay period (5 – 15 s) prior to memory test. It was found that non-conscious memory performance was above chance after all delay durations, and showed no signs of decline over time. Univariate fMRI analysis showed that the durable retention was associated with sustained BOLD signal change in the prefrontal cortex and cerebellum during the delay period. In Study II we used continuous flash suppression (CFS) to render stimuli (faces and tools) non-conscious, and a variable delay period (5 or 15 s) prior to memory test. The durable retention of up to 15 s was replicated, and it was found that stimuli identity and spatial position was retained until prospective use. In Study III we used CFS to render tools non-conscious, and a variable delay period (5 – 15 s) prior to memory test. It was found that memory performance was not better than chance. However, by using multi-voxel pattern analysis it was nonetheless possible to detect the presence vs. absence of non-conscious stimuli in the frontal cortex,and their spatial position (left vs. right) in the occipital cortex during the delay.

    Conclusions: Overall these findings suggest that non-consciously presented information (identity and/or position) can be retained for several seconds,and is associated with BOLD signal in frontal and posterior regions. These findings are consistent with working memory maintenance of non-consciously presented information, and thereby constrain models of working memory and theories of consciousness.

  • 57.
    Bergström, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    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).
    Maintenance of non-consciously presented information engages the prefrontal cortex2014In: Frontiers in Human Neuroscience, ISSN 1662-5161, E-ISSN 1662-5161, Vol. 8, p. 938-Article in journal (Refereed)
    Abstract [en]

    Conscious processing is generally seen as required for flexible and willful actions, as well as for tasks that require durable information maintenance. Here we present research that questions the assumption that only consciously perceived information is durable (>500 ms). Using the attentional blink (AB) phenomenon, we rendered otherwise relatively clearly perceived letters non conscious. In a first experiment we systematically manipulated the delay between stimulus presentation and response, for the purpose of estimating the durability of non-conscious perceptual representations. For items reported not seen, we found that behavioral performance was better than chance across intervals up to 15 s. In a second experiment we used fMRI to investigate the neural correlates underlying the maintenance of non conscious perceptual representations. Critically, the relatively long delay period demonstrated in experiment 1 enabled isolation of the signal change specifically related to the maintenance period, separate from stimulus presentation and response. We found sustained BOLD signal change in the right mid-lateral prefrontal cortex, orbitofrontal cortex, and crus II of the cerebellum during maintenance of non consciously perceived information. These findings are consistent with the controversial claim that working-memory mechanisms are involved in the short-term maintenance of non-conscious perceptual representations.

  • 58.
    Bergström, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Faculty of Psychology and Educational Sciences, University of Coimbra, Portugal.
    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).
    Neural evidence for non-conscious working memory2018In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 28, no 9, p. 3217-3228Article in journal (Refereed)
    Abstract [en]

    Recent studies have found that non-consciously perceived information can be retained for several seconds, a feat that has been attributed to non-conscious working memory processes. However, these studies have mainly relied on subjective measures of visual experience, and the neural processes responsible for non-conscious short-term retention remains unclear. Here we used continuous flash suppression to render stimuli non-conscious in a delayed match-to-sample task together with fMRI to investigate the neural correlates of non-conscious short-term (5-15 s) retention. The participants' behavioral performance was at chance level when they reported no visual experience of the sample stimulus. Critically, multivariate pattern analyses of BOLD signal during the delay phase could classify presence versus absence of sample stimuli based on signal patterns in frontal cortex, and its spatial position based on signal patterns in occipital cortex. In addition, univariate analyses revealed increased BOLD signal change in prefrontal regions during memory recognition. Thus, our findings demonstrate short-term maintenance of information presented non-consciously, defined by chance performance behaviorally. This non-consciously retained information seems to rely on persistent neural activity in frontal and occipital cortex, and may engage further cognitive control processes during memory recognition.

  • 59.
    Bergström, Petra
    et al.
    Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    von Otter, Malin
    Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Nilsson, Staffan
    Institute of Mathematical Sciences, Department of Mathematical Statistics, Chalmers University of Technology, Gothenburg, Sweden.
    Nilsson, Ann-Charloth
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nilsson, Michael
    Institute of Neuroscience and Physiology, Centre for Brain Repair and Rehabilitation, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden and Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hammarsten, Ola
    Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Zetterberg, Henrik
    Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden and UCL Institute of Neurology, London, UK.
    Association of NFE2L2 and KEAP1 haplotypes with amyotrophic lateral sclerosis2014In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, Vol. 15, no 1-2, p. 130-137Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron syndrome influenced by oxidative stress. The transcription factor Nrf2 and its repressor Keap1 constitute an important defence system in cellular protection against oxidative stress. Here we hypothesize that common genetic variations in the genes NFE2L2 and KEAP1, encoding Nrf2 and Keap1, may influence the risk and phenotype of ALS. Five hundred and twenty-two Swedish patients with sporadic ALS (SALS) and 564 Swedish control subjects were studied. Eight tag SNPs in NFE2L2 and three tag SNPs in KEAP1 were genotyped by allelic discrimination and three functional NFE2L2 promoter SNPs were genotyped by sequencing. One NFE2L2 haplotype (GGGAC) was associated with decreased risk of SALS (OR = 0.62 per allele, p = 0.003) and one haplotype in KEAP1 (CGG) was associated with later SALS onset (+3.4 years per allele, p = 0.015). When stratified by subgroup, one haplotype in NFE2L2, GAGCAGA including three functional promoter SNPs associated with high Nrf2 protein expression, was associated with 4.0 years later disease onset per allele in subgroup ALS (p = 0.008). In conclusion, these results suggest that variations in NFE2L2 and KEAP1, encoding two central proteins in cellular oxidative stress defence, may influence SALS pathogenesis.

  • 60.
    Birznieks, Ingvars
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Jenmalm, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Goodwin, Antony W
    University of Melbourne, Victoria.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Encoding of direction of fingertip forces by human tactile afferents2001In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 21, no 20, p. 8222-8237Article in journal (Refereed)
    Abstract [en]

    In most manipulations, we use our fingertips to apply time-varying forces to the target object in controlled directions. Here we used microneurography to assess how single tactile afferents encode the direction of fingertip forces at magnitudes, rates, and directions comparable to those arising in everyday manipulations. Using a flat stimulus surface, we applied forces to a standard site on the fingertip while recording impulse activity in 196 tactile afferents with receptive fields distributed over the entire terminal phalanx. Forces were applied in one of five directions: normal force and forces at a 20 degrees angle from the normal in the radial, distal, ulnar, or proximal directions. Nearly all afferents responded, and the responses in most slowly adapting (SA)-I, SA-II, and fast adapting (FA)-I afferents were broadly tuned to a preferred direction of force. Among afferents of each type, the preferred directions were distributed in all angular directions with reference to the stimulation site, but not uniformly. The SA-I population was biased for tangential force components in the distal direction, the SA-II population was biased in the proximal direction, and the FA-I population was biased in the proximal and radial directions. Anisotropic mechanical properties of the fingertip and the spatial relationship between the receptive field center of the afferent and the stimulus site appeared to influence the preferred direction in a manner dependent on afferent type. We conclude that tactile afferents from the whole terminal phalanx potentially contribute to the encoding of direction of fingertip forces similar to those that occur when subjects manipulate objects under natural conditions.

  • 61.
    Biström, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gustafsson, R.
    Engdahl, E.
    Bomfim, I. L.
    Huang, J.
    Jons, D.
    Andersen, O.
    Hortlund, M.
    Alonso-Magdalena, L.
    Waterboer, T.
    Kockum, I.
    Olsson, T.
    Fogdell-Hahn, A.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Late Epstein-Barr virus infection and a second virus are linked to multiple sclerosis risk2016In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 22, p. 187-187Article in journal (Refereed)
  • 62.
    Björklund, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Radovanovic, S
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Ljubisavljevic, M
    Windhorst, U
    Johansson, H
    Muscle stretch-induced modulation of noxiously activated dorsal horn neurons of feline spinal cord2004In: Neuroscience research, ISSN 0168-0102, E-ISSN 1872-8111, Vol. 48, no 2, p. 175-184Article in journal (Refereed)
    Abstract [en]

    The present work was designed to check for the possibility of interactions between mechanical innocuous and chemically induced noxious muscle afferent inputs on discharge behavior of nociceptive superficial dorsal horn neurons (SDHNs) of the spinal cord in decerebrated cats. The innocuous and noxious stimuli were applied separately and in combination, so that the effects of the innocuous stimulus on nociceptive processing could be evaluated. The innocuous stimulus consisted of ramp-and-hold stretches of the gastrocnemius muscles, whereas the noxious stimulus consisted of i.a. injections of bradykinin (BK; 0.5-1 ml, 50 microg/ml) into the arterial circulation of same muscles. Only neurons up to approximately 1mm depth and those that responded to noxious pinch of the gastrocnemius muscles were selected for further analysis. The activity of 16 dorsal horn neurons was recorded extracellularly with high-impedance glass microelectrodes, out of which seven responded to stretch, while 12 neurons responded to bradykinin injections. The bradykinin injections induced three types of responses: excitatory, inhibitory and mixed. The majority of the neurons that showed excitatory and mixed responses to bradykinin were also influenced by stretches applied directly after the bradykinin injection. In these neurons, the stretch usually counteracted the bradykinin-induced response, i.e. shortening and reducing bradykinin-induced excitation and re-exciting the cells after bradykinin-induced inhibition. The mechanism of the stretch modulation is proposed to reside in a segmental spinal control of the nociceptive transmission.

  • 63.
    Björnfot, Cecilia
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Multiband functional magnetic resonance imaging (fMRI) for functional connectivity assessments2018Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    During resting state the brain exhibits synchronized activity within all major brain networks. Using blood oxygen level dependent (BOLD) resting state functional magnetic resonance imaging (fMRI) based detection it is possible to quantify the degree of correlation, connectivity, between regions of interest and assess information regarding the integrity of the inter-regional functional integration. A newly available multiband echo planar imaging (EPI) fMRI sequence allows for faster scan times which possibly allows us to better examine large-scale networks and increase the understanding of brain function/dysfunction. This thesis will assess how the newly developed sequence compares to a conventional EPI sequence for detecting resting state connectivity of canonical brain networks. The data acquisitions were made on a 3 Tesla scanner using a 32 channel head coil. The hypothesis was that the multiband sequence would produce a better result since it has faster sampling rate, thus more data points in its time-series to support the statistical analyses.

    Using Pearson’s linear correlation between the average time-series (approximately 12 minutes long) within a seed-region and all voxels contained in the image volume, correlation maps where created for each of the eight participants using data normalized to Montreal Neurological Institute (MNI) space. The resting state networks (RSN) were then found by performing a one sample T-test on group level. Six seed-coordinates, based on literature, where used revealing the the homotopic connections in anterior Hippocampus, Motor cortex, Dorsal attention, Visual and the Default mode network (DMN) as well for an anterior-posterior connection in the DMN.

    By comparing the maximum T-values within the regions for the RSN no systematic difference could be found between the multiband and conventional fMRI data. Further tests were conducted to evaluate if the sequences would differentiate in their results if the acquisition time was shortened, i.e shortening the time-series in the voxels. However no such difference could be established.Importantly, the results are specific to the 32 channel head coil used in the current study. Presumably recently available and improved coil designs could better exploit the multiband technique.

  • 64. Blain, C R V
    et al.
    Brunton, S
    Williams, V C
    Leemans, A
    Turner, M R
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Catani, M
    Stanton, B R
    Ganesalingham, J
    Jones, D K
    Williams, S C R
    Leigh, P N
    Simmons, A
    Differential corticospinal tract degeneration in homozygous 'D90A' SOD-1 ALS and sporadic ALS2011In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 82, no 8, p. 843-849Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The homogeneous genotype and stereotyped phenotype of a unique familial form of amyotrophic lateral sclerosis (ALS) (patients homozygous for aspartate-to-alanine mutations in codon 90 (homD90A) superoxide dismutase 1) provides an ideal model for studying genotype/phenotype interactions and pathological features compared with heterogeneous apparently sporadic ALS. The authors aimed to use diffusion tensor tractography to quantify and compare changes in the intracerebral corticospinal tracts of patients with both forms of ALS, building on previous work using whole-brain voxelwise group analysis.

    METHOD: 21 sporadic ALS patients, seven homD90A patients and 20 healthy controls underwent 1.5 T diffusion tensor MRI. Patients were assessed using 'upper motor neuron burden,' El Escorial and ALSFR-R scales. The intracranial corticospinal tract was assessed using diffusion tensor tractography measures of fractional anisotropy (FA), mean diffusivity, and radial and axial diffusivity obtained from its entire length.

    RESULTS: Corticospinal tract FA was reduced in sporadic ALS patients compared with both homD90A ALS patients and controls. The diffusion measures in sporadic ALS patients were consistent with anterograde (Wallerian) degeneration of the corticospinal tracts. In sporadic ALS, corticospinal tract FA was related to clinical measures. Despite a similar degree of clinical upper motor neuron dysfunction and disability in homD90A ALS patients compared with sporadic ALS, there were no abnormalities in corticospinal tract diffusion measures compared with controls.

    CONCLUSIONS: Diffusion tensor tractography has shown axonal degeneration within the intracerebral portion of the corticospinal tract in sporadic ALS patients, but not those with a homogeneous form of familial ALS. This suggests significant genotypic influences on the phenotype of ALS and may provide clues to slower progression of disease in homD90A patients.

  • 65.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    When the head is too big for the frame2014In: Stereotactic and Functional Neurosurgery, ISSN 1011-6125, E-ISSN 1423-0372, Vol. 92, no 4, p. 264-264Article in journal (Refereed)
  • 66.
    Blomstedt, Patric
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Bjartmarz, Hjalmar
    Intracerebral infections as a complication of deep brain stimulation2012In: Stereotactic and Functional Neurosurgery, ISSN 1011-6125, E-ISSN 1423-0372, Vol. 90, no 2, p. 92-96Article in journal (Refereed)
    Abstract [en]

    Background: Intracerebral infections after deep brain stimulation (DBS) are rare. The published material is limited to 2 case reports. A review of 20 publications of 3,818 patients focusing on complications of DBS did not reveal one single case. For that reason, we decided to present our own experience of 4 patients with this complication.

    Objectives: To analyze and present our material regarding intracerebral infections after DBS.

    Methods: Four patients with intracerebral infection after DBS were retrospectively analyzed. Results: The 4 patients exhibited signs of intracerebral infection 2-14 days after DBS for Parkinson's disease. CT and MRI verified signs of possible cerebral involvement. In 3 patients, positive cultures were obtained from the extracted electrodes. All patients recovered completely following treatment with antibiotics and removal of the implanted hardware. Two of the patients were later re-implanted.

    Conclusions: Intracerebral infection is a rare complication of DBS. It does, however, occur occasionally and should be taken into consideration when evaluating the risks of DBS.

    Copyright (c) 2012 S. Karger AG, Basel

  • 67.
    Boraxbekk, Carl-Johan
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Danish Research Center for Magnetic Research (DRCMR), Centre forFunctional and Diagnostic Imaging and Research, Copenhagen Univer-sity Hospital Hvidovre, Hvidovre, Denmark.
    Non-invasive brain stimulation and neuro-enhancement in aging2018In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 9, p. 464-465Article in journal (Refereed)
  • 68.
    Boraxbekk, Carl-Johan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Ames, David
    Kochan, Nicole
    Lee, Teresa
    Thalamuthu, Anbupalam
    Wen, Wei
    Armstrong, Nicola
    Kwok, John
    Schofield, Peter
    Reppermund, Simone
    Wright, Margaret
    Trollor, Julian
    Brodaty, Henry
    Sachdev, Perminder
    Mather, Karen
    Investigating the influence of KIBRA and CLSTN2 genetic polymorphisms on cross-sectional and longitudinal measures of memory performance and hippocampal volume in older individuals2015In: Neuropsychologia, ISSN 0028-3932, E-ISSN 1873-3514, Vol. 78, p. 10-17Article in journal (Refereed)
    Abstract [en]

    The variability of episodic memory decline and hippocampal atrophy observed with increasing age may partly be explained by genetic factors. KIBRA (kidney and brain expressed protein) and CLSTN2 (calsyntenin 2) are two candidate genes previously linked to episodic memory performance and volume of the hippocampus, a key memory structure. However, whether polymorphisms in these two genes also influence age-related longitudinal memory decline and hippocampal atrophy is still unknown. Using data from two independent cohorts, the Sydney Memory and Ageing Study and the Older Australian Twins Study, we investigated whether the KIBRA and CLSTN2 genetic polymorphisms (rs17070145 and rs6439886) are associated with episodic memory performance and hippocampal volume in older adults (65–90 years at baseline). We were able to examine these polymorphisms in relation to memory and hippocampal volume using cross-sectional data and, more importantly, also using longitudinal data (2 years between testing occasions). Overall we did not find support for an association of KIBRA either alone or in combination with CLSTN2 with memory performance or hippocampal volume, nor did variation in these genes influence longitudinal memory decline or hippocampal atrophy in two cohorts of older adults.

  • 69.
    Boraxbekk, Carl-Johan
    et al.
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Hagkvist, Filip
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Lindner, Philip
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Department of Clinical Neuroscience, Karolinska Institutet; Department of Psychology, Stockholm University.
    Motor and mental training in older people: transfer, interference, and associated functional neural responses2016In: Neuropsychologia, ISSN 0028-3932, E-ISSN 1873-3514, Vol. 89, p. 371-377Article in journal (Refereed)
    Abstract [en]

    Learning new motor skills may become more difficult with advanced age. In the present study, we randomized 56 older individuals, including 30 women (mean age 70.6 years), to 6 weeks of motor training, mental (motor imagery) training, or a combination of motor and mental training of a finger tapping sequence. Performance improvements and post-training functional magnetic resonance imaging (fMRI) were used to investigate performance gains and associated underlying neural processes. Motor-only training and a combination of motor and mental training improved performance in the trained task more than mental-only training. The fMRI data showed that motor training was associated with a representation in the premotor cortex and mental training with a representation in the secondary visual cortex. Combining motor and mental training resulted in both premotor and visual cortex representations. During fMRI scanning, reduced performance was observed in the combined motor and mental training group, possibly indicating interference between the two training methods. We concluded that motor and motor imagery training in older individuals is associated with different functional brain responses. Furthermore, adding mental training to motor training did not result in additional performance gains compared to motor-only training and combining training methods may result in interference between representations, reducing performance.

  • 70.
    Boraxbekk, Carl-Johan
    et al.
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Aging Research Center (ARC), Karolinska Institute, Stockholm, Sweden.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Physical activity over a decade modifies age-related decline in perfusion, gray matter volume, and functional connectivity of the posterior default mode network: a multimodal approach2016In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 131, p. 133-141Article in journal (Refereed)
    Abstract [en]

    One step toward healthy brain aging may be to entertain a physically active lifestyle. Studies investigating physical activity effects on brain integrity have, however, mainly been based on single brain markers, and few used a multimodal imaging approach. In the present study, we used cohort data from the Betula study to examine the relationships between scores reflecting current and accumulated physical activity and brain health. More specifically, we first examined if physical activity scores modulated negative effects of age on seven resting state networks previously identified by Salami, Pudas, and Nyberg (2014). The results revealed that one of the most age-sensitive RSN was positively altered by physical activity, namely, the posterior default-mode network involving the posterior cingulate cortex (PCC). Second, within this physical activity-sensitive RSN, we further analyzed the association between physical activity and gray matter (GM) volumes, white matter integrity, and cerebral perfusion using linear regression models. Regions within the identified DMN displayed larger GM volumes and stronger perfusion in relation to both current and 10-years accumulated scores of physical activity. No associations of physical activity and white matter integrity were observed. Collectively, our findings demonstrate strengthened PCC–cortical connectivity within the DMN, larger PCC GM volume, and higher PCC perfusion as a function of physical activity. In turn, these findings may provide insights into the mechanisms of how long-term regular exercise can contribute to healthy brain aging.

  • 71.
    Boraxbekk, Carl-Johan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Centre for Population Studies (CPS).
    Stomby, Andreas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ryberg, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lindahl, Bernt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Larsson, Christel
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Göteborgs Universitet.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Diet-Induced Weight Loss alters Functional Brain Responses during an Episodic Memory Task2015In: Obesity Facts, ISSN 1662-4025, E-ISSN 1662-4033, Vol. 8, p. 261-272Article in journal (Refereed)
    Abstract [en]

    Objective: It has been suggested that overweight is negatively associated with cognitive functions. The aim of this study was to investigate whether a reduction in body weight by dietary interventions could improve episodic memory performance and alter associated functional brain responses in overweight and obese women. Methods: 20 overweight postmenopausal women were randomized to either a modified paleolithic diet or a standard diet adhering to the Nordic Nutrition Recommendations for 6 months. We used functional magnetic resonance imaging to examine brain function during an episodic memory task as well as anthropometric and biochemical data before and after the interventions. Results: Episodic memory performance improved significantly (p = 0.010) after the dietary interventions. Concomitantly, brain activity increased in the anterior part of the right hippocampus during memory encoding, without differences between diets. This was associated with decreased levels of plasma free fatty acids (FFA). Brain activity increased in pre-frontal cortex and superior/middle temporal gyri. The magnitude of increase correlated with waist circumference reduction. During episodic retrieval, brain activity decreased in inferior and middle frontal gyri, and increased in middle/superior temporal gyri. Conclusions: Diet-induced weight loss, associated with decreased levels of plasma FFA, improves episodic memory linked to increased hippocampal activity.

  • 72.
    Brasselet, Romain
    et al.
    Université Pierre et Marie Curie, Paris.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Arleo, Angelo
    Université Pierre et Marie Curie, Paris.
    Quantifying neurotransmission reliability through metrics-based information analysis2011In: Neural Computation, ISSN 0899-7667, E-ISSN 1530-888X, Vol. 23, no 4, p. 852-881Article in journal (Refereed)
    Abstract [en]

    We set forth an information-theoretical measure to quantify neurotransmission reliability while taking into full account the metrical properties of the spike train space. This parametric information analysis relies on similarity measures induced by the metrical relations between neural responses as spikes flow in. Thus, in order to assess the entropy, the conditional entropy, and the overall information transfer, this method does not require any a priori decoding algorithm to partition the space into equivalence classes. It therefore allows the optimal parameters of a class of distances to be determined with respect to information transmission. To validate the proposed information-theoretical approach, we study precise temporal decoding of human somatosensory signals recorded using microneurography experiments. For this analysis, we employ a similarity measure based on the Victor-Purpura spike train metrics. We show that with appropriate parameters of this distance, the relative spike times of the mechanoreceptors? responses convey enough information to perform optimal discrimination?defined as maximum metrical information and zero conditional entropy?of 81 distinct stimuli within 40 ms of the first afferent spike. The proposed information-theoretical measure proves to be a suitable generalization of Shannon mutual information in order to consider the metrics of temporal codes explicitly. It allows neurotransmission reliability to be assessed in the presence of large spike train spaces (e.g., neural population codes) with high temporal precision.

  • 73. Brehmer, Yvonne
    et al.
    Rieckmann, Anna
    Bellander, Martin
    Westerberg, Helena
    Fischer, Håkan
    Bäckman, Lars
    Neural correlates of training-related working-memory gains in old age.2011In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 58, no 4, p. 1110-20Article in journal (Refereed)
    Abstract [en]

    Working memory (WM) functioning declines in old age. Due to its impact on many higher-order cognitive functions, investigating whether training can modify WM performance has recently been of great interest. We examined the relationship between behavioral performance and neural activity following five weeks of intensive WM training in 23 healthy older adults (M=63.7 years). 12 participants received adaptive training (i.e. individually adjusted task difficulty to bring individuals to their performance maximum), whereas the others served as active controls (i.e. fixed low-level practice). Brain activity was measured before and after training, using fMRI, while subjects performed a WM task under two difficulty conditions. Although there were no training-related changes in WM during scanning, neocortical brain activity decreased post training and these decreases were larger in the adaptive training group than in the controls under high WM load. This pattern suggests intervention-related increases in neural efficiency. Further, there were disproportionate gains in the adaptive training group in trained as well as in non-trained (i.e. attention, episodic memory) tasks assessed outside the scanner, indicating the efficacy of the training regimen. Critically, the degree of training-related changes in brain activity (i.e. neocortical decreases and subcortical increases) was related to the maximum gain score achieved during the intervention period. This relationship suggests that the decreased activity, but also specific activity increases, observed were functionally relevant.

  • 74. Brenner, David
    et al.
    Mueller, Kathrin
    Wieland, Thomas
    Weydt, Patrick
    Boehm, Sarah
    Lule, Dorothee
    Huebers, Annemarie
    Neuwirth, Christoph
    Weber, Markus
    Borck, Guntram
    Wahlqvist, Magnus
    Danzer, Karin M.
    Volk, Alexander E.
    Meitinger, Thomas
    Strom, Tim M.
    Otto, Markus
    Kassubek, Jan
    Ludolph, Albert C.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Neurology Department, Ulm University, Ulm, Germany.
    Weishaupt, Jochen H.
    NEK1 mutations in familial amyotrophic lateral sclerosis2016In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 139, p. CP14-CP17Article in journal (Refereed)
  • 75.
    Brenner, David
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Yilmaz, Rüstem
    Müller, Kathrin
    Grehl, Torsten
    Petri, Susanne
    Meyer, Thomas
    Grosskreutz, Julian
    Weydt, Patrick
    Ruf, Wolfgang
    Neuwirth, Christoph
    Weber, Markus
    Pinto, Susana
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience. Department of Neurosciences and Mental Health, Hospital de Santa Maria-CHLN, Lisbon, Portugal.
    Claeys, Kristl G.
    Schrank, Berthold
    Jordan, Berit
    Knehr, Antje
    Günther, Kornelia
    Hübers, Annemarie
    Zeller, Daniel
    Kubisch, Christian
    Jablonka, Sibylle
    Sendtner, Michael
    Klopstock, Thomas
    de Carvalho, Mamede
    Sperfeld, Anne
    Borck, Guntram
    Volk, Alexander E.
    Dorst, Johannes
    Weis, Joachim
    Otto, Markus
    Schuster, Joachim
    Del Tredici, Kelly
    Braak, Heiko
    Danzer, Karin M.
    Freischmidt, Axel
    Meitinger, Thomas
    Strom, Tim M.
    Ludolph, Albert C.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience. Neurology Department, Ulm University, Ulm, Germany.
    Weishaupt, Jochen H.
    Hot-spot KIF5A mutations cause familial ALS2018In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 141, p. 688-697Article in journal (Refereed)
    Abstract [en]

    Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 x 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p. Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 x 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.

  • 76. Brenner, P.
    et al.
    Burkill, S.
    Jokinen, Jussi
    Umeå University, Faculty of Medicine, Department of Clinical Sciences. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Moore, A.
    Geissbuehler, Y.
    Hillert, J.
    Bahmanyar, S.
    Montgomery, S.
    Multiple sclerosis and risk of completed and attempted suicide - a national cohort study2015In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 21, p. 23-24Article in journal (Other academic)
  • 77.
    Brohlin, Maria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Mesenchymal stem cells for repair of the peripheral and central nervous system2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Bone marrow-derived mesenchymal stem cells (MSC) have been shown to provide neuroprotection after transplantation into the injured nervous system. The present thesis investigates whether adult human and rat MSC differentiated along a Schwann cell lineage could increase their expression of neurotrophic factors and promote regeneration after transplantation into the injured peripheral nerve and spinal cord.

    Human and rat mesenchymal stem cells (hMSC and rMSC) expressed characteristic stem cell surface markers, mRNA transcripts for different neurotrophic factors and demonstrated multi-lineage differentiation potential. Following treatment with a cocktail of growth factors, the hMSC and rMSC expressed typical Schwann cells markers at both the transcriptional and translational level and significantly increased production of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF).

    Age and time in culture are of relevance for clinical settings and growth-promoting effects of hMSC from young donors (16-18 years) and old donors (67-75 years) were compared. Undifferentiated hMSC from both young and old donors increased total neurite length of cultured dorsal root ganglion (DRG) neurons. Differentiation of hMSC from the young donors, but not the eldery donors, further enhanced the neurite outgrowth. Undifferentiated hMSC were cultured for eleven weeks in order to examine the effect of in vitro expansion time on neurite outgrowth. hMSC from the young donors maintained their proliferation rate and their ability to enhance neurite outgrowth from DRG neurons.

    Using a sciatic nerve injury model, a 10mm gap was bridged with either an empty tubular fibrin glue conduit, or conduits containing hMSC, with and without cyclosporine treatment. Cells were labeled with PKH26 prior to transplantation. At 3 weeks after injury the conduits with cells and immunosuppression increased regeneration compared with an empty conduit. PKH26 labeled human cells survived in the rat model and the inflammatory reaction could be suppressed by cyclosporine.

    After cervical C4 hemisection, BrdU/GFP-labeled rMSC were injected into the lateral funiculus rostral and caudal to the spinal cord lesion site. Spinal cords were analyzed 2-8 weeks after transplantation. Transplanted MSC remained at the injection sites and in the trauma zone for several weeks and were often associated with numerous neurofilament-positive axons. Transplanted rMSC induced up-regulation of vascular endothelial growth factor in spinal cord tissue rostral to the injury site, but did not affect expression of brain-derived neurotrophic factor. Although rMSC provided neuroprotection for rubrospinal neurons and significantly attenuated astroglial and microglial reaction, cell transplantation caused aberrant sprouting of calcitonin gene-related peptide immunostained sensory axons in the dorsal horn.

    In summary these results demonstrate that both rat and human MSC can be differentiated towards the glial cell lineage, and show functional characteristics similar to Schwann cells. hMSC from the young donors represent a more favorable source for neurotransplantation since they maintain proliferation rate and preserve their growth-promoting effects in long-term cultures. The data also suggest that differentiated MSC increase expression of neurotrophic factors and support regeneration after peripheral nerve and spinal cord injury.

  • 78.
    Brohlin, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikova, Liudmila
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Aging effect on neurotrophic activity of human mesenchymal stem cells2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, p. e45052-Article in journal (Refereed)
    Abstract [en]

    Clinical efficacy of stem cells for nerve repair is likely to be influenced by issues including donor age and in vitro expansion time. We isolated human mesenchymal stem cells (MSC) from bone marrow of young (16–18 years) and old (67–75 years) donors and analyzed their capacity to differentiate and promote neurite outgrowth from dorsal root ganglia (DRG) neurons. Treatment of MSC with growth factors (forskolin, basic fibroblast growth factor, platelet derived growth factor-AA and glial growth factor-2) induced protein expression of the glial cell marker S100 in cultures from young but not old donors. MSC expressed various neurotrophic factor mRNA transcripts. Growth factor treatment enhanced the levels of BDNF and VEGF transcripts with corresponding increases in protein release in both donor cell groups. MSC in co-culture with DRG neurons significantly enhanced total neurite length which, in the case of young but not old donors, was further potentiated by treatment of the MSC with the growth factors. Stem cells from young donors maintained their proliferation rate over a time course of 9 weeks whereas those from the old donors showed increased population doubling times. MSC from young donors, differentiated with growth factors after long-term culture, maintained their ability to enhance neurite outgrowth of DRG. Therefore, MSC isolated from young donors are likely to be a favourable cell source for nerve repair.

  • 79.
    Brohlin, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Mahay, Daljeet
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Terenghi, Giorgio
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Shawcross, Susan G
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Characterisation of human mesenchymal stem cells following differentiation into Schwann cell-like cells2009In: Neuroscience research, ISSN 0168-0102, E-ISSN 1872-8111, Vol. 64, no 1, p. 41-49Article in journal (Refereed)
    Abstract [en]

    Cell-based therapies provide a clinically applicable and available alternative to nerve autografts. Our previous studies have characterised rat-derived mesenchymal stem cells (MSC) and here we have investigated the phenotypic, molecular and functional characteristics of human-derived MSC (hMSC) differentiated along a Schwann cell lineage. The hMSC were isolated from healthy human donors and the identity of the undifferentiated hMSC was confirmed by the detection of MSC specific cells surface markers. The hMSC were differentiated along a glial cell lineage using an established cocktail of growth factors including glial growth factor-2. Following differentiation, the hMSC expressed the key Schwann cell (SC) markers at both the transcriptional and translational level. More importantly, we show the functional effect of hMSC on neurite outgrowth using an in vitro co-culture model system with rat-derived primary sensory neurons. The number of DRG sprouting neurites was significantly enhanced in the presence of differentiated hMSC; neurite length and density (branching) were also increased. These results provide evidence that hMSC can undergo molecular, morphological and functional changes to adopt a SC-like behaviour and, therefore, could be suitable as SC substitutes for nerve repair in clinical applications.

  • 80. 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.

  • 81. Bryan, Thomas
    et al.
    Luo, Xiliang
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Morozova-Roche, Ludmilla A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Davis, Jason J.
    The robust electrochemical detection of a Parkinson's disease marker in whole blood sera2012In: Chemical Science, ISSN 2041-6520, Vol. 3, no 12, p. 3468-3473Article in journal (Refereed)
    Abstract [en]

    Protein aggregation, leading to amyloid deposition in the brain, is implicated in the pathology of a number of increasingly prevalent neurodegeneration states such as Parkinson's disease (PD), Alzheimer's disease and prion diseases. The body's protective response to the formation of such deposits is to generate specific autoimmune antibodies. Alpha-synuclein, a natively unfolded protein relatively abundant in the brain, is the main constituent of Lewy body amyloid dispositions in PD. Previous assays determining content of alpha-synuclein in bodily fluids have proven to be largely inconclusive. Here we have taken a novel approach in utilising alpha-synuclein modified electrodes to sample the autoantibodies generated as the body responds to changes in its homeostasis. We show that these electroanalytical assays not only robustly distinguish between disease state and control individuals but also map out disease progression with unprecedented sensitivity and clarity. The impedimetric electrode surfaces are highly specific, reusable, exhibit a linear range from 0.5 to 10 nM and a detection limit of 55 +/- 3 pM. We believe electroanalyses such as these, possible with less than 10 microlitres of fluid and a total assay time of only a few minutes, to be of value for early diagnosis of PD and possibly other alpha-synucleinopathies, and for monitoring disease progression and effects of possible disease modifying interventions.

  • 82.
    Brändström, Helge
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Sundelin, Anna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Hoseason, Daniela
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Sundström, Nina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Johansson, Göran
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Winsö, Ola
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Koskinen, Lars-Owe
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Haney, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Risk for intracranial pressure increase related to enclosed air in post-craniotomy patients during air ambulance transport: a retrospective cohort study with simulation2017In: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, ISSN 1757-7241, E-ISSN 1757-7241, Vol. 25, article id 50Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Post-craniotomy intracranial air can be present in patients scheduled for air ambulance transport to their home hospital. We aimed to assess risk for in-flight intracranial pressure (ICP) increases related to observed intracranial air volumes, hypothetical sea level pre-transport ICP, and different potential flight levels and cabin pressures. METHODS: A cohort of consecutive subdural hematoma evacuation patients from one University Medical Centre was assessed with post-operative intracranial air volume measurements by computed tomography. Intracranial pressure changes related to estimated intracranial air volume effects of changing atmospheric pressure (simulating flight and cabin pressure changes up to 8000 ft) were simulated using an established model for intracranial pressure and volume relations. RESULTS: Approximately one third of the cohort had post-operative intracranial air. Of these, approximately one third had intracranial air volumes less than 11 ml. The simulation estimated that the expected changes in intracranial pressure during 'flight' would not result in intracranial hypertension. For intracranial air volumes above 11 ml, the simulation suggested that it was possible that intracranial hypertension could develop 'inflight' related to cabin pressure drop. Depending on the pre-flight intracranial pressure and air volume, this could occur quite early during the assent phase in the flight profile. DISCUSSION: These findings support the idea that there should be radiographic verification of the presence or absence of intracranial air after craniotomy for patients planned for long distance air transport. CONCLUSIONS: Very small amounts of air are clinically inconsequential. Otherwise, air transport with maintained ground-level cabin pressure should be a priority for these patients.

  • 83.
    Brännström, Kristoffer
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Öhman, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nilsson, Lina
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pihl, Mathias
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sandblad, Linda
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    The N-terminal Region of Amyloid β Controls the Aggregation Rate and Fibril Stability at Low pH Through a Gain of Function Mechanism2014In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 136, no 31, p. 10956-10964Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease is linked to a pathological polymerization of the endogenous amyloid β-peptide (Aβ) that ultimately forms amyloid plaques within the human brain. We used surface plasmon resonance (SPR) to measure the kinetic properties of Aβ fibril formation under different conditions during the polymerization process. For all polymerization processes, a critical concentration of free monomers, as defined by the dissociation equilibrium constant (KD), is required for the buildup of the polymer, for example, amyloid fibrils. At concentrations below the KD, polymerization cannot occur. However, the KD for Aβ has previously been shown to be several orders of magnitude higher than the concentrations found in the cerebrospinal and interstitial fluids of the human brain, and the mechanism by which Aβ amyloid forms in vivo has been a matter of debate. Using SPR, we found that the KD of Aβ dramatically decreases as a result of lowering the pH. Importantly, this effect enables Aβ to polymerize within a picomolar concentration range that is close to the physiological Aβ concentration within the human brain. The stabilizing effect is dynamic, fully reversible, and notably pronounced within the pH range found within the endosomal and lysosomal pathways. Through sequential truncation, we show that the N-terminal region of Aβ contributes to the enhanced fibrillar stability due to a gain of function mechanism at low pH. Our results present a possible route for amyloid formation at very low Aβ concentrations and raise the question of whether amyloid formation in vivo is restricted to a low pH environment. These results have general implications for the development of therapeutic interventions.

  • 84.
    Brännström, Thomas
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Bergh, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ekhtiari Bidhendi, Elaheh
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Marklund, Stefan M.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Mutant SOD1 aggregates from human ventral horn transmit templated aggregation and fatal ALS-like disease2019In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 29, p. 90-90Article in journal (Other academic)
  • 85. Burgunder, J-M
    et al.
    Schöls, L
    Baets, J
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gasser, T
    Szolnoki, Z
    Fontaine, B
    Van Broeckhoven, C
    Di Donato, S
    De Jonghe, P
    Lynch, T
    Mariotti, C
    Spinazzola, A
    Tabrizi, S J
    Tallaksen, C
    Zeviani, M
    Harbo, H F
    Finsterer, J
    EFNS guidelines for the molecular diagnosis of neurogenetic disorders: motoneuron, peripheral nerve and muscle disorders2011In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 18, no 2, p. 207-E20Article in journal (Refereed)
    Abstract [en]

    Objectives: These EFNS guidelines on the molecular diagnosis of motoneuron disorders, neuropathies and myopathies are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated. Search strategy: To collect data about planning, conditions and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers and guideline recommendations reviewed. Results: The best level of evidence for genetic testing recommendation (B) can be found for the disorders with specific presentations, including familial amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, Charcot-Marie-Tooth 1A, myotonic dystrophy and Duchenne muscular dystrophy. For a number of less common disorders, a precise description of the phenotype, including the use of immunologic methods in the case of myopathies, is considered as good clinical practice to guide molecular genetic testing. Conclusion: These guidelines are provisional and the future availability of molecular-genetic epidemiological data about the neurogenetic disorders under discussion in this article will allow improved recommendation with an increased level of evidence.

  • 86. Burman, Joachim
    et al.
    Svensson, Emma
    Fransson, Moa
    Loskog, Angelica S. I.
    Zetterberg, Henrik
    Raininko, Raili
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Fagius, Jan
    Mangsbo, Sara M.
    The cerebrospinal fluid cytokine signature of multiple sclerosis: A homogenous response that does not conform to the Th1/Th2/Th17 convention2014In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 277, no 1-2, p. 153-159Article in journal (Refereed)
    Abstract [en]

    In this cross-sectional study, we wanted to identify key cytokines characteristic of different stages of multiple sclerosis (MS). To this end, cerebrospinal fluid from patients with MS was investigated with a multiplexed fluorescent bead-based immunoassay. In total 43 cytokines were assessed and related to clinical and imaging data. Increased levels of CCL22, CXCL10 and sCD40L characterized relapsing-remitting MS patients with the presence of gadolinium-enhancing lesions; decreased CCL2 and increased CXCL1 and CCL5 were typical of relapsing-remitting MS patients irrespectively of the presence of gadolinium-enhancing lesions. These homogenous patterns of cytokine activation do not conform to conventional Th1/Th2/Th17 responses. (C) 2014 Elsevier B.V. All rights reserved.

  • 87. Bäckman, Lars
    et al.
    Lindenberger, Ulman
    Li, Shu-Chen
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Linking cognitive aging to alterations in dopamine neurotransmitter functioning: Recent data and future avenues2010In: Neuroscience and Biobehavioral Reviews, ISSN 0149-7634, E-ISSN 1873-7528, Vol. 34, no 5, p. 670-677Article, review/survey (Refereed)
    Abstract [en]

    Molecular-imaging studies of dopaminergic neurotransmission measure biomarkers of dopamine (DA), such as the DA transporter and D(1) and D(2) receptor densities in the living brain. These studies indicate that individual differences in DA functions are linked to cognitive performance irrespective of age, and serve as powerful mediators of age-related decline in executive functioning, episodic memory, and perceptual speed. This focused review targets several recent findings pertaining to these relationships. Specifically, we discuss novel evidence concerning (a) the role of DA in within-person cognitive variability; (b) age-related differences in DA release during cognitive processing; (c) DA release following cognitive training in younger and older adults; and (d) the relationship between DA and task-induced functional brain activity. Based on these lines of empirical inquiry, we outline a series of avenues for future research on aging, DA, and cognition.

  • 88. Bäckman, Lars
    et al.
    Waris, Otto
    Johansson, Jarkko
    Andersson, Micael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Rinne, Juha O.
    Alakurtti, Kati
    Soveri, Anna
    Laine, Matti
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Increased dopamine release after working-memory updating training: Neurochemical correlates of transfer2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 7160Article in journal (Refereed)
    Abstract [en]

    Previous work demonstrates that working-memory (WM) updating training results in improved performance on a letter-memory criterion task, transfers to an untrained n-back task, and increases striatal dopamine (DA) activity during the criterion task. Here, we sought to replicate and extend these findings by also examining neurochemical correlates of transfer. Four positron emission tomography (PET) scans using the radioligand raclopride were performed. Two of these assessed DAD2 binding (letter memory; n-back) before 5 weeks of updating training, and the same two scans were performed post training. Key findings were (a) pronounced training-related behavioral gains in the lettermemory criterion task, (b) altered striatal DAD2 binding potential after training during letter-memory performance, suggesting training-induced increases in DA release, and (c) increased striatal DA activity also during the n-back transfer task after the intervention, but no concomitant behavioral transfer. The fact that the training-related DA alterations during the transfer task were not accompanied by behavioral transfer suggests that increased DA release may be a necessary, but not sufficient, condition for behavioral transfer to occur.

  • 89.
    Bäckström, David C
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    The biology of cognitive decline and reduced survival in Parkinson disease: prognostic factors in a population-based cohort2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Parkinson disease (PD) is a progressive neurodegenerative disease that affects about 1% of the population over 60 years. The cardinal symptoms are motor disabilities but cognitive decline is also common. About 50% of all persons with PD develop dementia within 10 years after disease onset. Dementia in PD account for high social costs and has large, negative effects on quality of life. 

    Aims. The aim of the study was to investigate clinical, neurobiological and genetic factors of importance for progression and for the prognosis in PD and parkinsonism. First, we aimed to describe mortality and risk factors for death, including possible associations with cognitive dysfunction, in patients with idiopathic parkinsonism. Second, we aimed to study if biomarkers in the cerebrospinal fluid (CSF) are useful for the diagnosis of different forms of idiopathic parkinsonism and prediction of cognitive decline in PD. 

    Methods. A population-based cohort consisting of patients with new-onset, idiopathic parkinsonism was studied prospectively. After screening in a catchment area of ~142 000 inhabitants in Sweden, 182 patients with parkinsonism were included. The patients were investigated comprehensively, including neuropsychological testing, multimodal neuroimaging and genetic and biosample analyses. During follow up, 143 patients were diagnosed with PD, 13 with multiple system atrophy (MSA), and 18 with progressive supranuclear palsy (PSP). A total of 109 patients died. 

    Results. Patients with MSA and PSP had the shortest life expectancy. PD patients who presented with normal cognitive function had a largely normal life expectancy. In contrast, the mortality was increased in PD patients with cognitive impairment, freezing of gait, hyposmia, and mildly elevated leukocytes in the CSF. Of importance for the prognosis, patients with PD with an early CSF pattern of high Neurofilament light protein, low β-amyloid, and high heart fatty acid binding protein had an 11.8 times increased risk of developing PD dementia (95% CI 3.3-42.1, p <0.001), compared with PD patients with a more ”normal” CSF pattern. Variation in genes associated with dopamine function was also associated with some effects on cognitive functions in PD. 

    Conclusions. PD subtypes, for instance the subtype characterized by cognitive decline, have distinguishing clinical, neurochemical and neurobiological traits, which are of importance for the prognosis and the survival. An early CSF analysis is useful for predicting cognitive decline. The finding of a low-grade immune reaction in the CSF of patients with PD may have clinical implications. In clinical practice, CSF biomarkers could be useful for improving diagnosis and prognostication.

  • 90.
    Bäckström, David C
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Eriksson Domellöf, Magdalena
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Olsson, Bob
    Öhrfelt, Annika
    Trupp, Miles
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Zetterberg, Henrik
    Blennow, Kaj
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Cerebrospinal Fluid Patterns and the Risk of Future Dementia in Early, Incident Parkinson Disease2015In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 72, no 10, p. 1175-1182Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: Alterations in cerebrospinal fluid (CSF) have been found in Parkinson disease (PD) and in PD dementia (PDD), but the prognostic importance of such changes is not well known. In vivo biomarkers for disease processes in PD are important for future development of disease-modifying therapies. OBJECTIVE: To assess the diagnostic and prognostic value of a panel of CSF biomarkers in patients with early PD and related disorders. DESIGN, SETTING, AND PARTICIPANTS: Regional population-based, prospective cohort study of idiopathic parkinsonism that included patients diagnosed between January 1, 2004, and April 30, 2009, by amovement disorder team at a university hospital that represented the only neurology clinic in the region. Participants were 128 nondemented patients with new-onset parkinsonism (104 with PD, 11 with multiple system atrophy, and 13 with progressive supranuclear palsy) who were followed up for 5 to 9 years. At baseline, CSF from 30 healthy control participants was obtained for comparison. MAIN OUTCOMES AND MEASURES: Cerebrospinal fluid concentrations of neurofilament light chain protein, Aβ1-42, total tau, phosphorylated tau, α-synuclein, and heart fatty acid-binding protein were quantified by 2 blinded measurements (at baseline and after 1 year). Follow-up included an extensive neuropsychological assessment. As PD outcome variables, mild cognitive impairment and incident PDD were diagnosed based on published criteria. RESULTS: Among the 128 study participants, the 104 patients with early PD had a different CSF pattern compared with the 13 patients with progressive supranuclear palsy (baseline area under the receiver operating characteristic curve, 0.87; P < .0001) and the 30 control participants (baseline area under the receiver operating characteristic curve, 0.69; P = .0021). A CSF biomarker pattern associated with the development of PDD was observed. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein at baseline were related to future PDD as analyzed by Cox proportional hazards regression models. Combined, these early biomarkers predicted PDD with high accuracy (hazard ratio, 11.8; 95% CI, 3.3-42.1; P = .0001) after adjusting for possible confounders. CONCLUSIONS AND RELEVANCE: The analyzed CSF biomarkers have potential usefulness as a diagnostic tool in patients with parkinsonism. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein were related to future PDD, providing new insights into the etiology of PDD.

  • 91.
    Bäckström, David C
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    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).
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Zetterberg, Henrik
    Blennow, Kaj
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lenfeldt, Niklas
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Neurofilament concentration in CSF correlates with disease severity, survival and imaging measures of neurodegeneration in incident Parkinson diseaseManuscript (preprint) (Other academic)
  • 92.
    Bäckström, Torbjörn
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Haage, D.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Löfgren, Mats
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, I. M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Strömberg, J.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, S.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Andreen, Lotta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Ossewaarde, L.
    van Wingen, G. A.
    Turkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bengtsson, S. K.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons2011In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 191, no Special issue, p. 46-54Article, review/survey (Refereed)
    Abstract [en]

    Some women have negative mood symptoms, caused by progestagens in hormonal contraceptives or sequential hormone therapy or by progesterone in the luteal phase of the menstrual cycle, which may be attributed to metabolites acting on the GABA-A receptor. The GABA system is the major inhibitory system in the adult CNS and most positive modulators of the GABA-A receptor (benzodiazepines, barbiturates, alcohol, GABA steroids), induce inhibitory (e.g. anesthetic, sedative, anticonvulsant, anxiolytic) effects. However, some individuals have adverse effects (seizures, increased pain, anxiety, irritability, aggression) upon exposure. Positive GABA-A receptor modulators induce strong paradoxical effects including negative mood in 3%-8% of those exposed, while up to 25% have moderate symptoms. The effect is biphasic: low concentrations induce an adverse anxiogenic effect while higher concentrations decrease this effect and show inhibitory, calming properties. The prevalence of premenstrual dysphoric disorder (PMDD) is also 3%-8% among women in fertile ages, and up to 25% have more moderate symptoms of premenstrual syndrome (PMS). Patients with PMDD have severe luteal phase-related symptoms and show changes in GABA-A receptor sensitivity and GABA concentrations. Findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor, which may be explained by one or more of three hypotheses regarding the paradoxical effect of GABA steroids on behavior: (1) under certain conditions, such as puberty, the relative fraction of certain GABA-A receptor subtypes may be altered, and at those subtypes the GABA steroids may act as negative modulators in contrast to their usual role as positive modulators; (2) in certain brain areas of vulnerable women the transmembrane C1(-) gradient may be altered by factors such as estrogens that favor excitability; (3) inhibition of inhibitory neurons may promote disinhibition, and hence excitability. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain. (C) 2011 Published by Elsevier Ltd on behalf of IBRO.

  • 93. Cabeza, Roberto
    et al.
    Albert, Marilyn
    Belleville, Sylvie
    Craik, Fergus I. M.
    Duarte, Audrey
    Grady, Cheryl L.
    Lindenberger, Ulman
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Park, Denise C.
    Reuter-Lorenz, Patricia A.
    Rugg, Michael D.
    Steffener, Jason
    Rajah, M. Natasha
    Maintenance, reserve and compensation: the cognitive neuroscience of healthy ageing2018In: Nature Reviews Neuroscience, ISSN 1471-003X, E-ISSN 1471-0048, Vol. 19, no 11, p. 701-710Article, review/survey (Refereed)
    Abstract [en]

    Cognitive ageing research examines the cognitive abilities that are preserved and/or those that decline with advanced age. There is great individual variability in cognitive ageing trajectories. Some older adults show little decline in cognitive ability compared with young adults and are thus termed ‘optimally ageing’. By contrast, others exhibit substantial cognitive decline and may develop dementia. Human neuroimaging research has led to a number of important advances in our understanding of the neural mechanisms underlying these two outcomes. However, interpreting the age-related changes and differences in brain structure, activation and functional connectivity that this research reveals is an ongoing challenge. Ambiguous terminology is a major source of difficulty in this venture. Three terms in particular — compensation, maintenance and reserve — have been used in a number of different ways, and researchers continue to disagree about the kinds of evidence or patterns of results that are required to interpret findings related to these concepts. As such inconsistencies can impede progress in both theoretical and empirical research, here, we aim to clarify and propose consensual definitions of these terms.

  • 94. Cabeza, Roberto
    et al.
    Albert, Marilyn
    Belleville, Sylvie
    Craik, Fergus I. M.
    Duarte, Audrey
    Grady, Cheryl L.
    Lindenberger, Ulman
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Park, Denise C.
    Reuter-Lorenz, Patricia A.
    Rugg, Michael D.
    Steffener, Jason
    Rajah, M. Natasha
    Reply to 'Mechanisms underlying resilience in ageing'2019In: Nature Reviews Neuroscience, ISSN 1471-003X, E-ISSN 1471-0048, Vol. 20, no 4, p. 247-247Article in journal (Refereed)
  • 95. Cabeza, Roberto
    et al.
    Nyberg, LarsUmeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.Park, Denise
    Cognitive neuroscience of aging: linking cognitive and cerebral aging2005Collection (editor) (Other academic)
    Abstract [en]

    Until recently, the cognitive and neural mechanisms of age-related changes in cognition were usually studied independently of each other.

    On one hand, studies in the domain of cognitive psychology of aging investigated the effects of aging on behavioral measures of cognition and characterized a variety of age-related deficits in memory, attention, and the like. On the other hand, studies in the domain of neuroscience of aging investigated the effects of aging on the anatomy and physiology of the brain and described forms of age-related neural decline, such as cerebral atrophy and synaptic loss. Although it is reasonable to assume that cognitive aging is largely a consequence of cerebral aging, the relationships between these two phenomena are still largely unknown. Fortunately, this void is being rapidly resolved by studies focusing on the relationships between the effects of aging on the cognition and on the brain. This group of studies constitutes the new discipline of cognitive neuroscience of aging (CNA). Although CNA has a long past, only lately has it achieved the critical mass to be considered an autonomous discipline. The main goal of this book is to provide an introduction to this exciting new field.

  • 96. Cadilhac, Dominique A.
    et al.
    Amatya, Bhasker
    Lalor, Erin
    Rudd, Anthony
    Lindsay, Patrice
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Is There Evidence That Performance Measurement in Stroke Has Influenced Health Policy and Changes to Health Systems?2012In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 43, no 12, p. 3413-3420Article, review/survey (Refereed)
  • 97. Cancelliere, Carol
    et al.
    Cassidy, J David
    Cote, Pierre
    Hincapie, Cesar A
    Harvigsen, Jan
    Carrol, Linda J
    Marras, Connie
    Boyle, Eleanor
    Kristman, Vicki
    Hung, Ryan
    Stålnacke, Britt-Marie
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine.
    Rumney, Peter
    Coronado, Victor
    Holm, Lena W
    Borg, Jörgen
    Nygren-de Boussard, Catharina
    af Geijerstam, Jean-Luc
    Keightley, Michelle
    Protocol for a systematic review of prognosis after mild traumatic brain injury: an update of the WHO Collaborating Centre Task Force findings2012In: Systematic Reviews, ISSN 2046-4053, no 1, p. 17-Article in journal (Refereed)
    Abstract [en]

    Background: Mild traumatic brain injury (MTBI) is a major public-health concern and represents 70-90% of all treated traumatic brain injuries. The last best-evidence synthesis, conducted by the WHO Collaborating Centre for Neurotrauma, Prevention, Management and Rehabilitation in 2002, found few quality studies on prognosis. The objective of this review is to update these findings. Specifically, we aim to describe the course, identify modifiable prognostic factors, determine long-term sequelae, and identify effects of interventions for MTBI. Finally, we will identify gaps in the literature, and make recommendations for future research.

    Methods: The databases MEDLINE, PsychINFO, Embase, CINAHL and SPORTDiscus were systematically searched (2001 to date). The search terms included 'traumatic brain injury', 'craniocerebral trauma', 'prognosis', and 'recovery of function'. Reference lists of eligible papers were also searched. Studies were screened according to pre-defined inclusion and exclusion criteria. Inclusion criteria included original, published peer-reviewed research reports in English, French, Swedish, Norwegian, Danish and Spanish, and human participants of all ages with an accepted definition of MTBI. Exclusion criteria included publication types other than systematic reviews, meta-analyses, randomized controlled trials, cohort studies, and case-control studies; as well as cadaveric, biomechanical, and laboratory studies. All eligible papers were critically appraised using a modification of the Scottish Intercollegiate Guidelines Network (SIGN) criteria. Two reviewers performed independent, in-depth reviews of each eligible study, and a third reviewer was consulted for disagreements. Data from accepted papers were extracted into evidence tables, and the evidence was synthesized according to the modified SIGN criteria.

    Conclusion: The results of this study form the basis for a better understanding of recovery after MTBI, and will allow development of prediction tools and recommendation of interventions, as well as informing health policy and setting a future research agenda.

  • 98. Canosa, Antonio
    et al.
    De Marco, Giovanni
    Lomartire, Annarosa
    Rinaudo, Maria Teresa
    Di Cunto, Ferdinando
    Turco, Emilia
    Barberis, Marco
    Brunetti, Maura
    Casale, Federico
    Moglia, Cristina
    Calvo, Andrea
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Mora, Gabriele
    Chio, Adriano
    A novel p.Ser108LeufsTer15 SOD1 mutation leading to the formation of a premature stop codon in an apparently sporadic ALS patient: insights into the underlying pathomechanisms2018In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 72Article in journal (Refereed)
    Abstract [en]

    We report an apparently sporadic amyotrophic lateral sclerosis patient carrying a heterozygous novel frameshift SOD1 mutation (p.Ser108LeufsTer15), predicted to cause a premature protein truncation. RTPCR analysis of SOD1 mRNA and SDS-PAGE/Western blot analysis of PBMC demonstrated that mRNA from the mutant allele is expressed at levels similar to those of the wild-type allele, but the truncated protein is undetectable also in the insoluble fraction and after proteasome inhibition. Accordingly, the dismutation activity in erythrocytes is halved. Thus, the pathogenic mechanism associated with this mutation might be based on an insufficient activity of SOD1 that would make motor neurons more vulnerable to oxidative injury. However, it cannot be excluded that p.Ser108LeufsTer15 SOD1 is present in the nervous tissue and, being less charged and hence having less repulsive forces than the wild-type protein, may trigger toxic mechanisms as a consequence of its propensity to aggregate. 

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

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

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

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

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

  • 100. Casar-Borota, O.
    et al.
    Jacobsson, Johan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Libelius, Rolf
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Moslemi, A. R.
    Hedberg, C.
    Oldfors, A.
    A novel dynamin-2 gene mutation associated with a late-onset centronuclear myopathy with unusual clinical presentation and necklace fibres2012In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 22, no 9-10, p. 843-843Article in journal (Other academic)
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