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  • 201. Guitart-Masip, Marc
    et al.
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Aging Research Center, Karolinska Institute, Stockholm, Sweden .
    Garrett, Douglas
    Rieckmann, Anna
    Center for Brain Science, Harvard University, Cambridge, USA.
    Lindenberger, Ulman
    Bäckman, Lars
    BOLD Variability is Related to Dopaminergic Neurotransmission and Cognitive Aging2016In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 26, no 5, p. 2074-2083Article in journal (Refereed)
    Abstract [en]

    Dopamine (DA) losses are associated with various aging-related cognitive deficits. Typically, higher moment-to-moment brain signal variability in large-scale patterns of voxels in neocortical regions is linked to better cognitive performance and younger adult age, yet the physiological mechanisms regulating brain signal variability are unknown. We explored the relationship among adult age, DA availability, and blood oxygen level-dependent (BOLD) signal variability, while younger and older participants performed a spatial working memory (SWM) task. We quantified striatal and extrastriatal DA D1 receptor density with [(11)C]SCH23390 and positron emission tomography in all participants. We found that BOLD variability in a neocortical region was negatively related to age and positively related to SWM performance. In contrast, BOLD variability in subcortical regions and bilateral hippocampus was positively related to age and slower responses, and negatively related to D1 density in caudate and dorsolateral prefrontal cortex. Furthermore, BOLD variability in neocortical regions was positively associated with task-related disengagement of the default-mode network, a network whose activation needs to be suppressed for efficient SWM processing. Our results show that age-related DA losses contribute to changes in brain signal variability in subcortical regions and suggest a potential mechanism, by which neocortical BOLD variability supports cognitive performance.

  • 202.
    Gussing, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    NQO1 activity in the main and the accessory olfactory systems correlates with the zonal topography of projection maps2004In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 19, no 9, p. 2511-2518Article in journal (Refereed)
    Abstract [en]

    The mouse olfactory epithelium (OE) is divided into spatial zones, each containing neurons expressing zone-specific subsets of odorant receptor genes. Likewise, the vomeronasal (VN) organ is organized into apical and basal subpopulations of neurons expressing different VN receptor gene families. Axons projecting from the different OE zones and VN subpopulations form synapses within circumscribed regions in the glomerular layer of the olfactory bulb (OB) and accessory olfactory bulb (AOB), respectively. We here show that mature neurons in one defined zone selectively express NADPH:quinone oxidoreductase (NQO1), an enzyme that catalyses reduction of quinones. Immunohistochemistry and in situ hybridization analyses show non-overlapping expression of NQO1 and the Rb8 neural cell adhesion molecule (RNCAM/OCAM) in OE and axon terminals within glomeruli of the OB. In addition, NQO1 immunoreactivity reveals selective, zone-specific axon fasciculation in the olfactory nerve. VN subpopulations do not show complementary patterns of RNCAM and NQO1 immunoreactivity, instead both genes are co-expressed in apical VN neurons that project to the rostral AOB. These results indicate that one division of both the accessory and the main olfactory projection maps are composed of sensory neurons that are specialized to reduce environmental and/or endogenously produced quinones via an NQO1-dependent mechanism. The role of NQO1 in bioactivation of quinoidal drugs also points to a connection between zone-specific NQO1 expression and zone-specific toxicity of certain olfactory toxins.

  • 203. Gustavsson, Anders
    et al.
    Svensson, Mikael
    Jacobi, Frank
    Allgulander, Christer
    Alonso, Jordi
    Beghi, Ettore
    Dodel, Richard
    Ekman, Mattias
    Faravelli, Carlo
    Fratiglioni, Laura
    Gannon, Brenda
    Jones, David Hilton
    Jennum, Poul
    Jordanova, Albena
    Jönsson, Linus
    Karampampa, Korinna
    Knapp, Martin
    Kobelt, Gisela
    Kurth, Tobias
    Lieb, Roselind
    Linde, Mattias
    Ljungcrantz, Christina
    Maercker, Andreas
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Moscarelli, Massimo
    Musayev, Amir
    Norwood, Fiona
    Preisig, Martin
    Pugliatti, Maura
    Rehm, Juergen
    Salvador-Carulla, Luis
    Schlehofer, Brigitte
    Simon, Roland
    Steinhausen, Hans-Christoph
    Stovner, Lars Jacob
    Vallat, Jean-Michel
    Van den Bergh, Peter
    van Os, Jim
    Vos, Pieter
    Xu, Weili
    Wittchen, Hans-Ulrich
    Jönsson, Bengt
    Olesen, Jes
    Cost of disorders of the brain in Europe 20102011In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 21, no 10, p. 718-779Article in journal (Refereed)
    Abstract [en]

    Background: The spectrum of disorders of the brain is large, covering hundreds of disorders that are listed in either the mental or neurological disorder chapters of the established international diagnostic classification systems. These disorders have a high prevalence as well as short- and long-term impairments and disabilities. Therefore they are an emotional, financial and social burden to the patients, their families and their social network. In a 2005 landmark study, we estimated for the first time the annual cost of 12 major groups of disorders of the brain in Europe and gave a conservative estimate of €386 billion for the year 2004. This estimate was limited in scope and conservative due to the lack of sufficiently comprehensive epidemiological and/or economic data on several important diagnostic groups. We are now in a position to substantially improve and revise the 2004 estimates. In the present report we cover 19 major groups of disorders, 7 more than previously, ofan increased range of age groups and more cost items. We therefore present much improved cost estimates. Our revised estimates also now include the new EU member states, and hence a population of 514 million people.

    Aims: To estimate the number of persons with defined disorders of the brain in Europe in 2010, the total cost per person related to each disease in terms of direct and indirect costs, and an estimate of the total cost per disorder and country.

    Methods: The best available estimates of the prevalence and cost per person for 19 groups of disorders of the brain (covering well over 100 specific disorders) were identified via a systematic review of the published literature. Together with the twelve disorders included in 2004, the following range of mental and neurologic groups of disorders is covered: addictive disorders, affective disorders, anxiety disorders, brain tumor, childhood and adolescent disorders (developmental disorders),dementia, eating disorders, epilepsy, mental retardation, migraine, multiple sclerosis,neuromuscular disorders, Parkinson's disease, personality disorders, psychotic disorders, sleep disorders, somatoform disorders, stroke, and traumatic brain injury. Epidemiologic panels were charged to complete the literature review for each disorder in order to estimate the 12-month prevalence, and health economic panels were charged to estimate best cost-estimates. A cost model was developed to combine the epidemiologic and economic data and estimate the total cost of each disorder in each of 30 European countries (EU27 + Iceland, Norway and Switzerland). The cost model was populated with national statistics from Eurostat to adjust all costs to 2010 values, converting all local currencies to Euro, imputing costs for countries where no data were available, and aggregating country estimates to purchasing power parity adjusted estimates for the total cost of disorders of the brain in Europe 2010.

    Results: The total cost of disorders of the brain was estimated at €798 billion in 2010. Direct costs constitute the majority of costs (37% direct healthcare costs and 23% direct non-medical costs) whereas the remaining 40% were indirect costs associated with patients' production losses. On average, the estimated cost per person with a disorder of the brain in Europe ranged between €285 for headache and €30,000 for neuromuscular disorders. The European per capita cost of disorders of the brain was €1550 on average but varied by country. The cost (in billion €PPP 2010) of the disorders of the brain included in this study was as follows: addiction: €65.7; anxiety disorders: €74.4; brain tumor: €5.2; child/adolescent disorders: €21.3; dementia: €105.2; eating disorders: €0.8; epilepsy: €13.8; headache: €43.5; mental retardation: €43.3; mood disorders: €113.4; multiple sclerosis: €14.6; neuromuscular disorders: €7.7; Parkinson's disease: €13.9; personality disorders: €27.3; psychotic disorders: €93.9; sleep disorders: €35.4; somatoform disorder: €21.2; stroke: €64.1; traumatic brain injury: €33.0. It should be noted that the revised estimate of those disorders included in the previous 2004 report constituted €477 billion, by and large confirming our previous study results after considering the inflation and population increase since 2004. Further, our results were consistent with administrative data on the health care expenditure in Europe, and comparable to previous studies on the cost of specific disorders in Europe. Our estimates were lower than comparable estimates from the US.

    Discussion: This study was based on the best currently available data in Europe and our model enabled extrapolation to countries where no data could be found. Still, the scarcity of data is an important source of uncertainty in our estimates and may imply over- or underestimations in some disorders and countries. Even though this review included many disorders, diagnoses, age groups and cost items that were omitted in 2004, there are still remaining disorders that could not be included due to limitations in the available data. We therefore consider our estimate of the total cost of the disorders of the brain in Europe to be conservative. In terms of the health economic burden outlined in this report, disorders of the brain likely constitute the number one economic challenge for European health care, now and in the future. Data presented in this report should be considered by all stakeholder groups, including policy makers, industry and patient advocacy groups, to reconsider the current science, research and public health agenda and define a coordinated plan of action of various levels to address the associated challenges.

    Recommendations: Political action is required in light of the present high cost of disorders of the brain. Funding of brain research must be increased; care for patients with brain disorders as well as teaching at medical schools and other health related educations must be quantitatively and qualitatively improved, including psychological treatments. The current move of the pharmaceutical industry away from brain related indications must be halted and reversed. Continued research into the cost of the many disorders not included in the present study is warranted. It is essential that not only the EU but also the national governments forcefully support these initiatives.

  • 204. Gustavsson, Anders
    et al.
    Svensson, Mikael
    Jacobi, Frank
    Allgulander, Christer
    Alonso, Jordi
    Beghi, Ettore
    Dodel, Richard
    Ekman, Mattias
    Faravelli, Carlo
    Fratiglioni, Laura
    Gannon, Brenda
    Jones, David Hilton
    Jennum, Pout
    Jordanova, Albena
    Jonsson, Linus
    Karampampa, Korinna
    Knapp, Martin
    Kobelt, Gisela
    Kurth, Tobias
    Lieb, Roselind
    Linde, Mattias
    Ljungcrantz, Christina
    Maercker, Andreas
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Moscarelli, Massimo
    Musayev, Amir
    Norwood, Fiona
    Preisig, Martin
    Pugliatti, Maura
    Rehm, Juergen
    Salvador-Carulla, Luis
    Schlehofer, Brigitte
    Simon, Roland
    Steinhausen, Hans-Christoph
    Stovner, Lars Jacob
    Vallat, Jean-Michel
    Van den Bergh, Peter
    van Os, Jim
    Vos, Pieter E
    Xu, Weili
    Wittchen, Hans-Ulrich
    Jonsson, Bengt
    Olesen, Jes
    Corrigendum to “Cost of disorders of the brain in Europe 2010” [Eur. Neuropsychopharmacol. 21 (2011) 718–779]2012In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, no 3, p. 237-238Article in journal (Refereed)
  • 205.
    Gustavsson, Jonatan
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Alterations in resting-state amplitude associated to cognitive impairments and chronic fatigue among TBI patients2019Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Traumatic brain injury (TBI) is the most common cause of injury to the human brain and one of the most common causes of disabilities. Following a TBI, the experience can vary greatly depending on the severity of the injury. Some of the patients with mild TBI make a full recovery without any consistent symptoms or disabilities, while many of the others, including moderately-to-severely injured, will experience long-term neuro-cognitive symptoms. Out of a range of symptoms, mental fatigue is one of the most common ones reported among TBI patients. Moreover, despite fatigue being widely recognised as a serious problem shared across many neurodegenerative diseases, the underlying mechanisms are unclear. This study utilized neuropsychological data and functional resting-state data to examine possible alterations in functional connectivity between post-traumatic brain injury fatigue (PTBIF) patients and healthy controls. Resting-state data from 54 PTBIF patients and 27 controls were used to analyse different dimensions of functional connectivity by combining independent component analysis (ICA) with fractional amplitude of low-frequency fluctuation analysis (fALFF). Neuropsychological data showed that PTBIF patients were impaired performance-wise compared to controls. Seventeen resting-state networks (RSNs) were identified by the ICA. However, a multivariate analysis did not yield any significant results. Nevertheless, the fALFF analysis yielded significant differences showing decreased amplitude in RSNs essential to cognitive functioning among the PTBIF patients compared to controls. Our results showed association between decreased fALFF, cognitive impairment and self-experienced fatigue, suggesting the usage of resting-state fALFF as biomarkers for underlying physiological causes of impairments.

  • 206. Güzey, Cüneyt
    et al.
    Allard, Per
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Spigset, Olav
    Radioligand binding to brain dopamine and serotonin receptors and transporters in Parkinson's disease: relation to gene polymorphisms2012In: International Journal of Neuroscience, ISSN 0020-7454, E-ISSN 1563-5279, Vol. 122, no 3, p. 124-132Article in journal (Refereed)
    Abstract [en]

    The influence of variations in genes coding for dopamine and serotonin transporters and receptors on the expression of these structures in the brains of patients with Parkinson's disease (PD) is not known. In order to investigate the significance of dopamine and serotonin transporter and receptor gene polymorphisms on the expression of dopamine and serotonin transporters and the dopamine D(2) and serotonin 5HT(2A) receptors in brain tissue in PD, we conducted a study on brain autopsy material from 16 patients diagnosed with clinical PD and 11 controls. The polymorphisms studied were DAT1 VTNR, DRD2 Taq1A, 5HTTLPR, and 5HTR2A 102 T>C, 516 C>T, His425Tyr and Thr25Asn. Compared to control subjects, patients with PD had a significantly lowered radioligand binding to the dopamine transporter in nucleus caudatus (P = 0.001) and putamen (P = 0.008), and to the serotonin transporter in gyrus cingulatus (P = 0.010) and nucleus caudatus (P = 0.032). We did not observe any significant associations between genetic polymorphisms and the extent of radioligand binding or between the polymorphisms and a diagnosis of PD. In conclusion, the density of brain dopamine and serotonin transporters in patients with PD was reduced. However, there were no associations between the investigated genotypes and the expression of the corresponding receptors and transporters.

  • 207. Habib, Reza
    et al.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Neural Correlates of Availability and Accessibility in Memory2008In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 8, no 7, p. 1720-1726Article in journal (Other academic)
    Abstract [en]

    Failure to remember can be due to not having information available in memory or to an inability to access information that is available. We used functional magnetic resonance imaging to examine brain responses during encoding and successive cued recall and associative recognition tests of paired associates. Items were classified into 3 categories based on performance on the 2 retrieval tests: 1) successfully remembered (both recalled and recognized), 2) inaccessible (not recalled but later recognized), and 3) forgotten (neither recalled nor recognized). During cued recall, availability in memory was signaled in a network of regions including bilateral medial temporal lobe, left middle temporal cortex, and the parietal cortex. Memory access resulted in heightened activity in these regions as well as in left inferior frontal cortex. Encoding-related activity in hippocampus and inferior temporal cortex predicted subsequent availability and left inferior frontal activity predicted subsequent access. These results suggest that failure to access information that is available in memory may reflect weaker memory representations.

  • 208. Halje, Par
    et al.
    Brys, Ivani
    Mariman, Juan J.
    da Cunha, Claudio
    Fuentes, Romulo
    Petersson, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Oscillations in cortico-basal ganglia circuits: implications for Parkinson's disease and other neurologic and psychiatric conditions2019In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 122, no 1, p. 203-231Article, review/survey (Refereed)
    Abstract [en]

    Cortico-basal ganglia circuits are thought to play a crucial role in the selection and control of motor behaviors and have also been implicated in the processing of motivational content and in higher cognitive functions. During the last two decades, electro-physiological recordings in basal ganglia circuits have shown that several disease conditions are associated with specific changes in the temporal patterns of neuronal activity. In particular, synchronized oscillations have been a frequent finding suggesting that excessive synchronization of neuronal activity may be a pathophysiological mechanism involved in a wide range of neurologic and psychiatric conditions. We here review the experimental support for this hypothesis primarily in relation to Parkinson's disease but also in relation to dystonia, essential tremor, epilepsy, and psychosis/schizophrenia.

  • 209. Hamel, Wolfgang
    et al.
    Koeppen, Johannes A.
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. nit of Functional Neurosurgery, UCL Institute of Neurology, London, UK.
    Krack, Paul
    Moll, Christian K. E.
    The Pioneering and Unknown Stereotactic Approach of Roeder and Orthner from Gottingen. Part I. Surgical Technique for Tailoring Individualized Stereotactic Lesions2016In: Stereotactic and Functional Neurosurgery, ISSN 1011-6125, E-ISSN 1423-0372, Vol. 94, no 4, p. 240-253Article in journal (Refereed)
    Abstract [en]

    During the 1950s through the 1970s, Hans Orthner and Fritz Roeder, two German neurologists from Gottingen, developed a sophisticated technique to perform functional stereotactic surgery with outstanding accuracy. They introduced direct air ventriculography performed in the same surgical session as the ablative stereotactic procedure. For individualized surgical targeting, Orthner prepared a stereo tactic atlas (>60 brains) with an ingenious brain-slicing device, the Gottinger macrotome. Brains were grouped based on similarity of six different head and ventricle measurements. A brain cluster representing the best match for a patient was selected for stereotactic targeting. Stereotactic lesions were tailored in an individual manner and shaped by stringing together multiple small coagulations following in-traoperative test stimulation. This was achieved from a single probe trajectory by using well-engineered string electrodes with calibrated curving and involved laborious calculations. Only high-frequency thermocoagulation was regarded as appropriate for lesioning. With this meticulous technique, the most advanced stereotactic procedures were performed, including bilateral pallidotomy that ultimately could be restricted to the ansa lenticularis and ventromedial hypothalamotomy, the most delicate stereotactic operation performed to date. Outside Gottingen, this technique has only been used by Prof. Dieter Muller in Hamburg, Germany. This elaborate stereotactic approach is widely unknown and deserves to be discussed in a historical context. 

  • 210. Hamodeh, Salah
    et al.
    Bozkurt, Ayse
    Mao, Haian
    Sultan, Fahad
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Department of Cognitive Neurology, HIH for Clinical Brain Research, Otfried-Müller-Str. 27, 72076 Tübingen, Germany.
    Uncovering specific changes in network wiring underlying the primate cerebrotype2017In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 222, no 7, p. 3255-3266Article in journal (Refereed)
    Abstract [en]

    Regular scaling of brain networks during evolution has been proposed to be the major process leading to enlarged brains. Alternative views, however, suggest that deviations from regular scaling were crucial to the evolution of the primate brain and the emergence of different cerebrotypes. Here, we examined the scaling within the major link between the cerebellum and the cerebral cortex by studying the deep cerebellar nuclei (DCN). We compared the major axonal and dendritic wiring in the DCN of rodents and monkeys in search of regular scaling. We were able to confirm regular scaling within the density of neurons, the general dendritic length per neuron and the Purkinje cell axon length. However, we also observed specific modification of the scaling rules within the primates' largest and phylogenetically newest DCN, the dentate nucleus (LN/dentate). Our analysis shows a deviation from regular scaling in the predicted dendritic length per neuron in the LN/dentate. This reduction in the dendritic length is also associated with a smaller dendritic region-of-influence of these neurons. We also detected specific changes in the dendritic diameter distribution, supporting the theory that there is a shift in the neuronal population of the LN/dentate towards neurons that exhibit spatially restricted, clustered branching trees. The smaller dendritic fields would enable a larger number of network modules to be accommodated in the primate LN/dentate and would provide an explanation for the unique folded structure of the primate LN/dentate. Our results show that, in some brain regions, connectivity maximization (i.e., an increase of dendritic fields) is not the sole optimum and that increases in the number of network modules may be important for the emergence of a divergent primate cerebrotype.

  • 211.
    Hansson, C
    et al.
    Sahlgrenska Academy at the University of Gothenburg.
    Haage, D
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Sahlgrenska Academy at the University of Gothenburg.
    Taube, M
    Sahlgrenska Academy at the University of Gothenburg.
    Egecioglu, E
    Sahlgrenska Academy at the University of Gothenburg.
    Salomé, N
    Sahlgrenska Academy at the University of Gothenburg.
    Dickson, S L
    Sahlgrenska Academy at the University of Gothenburg.
    Central administration of ghrelin alters emotional responses in rats: behavioural, electrophysiological and molecular evidence2011In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 180, p. 201-211Article in journal (Refereed)
    Abstract [en]

    The orexigenic and pro-obesity hormone ghrelin targets key hypothalamic and mesolimbic circuits involved in energy balance, appetite and reward. Given that such circuits are closely integrated with those regulating mood and cognition, we sought to determine whether chronic (>2 weeks) CNS exposure to ghrelin alters anxiety- and depression-like behaviour in rats as well as some physiological correlates. Rats bearing chronically implanted i.c.v. catheters were treated with ghrelin (10 μg/d) or vehicle for 4 weeks. Tests used to assess anxiety- and depression-like behaviour were undertaken during weeks 3-4 of the infusion. These revealed an increase in anxiety- and depression-like behaviour in the ghrelin-treated rats relative to controls. At the end of the 4-week infusion, brains were removed and the amygdala dissected for subsequent qPCR analysis that revealed changes in expression of a number of genes representing key systems implicated in these behavioural changes. Finally, given the key role of the dorsal raphe serotonin system in emotional reactivity, we examined the electrophysiological response of dorsal raphe neurons after a ghrelin challenge, and found mainly inhibitory responses in this region. We demonstrate that the central ghrelin signalling system is involved in emotional reactivity in rats, eliciting pro-anxiety and pro-depression effects and have begun to explore novel target systems for ghrelin that may be of importance for these effects.

  • 212.
    Hansson Mild, Kjell
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Møllerløkken, Ole Jacob
    Occupational Exposure to Magnetic Field inTranscranial Magnetic Stimulation Treatment2018In: Transcranial Magnetic Stimulation in Neuropsychiatry / [ed] Ustohal, Libor, IntechOpen , 2018, p. 143-149Chapter in book (Refereed)
    Abstract [en]

    Transcranial magnetic stimulation (TMS) is used both as a diagnostic instrument and for therapy, available only at some psychiatric clinics for treatment of depression and at clinical neurophysiology where TMS is used for diagnosis of nerve damage. The Swedish National Board of Health and Welfare issued a referral edition about the use of repetitive TMS as an alternative treatment for depression. This may lead to a major increase in the application of TMS to treat depression. TMS is based on induction of an electric (E) field inside the brain by application of an external magnetic field with rapid rise and fall time. The E field in the brain has been calculated when different coils were used for the treatment. The reported E fields are of the order of tens to hundreds of volts per meter and the induced current density is estimated at tens of A/m2. This field can depolarize neurons or modulate cortical excitability by selecting the appropriate parameters for stimulation and the duration of the treatment session. The mechanisms of action of neurostimulation still remain incompletely understood.

  • 213.
    Harandi, Vahid M
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Gaied, Aida RN
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Liu, Jing-Xia
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Unchanged neurotrophic factors and their receptors correlate with sparing in extraocular muscles in amyotrophic lateral sclerosis2016In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 57, no 15, p. 6831-6842Article in journal (Refereed)
    Abstract [en]

    Purpose: To investigate the impact of amyotrophic lateral sclerosis (ALS) on the extraocular muscles (EOMs) by examining the distribution of neurotrophic factors (NTFs) and their receptors in EOMs and limb muscles from ALS transgenic mice.

    Methods: Muscle samples collected from transgenic mice overexpressing human superoxide dismutase type 1 mutations (SOD1G93A, the most widely used mouse model of ALS) at 50 and 150 days as well as age-matched controls were analyzed with immunohistochemistry using antibodies against brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4), glial cell line-derived neurotrophic factor (GDNF), and the neurotrophin receptors p75NTR, tyrosine kinase (Trk) receptor TrkB and TrkC, and GDNF family receptor alpha-1 (GFRα-1).

    Results: There was an intrinsic difference in NTF expression between EOMs and limb muscles in control mice: EOMs presented significantly lower number of neuromuscular junctions (NMJs) labeled for BDNF and NT-4 at 50 days, and for BDNF and GDNF at 150 days, compared with the control limb muscles of corresponding age. In ALS transgenic mice at 150 days, NTF expression in limb muscles was significantly changed but not in EOMs: the limb muscles presented a significant decline in the number of NMJs labeled for BDNF, NT-4, GDNF, p75NTR, TrkB, and TrkC, which was not observed in EOMs.

    Conclusions: The significant differences in expression of NTFs on NMJs between EOMs and limb muscles in both control and ALS transgenic mice suggest that NTF may be involved in the pathogenesis of ALS and the resistance of EOMs to the disease.

  • 214.
    Hariz, Gun-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Occupational Therapy. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Limousin, Patricia
    Hamberg, Katarina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    "DBS means everything - for some time": Patients' Perspectives on Daily Life with Deep Brain Stimulation for Parkinson's Disease2016In: Journal of Parkinson's Disease, ISSN 1877-7171, E-ISSN 1877-718X, Vol. 6, no 2, p. 335-347Article in journal (Refereed)
    Abstract [en]

    Background: Deep brain stimulation (DBS) is an established treatment for Parkinson's disease. However, patients' own perceptions of the impact of DBS on their daily living is not fully explored. 

    Objective: We aimed to collect and analyse patients' narratives about their everyday experiences of being on chronic DBS. 

    Methods: Semi-structured interviews with open-ended questions were conducted with 42 patients (11 women) who had been on DBS for a mean of three years. The questions were related to patients' ordinary daily life and eventual changes, both negative and positive, brought about by DBS. The interviews were transcribed verbatim and analysed according to the difference and similarity technique in grounded theory. 

    Results: From the patients' narratives the core category `DBS means everything - for some time' was established, and supported by the following categories: 1) Relief from invasive tremor. 2) A rescue from cramps and pain. 3) Easier movement swings and more predictable living space. 4) Hard, but compared to previous suffering, bearable adverse events. 5) Parkinson's disease is progressing despite DBS. 

    Conclusions: The analysis of the participants' narratives shed light on patients' unique perceptions and perspectives of the impact of DBS on their everyday lives. Patients with advanced PD highly appreciated the positive impact of DBS on their daily life even if this impact is limited in time. For the majority, the relief from the severe parkinsonian symptoms, especially tremor and painful cramps, outweighed the side effects of DBS. The study provided information not readily captured by pre-formulated questionnaires and scales.

  • 215.
    Hariz, Gun-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Occupational Therapy. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Limousin, Patricia
    UCL Institute of Neurology, Sobell Department of Motor Neuroscience and Movement Disorders, Unit of Functional Neurosurgery, London, United Kingdom.
    Tisch, Stephen
    Department of Neurology, St. Vincent’s Hospital, Darlinghurst, NSW, Australia.
    Jahanshahi, Marjan
    UCL Institute of Neurology, Sobell Department of Motor Neuroscience and Movement Disorders, Unit of Functional Neurosurgery, London, United Kingdom.
    Fjellman-Wiklund, Anncristine
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Patients' perceptions of life shift after deep brain stimulation for primary dystonia: a qualitative study2011In: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 26, no 11, p. 2101-2106Article in journal (Refereed)
    Abstract [en]

    Studies of deep brain stimulation for dystonia have shown significant motor improvement. However, patients' perceptions of surgery and its effects have been less studied. We aimed to explore perceptions of changes in life in patients with primary dystonia after deep brain stimulation. Thirteen patients underwent thematic interviews 8-60 months after pallidal deep brain stimulation. Interviews were transcribed verbatim and analyzed with grounded theory. Patients described a profound impact of dystonia on daily life. After surgery, physical changes with a more upright posture and fewer spasms translated into an easier, more satisfying life with greater confidence. Notwithstanding this positive outcome, the transition from a limited life before surgery to opportunities for a better life exhibited obstacles: The "new life" after deep brain stimulation was stressful, including concern about being dependent on the stimulator as well as having to deal with interfering side effects from deep brain stimulation. The whole coping process meant that patients had to quickly shift focus from struggling to adapt to a slowly progressive disorder to adjustment to a life with possibilities, but also with new challenges. In this demanding transition process, patients wished to be offered better professional guidance and support. Even though deep brain stimulation provides people with primary dystonia with a potential for better mobility and more confidence, patients experienced new challenges and expressed the need for support and counseling after surgery. Grounded theory is a useful method to highlight patients' own experience and contributes to a deeper understanding of the impact of deep brain stimulation on patients with dystonia.

  • 216.
    Hariz, Gun-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Occupational Therapy. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nakajama, Takeshi
    UCL Institute of Neurology, Queen Square, London, UK; Department of Neurosurgery, Tokyo Women’s Medical University, Tokyo, Japan.
    Limousin, Patricia
    UCL Institute of Neurology, Queen Square, London, UK.
    Foltynie, Tom
    UCL Institute of Neurology, Queen Square, London, UK.
    Zrinzo, Ludvic
    UCL Institute of Neurology, Queen Square, London, UK.
    Jahanshahi, Marjan
    UCL Institute of Neurology, Queen Square, London, UK.
    Hamberg, Katarina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Gender distribution of patients with Parkinson's disease treated with subthalamic deep brain stimulation: a review of the 2000-2009 literature2011In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 17, no 3, p. 146-149Article, review/survey (Refereed)
    Abstract [en]

    Purpose: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been the mainstream surgical procedure for advanced Parkinson’s disease (PD) during the last decade. Reports from a few individual centres have hinted that women who receive STN DBS are under-represented. We aimed to evaluate the gender distribution of patients with PD who had received STN DBS during the last ten years, and to discuss the findings in relation to studies on gender prevalence of PD.

    Methods: A search of the PubMed database of clinical papers in English language related to STN DBS between 2000 and 2009 was conducted. Care was taken to minimize redundancies in reporting of published patients. The proportion of men and women were expressed in total and according to pre-defined geographic regions.

    Results: One hundred and thirty five papers were eligible for review. The gender of the patients was specified in 119 papers on a total of 3880 patients, of which 63% were men. According to geographic origin of publications, the percentage of men with STN DBS was 68% in North America, 62% in Europe, 69% in Australia and 50% in Asia.

    Conclusions: The proportion of male patients who undergo STN DBS seems to exceed the reported male/female ratio of patients with PD.

  • 217.
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Once STN DBS, Always STN DBS?-Clinical, Ethical, and Financial Reflections on Deep Brain Stimulation for Parkinson's Disease2016In: MOVEMENT DISORDERS CLINICAL PRACTICE, ISSN 2330-1619, Vol. 3, no 3, p. 285-287Article in journal (Refereed)
  • 218.
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Simon Sainsbury Chair of Functional Neurosurgery,Unit of Functional Neurosurgery,UCL — Institute of Neurology,Queen Square, London, UK.
    Stereotactic Ablative Surgery Does Not Just Mean "Adding Another Lesion"2017In: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 32, no 7, p. 1112-1113Article in journal (Refereed)
  • 219.
    Hariz, Marwan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. UCL-Institute of Neurology, London, United Kingdom.
    Obeso, Jose A.
    What would Dr. James Parkinson think today?: I. The role of functional neurosurgery for Parkinson's disease2017In: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 32, no 1, p. 2-4Article in journal (Refereed)
  • 220.
    Hart, Andrew McKay
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Blond-McIndoe Laboratories, Royal Free and University College Medical School, University Department of Surgery, Royal Free Campus, Rowland Hill Street, London, UK.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    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.
    Terenghi, Giorgio
    Blond-McIndoe Laboratories, Royal Free and University College Medical School, University Department of Surgery, Royal Free Campus, Rowland Hill Street, London, UK.
    Primary sensory neurons and satellite cells after peripheral axotomy in the adult rat: timecourse of cell death & elimination2002In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 142, no 3, p. 308-318Article in journal (Refereed)
    Abstract [en]

    The timecourse of cell death in adult dorsal root ganglia after peripheral axotomy has not been fully characterised. It is not clear whether neuronal death begins within I week of axotomy or continues beyond 2 months after axotomy. Similarly, neither the timecourse of satellite cell death in the adult, nor the effect of nerve repair has been described. L4 and L5 dorsal root ganglia were harvested at 1-14 days, 1-6 months after sciatic nerve division in the adult rat, in accordance with the Animals (Scientific Procedures) Act 1986. In separate groups the nerve was repaired either immediately or following a 1-week delay, and the ganglia were harvested 2 weeks after the initial transection. Microwave permeabilisation and triple staining enabled combined TUNEL staining, morphological examination and neuron counting by the stereological optical dissector technique. TUNEL-positive neurons, exhibiting a range of morphologies, were seen at all timepoints (peak 25 cells/group 2 weeks after axotomy) in axotomised ganglia only. TUNEL-positive satellite cell numbers peaked 2 months after axotomy and were more numerous in axotomised than control ganglia. L4 control ganglia contained 13,983 (SD 568) neurons and L5, 16,285 (SD 1,313). Neuron loss was greater in L5 than L4 axotomised ganglia, began at I week (15%, P=0.045) post-axotomy, reached 35% at 2 months (P<0.001) and was not significantly greater at 4 months or 6 months. Volume of axotomised ganglia fell to 19% of control by 6 months (P<0.001). In animals that underwent nerve repair, both the number of TUNEL-positive neurons and neuron loss were reduced. Immediate repair was more protective than repair after a 1-week delay. Thus TUNEL positivity precedes actual neuron loss, reflecting the time taken to complete cell death and elimination. Neuronal death begins within I day of peripheral axotomy, the majority occurs within the first 2 months, and limited death is still occurring at 6 months. Neuronal death is modulated by peripheral nerve repair and by its timing after axotomy. Secondary satellite cell death also occurs, peaking 2 months after axotomy. These results provide a logical framework for future research into neuronal and satellite cell death within the dorsal root ganglia and provide further insight into the process of axotomy induced neuronal death.

  • 221.
    Hart, Andrew McKay
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Blond-McIndoe Centre, Royal Free & University College Medical School, University Department of Surgery, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK.
    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.
    Youle, Mike
    Royal Free Centre for HIV Medicine, Royal Free Hospital, London, UK.
    Terenghi, Giorgio
    Blond-McIndoe Centre, Royal Free & University College Medical School, University Department of Surgery, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK.
    Systemic acetyl-L-carnitine eliminates sensory neuronal loss after peripheral axotomy: a new clinical approach in the management of peripheral nerve trauma2002In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 145, no 2, p. 182-189Article in journal (Refereed)
    Abstract [en]

    Several hundred thousand peripheral nerve injuries occur each year in Europe alone. Largely due to the death of around 40% of primary sensory neurons, sensory outcome remains disappointingly poor despite considerable advances in surgical technique; yet no clinical therapies currently exist to prevent this neuronal death. Acetyl-L-carnitine (ALCAR) is a physiological peptide with roles in mitochondrial bioenergetic function, which may also increase binding of nerve growth factor by sensory neurons. Following unilateral sciatic nerve transection, adult rats received either one of two doses of ALCAR or sham, or no treatment. Either 2 weeks or 2 months later, L4 and L5 dorsal root ganglia were harvested bilaterally, in accordance with the Animal (Scientific Procedures) Act 1986. Neuronal death was quantified with a combination of TUNEL [TdT (terminal deoxyribonucleotidyl transferase) uptake nick end labelling] and neuron counts obtained using the optical disector technique. Sham treatment had no effect upon neuronal death. ALCAR treatment caused a large reduction in the number of TUNEL-positive neurons 2 weeks after axotomy (sham treatment 33/group; low-dose ALCAR 6/group, P=0.132; high-dose ALCAR 3/group, P<0.05), and almost eliminated neuron loss (sham treatment 21%; low-dose ALCAR 0%, P=0.007; high-dose ALCAR 2%, P<0.013). Two months after axotomy the neuroprotective effect of high-dose ALCAR treatment was preserved for both TUNEL counts (no treatment five/group; high-dose ALCAR one/group) and neuron loss (no treatment 35%; high-dose ALCAR -4%, P<0.001). These results provide further evidence for the role of mitochondrial bioenergetic dysfunction in post-traumatic sensory neuronal death, and also suggest that acetyl-L-carnitine may be the first agent suitable for clinical use in the prevention of neuronal death after peripheral nerve trauma.

  • 222. Hascup, E. R.
    et al.
    Hascup, K. N.
    Talauliker, P. M.
    Price, D. A.
    Pomerleau, F.
    Quintero, J. E.
    Huettl, P.
    Gratton, A.
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Gerhardt, G. A.
    Sub-second measurements of glutamate and other neurotransmitter signaling using enzyme-based ceramic microelectrode arrays2013In: Microelectrode Biosensors (Part II) / [ed] Stéphane Marinesco and Nicholas Dale, Humana Press, 2013, p. 179-199Conference paper (Refereed)
    Abstract [en]

    We have set out to develop a novel, implantable microelectrode array that has the capabilities to detect neurotransmitters with enhanced sensitivity, selectivity, and temporal sampling capabilities compared to other current technologies. We have shown that this device maintains recording performance during chronic measurements of extracellular neurotransmitter levels for at least 7 days postimplantation, single-unit neuronal activity for as long as 6 months, and provides enhanced biocompatibility compared to current technologies. As we continue to refine and improve our recording capability, we are able to incorporate the chronic microelectrode array technology into multimodal experimental paradigms, such as behavioral testing, pharmacological intervention (local and systemic), or combined measurements of neurotransmitter levels and neuronal activity (local field potential). Furthermore, the improvements made with the microelectrode technology discussed in this chapter have the potential to conduct longitudinal analyses that can benefit a wide range of translational efforts, including studies on learning and memory, aging, neurodegenerative disease progression, and traumatic brain injury neuropathology.

  • 223.
    Hashemian, Sanaz Alsadat
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Marschinke, Franziska
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Blocking cd47/ox101 makes the astrocytes permissive for nerve fiber growth2011In: Glia: 10th European meeting on Glial Cells in Health and Disease, New York, N.Y.: Wiley-Liss, Inc. , 2011, Vol. 59, p. S105-S106Conference paper (Refereed)
    Abstract [en]

    Crosstalk between astroglia and nerve fiber outgrowth might be an underlying mechanism for regeneration of nerve fibers and can be used in treatment of neurodegenerative diseases. This crosstalk might occur through the integrin-associated protein (CD47 in mouse or OX101 in rat), which serves as a ligand for signal regulatory protein-α (Sirpα) (P84/SHPS-1 in mouse or OX41 in rat), and as a receptor for thrombospondin (TSP). In the present study the localization of OX101 was assessed in organotypic tissue cultures from ventral mesencephalon (VM) of embryonic day (E) 14 rat fetuses, and its presence in astrocytes was observed. Thereafter, the effect of OX101 was blocked in E14 VM cultures by treatment with OX101 antibodies. A robust tyrosine hydroxylase (TH)- positive nerve fiber outgrowth was observed using immuohistochemistry. In addition, the neurons had migrated from the tissue slice. This result was in parallel with results achieved from E14 cultures of CD47 knockout mice, in which TH–positive nerve fiber growth was robust and independent of the presence of astrocytes, whilst in wildtype cultures nerve fibers were restricted to the astrocytes. Thus, these data demonstrate that CD47/OX101 can be an important molecule, which normally is produced by astrocytes and in its absence, the astrocytes become more permissive for nerve fiber growth.

  • 224.
    Hashemian, Sanaz
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Marschinke, Franziska
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    af Bjerkén, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Degradation of proteoglycans affects astrocytes and neurite formation in organotypic tissue cultures2014In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1564, p. 22-32Article in journal (Refereed)
    Abstract [en]

    Chondroitin sulfate proteoglycans (CSPGs) promote nerve growth during development, and inhibit axonal growth in the adult CNS after injury. Chondroitinase ABC (ChABC) and methyl-umbelliferyl-β-d-xyloside (β-xyloside), two enzymes that degrade CSPGs, promote regeneration after injury, however, they demonstrate opposing results in tissue culture. To elucidate the effect of the two enzymes, organotypic tissue cultures, treated with ChABC or β-xyloside, were employed to monitor nerve fiber outgrowth and astrocytic migration. Rat ventral mesencephalon (VM) and spinal cord (SC) from embryonic day (E) 14 and E18 were treated early, from the plating day for 14 days in vitro, or late where treatment was initiated after being cultured for 14 days. In the early treatment of E14 VM and SC cultures, astrocytic migration and nerve fiber outgrowth were hampered using both enzymes. Early treatment of E18 cultures reduced the astrocytic migration, while nerve growth was promoted by β-xyloside, but not by ChABC. In the late treated cultures of both E14 and E18 cultures, no differences in distances that astrocytes migrated or nerve fiber growth were observed. However, in β-xyloside-treated cultures, the confluency of astrocytic monolayer was disrupted. In E18 cultures both early and late treatments, neuronal migration was present in control cultures, which was preserved using ChABC but not β-xyloside. In conclusion, ChABC and β-xyloside had similar effects and hampered nerve fiber growth and astrocytic migration in E14 cultures. In E18 cultures nerve fiber growth was stimulated and neuronal migration was hampered after β-xyloside treatment while ChABC treatment did not exert these effects.

  • 225.
    Hashemian, Sanaz
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Phillips, James B
    Department of Life Health & Chemical Sciences, The Open University.
    af Bjerkén, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    The age of the astrocytes affects neuronal growthManuscript (preprint) (Other academic)
  • 226.
    Hashemian, Sanazalsadat
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Interaction between nerve fiber formation and astrocytes2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Parkinson’s disease, the second most common neurodegenerative disorder,is characterized by loss of nigrostriatal dopaminergic neurons. To date,there is no defined cause and cure for the disease. An ideal treatmentstrategy is to replace the lost neurons by transplanting fetal dopaminergicneurons to the brain of parkinsonian patients. Clinical trials have beenperformed and the outcome was variable where one significant obstaclewas the limited graft reinnervation of the host brain. To study this issue,organotypic tissue culture can be utilized to monitor dopaminergic nervefiber outgrowth in vitro and their association with astrocytes. Using thisculture technique, dopaminergic nerve fibers appear in twomorphologically and temporally different types. The early appearing nervefibers are formed in the absence of astrocytes, reach long distances, andare called non-glial-associated tyrosine hydroxylase (TH) -positive nervefibers. After a few days, the second sequence of nerve fibers, the glialassociatedTH-positive nerve fibers, are formed, and their growth arelimited to the presence of astrocytes, that migrate and form a monolayersurrounding the plated tissue. The aim of this thesis was to study theinteraction between nerve fiber formation and astrocytes with a specialfocus on the long-distance growing nerve fibers. Ventral mesencephalic(VM) organotypic slice cultures from embryonic day (E) 12, E14, and E18were incubated for 14, 21, 28, and 35 days in vitro (DIV). The resultsrevealed that the two morphologically different processes were found incultures from the younger stages, while no non-glial-associated growthwas found in cultures of tissue from E18. Instead neurons had migratedonto the migrating astrocytes. Astrocytes migrated longer distances intissue from older stages, and the migration reached a plateau at 21 DIV.Co-cultures of E14 VM tissue pieces and cell suspension of matureastrocytes promoted migration of neurons, as seen in E18 cultures. Thus,9the maturity of the astrocytes was an important factor for nerve fiberoutgrowth. Hence, targeting molecules secreted by astrocytes might bebeneficial for regeneration. Chondroitin sulfate proteoglycan (CSPG), amember of proteoglycan family, is produced by the astrocytes and has adual role of being permissive during development and inhibitory afterbrain injury in adult brain. Cultures were treated with chondroitinase ABC(ChABC) or methyl-umbelliferyl-β-D-xyloside (β-xyloside) in twodifferent protocols, early and late treatments. The results from the earlytreated cultures showed that both compounds inhibited the outgrowth ofnerve fibers and astrocytic migration in cultures from E14 tissue, while β-xyloside but not ChABC promoted the non-glial-associated growth incultures derived from E18 fetuses. In addition, β-xyloside but not ChABCinhibited neuronal migration in E18 cultures. Taken together, β-xylosideappeared more effective than ChABC in promoting nerve fiber growth.Another potential candidate, integrin-associated protein CD47, was studiedbecause of its role in synaptogenesis, which is important for nerve fibergrowth. Cultures from E14 CD47 knockout (CD47-/-) mice were plated andcompared to their wildtypes. CD47-/- cultures displayed a massive and longnon-glial-associated TH-positive nerve fiber outgrowth despite theirnormal astrocytic migration. Blocking either signal regulatory protein-α(SIRPα) or thrombospondin-1 (TSP-1), which bind to CD47, had nogrowth promoting effect. In conclusion, to promote nerve growth, youngertissue can grow for longer distances than older tissue, and inhibiting CSPGproduction promotes nerve growth in older tissue, while gene deletion ofCD47 makes the astrocytes permissive for a robust nerve fiber growth.

  • 227.
    Haukenes, Inger
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Norwegian Inst Publ Hlth, Div Mental Hlth, Dept Publ Mental Hlth, Bergen, Norway.
    Hensing, G.
    Stålnacke, Britt-Marie
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine.
    Hammarström, Anne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Social medicine. Norwegian Inst Publ Hlth, Div Mental Hlth, Dept Publ Mental Hlth, Bergen, Norway.
    Does pain severity guide selection to multimodal pain rehabilitation across gender?2015In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 19, no 6, p. 826-833Article in journal (Refereed)
    Abstract [en]

    Background Studies have addressed the effect of multimodal pain rehabilitation (MMR), whereas criteria for selection are sparse. This study examines whether higher scores on musculoskeletal pain measures are associated with selection to MMR, and whether this differs across gender.

    Method A clinical population of 262 male and 589 female patients was recruited consecutively during 3 years, 2007-2010. The patients were referred from primary care to a pain rehabilitation clinic in Northern Sweden for assessment and selection to MMR. Register-based data on self-reported pain were linked to patients' records where outcome (MMR or not) was stated. We modelled odds ratios for selection to MMR by higher scores on validated pain measures (pain severity, interference with daily life, pain sites and localized pain vs. varying pain location). Covariates were age, educational level and multiple pain measures. Anxiety and depression (Hospital, Anxiety and Depression Scale) and working status were used in sensitivity tests.

    Results Higher scores of self-reported pain were not associated with selection to MMR in multivariate models. Among women, higher scores on pain severity, pain sites and varying pain location (localized pain=reference) were negatively associated with selection to MMR. After adjustment for multiple pain measures, the negative odds ratio for varying location persisted (OR=0.59, 95% CI=0.39-0.89).

    Conclusion Higher scores on self-reported pain did not guide selection to MMR and a negative trend was found among women. Studies of referral patterns and decision processes may contribute to a better understanding of the clinical practice that decides selection to MMR.

  • 228. Hedden, Trey
    et al.
    Schultz, Aaron P
    Rieckmann, Anna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Mormino, Elizabeth C
    Johnson, Keith A
    Sperling, Reisa A
    Buckner, Randy L
    Multiple Brain Markers are Linked to Age-Related Variation in Cognition2016In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 26, no 4, p. 1388-1400Article in journal (Refereed)
    Abstract [en]

    Age-related alterations in brain structure and function have been challenging to link to cognition due to potential overlapping influences of multiple neurobiological cascades. We examined multiple brain markers associated with age-related variation in cognition. Clinically normal older humans aged 65-90 from the Harvard Aging Brain Study (N = 186) were characterized on a priori magnetic resonance imaging markers of gray matter thickness and volume, white matter hyperintensities, fractional anisotropy (FA), resting-state functional connectivity, positron emission tomography markers of glucose metabolism and amyloid burden, and cognitive factors of processing speed, executive function, and episodic memory. Partial correlation and mediation analyses estimated age-related variance in cognition shared with individual brain markers and unique to each marker. The largest relationships linked FA and striatum volume to processing speed and executive function, and hippocampal volume to episodic memory. Of the age-related variance in cognition, 70-80% was accounted for by combining all brain markers (but only ∼20% of total variance). Age had significant indirect effects on cognition via brain markers, with significant markers varying across cognitive domains. These results suggest that most age-related variation in cognition is shared among multiple brain markers, but potential specificity between some brain markers and cognitive domains motivates additional study of age-related markers of neural health.

  • 229.
    Hedlund, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Lindström, Britta
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Sojka, Peter
    Department of Health Sciences, Mid-Sweden University, Östersund, Sweden.
    Lundström, Ronnie
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Boraxbekk, Carl-Johan
    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).
    Is better preservation of eccentric strength after stroke due to altered prefrontal function?2016In: Neurocase, ISSN 1355-4794, E-ISSN 1465-3656, Vol. 22, no 2, p. 229-242Article in journal (Refereed)
    Abstract [en]

    Ventrolateral prefrontal cortex (VLPFC) is part of a network that exerts inhibitory control over the motor cortex (MC). Recently, we demonstrated that VLPFC was more activated during imagined maximum eccentric than during imagined concentric contractions in healthy participants. This was accompanied with lower activation levels within motor regions during imagined eccentric contractions. The aim was to test a novel hypothesis of an involvement of VLPFC in contraction mode-specific modulation of force. Functional magnetic resonance imaging was used to examine differences in VLPFC and motor regions during the concentric and the eccentric phases of imagined maximum contractions in a selected sample of subjects with stroke (n = 4). The subjects were included as they exhibited disturbed modulation of force. The previously demonstrated pattern within VLPFC was evident only on the contralesional hemisphere. On the ipsilesional hemisphere, the recruitment in VLPFC was similar for both modes of contractions. The findings support a hypothesis of the involvement of VLPFC in contraction mode-specific modulation of maximum force production. A disturbance of this system might underlie the lack of contraction mode-specific modulation commonly found among stroke subjects, often expressed as an increased ratio between eccentric and concentric strength.

  • 230.
    Heldestad Lilliesköld, Victoria
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Method-of-limits: Cold and warm perception thresholds at proximal and distal body regions2018In: Clinical neurophysiology practice, ISSN 2467-981X, Vol. 3, p. 134-140Article in journal (Refereed)
    Abstract [en]

    Objective: Thermal quantitative sensory testing with the 'Method-of-Limits' is an established rationale for detection of small nerve fiber dysfunction, but adequate reference values are crucial for such evaluations, regardless of the underlying cause. This study assessed reference data for cold- (CPT) and warm- (WPT) perception thresholds at both proximal and distal sites in eight body regions of the lower and upper extremities, all determined within the same test session for each subject.

    Methods: Seventy-five healthy subjects (aged 16-72 years) were tested according to the method-of-limit for CPT and WPT at the dorsum of the foot, the medial and lateral lower leg, the ventral thigh, the thenar eminence, the radial and ulnar part of the lower arm, and the anterior deltoid part of the upper arm.

    Results: Overall, thermal perception thresholds (TPT) varied with test location, but were higher in the lower than in the upper part of the body, also WPT were generally higher than CPT. TPT at the dorsum foot highly correlated with age, while inconsistent correlations were noted between TPT and age or height at other tested locations.

    Conclusion: This study describes for the first time reference values at eight defined body regions, at both proximal and distal sites.

    Significance: The report enables refined evaluations of general small nerve fiber function, as assessed by quantitative thermal sensory testing with the Method-of-Limits.

  • 231.
    Heldestad, Victoria
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Sellersjö, Lisa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Reproducibility and influence of test modality order on thermal perception and thermal pain thresholds in quantitative sensory testing2010In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 121, no 11, p. 1878-1885Article in journal (Refereed)
    Abstract [en]

    The findings show that QST with the MLI is a reliable tool for indirect evaluation of human small nerve fiber function.

  • 232.
    Heldestad, Victoria
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Thermal perception thresholds: reference data and response characteristicsManuscript (preprint) (Other academic)
    Abstract [en]

    Objective: To establish reference data for separate cold and warm perception thresholds at quantitative sensory testing with the method-of-limits at eight different body regions, and to evaluate the psychophysical response characteristics to consecutive cold and warm stimuli.

    Methods: 75 healthy subjects were tested at the dorsum of the foot, the medial and lateral lower leg, the ventral thigh, the thenar eminence, the radial and ulnar part of the lower arm, and the anterior deltoid part of the upper arm. Thermal perception thresholds were assessed with the method of limits, and estimated from the average responses during ten consecutive cold and warm stimuli.

    Results: At all tested sites, the TPT were significantly higher in the lower part of the body compared to the upper, and also the warm thresholds were significantly higher than the cold thresholds. Inconsistent correlations were noted between thermal perception thresholds and age or height, but thresholds at the dorsal foot were highly correlated with age.

    Conclusions: Reference data from separate body regions in the lower and upper extremities are essential for adequate evaluation of thermal detection and perception capacity. At testing of thermal thresholds in individual subjects the thermal perception generally decreases distally in elderly and particularly in the lower extremities.

  • 233.
    Heldestad, Victoria
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Hörnsten, Rolf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Obayashi, Konen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Comparison of quantitative sensory testing and heart rate variability in Swedish Val30Met ATTR2011In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 18, no 4, p. 183-190Article in journal (Refereed)
    Abstract [en]

    Patients with transthyretin amyloidosis (ATTR) polyneuropathy, a hereditary fatal disease, often report defects in both thermal perception and autonomic nervous system function as their first clinical symptoms. While elevated thermal perception thresholds (TPT) for cold and warmth only recently have been shown as an early marker of small nerve fiber dysfunction in these patients, heart rate variability (HRV) has frequently been used to quantify autonomic neuropathy. The main purpose with this report was to elucidate a possible relationship between estimates of HRV and TPT in a selected group of early and late-onset Swedish Val30Met ATTR patients. The results show significantly more pronounced elevation of TPT in early compared to late-onset patients. Significant correlations between HRV and TPT were found among late-onset cases, indicating a possible relationship between loss of thin nerve fibers in somatic and autonomic nerves, while generally no such relationships were found among early-onset cases. This observation emphasizes the importance of testing both HRV and TPT to ensure optimal early detection of neuropathic changes in an as wide as possible range of small nerve fibers in suspected ATTR patients. This is of particular importance as the phenotype of the ATTR disease varies between groups with different age of onset.

  • 234. Henningsson, Susanne
    et al.
    Westberg, Lars
    Nilsson, Staffan
    Lundström, Bengt
    Ekselius, Lisa
    Bodlund, Owe
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Lindström, Eva
    Hellstrand, Monika
    Rosmond, Roland
    Eriksson, Elias
    Landén, Mikael
    Sex steroid-related genes and male-to-female transsexualism2005In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 30, no 7, p. 657-664Article in journal (Refereed)
    Abstract [en]

    Transsexualism is characterised by Lifelong discomfort with the assigned sex and a strong identification with the opposite sex. The cause of transsexualism is unknown, but it has been suggested that an aberration in the early sexual differentiation of various brain structures may be involved. Animal experiments have revealed that the sexual differentiation of the brain is mainly due to an influence of testosterone, acting both via androgen receptors (ARs) and-after aromatase-catalyzed conversion to estradiol-via estrogen receptors (ERs). The present study examined the possible importance of three polymorphisms and their pairwise interactions for the development of male-to-female transsexualism: a CAG repeat sequence in the first exon of the AR gene, a tetra nucleotide repeat polymorphism in intron 4 of the aromatase gene, and a CA repeat polymorphism in intron 5 of the ER beta gene. Subjects were 29 Caucasian male-to-female transsexuals and 229 healthy mate controls. Transsexuals differed from controls with respect to the mean Length of the ER repeat polymorphism, but not with respect to the length of the other two studied polymorphisms. However, binary logistic regression analysis revealed significant partial effects for all three polymorphisms, as well as for the interaction between the AR and aromatase gene polymorphisms, on the risk of developing transsexualism. Given the small number of transsexuals in the study, the results should be interpreted with the utmost caution. Further study of the putative role of these and other sex steroid-related genes for the development of transsexualism may, however, be worthwhile.

  • 235. Hens, Kristien
    et al.
    Cutas, DanielaUmeå University, Faculty of Arts, Department of historical, philosophical and religious studies. Department of Philosopy, Linguistics and Theory of Science University of Gothenburg Gothenburg, Sweden.Horstkötter, Dorothee
    Parental responsibility in the context of neuroscience and genetics2017Collection (editor) (Refereed)
    Abstract [en]

    Should parents aim to make their children as normal as possible to increase their chances to "fit in"? Are neurological and mental health conditions a part of children's identity and if so, should parents aim to remove or treat these? Should they aim to instill self-control in their children? Should prospective parents take steps to insure that, of all the children they could have, they choose the ones with the best likely start in life?

    This volume explores all of these questions and more. Against the background of recent findings and expected advances in neuroscience and genetics, the extent and limits of parental responsibility are increasingly unclear. Awareness of the effects of parental choices on children's wellbeing, as well as evolving norms about the moral status of children, have further increased expectations from (prospective) parents to take up and act on their changing responsibilities. The contributors discuss conceptual issues such as the meaning and sources of moral responsibility, normality, treatment, and identity. They also explore more practical issues such as how responsibility for children is practiced in Yoruba culture in Nigeria or how parents and health professionals in Belgium perceive the dilemmas generated by prenatal diagnosis.

  • 236.
    Hesselman Borg, Johanna
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Westerståhl, Maria
    Institutionen för laboratoriemedicin, Karolinska institutet.
    Lundell, Sara
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Madison, Guy
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Aasa, Ulrika
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Longitudinal study exploring factors associated with neck/shoulder pain at 52 years of age2016In: Journal of Pain Research, ISSN 1178-7090, E-ISSN 1178-7090, Vol. 9, p. 303-310Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To investigate the ability of work-related measurements, body composition, physical activity, and fitness levels to predict neck/shoulder pain (upper body pain, UBP) at the age of 52 years. Another aim was to investigate the cross-sectional relationships between UBP, work-related factors, and individual factors at the age of 52 years.

    METHODS: We followed a randomly selected cohort of 429 adolescents that was recruited in 1974 (baseline), when they were 16 years old. The participants completed physical fitness tests, questions about sociodemographic and lifestyle factors at 16, 34, and 52 years of age, and questions about work-related factors and pain in the follow-ups. Logistic regression analyses were used to examine the associations between UBP and the other variables.

    RESULTS: Univariate logistic regression analyses showed that high body mass index and the work-related factors, low control, and low social support at the age of 34 years were related to UBP at the age of 52 years. For social support, there was an interaction between men and women where the relationship between low social support and the experience of pain was more evident for women. Among women, body mass index and social support remained significantly related in the multivariate analyses. For men, social support remained significantly related. Cross-sectional relationships at the age of 52 differed from the longitudinal in the sense that measures of joint flexibility and work posture were also significantly associated with UBP.

    CONCLUSION: The fact that the cross-sectional differed from the longitudinal relationships strengthens the importance of performing longitudinal studies when studying factors that might influence the initiation of pain. UBP preventative measures might need to include both lifestyle (such as dietary habits and physical activity to ensure that the individuals are not becoming overweight) and work-related factors such as social support.

  • 237. Hibar, Derrek P.
    et al.
    Stein, Jason L.
    Renteria, Miguel E.
    Arias-Vasquez, Alejandro
    Desrivieres, Sylvane
    Jahanshad, Neda
    Toro, Roberto
    Wittfeld, Katharina
    Abramovic, Lucija
    Andersson, Micael
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Aribisala, Benjamin S.
    Armstrong, Nicola J.
    Bernard, Manon
    Bohlken, Marc M.
    Boks, Marco P.
    Bralten, Janita
    Brown, Andrew A.
    Chakravarty, M. Mallar
    Chen, Qiang
    Ching, Christopher R. K.
    Cuellar-Partida, Gabriel
    den Braber, Anouk
    Giddaluru, Sudheer
    Goldman, Aaron L.
    Grimm, Oliver
    Guadalupe, Tulio
    Hass, Johanna
    Woldehawariat, Girma
    Holmes, Avram J.
    Hoogman, Martine
    Janowitz, Deborah
    Jia, Tianye
    Kim, Sungeun
    Klein, Marieke
    Kraemer, Bernd
    Lee, Phil H.
    Loohuis, Loes M. Olde
    Luciano, Michelle
    Macare, Christine
    Mather, Karen A.
    Mattheisen, Manuel
    Milaneschi, Yuri
    Nho, Kwangsik
    Papmeyer, Martina
    Ramasamy, Adaikalavan
    Risacher, Shannon L.
    Roiz-Santianez, Roberto
    Rose, Emma J.
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Saemann, Philipp G.
    Schmaal, Lianne
    Schork, Andrew J.
    Shin, Jean
    Strike, Lachlan T.
    Teumer, Alexander
    van Donkelaar, Marjolein M. J.
    van Eijk, Kristel R.
    Walters, Raymond K.
    Westlye, Lars T.
    Whelan, Christopher D.
    Winkler, Anderson M.
    Zwiers, Marcel P.
    Alhusaini, Saud
    Athanasiu, Lavinia
    Ehrlich, Stefan
    Hakobjan, Marina M. H.
    Hartberg, Cecilie B.
    Haukvik, Unn K.
    Heister, Angelien J. G. A. M.
    Hoehn, David
    Kasperaviciute, Dalia
    Liewald, David C. M.
    Lopez, Lorna M.
    Makkinje, Remco R. R.
    Matarin, Mar
    Naber, Marlies A. M.
    McKay, D. Reese
    Needham, Margaret
    Nugent, Allison C.
    Puetz, Benno
    Royle, Natalie A.
    Shen, Li
    Sprooten, Emma
    Trabzuni, Daniah
    van der Marel, Saskia S. L.
    van Hulzen, Kimm J. E.
    Walton, Esther
    Wolf, Christiane
    Almasy, Laura
    Ames, David
    Arepalli, Sampath
    Assareh, Amelia A.
    Bastin, Mark E.
    Brodaty, Henry
    Bulayeva, Kazima B.
    Carless, Melanie A.
    Cichon, Sven
    Corvin, Aiden
    Curran, Joanne E.
    Czisch, Michael
    de Zubicaray, Greig I.
    Dillman, Allissa
    Duggirala, Ravi
    Dyer, Thomas D.
    Erk, Susanne
    Fedko, Iryna O.
    Ferrucci, Luigi
    Foroud, Tatiana M.
    Fox, Peter T.
    Fukunaga, Masaki
    Gibbs, J. Raphael
    Goering, Harald H. H.
    Green, Robert C.
    Guelfi, Sebastian
    Hansell, Narelle K.
    Hartman, Catharina A.
    Hegenscheid, Katrin
    Heinz, Andreas
    Hernandez, Dena G.
    Heslenfeld, Dirk J.
    Hoekstra, Pieter J.
    Holsboer, Florian
    Homuth, Georg
    Hottenga, Jouke-Jan
    Ikeda, Masashi
    Jack, Clifford R., Jr.
    Jenkinson, Mark
    Johnson, Robert
    Kanai, Ryota
    Keil, Maria
    Kent, Jack W., Jr.
    Kochunov, Peter
    Kwok, John B.
    Lawrie, Stephen M.
    Liu, Xinmin
    Longo, Dan L.
    McMahon, Katie L.
    Meisenzah, Eva
    Melle, Ingrid
    Mahnke, Sebastian
    Montgomery, Grant W.
    Mostert, Jeanette C.
    Muehleisen, Thomas W.
    Nalls, Michael A.
    Nichols, Thomas E.
    Nilsson, Lars G.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Noethen, Markus M.
    Ohi, Kazutaka
    Olvera, Rene L.
    Perez-Iglesias, Rocio
    Pike, G. Bruce
    Potkin, Steven G.
    Reinvang, Ivar
    Reppermund, Simone
    Rietschel, Marcella
    Romanczuk-Seiferth, Nina
    Rosen, Glenn D.
    Rujescu, Dan
    Schnell, Knut
    Schofield, Peter R.
    Smith, Colin
    Steen, Vidar M.
    Sussmann, Jessika E.
    Thalamuthu, Anbupalam
    Toga, Arthur W.
    Traynor, Bryan J.
    Troncoso, Juan
    Turner, Jessica A.
    Valdes Hernandez, Maria C.
    van't Ent, Dennis
    van der Brug, Marcel
    van der Wee, Nic J. A.
    van Tol, Marie-Jose
    Veltman, Dick J.
    Wassink, Thomas H.
    Westman, Eric
    Zielke, Ronald H.
    Zonderman, Alan B.
    Ashbrook, David G.
    Hager, Reinmar
    Lu, Lu
    McMahon, Francis J.
    Morris, Derek W.
    Williams, Robert W.
    Brunner, Han G.
    Buckner, Randy L.
    Buitelaar, Jan K.
    Cahn, Wiepke
    Calhoun, Vince D.
    Cavalleri, Gianpiero L.
    Crespo-Facorro, Benedicto
    Dale, Anders M.
    Davies, Gareth E.
    Delanty, Norman
    Depondt, Chantal
    Djurovic, Srdjan
    Drevets, Wayne C.
    Espeseth, Thomas
    Gollub, Randy L.
    Ho, Beng-Choon
    Hoffman, Wolfgang
    Hosten, Norbert
    Kahn, Rene S.
    Le Hellard, Stephanie
    Meyer-Lindenberg, Andreas
    Mueller-Myhsok, Bertram
    Nauck, Matthias
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Pandolfo, Massimo
    Penninx, Brenda W. J. H.
    Roffman, Joshua L.
    Sisodiya, Sanjay M.
    Smoller, Jordan W.
    van Bokhoven, Hans
    van Haren, Neeltje E. M.
    Voelzke, Henry
    Walter, Henrik
    Weiner, Michael W.
    Wen, Wei
    White, Tonya
    Agartz, Ingrid
    Andreassen, Ole A.
    Blangero, John
    Boomsma, Dorret I.
    Brouwer, Rachel M.
    Cannon, Dara M.
    Cookson, Mark R.
    de Geus, Eco J. C.
    Deary, Ian J.
    Donohoe, Gary
    Fernandez, Guillen
    Fisher, Simon E.
    Francks, Clyde
    Glahn, David C.
    Grabe, Hans J.
    Gruber, Oliver
    Hardy, John
    Hashimoto, Ryota
    Pol, Hilleke E. Hulshoff
    Joensson, Erik G.
    Kloszewska, Iwona
    Lovestone, Simon
    Mattay, Venkata S.
    Mecocci, Patrizia
    McDonald, Colm
    McIntosh, Andrew M.
    Ophoff, Roel A.
    Paus, Tomas
    Pausova, Zdenka
    Ryten, Mina
    Sachdev, Perminder S.
    Saykin, Andrew J.
    Simmons, Andy
    Singleton, Andrew
    Soininen, Hilkka
    Wardlaw, Joanna M.
    Weale, Michael E.
    Weinberger, Daniel R.
    Adams, Hieab H. H.
    Launer, Lenore J.
    Seiler, Stephan
    Schmidt, Reinhold
    Chauhan, Ganesh
    Satizabal, Claudia L.
    Becker, James T.
    Yanek, Lisa
    van der Lee, Sven J.
    Ebling, Maritza
    Fischl, Bruce
    Longstreth, W. T., Jr.
    Greve, Douglas
    Schmidt, Helena
    Nyquist, Paul
    Vinke, Louis N.
    van Duijn, Cornelia M.
    Xue, Luting
    Mazoyer, Bernard
    Bis, Joshua C.
    Gudnason, Vilmundur
    Seshadri, Sudha
    Ikram, M. Arfan
    Martin, Nicholas G.
    Wright, Margaret J.
    Schumann, Gunter
    Franke, Barbara
    Thompson, Paul M., Jr.
    Medland, Sarah E.
    Common genetic variants influence human subcortical brain structures2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 520, no 7546, p. 224-U216Article in journal (Refereed)
    Abstract [en]

    The highly complex structure of the human brain is strongly shaped by genetic influences(1). Subcortical brain regions form circuits with cortical areas to coordinate movement(2), learning, memory(3) and motivation(4), and altered circuits can lead to abnormal behaviour and disease(5). To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume(5) and intracranial volume(6). These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 X 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

  • 238. Hohsfield, Lindsay A.
    et al.
    Daschil, Nina
    Orädd, Greger
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Humpel, Christian
    Vascular pathology of 20-month-old hypercholesterolemia mice in comparison to triple-transgenic and APPSwDI Alzheimer's disease mouse models2014In: Molecular and cellular neuroscience, ISSN 1044-7431, Vol. 63, p. 83-95Article in journal (Refereed)
    Abstract [en]

    Several studies have shown that elevated plasma cholesterol levels (i.e. hypercholesterolemia) serve as a risk factor for late-onset Alzheimer's disease (AD). However, it remains unclear how hypercholesterolemia may contribute to the onset and progression of AD pathology. In order to determine the role of hypercholesterolemia at various stages of AD, we evaluated the effects of high cholesterol diet (5% cholesterol) in wild-type (WT; C57BL6) and triple-transgenic AD (3xTg-AD: Psen1, APPSwe, tauB301L) mice at 7, 14, and 20 months. The transgenic APP-Swedish/Dutch/Iowa AD mouse model (APPSwDI) was used as a control since these animals are more pathologically-accelerated and are known to exhibit extensive plaque deposition and cerebral amyloid angiopathy. Here, we describe the effects of high cholesterol diet on: (1) cognitive function and stress, (2) AD-associated pathologies, (3) neuroinflammation, (4) blood-brain barrier disruption and ventricle size, and (5) vascular dysfunction. Our data show that high dietary cholesterol increases weight, slightly impairs cognitive function, promotes glial cell activation and complement-related pathways, enhances the infiltration of blood-derived proteins and alters vascular integrity, however, it does not induce AD-related pathologies. While normal-fed 3xTg-AD mice display a typical AD-like pathology in addition to severe cognitive impairment and neuroinflammation at 20 months of age, vascular alterations are less pronounced. No microbleedings were seen by MRI, however, the ventricle size was enlarged. Triple-transgenic AD mice, on the other hand, fed a high cholesterol diet do not survive past 14 months of age. Our data indicates that cholesterol does not markedly potentiate AD-related pathology, nor does it cause significant impairments in cognition. However, it appears that high cholesterol diet markedly increases stress-related plasma corticosterone levels as well as some vessel pathologies. Together, our findings represent the first demonstration of prolonged high cholesterol diet and the examination of its effects at various stages of cerebrovascular- and AD-related disease.

  • 239.
    Holm, Linus
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Karampela, Olympia
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Ullén, Fredrik
    Department of Neuroscience, Karolinska Institutet.
    Madison, Guy
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Executive control and working memory are involved in sub-second repetitive motor timing2017In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 235, no 3, p. 787-798Article in journal (Refereed)
    Abstract [en]

    The nature of the relationship between timing and cognition remains poorly understood. Cognitive control is known to be involved in discrete timing tasks involving durations above 1 s, but has not yet been demonstrated for repetitive motor timing below 1 s. We examined the latter in two continuation tapping experiments, by varying the cognitive load in a concurrent task. In Experiment 1, participants repeated a fixed three finger sequence (low executive load) or a pseudorandom sequence (high load) with either 524-, 733-, 1024- or 1431-ms inter-onset intervals (IOIs). High load increased timing variability for 524 and 733-ms IOIs but not for the longer IOIs. Experiment 2 attempted to replicate this finding for a concurrent memory task. Participants retained three letters (low working memory load) or seven letters (high load) while producing intervals (524- and 733-ms IOIs) with a drum stick. High load increased timing variability for both IOIs. Taken together, the experiments demonstrate that cognitive control processes influence sub-second repetitive motor timing.

  • 240.
    Holm, Linus
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Ullén, Fredrik
    Karolinska institutet, Institutionen för kvinnor och barns hälsa, Stockholm Brain Institute.
    Madison, Guy
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Intelligence and temporal accuracy of behaviour: unique and shared associations with reaction time and motor timing2011In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 214, no 2, p. 175-183Article in journal (Refereed)
    Abstract [en]

    Intelligence is associated with accuracy in a wide range of timing tasks. One source of such associations is likely to be individual differences in top-down control, e.g. sustained attention, that influence performance in both temporal tasks and other cognitively controlled behaviors. In addition, we have studied relations between intelligence and a simple rhythmic motor task, isochronous serial interval production (ISIP), and found a substantial component of that relation, which is independent of fluctuations in top-down control. The main purpose of the present study was to investigate whether such bottom-up mechanisms are involved also in the relation between intelligence and reaction time (RT) tasks. We thus investigated if common variance between the ISIP and RT tasks underlies their respective associations with intelligence. 112 participants performed a simple RT task, a choice RT task and the ISIP task. Intelligence was assessed with the Raven SPM Plus. The analysed timing variables included mean and variability in the RT tasks and two variance components in the ISIP task. As predicted, RT and ISIP variables were associated with intelligence. The timing variables were positively intercorrelated and a principal component analysis revealed a substantial first principal component that was strongly related to all timing variables, and positively correlated with intelligence. Furthermore, a commonality analysis demonstrated that the relations between intelligence and the timing variables involved a commonality between the timing variables as well as unique contributions from choice RT and ISIP. We discuss possible implications of these findings, and argue that they support our main hypothesis, i.e. that relations between intelligence and RT tasks have a bottom-up component.

  • 241.
    Holmberg, Ellinor
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Allopregnanolone effects on food intake and weight gain2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background Obesity is currently one of the major causes of ill health and it is clear that overeatingis the cause of obesity. However, the actions of many endogenous factors that contribute to overeating are still not well understood. Gamma-aminobutyric acid (GABA)-ergic transmission has been shown to be of great importance for food intake regulation. The progesterone metabolite allopregnanolone is a potent positive GABAA receptor modulating steroid (GAMS) and in humans, elevated allopregnanolone levels have been suggested to be involved in increased food intake, and also with overweight and obesity. GABAA receptors that express the α2 and α3 subunits are proposed to be the main subtypes involved in food intake regulation. Therefore, the aims of the work in this thesis were to further investigate the effect of allopregnanolone on food intake, feeding behaviour, possible effects on weight gain and also to characterize a possible antagonist at α2β3γ2and α3β3γ2 GABAA receptors.

    Methods Allopregnanolone effects on food intake of different food items were recorded in male Wistar rats. Feeding patterns were analyzed. Food preference tests were also conducted and rats were repeatedly exposed to allopregnanolone under different feeding conditions to elucidate possible effects on body weight gain. To deeper investigate GABAA receptor subtypes suggested to be involved in food intake regulation, electrophysiological whole-cell patch-clamp recordings were performed to identify the specificity of the GAMS antagonist UC1020, at human α2β3γ2 and α3β3γ2 GABAA receptors expressed in HEK293-cells.

    Results Allopregnanolone increased the intake of standard chow, cookies and a high fat diet in male Wistar rats. Preferentially, allopregnanolone increased the rats´intake of the more calorie dense food type. Allopregnanolone reduced feeding latency and prolonged feeding duration. The increased chow intake induced by allopregnanolone was more pronounced at the beginning of the rats´ active period compared to the inactive. Repeated allopregnanolone administration during 5 consecutive days led to an increased body weight gain, more evident in schedule fed rats on a high fat diet. Both obesity prone and obesity resistant rats gained significantly more weight with repeated allopregnanolone exposure and the increased body weight gain correlated with increased food intake. The compound UC1020 was a potent antagonist of GAMS-enhanced GABA evoked currents at human α3β3γ2 GABAA receptors, whereas it had no effect at α2β3γ2 GABAA receptors.

    Conclusions Our findings indicate that allopregnanolone induced hyperphagia may be one of the endogenous factors involved in weight gain, especially when the diet is energy-rich. The compound UC1020 may prove useful for investigating the involvement of the α2 and α3 GABAA receptor subtypes in GAMS-induced hyperphagia.

  • 242.
    Holmberg, Ellinor
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Johansson, Maja
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Haage, David
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Allopregnanolone preferentially induces energy-rich food intake in male Wistar rats2014In: Physiological Reports, E-ISSN 2051-817X, Vol. 2, no 12, p. e12190-Article in journal (Refereed)
    Abstract [en]

    Obesity is an increasing problem and identification of the driving forces for overeating of energy-rich food is important. Previous studies show that the stress and sex steroid allopregnanolone has a hyperphagic effect on both bland food and palatable food. If allopregnanolone induces a preference for more palatable or for more energy-rich food is not known. The aim of this study  was to elucidate the influence of allopregnanolone on food preference. Male Wistar rats were subjected to two different food preference tests: a choice between standard chow and cookies (which have a higher energy content and also are more palatable than chow), and a choice between a low caloric sucrose solution and standard chow (which has a higher energy content and is less palatable than sucrose). Food intake was measured for 1 h after acute subcutaneous injections of allopregnanolone. In the choice between cookies and chow allopregnanolone significantly increased only the intake of cookies.When the standard chow was the item present with the highest caloric load, the chow intake was increased and allopregnanolone had no effect on intake of the 10% sucrose solution. The increased energy intakes induced by the high allopregnanolone dose compared to vehicle were very similar in the two tests,120% increase for cookies and 150% increase for chow. It appears that in allopregnanolone-induced hyperphagia, rats choose the food with the highest energy content regardless of its palatability.

  • 243.
    Holmberg, Ellinor
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Maja
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Löfgren, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Haage, David
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Repeated allopregnanolone exposure induces weight gain in schedule fed rats on high fat diet2015In: Physiology and Behavior, ISSN 0031-9384, E-ISSN 1873-507X, Vol. 140, p. 1-7Article in journal (Refereed)
    Abstract [en]

    Ingestion of energy rich high fat diets is one of the determining factors associated with the obesity epidemic. Therefore, much can be learned from studies of obesity-related substances given to animals fed a high fat diet.The progesterone metabolite allopregnanolone is a potent positive modulator of the gamma-aminobutyric acid(GABA)A-receptor, and both allopregnanolone and GABA have been implicated in evoking hyperphagia. In this study, food intake and body weight gain were investigated during repeated allopregnanolone exposure. Male Wistar rats were studied when fed chow ad libitum, with chow access for 4h per day or with 45% high fat pellets for 4 h per day. Rats on the high fat diet were separated into obesity prone and obesity resistant individuals.Subcutaneous injections of allopregnanolone were given once daily overfive consecutive days. Repeated exposure to allopregnanolone lead to increased weight gain, significantly so in schedule fed rats on a high fat diet. The increased weight gain was correlated to an increased energy intake. Both obesity resistant and obesityprone rats responded to allopregnanolone with increased weight gain. Obesity resistant rats treated with allopregnanolone increased their energy intake and ate as much as vehicle treated obesity prone rats. Their weight gain was also increased to the level of obesity prone rats injected with just the vehicle carrier oil. Thus, it appears that allopregnanolone may be one of the endogenous factors involved in weight gain, especiallywhen the diet is rich in fat.

  • 244. Holmen, C.
    et al.
    Piehl, F.
    Hillert, J.
    Nilsson, P.
    Dahle, C.
    Feltelius, N.
    Svenningsson, Anders
    Norrlands Universitetssjukhus, Umeå.
    Lycke, J.
    Fagius, J.
    Valentin, F.
    Martin, C.
    Olsson, T.
    The 'Immunomodulation and Multiple Sclerosis Epidemiology' (IMSE) study: a Swedish nationwide pharmaco-epidemiological and genetic study focused on long-term safety and efficacy of natalizumab (Tysabri)2012In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, p. 751-751Article in journal (Other academic)
  • 245.
    Holmlund, Petter
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Johansson, Elias
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Qvarlander, Sara
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Ambarki, Khalid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Koskinen, Lars-Owe D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Human jugular vein collapse in the upright posture: implications for postural intracranial pressure regulation2017In: Fluids and Barriers of the CNS, ISSN 2045-8118, E-ISSN 2045-8118, Vol. 14, article id 17Article in journal (Refereed)
    Abstract [en]

    Background: Intracranial pressure (ICP) is directly related to cranial dural venous pressure (P-dural). In the upright posture, P-dural is affected by the collapse of the internal jugular veins (IJVs) but this regulation of the venous pressure has not been fully understood. A potential biomechanical description of this regulation involves a transmission of surrounding atmospheric pressure to the internal venous pressure of the collapsed IJVs. This can be accomplished if hydrostatic effects are cancelled by the viscous losses in these collapsed veins, resulting in specific IJV cross-sectional areas that can be predicted from flow velocity and vessel inclination. Methods: We evaluated this potential mechanism in vivo by comparing predicted area to measured IJV area in healthy subjects. Seventeen healthy volunteers (age 45 +/- 9 years) were examined using ultrasound to assess IJV area and flow velocity. Ultrasound measurements were performed in supine and sitting positions. Results: IJV area was 94.5 mm(2) in supine and decreased to 6.5 +/- 5.1 mm(2) in sitting position, which agreed with the predicted IJV area of 8.7 +/- 5.2 mm(2) (equivalence limit +/- 5 mm(2), one-sided t tests, p = 0.03, 33 IJVs). Conclusions: The agreement between predicted and measured IJV area in sitting supports the occurrence of a hydrostatic-viscous pressure balance in the IJVs, which would result in a constant pressure segment in these collapsed veins, corresponding to a zero transmural pressure. This balance could thus serve as the mechanism by which collapse of the IJVs regulates P-dural and consequently ICP in the upright posture.

  • 246.
    Holmlund, Petter
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Johansson, Elias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Qvarlander, Sara
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Ambarki, Khalid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Koskinen, Lars-Owe D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Jugular vein collapse in upright and its relation to intracranial pressure regulation2017In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 37, p. 297-297Article in journal (Refereed)
  • 247. Holtermann, A
    et al.
    Grönlund, Christer
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Karlsson, J Stefan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Roeleveld, K
    Fatigue induced changes in motor unit synchronization and its relation to force tremor in different parts of the biceps brachii muscleManuscript (preprint) (Other academic)
  • 248. Holtermann, Andreas
    et al.
    Roeleveld, Karin
    Karlsson, J Stefan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Inhomogeneities in muscle activation reveal motor unit recruitment2005In: J Electromyogr Kinesiol, ISSN 1050-6411, Vol. 15, no 2, p. 131-137Article in journal (Refereed)
  • 249.
    Horvath, Istvan
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Iashchishyn, Igor A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Department of General Chemistry, Sumy State University, Ukraine.
    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.
    Immunochemical Detection of alpha-Synuclein Autoantibodies in Parkinson's Disease: Correlation between Plasma and Cerebrospinal Fluid Levels2017In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 8, no 6, p. 1170-1176Article in journal (Refereed)
    Abstract [en]

    Autoantibodies to Parkinson's disease (PD) amyloidogenic protein, a-synuclein, were recognized as a prospective biomarker for early disease diagnostics, yet there is inconsistency in previous reports, potentially related to PD status. Therefore, plasma and cerebrospinal fluid (CSF) of the cross-sectional cohort of 60 individuals, including recently diagnosed PD patients with mild and moderate PD and age-matched controls, were examined by enzyme-linked immunosorbent assay (ELISA). Nonparametric statistics was used for data analysis. We found significantly elevated levels of a-synuclein autoantibodies in both plasma and CSF in mild PD compared to controls, followed by some decrease in moderate PD. Receiver operating characteristic and effect size analyses confirmed the diagnostic power of a-synuclein antibodies in both plasma and CSF. For the first time, we showed the correlation between plasma and CSF a-synuclein antibody levels for mild, moderate, and combined PD groups. This indicates the potentiality of a-synuclein antibodies as PD biomarker and the increased diagnostic power of their simultaneous analysis in plasma and CSF.

  • 250.
    Horvath, Istvan
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Jia, Xueen
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Science and Technology, Department of Physics.
    Johansson, Per
    Wang, Chao
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Moskalenko, Roman
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Department of Pathology, Sumy State University, Sumy 40000, Ukraine.
    Steinau, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wågberg, Thomas
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Svensson, Johan
    Zetterberg, Henrik
    Morozova-Roche, Ludmilla A
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Pro-inflammatory S100A9 Protein as a Robust Biomarker Differentiating Early Stages of Cognitive Impairment in Alzheimer's Disease2016In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 7, no 1, p. 34-39Article in journal (Refereed)
    Abstract [en]

    Pro-inflammatory protein S100A9 was established as a biomarker of dementia progression and compared with others such as Aβ1-42 and tau-proteins. CSF samples from 104 stringently diagnosed individuals divided into five subgroups were analyzed, including nondemented controls, stable mild cognitive impairment (SMCI), mild cognitive impairment due to Alzheimer's disease (MCI-AD), Alzheimer's disease (AD), and vascular dementia (VaD) patients. ELISA, dot-blotting, and electrochemical impedance spectroscopy were used as research methods. The S100A9 and Aβ1-42 levels correlated with each other: their CSF content decreased already at the SMCI stage and declined further under MCI-AD, AD, and VaD conditions. Immunohistochemical analysis also revealed involvement of both Aβ1-42 and S100A9 in the amyloid-neuroinflammatory cascade already during SMCI. Tau proteins were not yet altered in SMCI; however their contents increased during MCI-AD and AD, diagnosing later dementia stages. Thus, four biomarkers together, reflecting different underlying pathological causes, can accurately differentiate dementia progression and also distinguish AD from VaD.

2345678 201 - 250 of 679
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