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

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

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

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

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

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

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

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

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

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

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

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

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

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

  • 107. Casar-Borota, O.
    et al.
    Jacobsson, Johan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Libelius, Rolf
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Moslemi, A. R.
    Hedberg, C.
    Oldfors, A.
    A novel dynamin-2 gene mutation associated with a late-onset centronuclear myopathy with unusual clinical presentation and necklace fibres2012In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 22, no 9-10, p. 843-843Article in journal (Other academic)
  • 108. Casar-Borota, Olivera
    et al.
    Jacobsson, Johan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Libelius, Rolf
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hedberg Oldfors, Carola
    Malfatti, Edoardo
    Romero, Norma Beatriz
    Oldfors, Anders
    A novel dynamin-2 gene mutation associated with a late-onset centronuclear myopathy with necklace fibres2015In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 25, no 4, p. 345-348Article in journal (Refereed)
    Abstract [en]

    Nuclear centralisation and internalisation, sarcoplasmic radiating strands and type 1 muscle fibre predominance and hypotrophy characterise dynamin-2 (DNM2) associated centronuclear myopathy, whereas necklace fibres are typically seen in late onset myotubularin-1 (MTM1)-related myopathy. We report a woman with unilateral symptoms probably related to brachial plexus neuritis. Electromyography revealed localised neuropathic and generalised myopathic abnormalities. The typical features of DNM2 centronuclear myopathy with additional necklace fibres were found in the muscle biopsy. Sequencing of the DNM2 and MTM1 genes revealed a novel heterozygous missense mutation in exon 18 of the DNM2, leading to replacement of highly conserved proline at position 647 by arginine. The muscle symptoms have not progressed during the 3-year follow-up. However, the patient has developed bilateral subtle lens opacities. Our findings support the concept that necklace fibres may occasionally be found in DNM2-related myopathy, possibly indicating a common pathogenic mechanism in DNM2 and MTM1 associated centronuclear myopathy.

  • 109. Cenci, M. Angela
    et al.
    Jörntell, Henrik
    Petersson, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). The Group for Integrative Neurophysiology and Neurotechnology, Neuronano Research Centre, Department Experimental Medical Science, Lund University, Lund, Sweden.
    On the neuronal circuitry mediating l-DOPA-induced dyskinesia2018In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 125, no 8, p. 1157-1169Article, review/survey (Refereed)
    Abstract [en]

    With the advent of rodent models of l-DOPA-induced dyskinesia (LID), a growing literature has linked molecular changes in the striatum to the development and expression of abnormal involuntary movements. Changes in information processing at the striatal level are assumed to impact on the activity of downstream basal ganglia nuclei, which in turn influence brain-wide networks, but very little is actually known about systems-level mechanisms of dyskinesia. As an aid to approach this topic, we here review the anatomical and physiological organisation of cortico-basal ganglia-thalamocortical circuits, and the changes affecting these circuits in animal models of parkinsonism and LID. We then review recent findings indicating that an abnormal cerebellar compensation plays a causal role in LID, and that structures outside of the classical motor circuits are implicated too. In summarizing the available data, we also propose hypotheses and identify important knowledge gaps worthy of further investigation. In addition to informing novel therapeutic approaches, the study of LID can provide new clues about the interplay between different brain circuits in the control of movement.

  • 110. Ceulemans, Shana
    et al.
    De Zutter, Sonia
    Heyrman, Lien
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nilsson, Lars-Goran
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Del-Favero, Jurgen
    Claes, Stephan
    Evidence for the involvement of the glucocorticoid receptor gene in bipolar disorder in an isolated northern Swedish population2011In: Bipolar Disorders, ISSN 1398-5647, E-ISSN 1399-5618, Vol. 13, no 7-8, p. 614-623Article in journal (Refereed)
    Abstract [en]

    Objectives: Dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis is one of the most consistent findings in the pathophysiology of mood disorders. The potential role of genes related to HPA axis function has been investigated extensively in major depression. However, in bipolar disorder (BPD) such studies are scarce. We performed a systematic HapMap-based association study of six genes crucial for HPA axis function in relation to BPD.

    Methods: Haplotype tagging single nucleotide polymorphisms (htSNPs) were selected in order to identify all haplotypes with a frequency of more than 1% in the genes encoding the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), corticotrophin releasing hormone receptor 1 (CRH-R1) and 2 (CRH-R2), CRH binding protein (CRH-BP), and FK binding protein 5 (FKBP5). This resulted in a total selection of 225 SNPs that were genotyped and analyzed in 309 BPD patients and 364 matched control individuals all originating from an isolated northern Swedish population.

    Results: Consistent evidence for an association with BPD was found for NR3C1, the gene encoding GR. Almost all SNPs in two adjacent haplotype blocks contributed to the positive signal, comprised of significant single marker, sliding window, and haplotype-specific p-values. All these results point to a moderately frequent (10-15%) susceptibility haplotype covering the entire coding region and 3 > untranslated region (UTR) of NR3C1.

    Conclusions: This study contributes to the growing evidence for a role of the glucocorticoid receptor gene (NR3C1) in vulnerability to mood disorders, and BPD in particular, and warrants further in vitro investigation of the at-risk haplotypes with respect to disease etiology. However, this association might be restricted to this specific population, as it is observed in a rather small sample from an isolated population without replication, and data from large meta-analyses for genome-wide association studies in BPD do not show the GR as a very strong candidate.

  • 111.
    Chamoun, Mario-Christofer
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    An Alzheimer-type cerebrospinal fluid profile in early Parkinson's disease2019Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    In recent years, several studies have discovered traces of Alzheimer's (AD) biomarkers in a large portion of patients with Parkinson's disease (PD), which have been associated with subsequent dementia (PDD). However, the manifestation of AD biomarkers in PD is not fully understood. At present, few studies have investigated how common AD biomarkers are in newly diagnosed and unmedicated patients with PD. This cross-sectional cohort study investigated whether AD biomarkers were present in unmedicated and newly diagnosed patients with PD and patients with PD and overlapping clinical symptoms (cognitive impairment, depression, olfactory dysfunction). Cerebrospinal fluid (CSF) levels of AD biomarkers Amyloid-β-42 (Aβ42), phosphorylated-tau (p-tau), and total-tau (t-tau) were assessed in 343 patients with the mean age of 68,69 (SD=9,60), including 31 healthy controls with the mean age of 68,90 (SD=5,64). The participants were recruited from The New Parkinson Patient in Umea (NYPUM & PARKNY). The results showed a significant difference in CSF AD biomarkers between patients with PD and healthy controls, but not in patients with PD and overlapping clinical symptoms. The results point to the presence of AD pathology in early PD; however, the presence of AD pathology could not be further strengthened by the clinical overlapping symptoms. More prospective studies on newly diagnosed patients with PD need to be carried out to investigate the prognostic values of the presence of AD pathology found in PD.

  • 112. Chatzittofis, Andreas
    et al.
    Arver, Stefan
    Öberg, Katarina
    Hallberg, Jonas
    Nordström, Peter
    Jokinen, Jussi
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    HPA axis dysregulation in patients with hypersexual disorder2015In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 61, p. 53-53Article in journal (Other academic)
  • 113. Chen, Mengying
    et al.
    Xia, Dongqing
    Min, Cuiting
    Zhao, Xiaoke
    Chen, Yinhua
    Liu, Li
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Li, Xiaonan
    Neonatal repetitive pain in rats leads to impaired spatial learning and dysregulated hypothalamic-pituitary-adrenal axis function in later life2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 39159Article in journal (Refereed)
    Abstract [en]

    Preterm birth is a major health issue. As part of their life-saving care, most preterm infants require hospitalization and are inevitably exposed to repetitive skin-breaking procedures. The long-term effects of neonatal repetitive pain on cognitive and emotional behaviors involving hypothalamic-pituitary-adrenal (HPA) axis function in young and adult rats are unknown. From P8 to P85, mechanical hypersensitivity of the bilateral hindpaws was observed in the Needle group (P < 0.001). Compared with the Tactile group, the Needle group took longer to find the platform on P30 than on P29 (P = 0.03), with a decreased number of original platform site crossings during the probe trial of the Morris water maze test (P = 0.026). Moreover, the Needle group spent more time and took longer distances in the central area than the Tactile group in the Open-field test, both in prepubertal and adult rats (P < 0.05). The HPA axis function in the Needle group differed from the Tactile group (P < 0.05), with decreased stress responsiveness in prepuberty and puberty (P < 0.05) and increased stress responsiveness in adulthood (P < 0.05). This study indicates that repetitive pain that occurs during a critical period may cause severe consequences, with behavioral and neuroendocrine disturbances developing through prepuberty to adult life.

  • 114.
    Chermenina, Maria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    GDNF and alpha-synuclein in nigrostriatal degeneration2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Parkinson’s disease is a common neurological disorder with a complex etiology. The disease is characterized by a progressive loss of dopaminergic cells in the substantia nigra, which leads to motor function and sometimes cognitive function disabilities. One of the pathological hallmarks in Parkinson’s disease is the cytoplasmic inclusions called Lewy bodies found in the dopamine neurons. The aggregated protein α-synuclein is a main component of Lewy bodies. In view of severe symptoms and the upcoming of problematic side effects that are developed by the current most commonly used treatment in Parkinson’s disease, new treatment strategies need to be elucidated. One such strategy is replacing the lost dopamine neurons with new dopamine-rich tissue. To improve survival of the implanted neurons, neurotrophic factors have been used. Glial cell line-derived neurotrophic factor (GDNF), which was discovered in 1993, improves survival of ventral mesencephalic dopamine neurons and enhances dopamine nerve fiber formation according to several studies. Thus, GDNF can be used to improve dopamine-rich graft outgrowth into the host brain as well as inducing sprouting from endogenous remaining nerve fibers. This study was performed on Gdnf gene-deleted mice to investigate the role of GDNF on the nigrostriatal dopamine system. The transplantation technique was used to create a nigrostriatal microcircuit from ventral mesencephalon (VM) and the lateral ganglionic eminence (LGE) from different Gdnf gene-deleted mice. The tissue was grafted into the lateral ventricle of wildtype mice. The results revealed that reduced concentrations of GDNF, as a consequence from the Gdnf gene deletion, had effects on survival of dopamine neurons and the dopamine innervation of the nigrostriatal microcircuit. All transplants had survived at 3 months independently of Gdnf genotype, however, the grafts derived from Gdnf gene-deleted tissue had died at 6 months. Transplants with partial Gdnf gene deletion survived up to 12 months after transplantation. Moreover, the dopaminergic innervation of striatal co-grafts was impaired in Gdnf gene-deleted tissue. These results highlight the role of GDNF for long-term maintenance of the nigrostriatal dopamine system. To further investigate the role of GDNF expression on survival and organization of the nigrostriatal dopamine system, VM and LGE as single or combined to double co-grafts created from mismatches in Gdnf genotypes were transplanted into the lateral ventricle of wildtype mice. Survival of the single grafts was monitored over one year using a 9.4T MR scanner. The size of single LGE transplants was significantly reduced by the lack of GDNF already at 2 weeks postgrafting while the size of single VM was maintained over time, independently of GDNF expression. The double grafts were evaluated at 2 months, and the results revealed that lack of GDNF in LGE reduced the dopamine cell survival, while no loss of dopamine neurons was found in VM single grafts. The dopaminergic innervation of LGE was affected by absence of GDNF, which also caused a disorganization of the striatal portion of the co-grafts. Small, cytoplasmic inclusions were frequently found in the dopamine neurons in grafts lacking GDNF expression. These inclusions were not possible to classify as Lewy bodies by immunohistochemistry and the presence of phospho-α-synuclein and ubiquitin; however, mitochondrial dysfunction could not be excluded. To further study the death of the dopamine neurons by the deprivation of GDNF, the attention was turned to how Lewy bodies are developed. With respect to the high levels of α-synuclein that was found in the striatum, this area was selected as a target to inject the small molecule – FN075, which stimulates α-synuclein aggregation, to further investigate the role of α-synuclein in the formation of cytoplasmic inclusions. The results revealed that cytoplasmic inclusions, similar to those found in the grafts, was present at 1 month after the injection, while impairment in sensorimotor function was exhibited, the number of dopamine neurons was not changed at 6 months after the injection. Injecting the templator to the substantia nigra, however, significantly reduced the number of TH-positive neurons at 3 months after injection. In conclusion, these studies elucidate the role of GDNF for maintenance and survival of the nigrostriatal dopamine system and mechanisms of dopamine cell death using small molecules that template the α-synuclein aggregation.

  • 115.
    Chermenina, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Henrik, Antti
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    A novel animal model for Parkinson's disease based on in vivo effects of small-molecule of alpha-synucleinManuscript (preprint) (Other academic)
    Abstract [en]

    Amyloid fibrils of alpha-synuclein are major constituents of Lewy bodies, the pathological hallmark of Parkinson’s disease. Monomeric α-synuclein is involved in synaptic vesicle trafficking and long-term maintenance of neurons. The underlying mechanisms of Parkinson’s disease are not known but it has been proposed that oligomers of α-synuclein, formed during the aggregation process, are toxic to neurons. To search for a new animal model of Parkinson’s disease, here we capitalized on the in vitro discovery of a small-molecule templator of α-synuclein fibrillization, the 2-pyridone, FN075. FN075 and MS382, another 2-pyridone variant that act as an inhibitor of amyloids in vitro, were injected into the striatum or substantia nigra of normal C57Bl/6 mice. No acute toxicity of the compounds was detected, as there was 100 % survival of the injected mice. At 6 months after the striatal injection, sensorimotor functions were impaired with no reduction in TH-positive neurons in the substantia nigra in mice injected with FN075, whereas mice injected with MS382 or vehicle had no dysfunctions. Injection of FN075 into the substantia nigra revealed a significant loss of TH-positive neurons already at 3 months and TH-negative inclusion-like structures were detected in substantia nigra neurons of these mice. Thus, the results suggest that injection of a templator of α-synuclein aggregation into the brain of normal mice can serve as a novel experimental design for an animal model of Parkinson’s disease.

  • 116.
    Chermenina, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pokrzywa, Malgorzata
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Single injection of small-molecule amyloid accelerator results in cell death of nigral dopamine neurons in mice2015In: Parkinson's Disease, ISSN 2090-8083, E-ISSN 2042-0080, Vol. 1, article id 15024Article in journal (Refereed)
    Abstract [en]

    The assembly process of a-synuclein toward amyloid fibers is linked to neurodegeneration in Parkinson´s disease. In the present study, we capitalized on the in vitro discovery of a small-molecule accelerator of a-synuclein amyloid formation and assessed its effects when injected in brains of normal mice. An accelerator and an inhibitor of a-synuclein amyloid formation, as well as vehicle only, were injected into the striatum of normal mice and follwed by behavioral evaluation, immunohistochemistry, and metabolomics up to six months later. The effects of molecules injected into the substansia nigra of normal and a-synuclein knockout mice were also analyzed. When accelerator or inhibitor was injected into the brain of normal mice no acute compound toxicity was found. However, 6 months after single striatal injection of accelerator, mice sensorimotor functions were impaired, whereas mice injected with inhibitor had no dysfunctions. Injection of accelerator (but not inhibitor or vehicle) into the substantia nigra revealed singificant loss of tyrosine hydroxylase (TH)-positive neurons after 3 months. No loss of TH-positive neurons was found in a-synuclein knock-out mice injected with accelerator intor the substantia nigra. Metabolic serum profiles from accelerator-injected normal mice matched those of newly diagnosed Parkinson´s disease patients, whereas the profiles from inhibitor-injected normal mice matched controls. Single inoculation of a small-molecule amyloid accelerator may be a new approach for studies of early events during dopamine neurodegeneration in mice.

  • 117.
    Chermenina, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Schouten, P
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Nevalainen, Nina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Johansson, F
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Orädd, Greger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    GDNF is important for striatal organization and maintenance of dopamine neurons grown in the presence of the striatum2014In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 270, p. 1-11Article in journal (Refereed)
    Abstract [en]

    Glial cell-derived neurotrophic factor (GDNF) exerts neuroprotective and neurorestorative effects on neurons and GDNF plays a significant role in maintenance of the dopamine neurons utilizing grafting to create a nigrostriatal microcircuit of Gdnf knockout (Gdnf(-/-)) tissue. To further evaluate the role of GDNF on organization of the nigrostriatal system, single or double grafts of ventral mesencephalon (VM) and lateral ganglionic eminence (LGE) with mismatches in Gdnf genotypes were performed. The survival of single grafts was monitored utilizing magnetic resonance imaging (MRI) and cell survival and graft organization were evaluated with immunohistochemistry. The results revealed that the size of VM single grafts did not change over time independent of genotype, while the size of the LGE transplants was significantly reduced already at 2weeks postgrafting when lacking GDNF. Lack of GDNF did not significantly affect the survival of tyrosine hydroxylase (TH)-positive neurons in single VM grafts. However, the survival of TH-positive neurons was significantly reduced in VM derived from Gdnf(+/+) when co-grafted with LGE from the Gdnf(-/-) tissue. In contrast, lack of GDNF in the VM portion of co-grafts had no effect on the survival of TH-positive neurons when co-grafted with LGE from Gdnf(+/+) mice. The TH-positive innervation of co-grafts was sparse when the striatal co-grafts were derived from the Gdnf(-/-) tissue while dense and patchy when innervating LGE producing GDNF. The TH-positive innervation overlapped with the organization of dopamine and cyclic AMP-regulated phosphoprotein-relative molecular mass 32,000 (DARPP-32)-positive neurons, that was disorganized in LGE lacking GDNF production. In conclusion, GDNF is important for a proper striatal organization and for survival of TH-positive neurons in the presence of the striatal tissue.

  • 118.
    Ching, Rosanna C.
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    The role of exosomes in peripheral nerve regeneration2015In: Neural Regeneration Research, ISSN 1673-5374, E-ISSN 1876-7958, Vol. 10, no 5, p. 743-747Article, review/survey (Refereed)
    Abstract [en]

    Peripheral nerve injuries remain problematic to treat, with poor functional recovery commonly observed. Injuries resulting in a nerve gap create specific difficulties for axonal regeneration. Approaches to address these difficulties include autologous nerve grafts (which are currently the gold standard treatment) and synthetic conduits, with the latter option being able to be impregnated with Schwann cells or stem cells which provide an appropriate micro-environment for neuronal regeneration to occur. Transplanting stem cells, however, infers additional risk of malignant transformation as well as manufacturing difficulties and ethical concerns, and the use of autologous nerve grafts and Schwann cells requires the sacrifice of a functioning nerve. A new approach utilizing exosomes, secreted extracellular vesicles, could avoid these complications. In this review, we summarize the current literature on exosomes, and suggest how they could help to improve axonal regeneration following peripheral nerve injury.

  • 119.
    Christensen, Jens
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine. UCLH, ISEH, London, England; Pure Sports Clin, London, England.
    Andersson, Gustav
    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.
    Protease-activated receptors in the Achilles tendon-a potential explanation for the excessive pain signalling in tendinopathy2015In: Molecular Pain, ISSN 1744-8069, E-ISSN 1744-8069, Vol. 11, article id 13Article in journal (Refereed)
    Abstract [en]

    Background/Aim: Tendinopathies are pathological conditions of tissue remodelling occurring in the major tendons of the body, accompanied by excessive nociceptive signalling. Tendinopathies have been shown to exhibit an increase in the number of mast cells, which are capable of releasing histamine, tryptase and other substances upon activation, which may play a role in the development of tendinopathies. This study set out to describe the distribution patterns of a family of receptors called protease-activated receptors (PARs) within the Achilles tendon. These four receptors (PAR1, PAR2, PAR3, PAR4) are activated by proteases, including tryptase released from mast cells, and are involved in fibrosis, hyperalgesia and neovascularisation, which are changes seen in tendinopathies. Method: In order to study which structures involved in tendinopathy that these proteases can affect, biopsies from patients suffering of mid-portion Achilles tendinosis and healthy controls were collected and examined using immunohistochemistry. Tendon cells were cultured to study in vitro expression patterns. Results: The findings showed a distribution of PARs inside the tendon tissue proper, and in the paratendinous tissue, with all four being expressed on nerves and vascular structures. Double staining showed co-localisation of PARs with nociceptive fibres expressing substance P. Concerning tenocytes, PAR2, PAR3, and PAR4, were found in both biopsies of tendon tissue and cultured tendon cells. Conclusions: This study describes the expression patterns of PARs in the mid-portion of the Achilles tendon, which can help explain the tissue changes and increased pain signalling seen in tendinopathies. These findings also show that in-vitro studies of the effects of these receptors are plausible and that PARs are a possible therapeutic target in the future treatment strategies of tendinopathy.

  • 120. Cif, Laura
    et al.
    Ruge, Diane
    Gonzalez, Victoria
    Limousin, Patricia
    Vasques, Xavier
    Hariz, Marwan I.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Rothwell, John
    Coubes, Philippe
    The Influence of Deep Brain Stimulation Intensity and Duration on Symptoms Evolution in an OFF Stimulation Dystonia Study2013In: Brain stimulation, ISSN 1935-861X, Vol. 6, no 4, p. 500-505Article in journal (Refereed)
    Abstract [en]

    Background: Deep brain stimulation (DBS) of the internal globus pallidus (GPi) is an established therapy for primary generalized dystonia. However, the evolution of dystonia symptoms after DBS discontinuation after years of therapy has only rarely been reported. We therefore longitudinally studied the main physiological measurements known to be impaired in dystonia, with DBS ON and then again after termination of DBS, after at least five years of continuous DBS. Objective: We studied whether dystonia evolution after DBS discontinuation in patients benefiting from long-term GPi DBS is different from that observed in earlier stages of the therapy. Methods: In eleven DYT1 patients treated with bilateral GPi DBS for at least 5 years, dystonia was assessed ON-DBS, immediately after switch-off (OFF-DBS1) and 48 h after DBS termination (OFF-DBS2). We studied the influence of DBS intensity on dystonia when DBS was discontinued. Results: On average a significant difference in symptoms was measured only between ON-DBS and OFF-DBS1 conditions. Importantly, none of the patients returned to their preoperative dystonia severity, even 48 h after discontinuation. The amount of clinical deterioration in the OFF conditions positively correlated with higher stimulation current in the chronic ON-DBS condition. Conclusions: The duration of DBS application influences symptom evolution after DBS termination. DBS intensity seems to have a prominent role on evolution of dystonic symptoms when DBS is discontinued. In conclusion, DBS induces changing modulation of the motor network with less worsening of symptoms after long term stimulation, when DBS is stopped.

  • 121.
    Claeson, Anna-Sara
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Andersson, Linus
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Symptoms from masked acrolein exposure suggest altered trigeminal reactivity in chemical intolerance2017In: Neurotoxicology, ISSN 0161-813X, E-ISSN 1872-9711, Vol. 60, p. 92-98Article in journal (Refereed)
    Abstract [en]

    Background: Chemical intolerance (CI) is a widespread occupational and public health problem characterized by symptoms that reportedly result from low-levels of chemical exposure. The mechanisms behind CI are unknown, however modifications of the chemical senses (rather than toxic processes) have been suggested as key components. The aim of this study was to investigate whether individuals with self-reported CI report more sensory irritation during masked acrolein exposure compared to controls without CI. Methods: Individuals with CI (n = 18) and controls without CI (n = 19) were exposed in an exposure chamber. Each participant took part in two exposure conditions – one with heptane (the masking compound), and one with heptane and acrolein at a dose below previously reported sensory irritation thresholds. The exposures lasted for 60 min. Symptoms and confidence ratings were measured continuously throughout the exposure as were measurements of electrodermal activity and self-reported tear-film break-up time. Participants were blind to exposure condition. Results: Individuals with CI, compared with controls reported greater sensory irritation in the eyes, nose and throat when exposed to acrolein masked with heptane. There was no difference during exposure to heptane. Conclusions: Masked exposure to acrolein at a concentration below the previously reported detection threshold is perceived as more irritating by individuals with CI compared with controls. The results indicate that there is altered trigeminal reactivity in those with CI compared to controls.

  • 122. Conceicao, I
    et al.
    Coelho, T
    Plante-Bordeneuve, V
    Waddington Cruz, M
    Ericzon, BG
    Falk, RN
    Ikeda, S
    Maurer, M
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ando, Y
    Mazzeo, A
    Grogan, DR
    Baseline neurologic function in symptomatic patients in the Transthyretin Amyloidosis Outcomes Survey (THAOS)2011Conference paper (Refereed)
  • 123. Conceicao, I.
    et al.
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Coelho, T.
    Waddington Cruz, M.
    Schmidt, H.
    Buades, J.
    Campistol, J.
    Pouget, J.
    Berk, I.
    Adams, D.
    Phase 2 open-label extension study of patisiran, an investigational siRNA agent for hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN)2016In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 26, p. S142-S142Article in journal (Other academic)
    Abstract [en]

    Hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN), also known as familial amyloidotic polyneuropathy (FAP), is an inherited, progressive disease that can cause sensory, motor, and autonomic dysfunction, resulting in significant disability and death. Patisiran is an investigational, systemically administered small interfering RNA (siRNA) targeting wild-type and mutant TTR. A recently completed multi-center, multi-dose Phase 2 trial of patisiran in hATTR-PN patients (N = 29) showed >80% sustained mean knockdown of serum TTR when administered at a dose of 0.3 mg/kg every 3 weeks with a generally favorable safety profile. Phase 2 open label (OLE) study to evaluate patisiran's safety effect on serum TTR levels, impact on neuropathy impairment scores and QOL. Twenty-seven patients with hATTR-PN were enrolled; median age 64 years (range: 29–77 years). Patisiran was well tolerated throughout the23-months of follow-up. Five patients experienced SAEs (unrelated) including one discontinuation and subsequent death (gastroesophageal cancer). Flushing (25.9%) and infusion-related reactions (18.5%) were mild AEs; and did not result in any discontinuations. Approximately 80% sustained mean serum TTR lowering was obtained with a mean nadir of up to 93% between doses. Among the 20 evaluable patients, neuropathy impairment scores were stable with a mean change in mNIS+7 and NIS of 1.7 and 4.2 points, respectively. This compares favorably to 17–26 point mNIS+7/NIS increase at 18-months from prior hATTR-PN studies. Stabilization of quality of life (QOL) measures and significant improvement of distal thigh sweat gland nerve fiber density was observed. Long-term (>18 months) patisiran administration was generally well tolerated, resulted in sustained mean serum TTR lowering; supporting the hypothesis that TTR knockdown potentially halts neuropathy progression. As of March 2016, dosing continues; updated results will be presented.

  • 124. Cook, Caylee J.
    et al.
    Howard, Steven J.
    Scerif, Gaia
    Twine, Rhian
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health. MRC/Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
    Norris, Shane A.
    Draper, Catherine E.
    Associations of physical activity and gross motor skills with executive function in preschool children from low-income South African settings2019In: Developmental Science, ISSN 1363-755X, E-ISSN 1467-7687, Vol. 22, no 5, p. 1-13, article id e12820Article in journal (Refereed)
    Abstract [en]

    Executive function is foundational for cognitive development. Previous research has shown both gross motor skills and physical activity to be related to executive function. However, evidence for these relationships in the preschool years, as well as in low- and middle-income countries is lacking. Therefore, this study aimed to investigate the relationships between components of executive function (inhibition, shifting and working memory) and gross motor skills (locomotor skills and object control skills) in a sample of preschool children from urban and rural low-income settings in South Africa. Results revealed that inhibition and working memory, but not shifting, were associated with gross motor skills. More specifically: inhibition was associated with both locomotor [beta = 0.20, p = 0.047] and object control skills [beta = 0.24, p = 0.024], whereas working memory was only associated with locomotor skills [beta = 0.21, p = 0.039]. Physical activity was not associated with inhibition and shifting but was negatively associated with working memory. These results elaborate a growing evidence base linking executive function and gross motor skills in the early years, and it is the first to look at specific associations of locomotor and object control skills with executive function in the South African context (a low- and middle-income country).

  • 125. Cornelis, M C
    et al.
    Byrne, E M
    Esko, T
    Nalls, M A
    Ganna, A
    Paynter, N
    Monda, K L
    Amin, N
    Fischer, K
    Renstrom, F
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Ngwa, J S
    Huikari, V
    Cavadino, A
    Nolte, I M
    Teumer, A
    Yu, K
    Marques-Vidal, P
    Rawal, R
    Manichaikul, A
    Wojczynski, M K
    Vink, J M
    Zhao, J H
    Burlutsky, G
    Lahti, J
    Mikkilä, V
    Lemaitre, R N
    Eriksson, J
    Musani, S K
    Tanaka, T
    Geller, F
    Luan, J
    Hui, J
    Mägi, R
    Dimitriou, M
    Garcia, M E
    Ho, W-K
    Wright, M J
    Rose, L M
    Magnusson, P K E
    Pedersen, N L
    Couper, D
    Oostra, B A
    Hofman, A
    Ikram, M A
    Tiemeier, H W
    Uitterlinden, A G
    van Rooij, F J A
    Barroso, I
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Xue, L
    Kaakinen, M
    Milani, L
    Power, C
    Snieder, H
    Stolk, R P
    Baumeister, S E
    Biffar, R
    Gu, F
    Bastardot, F
    Kutalik, Z
    Jacobs, D R
    Forouhi, N G
    Mihailov, E
    Lind, L
    Lindgren, C
    Michaëlsson, K
    Morris, A
    Jensen, M
    Khaw, K-T
    Luben, R N
    Wang, J J
    Männistö, S
    Perälä, M-M
    Kähönen, M
    Lehtimäki, T
    Viikari, J
    Mozaffarian, D
    Mukamal, K
    Psaty, B M
    Döring, A
    Heath, A C
    Montgomery, G W
    Dahmen, N
    Carithers, T
    Tucker, K L
    Ferrucci, L
    Boyd, H A
    Melbye, M
    Treur, J L
    Mellström, D
    Hottenga, J J
    Prokopenko, I
    Tönjes, A
    Deloukas, P
    Kanoni, S
    Lorentzon, M
    Houston, D K
    Liu, Y
    Danesh, J
    Rasheed, A
    Mason, M A
    Zonderman, A B
    Franke, L
    Kristal, B S
    Karjalainen, J
    Reed, D R
    Westra, H-J
    Evans, M K
    Saleheen, D
    Harris, T B
    Dedoussis, G
    Curhan, G
    Stumvoll, M
    Beilby, J
    Pasquale, L R
    Feenstra, B
    Bandinelli, S
    Ordovas, J M
    Chan, A T
    Peters, U
    Ohlsson, C
    Gieger, C
    Martin, N G
    Waldenberger, M
    Siscovick, D S
    Raitakari, O
    Eriksson, J G
    Mitchell, P
    Hunter, D J
    Kraft, P
    Rimm, E B
    Boomsma, D I
    Borecki, I B
    Loos, R J F
    Wareham, N J
    Vollenweider, P
    Caporaso, N
    Grabe, H J
    Neuhouser, M L
    Wolffenbuttel, B H R
    Hu, F B
    Hyppönen, E
    Järvelin, M-R
    Cupples, L A
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Nutrition, Harvard School of Public Health, Boston, MA, USA; Lund Univ, Dept Clin Sci, Malmo, Sweden.
    Ridker, P M
    van Duijn, C M
    Heiss, G
    Metspalu, A
    North, K E
    Ingelsson, E
    Nettleton, J A
    van Dam, R M
    Chasman, D I
    Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption2015In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 20, no 5, p. 647-656Article in journal (Refereed)
    Abstract [en]

    Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91 462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.

  • 126. Couthouis, Julien
    et al.
    Hart, Michael P
    Shorter, James
    DeJesus-Hernandez, Mariely
    Erion, Renske
    Oristano, Rachel
    Liu, Annie X
    Ramos, Daniel
    Jethava, Niti
    Hosangadi, Divya
    Epstein, James
    Chiang, Ashley
    Diaz, Zamia
    Nakaya, Tadashi
    Ibrahim, Fadia
    Kim, Hyung-Jun
    Solski, Jennifer A
    Williams, Kelly L
    Mojsilovic-Petrovic, Jelena
    Ingre, Caroline
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Boylan, Kevin
    Graff-Radford, Neill R
    Dickson, Dennis W
    Clay-Falcone, Dana
    Elman, Lauren
    McCluskey, Leo
    Greene, Robert
    Kalb, Robert G
    Lee, Virginia M-Y
    Trojanowski, John Q
    Ludolph, Albert
    Robberecht, Wim
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Nicholson, Garth A
    Blair, Ian P
    King, Oliver D
    Bonini, Nancy M
    Van Deerlin, Vivianna
    Rademakers, Rosa
    Mourelatos, Zissimos
    Gitler, Aaron D
    A yeast functional screen predicts new candidate ALS disease genes2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 52, p. 20881-20890Article in journal (Refereed)
    Abstract [en]

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

  • 127. Cruz Alsina, Fernando
    et al.
    Javier Hita, Francisco
    Aldana Fontanet, Paula
    Irala, Dolores
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ledda, Fernanda
    Paratcha, Gustavo
    Lrig1 is a cell-intrinsic modulator of hippocampal dendrite complexity and BDNF signaling2016In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 17, no 4, p. 601-616Article in journal (Refereed)
    Abstract [en]

    Even though many extracellular factors have been identified as promoters of general dendritic growth and branching, little is known about the cell-intrinsic modulators that allow neurons to sculpt distinctive patterns of dendrite arborization. Here, we identify Lrig1, a nervous system-enriched LRR protein, as a key physiological regulator of dendrite complexity of hippocampal pyramidal neurons. Lrig1-deficient mice display morphological changes in proximal dendrite arborization and defects in social interaction. Specifically, knockdown of Lrig1 enhances both primary dendrite formation and proximal dendritic branching of hippocampal neurons, two phenotypes that resemble the effect of BDNF on these neurons. In addition, we show that Lrig1 physically interacts with TrkB and attenuates BDNF signaling. Gain and loss of function assays indicate that Lrig1 restricts BDNF-induced dendrite morphology. Together, our findings reveal a novel and essential role of Lrig1 in regulating morphogenic events that shape the hippocampal circuits and establish that the assembly of TrkB with Lrig1 represents a key mechanism for understanding how specific neuronal populations expand the repertoire of responses to BDNF during brain development.

  • 128. Czell, D.
    et al.
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Morita, M.
    Neuwirth, C.
    Perren, F.
    Weber, M.
    Phenotypes in Swiss Patients with Familial ALS Carrying TARDBP Mutations2013In: Neurodegenerative Diseases, ISSN 1660-2854, Vol. 12, no 3, p. 150-155Article in journal (Refereed)
    Abstract [en]

    Background: Recently, mutations in the TARDBP gene encoding the TAR DNA-binding protein 43 (TDP-43) have been identified in some familial annyotrophic lateral sclerosis (ALS) and sporadic ALS patients. The phenotype and frequency of TARDBP mutation carriers reportedly varies greatly among European populations. Objective: To define the phenotypic spectrum of TARDBP mutations and their frequency in a Swiss population. Methods: A total of 225 patients diagnosed with ALS (182 sporadic cases, 43 familial cases) were screened for TARDBP mutations. All patients were carefully examined and interviewed for a familial predisposition. Except for 1 patient who was followed at the University of Geneva, all patients were followed at the Kantonsspital St. Gallen. Results: 43 patients (19.5%) had a definite family history for ALS. A TARDBP mutation was identified in 4 of these (9.3%). Two female ALS patients carried the p.Asn352Ser mutation. Both had limb onset and a slowly progressive course of the disease. A novel mutation (p.Gly376Asp) was identified in a 44-year-old female patient. Survival amongst affected family members varied between 6 and 18 months. The patient and also the other siblings affected with ALS had an accessory nipple. A fourth male patient carried the p.Ala-90Val mutation. None of the patients had overt cognitive impairment. TARDBP mutations were not found among patients with sporadic forms of ALS. Conclusion: In this Swiss population, the frequency of familial ALS is higher than reported earlier in other populations. The novel p.Gly376Asp TARDBP mutation is associated with rapid disease progression and may be associated with an accessory nipple while the p.Asn352Ser mutation is associated with slow disease progression.

  • 129.
    Czell, David
    et al.
    Kantonsspital, Neuromuscular Dis Unit, ALS Clin, CH-9007 St Gallen, Switzerland.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Neuwirth, Christoph
    Kantonsspital, Neuromuscular Dis Unit, ALS Clin, CH-9007 St Gallen, Switzerland.
    Morita, Mitsuya
    Jichi Med Univ, Dept Neurol, Shimotsuke, Japan.
    Weber, Markus
    Kantonsspital, Neuromuscular Dis Unit, ALS Clin, CH-9007 St Gallen, Switzerland.
    Progressive aphasia as the presenting symptom in a patient with amyotrophic lateral sclerosis with a novel mutation in the OPTN gene2013In: Amyotrophic Lateral Sclerosis and Frontootemporal Degeneration, ISSN 2167-8421, Vol. 14, no 2, p. 138-140Article in journal (Refereed)
  • 130.
    Dabernig, Jörg
    et al.
    Glasgow Royal Infirmary.
    Ong, Keh O
    Glasgow Royal Infirmary.
    McGowan, Robert
    Glasgow Royal Infirmary.
    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.
    Payne, Anthony P
    University of Glasgow.
    Hart, Andrew M
    Glasgow Royal Infirmary.
    The anatomic and radiologic basis of the circumflex scapular artery perforator flap2010In: Annals of Plastic Surgery, ISSN 0148-7043, E-ISSN 1536-3708, Vol. 64, no 6, p. 784-788Article in journal (Refereed)
    Abstract [en]

    Microsurgical development has recently focused upon the perforator paradigm and primary thinning. Existing perforator flaps may require intramuscular dissection or lack reliable surface markings, whereas traditional scapular/parascapular flaps have low donor morbidity and reliable anatomy, but can be excessively bulky. Clinical application of a new flap based on a perforator from the circumflex scapular axis (CSA) has recently been published, but the vessel's anatomy has not been adequately characterized. The CSA was dissected in 115 sites in 69 cadavers. The number, external vessel diameter, and site of origin of perforators were measured relative to the CSA bifurcation. Color Doppler ultrasound was used to delineate the CSA and its perforators bilaterally in 40 volunteers. The number, origin relative to CSA bifurcation, diameter, length, and flow velocity of cutaneous perforators were determined. A CSA perforator was always present, running into the subdermal plexus, arising within 2.4 cm of the bifurcation. Cadaver studies: mean perforator diameter, 1.3 mm (SD, 0.66); 13% arose at bifurcation, 36% arose proximal (mean, 1.1 mm; SD, 0.63), and 52% distal to bifurcation (mean, 1.5 mm; SD, 0.88). Ultrasound: mean perforator diameter, 1.18 mm (SD, 0.41); mean flow velocity, 16.3 cm/s (SD, 3.65); perforator arose in 36% proximal, in 40% distal to bifurcation, and in 24% from the bifurcation. We definitively describe the anatomy of the perforator from the circumflex scapular artery upon which a new flap has been based. Its origin and dimensions are anatomically and radiologically reliable. The flap has certain potential benefits over existing perforator flaps.

  • 131.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    What are the nerve related changes in tendinopathies and their implications for the cause and/or treatment of pain?2007Conference paper (Refereed)
    Abstract [en]

    Three theoretical models for possible nerve-related changes that occur in tendinopathies, either as cause or effects of the condition, are suggested: 1) changes in innervation patterns, 2) changes in nerve signaling/responsiveness, and 3) changes in production of (non-neuronal) signal substances. The scientific literature on the subject is reviewed, and studies in support of all three theories are presented. The conclusions are as follows: Changes in innervation patterns in tendinopathies are not fully verified, and not sufficient to explain the pain that occurs in tendinopathy. Changes in nerve sensitization/responsiveness cannot be ruled out, since there is a clear morphological basis in the form of several types of receptors demonstrated on nerves in tendons. Finally, there is novel evidence in favor of a biochemical explanation model, including a local, non-neuronal, production of signal substances, and also findings of receptors for these substances on nerves (and tenocytes). In summary, many possible sites for intervention in treatment of tendinopathy are suggested.

  • 132. de Boer, Lieke
    et al.
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Chowdhury, Rumana
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Dolan, Raymond J.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Backman, Lars
    Guitart-Masip, Marc
    Dorsal striatal dopamine D1 receptor availability predicts an instrumental bias in action learning2019In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 1, p. 261-270Article in journal (Refereed)
    Abstract [en]

    Learning to act to obtain reward and inhibit to avoid punishment is easier compared with learning the opposite contingencies. This coupling of action and valence is often thought of as a Pavlovian bias, although recent research has shown it may also emerge through instrumental mechanisms. We measured this learning bias with a rewarded go/no-go task in 60 adults of different ages. Using computational modeling, we characterized the bias as being instrumental. To assess the role of endogenous dopamine (DA) in the expression of this bias, we quantified DA D1 receptor availability using positron emission tomography (PET) with the radioligand [11C]SCH23390. Using principal-component analysis on the binding potentials in a number of cortical and striatal regions of interest, we demonstrated that cortical, dorsal striatal, and ventral striatal areas provide independent sources of variance in DA D1 receptor availability. Interindividual variation in the dorsal striatal component was related to the strength of the instrumental bias during learning. These data suggest at least three anatomical sources of variance in DA D1 receptor availability separable using PET in humans, and we provide evidence that human dorsal striatal DA D1 receptors are involved in the modulation of instrumental learning biases.

  • 133. de Boer, Lieke
    et al.
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Dayan, Peter
    Backman, Lars
    Guitart-Masip, Marc
    Attenuation of dopamine-modulated prefrontal value signals underlies probabilistic reward learning deficits in old age2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e2642Article in journal (Refereed)
    Abstract [en]

    Probabilistic reward learning is characterised by individual differences that become acute in aging. This may be due to age-related dopamine (DA) decline affecting neural processing in striatum, prefrontal cortex, or both. We examined this by administering a probabilistic reward learning task to younger and older adults, and combining computational modelling of behaviour, fMRI and PET measurements of DA D1 availability. We found that anticipatory value signals in ventromedial prefrontal cortex (vmPFC) were attenuated in older adults. The strength of this signal predicted performance beyond age and was modulated by D1 availability in nucleus accumbens. These results uncover that a value-anticipation mechanism in vmPFC declines in aging, and that this mechanism is associated with DA D1 receptor availability.

  • 134.
    de Flon, Pierre
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Neurology, Östersund Hospital, Östersund, Sweden.
    Laurell, Katarina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Söderström, Lars
    Gunnarsson, Martin
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Improved treatment satisfaction after switching therapy to rituximab in relapsing-remitting MS2017In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 23, no 9, p. 1249-1257Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: New disease-modifying treatment strategies in multiple sclerosis offer possibilities for individualised treatment. In this study, we evaluated patient-reported outcome measures before and after a switch in therapy from first-line injectable treatments to rituximab.

    METHOD: A total of 75 patients with clinically stable relapsing-remitting multiple sclerosis (RRMS) receiving ongoing first-line injectable treatment at three Swedish centres had their treatment switched to rituximab in this open-label phase II multicentre study. Assessment of treatment satisfaction, patient-perceived impact of the disease on daily life, fatigue, cognitive symptoms and disease progression was performed 3 months before and at the time of the treatment shift and then for a subsequent 2-year period.

    RESULTS: The overall treatment satisfaction rating improved significantly from a mean of 4.8 (scale range: 1-7), while on injectable therapies, to a mean of 6.3 after 1 year of rituximab treatment ( p < 0.001). This improvement was sustained after 2 years. There was no significant change in scores for patient-perceived impact of disease, fatigue or disease progression.

    CONCLUSION: A shift in therapy from first-line injectables to rituximab in a cohort of clinically stable RRMS patients was followed by improved treatment satisfaction. This is clinically relevant as it may influence long-term adherence to immunomodulating therapy.

  • 135.
    de Flon, Pierre
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Soderstrom, L.
    Laurell, Katarina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gunnarsson, M.
    Svenningsson, A.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Clinical Sciences, Karolinska Institute, Stockholm, Sweden.
    Changes of cerebrospinal fluid cytokine profile as a result of switching from first line MS-therapies to rituximab2016In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 22, p. 622-622Article in journal (Refereed)
  • 136. de Frias, Cindy M
    et al.
    Annerbrink, Kristina
    Westberg, Lars
    Eriksson, Elias
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nilsson, Lars-Göran
    Catechol O-methyltransferase Val(158)Met polymorphism is associated with cognitive performance in nondemented adults2005In: Journal of cognitive neuroscience, ISSN 0898-929X, E-ISSN 1530-8898, Vol. 17, no 7, p. 1018-1025Article in journal (Refereed)
    Abstract [en]

    The catechol O-methyltransferase ( COMT) gene is essential in the metabolic degradation of dopamine in the prefrontal cortex. In the present study, we examined the effect of a Val 158 Met polymorphism in the COMT gene on individual differences and changes in cognition ( executive functions and visuospatial ability) in adulthood and old age. The participants were 292 nondemented men ( initially aged 35-85 years) from a random sample of the population (i.e., the Betula study) tested at two occasions with a 5-year interval. Confirmatory factor analyses were used to test the underlying structure of three indicators of executive functions ( verbal fluency, working memory, and Tower of Hanoi). Associations between COMT, age, executive functioning, and visuospatial ( block design) tasks were examined using repeated-measures analyses of variance. Carriers of the Val allele ( with higher enzyme activity) compared with carriers of the Met/Met genotype ( with low enzyme activity) performed worse on executive functioning and visuospatial tasks. Individuals with the Val/Val genotype declined in executive functioning over the 5-year period, whereas carriers of the Met allele remained stable in performance. An Age x COMT interaction for visuospatial ability located the effect for middle-aged men only. This COMT polymorphism is a plausible candidate gene for executive functioning and fluid intelligence in nondemented middle-aged and older adults.

  • 137.
    di Summa, Pietro G
    et al.
    University Hospital of Lausanne, University of Manchester.
    Kalbermatten, Daniel F
    University Hospital of Lausanne, University Hospital of Basel.
    Pralong, E
    University Hospital of Lausanne.
    Raffoul, W
    University Hospital of Lausanne.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Terenghi, Giorgio
    University of Manchester.
    Long-term in vivo regeneration of peripheral nerves through bioengineered nerve grafts2011In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 181, no 5, p. 278-291Article in journal (Refereed)
    Abstract [en]

    Although autologous nerve graft is still the first choice strategy in nerve reconstruction, it has the severe disadvantage of the sacrifice of a functional nerve. Cell transplantation in a bioartificial conduit is an alternative strategy to improve nerve regeneration. Nerve fibrin conduits were seeded with various cell types: primary Schwann cells (SC), SC-like differentiated bone marrow-derived mesenchymal stem cells (dMSC), SC-like differentiated adipose-derived stem cells (dASC). Two further control groups were fibrin conduits without cells and autografts. Conduits were used to bridge a 1 cm rat sciatic nerve gap in a long term experiment (16 weeks). Functional and morphological properties of regenerated nerves were investigated. A reduction in muscle atrophy was observed in the autograft and in all cell-seeded groups, when compared with the empty fibrin conduits. SC showed significant improvement in axon myelination and average fiber diameter of the regenerated nerves. dASC were the most effective cell population in terms of improvement of axonal and fiber diameter, evoked potentials at the level of the gastrocnemius muscle and regeneration of motoneurons, similar to the autografts. Given these results and other advantages of adipose derived stem cells such as ease of harvest and relative abundance, dASC could be a clinically translatable route towards new methods to enhance peripheral nerve repair.

  • 138.
    di Summa, Pietro G.
    et al.
    Department of Plastic, Reconstructive Surgery, University Hospital of Lausanne (CHUV), Rue du Bugnon 46, 1011 Lausanne, Switzerland. Electronic address: Pietro.Di-Summa@chuv.ch..
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Campisi, Corrado C.
    Department of Plastic, Reconstructive Surgery, University Hospital of Genova, Ospedale S. Martino, Largo Rossana Benzi 10, 16132 Genova, Italy.
    Raffoul, Wassim
    Department of Plastic, Reconstructive Surgery, University Hospital of Lausanne (CHUV), Rue du Bugnon 46, 1011 Lausanne, Switzerland.
    Kalbermatten, Daniel F.
    Department of Plastic, Reconstructive Surgery, University Hospital of Basel, Spitalstrasse 21, CH-4031 Basel, Switzerland.
    Collagen (NeuraGen(®)) nerve conduits and stem cells for peripheral nerve gap repair2014In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 572, p. 26-31Article in journal (Refereed)
    Abstract [en]

    Collagen nerve guides are used clinically for peripheral nerve defects, but their use is generally limited to lesions up to 3cm. In this study we combined collagen conduits with cells as an alternative strategy to support nerve regeneration over longer gaps. In vitro cell adherence to collagen conduits (NeuraGen(®) nerve guides) was assessed by scanning electron microscopy. For in vivo experiments, conduits were seeded with either Schwann cells (SC), SC-like differentiated bone marrow-derived mesenchymal stem cells (dMSC), SC-like differentiated adipose-derived stem cells (dASC) or left empty (control group), conduits were used to bridge a 1cm gap in the rat sciatic nerve and after 2-weeks immunohistochemical analysis was performed to assess axonal regeneration and SC infiltration. The regenerative cells showed good adherence to the collagen walls. Primary SC showed significant improvement in distal stump sprouting. No significant differences in proximal regeneration distances were noticed among experimental groups. dMSC and dASC-loaded conduits showed a diffuse sprouting pattern, while SC-loaded showed an enhanced cone pattern and a typical sprouting along the conduits walls, suggesting an increased affinity for the collagen type I fibrillar structure. NeuraGen(®) guides showed high affinity of regenerative cells and could be used as efficient vehicle for cell delivery. However, surface modifications (e.g. with extracellular matrix molecule peptides) of NeuraGen(®) guides could be used in future tissue-engineering applications to better exploit the cell potential.

  • 139.
    Dimitriou, Michael
    Umeå University, Faculty of Medicine, Integrative Medical Biology.
    Discharges in human muscle afferents during manual tasks2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Muscle spindles are complex sensory organs that have been strongly implicated in the control and perception of movements. Human muscle spindles in relaxed muscles behave as stretch receptors, responding to the length and velocity of their parent muscles. However, it has been unclear how they discharge during active movements since their discharges are also affected by fusimotor activity and extrafusal contractions. The vast majority of neurophysiological recordings of muscle afferents have been obtained under passive conditions, or active but behaviourally restricted conditions. These restrictions prevent predictions of human muscle afferent activity during purposeful multi-joint movements, naturally occurring during tasks such as hand shaping, grasping or key-pressing.

    An experimental protocol was therefore developed which allowed recordings of muscle receptor afferent activity using microneurography during unrestrained wrist and digit movements. Along with single afferent discharges, recordings were obtained of electromyographic activity of major forearm muscles and the kinematics of the wrist and digits. This approach allowed investigations of the factors shaping afferent discharge during everyday manual tasks, i.e., block-grasping and pressing sequences of keys, and during active sinusoidal joint movements. The afferents’ ability to encode information concerning the state of the muscle and joint kinematics during these tasks was also assessed.

    The responses of spindle afferents from load-bearing muscles were approximatelly 90 degrees more phase-advanced than expected on the length of their parent muscles. That is, the discharges of primary muscle spindle afferents were significantly affected by both velocity and acceleration, the discharges of secondary afferents by velocity, and neither afferent type was particularly affected by static muscle length. Accordingly, these afferents failed to encode length, encoded velocity well and acceleration poorly. The representation of muscle length and velocity was, however, significantly improved when the discharge activity of Golgi tendon afferents was taken into consideration along with muscle spindle activity. The discharge of primary afferents during both key-pressing and block-grasping was best correlated to the muscle velocities observed ~100-160 ms in the future. This predictive ability went beyond what could be expected from the spindles’ simultaneous sensitivity to velocity and acceleration, and could thus only be explained by implicating the fusimotor drive. In addition, evidence is presented that the fusimotor control of spindles was contingent on entire movement sequences during the key-pressing task.

    It is proposed that the phase relationship between the discharge rate of spindle afferents and the length of their parent muscles is load dependent. Moreover, muscle spindles seem to act as forward sensory models of their parent muscle, which makes sensorial feedback control possible despite neural delays.

  • 140.
    Dimitriou, Michael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Enhanced Muscle Afferent Signals during Motor Learning in Humans2016In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 26, no 8, p. 1062-1068Article in journal (Refereed)
    Abstract [en]

    Much has been revealed concerning human motor learning at the behavioral level [1, 2], but less is known about changes in the involved neural circuits and signals. By examining muscle spindle responses during a classic visuomotor adaptation task [3-6] performed by fully alert humans, I found substantial modulation of sensory afferent signals as a function of adaptation state. Specifically, spindle control was independent of concurrent muscle activity but was specific to movement direction (representing muscle lengthening versus shortening) and to different stages of learning. Increased spindle afferent responses to muscle stretch occurring early during learning reflected individual error size and were negatively related to subsequent antagonist activity (i.e., 60-80 ms thereafter). Relative increases in tonic afferent output early during learning were predictive of the subjects' adaptation rate. I also found that independent spindle control during sensory realignment (the "washout" stage) induced afferent signal "linearization" with respect to muscle length (i.e., signals were more tuned to hand position). The results demonstrate for the first time that motor learning also involves independent and state-related modulation of sensory mechanoreceptor signals. The current findings suggest that adaptive motor performance also relies on the independent control of sensors, not just of muscles. I propose that the "gamma" motor system innervating spindles acts to facilitate the acquisition and extraction of task-relevant information at the early stages of sensorimotor adaptation. This designates a more active and targeted role for the human proprioceptive system during motor learning.

  • 141.
    Dimitriou, Michael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Task-Dependent Modulation of Spinal and Transcortical Stretch Reflexes Linked to Motor Learning Rate2018In: Behavioral Neuroscience, ISSN 0735-7044, E-ISSN 1939-0084, Vol. 132, no 3, p. 194-209Article in journal (Refereed)
    Abstract [en]

    It is generally believed that task-dependent control of body configuration ("posture") is achieved by adjusting voluntary motor activity and transcortical "long-latency" reflexes. Spinal monosynaptic circuits are thought not to be engaged in such task-level control. Similarly, being in a state of motor learning has been strongly associated only with an upregulation of feedback responses at transcortical latencies and beyond. In two separate experiments, the current study examined the task-dependent modulation of stretch reflexes by perturbing the hand of human subjects while they were waiting for a "Go" signal to move at the different stages of a classic kinematic learning task (visuomotor rotation). Although the subjects had to resist all haptic perturbations equally across task stages, the study leveraged that task-dependent feedback controllers may already be "loaded" at the movement anticipation stage. In addition to an upregulation of reflex gains during early exposure to the visual distortion, I found a relative inhibition of reflex responses in the "washout" stage (sensory realignment state). For more distal muscles (brachioradialis) this inhibition also extended to the monosynaptic reflex response ("R1"). Moreover, these R1 gains reflected individual motor learning performance in the visuomotor task. The results demonstrate that the system's "control policy" in visuomotor adaptation can also include inhibition of proprioceptive reflexes, and that aspects of this policy can affect monosynaptic spinal circuits. The latter finding suggests a novel form of state-related control, probably realized by independent control of fusimotor neurons, through which segmental circuits can tune to higher-level features of a sensorimotor task.

  • 142.
    Domellof, Magdalena Eriksson
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Elgh, Eva
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    The relation between cognition and motor dysfunction in drug-naive newly diagnosed patients with parkinson's disease2011In: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 26, no 12, p. 2183-2189Article in journal (Refereed)
    Abstract [en]

    Recent studies have reported cognitive decline to be common in the early phase of Parkinson's disease. Imaging data connect working memory and executive functioning to the dopamine system. It has also been suggested that bradykinesia is the clinical manifestation most closely related to the nigrostriatal lesion. Exploring the relationship between motor dysfunction and cognition can help us find shared or overlapping systems serving different functions. This relationship has been sparsely investigated in population-based studies of untreated Parkinson's disease. The aim of the present study was to investigate the association between motor signs and cognitive performance in the early stages of Parkinson's disease before the intake of dopaminergic medication. Patients were identified in a population-based study of incident cases with idiopathic parkinsonism. Patients with the postural instability and gait disturbances phenotype were compared with patients with the tremor-dominant phenotype on demographics and cognitive measures. Associations between cognitive and motor scores were investigated, with age, education, and sex controlled for. Bradykinesia was associated with working memory and mental flexibility, whereas axial signs were associated with episodic memory and visuospatial functioning. No significant differences in the neuropsychological variables were found between the postural instability and gait disturbances phenotype and the tremor phenotype. Our results indicate a shared system for slow movement and inflexible thinking that may be controlled by a dopaminergic network different from dopaminergic networks involved in tremor and/or rigidity. The association between axial signs and memory and visuospatial function may point to overlapping systems or pathologies related to these abilities.

    (C) 2011 Movement Disorder Society

  • 143.
    Domellöf, Erik
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Johansson, Anna-Maria
    Umeå University, Faculty of Social Sciences, Department of Psychology. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Rönnqvist, Louise
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Developmental progression and side specialization in upper-limb movements from 4 to 8 years in children born preterm and fullterm2018In: Developmental Neuropsychology, ISSN 8756-5641, E-ISSN 1532-6942, Vol. 43, no 3, p. 219-234Article in journal (Refereed)
    Abstract [en]

    This study investigated developmental changes and differences in upper-limb movement organization from 4 to 8 years of age in children born preterm (PT) and fullterm (FT). Kinematic recordings of precision-demanding unimanual movements and lateral assessments were carried out in 37 children (18 PT). All children, particularly children born PT, displayed considerable gain in movement kinematics. Contrary to controls, children born PT displayed persistently less-evident side preference. Gestational age (GA) contributed significantly to kinematic differences shown, with larger upper-limb deviances in the lowest GAs, in agreement with cross-sectional findings of altered hemispheric connections and delayed side-specialization among children born very PT.

  • 144.
    Dominguez, Cecilia A
    et al.
    Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Kalliomäki, Maija
    Department of Surgical Sciences, Anaesthesiology/Pain research, Uppsala University, Uppsala, Sweden; Department of Anaesthesiology, University of Tammerfors, Tampere, Finland.
    Gunnarsson, Ulf
    Department of Clinical Science, Intervention and Technology (Surgery), Karolinska Institutet, Huddinge, Sweden.
    Moen, Aurora
    National Institute of Occupational Health, Oslo, Norway; Department of Molecular Biosciences, University of Oslo, Norway.
    Sandblom, Gabriel
    Department of Clinical Science, Intervention and Technology (Surgery), Karolinska Institutet, Huddinge, Sweden.
    Kockum, Ingrid
    Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Lavant, Ewa
    Department of Biomedical Laboratory Science, Faculty of Health and Society, Malmö University/Labmedicine Skåne, Clinical Chemistry, Malmö, Sweden.
    Olsson, Tomas
    Nyberg, Fred
    Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
    Rygh, Lars Jørgen
    Department of Anesthesiology and Intensive Care, Haukeland University Hospital, Bergen, Norway.
    Røe, Cecilie
    Department of Physical Medicine and Rehabilitation, Oslo University Hospital, Ullevaal, Norway.
    Gjerstad, Johannes
    National Institute of Occupational Health, Oslo, Norway; Department of Molecular Biosciences, University of Oslo, Norway.
    Gordh, Torsten
    Department of Surgical Sciences, Anaesthesiology/Pain research, Uppsala University, Uppsala, Sweden.
    Piehl, Fredrik
    Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    The DQB1*03:02 HLA haplotype is associated with increased risk of chronic pain after inguinal hernia surgery and lumbar disc herniation2013In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 154, no 3, p. 427-433Article in journal (Refereed)
    Abstract [en]

    Neuropathic pain conditions are common after nerve injuries and are suggested to be regulated in part by genetic factors. We have previously demonstrated a strong genetic influence of the rat major histocompatibility complex on development of neuropathic pain behavior after peripheral nerve injury. In order to study if the corresponding human leukocyte antigen complex (HLA) also influences susceptibility to pain, we performed an association study in patients that had undergone surgery for inguinal hernia (n=189). One group had developed a chronic pain state following the surgical procedure, while the control group had undergone the same type of operation, without any persistent pain. HLA DRB1genotyping revealed a significantly increased proportion of patients in the pain group carrying DRB1*04 compared to patients in the pain-free group. Additional typing of the DQB1 gene further strengthened the association; carriers of the DQB1*03:02 allele together with DRB1*04 displayed an increased risk of postsurgery pain with an odds risk of 3.16 (1.61-6.22) compared to noncarriers. This finding was subsequently replicated in the clinical material of patients with lumbar disc herniation (n=258), where carriers of the DQB1*03:02 allele displayed a slower recovery and increased pain. In conclusion, we here for the first time demonstrate that there is an HLA-dependent risk of developing pain after surgery or lumbar disc herniation; mediated by the DRB1*04 - DQB1*03:02 haplotype. Further experimental and clinical studies are needed to fine-map the HLA effect and to address underlying mechanisms.

  • 145. Dong, Bo
    et al.
    Holm, Linus
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Bao, Min
    Cortical mechanisms for afterimage formation: evidence from interocular grouping2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 41101Article in journal (Refereed)
    Abstract [en]

    Whether the retinal process alone or retinal and cortical processes jointly determine afterimage (AI) formation has long been debated. Based on the retinal rebound responses, recent work proposes that afterimage signals are exclusively generated in the retina, although later modified by cortical mechanisms. We tested this notion with the method of "indirect proof". Each eye was presented with a 2-by-2 checkerboard of horizontal and vertical grating patches. Each corresponding patch of the two checkerboards was perpendicular to each other, which produces binocular rivalry, and can generate percepts ranging from complete interocular grouping to either monocular pattern. The monocular percepts became more frequent with higher contrast. Due to adaptation, the visual system is less sensitive during the AIs than during the inductions with AI-similar contrast. If the retina is the only origin of AIs, comparable contrast appearance would require stronger retinal signals in the AIs than in the inductions, thus leading to more frequent monocular percepts in the AIs than in the inductions. Surprisingly, subjects saw the fully coherent stripes significantly more often in AIs. Our results thus contradict the retinal generation notion, and suggest that in addition to the retina, cortex is directly involved in the generation of AI signals.

  • 146.
    Dornheim, Marie
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Kaltsouni, Elisavet
    Umeå University, Faculty of Social Sciences, Department of Psychology. Umeå center for Functional Brain Imaging.
    Neural correlates of selective attention during working memory in presence of distraction2019Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Briefly maintaining information in working memory (WM) requires focusing on goal-specific information and filtering out irrelevant information. Selective attention has been indicated as critical in successful WM encoding and maintenance of the short-term information. Spatial selective attention mediates WM processing of goal-relevant information and concurrently inhibiting distractors. This is a result of reverberating top-down signals of a distributed frontoparietal network interacting with sensory areas. The current fMRI study used a delayed-match-to-sample task to explore the differential contribution of the network during WM information encoding and maintenance phases, by presenting relevant and distracting stimuli simultaneously. The aim of the study was to test for increased activity in frontoparietal network in the distractor presence compared to the target only condition during the encoding and maintenance phases. Moreover, by examining contralateral to target activation in both conditions, we investigated how the short-term representations would affect allocation of attention. Behavioral results showed a small but significant distractor interference. However, no evidence for top-down modulation in the distractor contexts was obtained from the univariate fMRI analyses, neither for the encoding nor the maintenance phase. Whole-brain and ROI analyses for contralateral activity to target location, revealed no links to the top-down network and attentional allocation. This study provided no definitive evidence on selective attention modulation during WM processing, which indicates the need for greater WM load manipulation in future designs.

  • 147.
    Dunås, Tora
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Zarrinkoob, Laleh
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Ambarki, Khalid
    Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    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. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Towards Automatic Identification of Cerebral Arteries in 4D Flow MRI2015In: 16th Nordic-Baltic Conference on Biomedical Engineering / [ed] Henrik Mindedal, Mikael Persson, 2015, Vol. 48, p. 40-43Conference paper (Refereed)
    Abstract [en]

    4D flow MRI is a powerful imaging technique which provides an angiographic image with information about blood flow in a large volume, time resolved over the cardiac cycle, in a short imaging time. This study aims to develop an automatic method for identification of cerebral arteries. The proposed method is based on an atlas of twelve arteries, developed from 4D flow MRI of 25 subjects. The atlas was constructed by normalizing all images to MNI-space, manually identifying the arteries and creating an average over the volume. The identification is done by extracting a vascular skeleton from the image, transforming it to MNI-space, labeling it with the atlas and transforming it back to subject space. The method was evaluated on a pilot cohort of 8 subjects. The rate of correctly identified arteries was 97%.

  • 148. Dutton, Edward
    et al.
    Madison, Guy
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Even "Bigger Gods" developed amongst the pastoralist followers of Moses and Mohammed: consistent with uncertainty and disadvantage, but not prosocality2016In: Behavioral and Brain Sciences, ISSN 0140-525X, E-ISSN 1469-1825, Vol. 39, p. 27-28, article id e11Article in journal (Refereed)
    Abstract [en]

    The gods of monotheistic religions, which began amongst pastoralists and defeated exiles, are closer to Big Gods than those associated with ancient city-based polities. The development of Big Gods is contingent upon a need to reduce uncertainty and negative feelings in combination with a relatively high level of prosociality, rather than a need to induce or assess prosociality.

  • 149.
    East, Emma
    et al.
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
    Johns, Noémie
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
    Georgiou, Melanie
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
    Golding, Jon P.
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
    Loughlin, A. Jane
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Phillips, James B.
    Department of Life Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK, Department of Biomaterials & Tissue Engineering, UCL Eastman Dental Institute, 256 Gray’s Inn Road, London WC1X 8LD, UK.
    A 3D in vitro model reveals differences in the astrocyte response elicited by potential stem cell therapies for CNS injury2013In: Regenerative Medicine, ISSN 1746-0751, E-ISSN 1746-076X, Vol. 8, no 6, p. 739-746Article in journal (Refereed)
    Abstract [en]

    AIM: This study aimed to develop a 3D culture model to test the extent to which transplanted stem cells modulate astrocyte reactivity, where exacerbated glial cell activation could be detrimental to CNS repair success.

    MATERIALS & METHODS: The reactivity of rat astrocytes to bone marrow mesenchymal stem cells, neural crest stem cells (NCSCs) and differentiated adipose-derived stem cells was assessed after 5 days. Schwann cells were used as a positive control.

    RESULTS: NCSCs and differentiated Schwann cell-like adipose-derived stem cells did not increase astrocyte reactivity. Highly reactive responses to bone marrow mesenchymal stem cells and Schwann cells were equivalent.

    CONCLUSION: This approach can screen therapeutic cells prior to in vivo testing, allowing cells likely to trigger a substantial astrocyte response to be identified at an early stage. NCSCs and differentiated Schwann cell-like adipose-derived stem cells may be useful in treating CNS damage without increasing astrogliosis.

  • 150. Ebner, Natalie C
    et al.
    Johnson, Matthew R
    Rieckmann, Anna
    Durbin, Kelly A
    Johnson, Marcia K
    Fischer, Håkan
    Processing own-age vs. other-age faces: neuro-behavioral correlates and effects of emotion.2013In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 78, p. 363-71Article in journal (Refereed)
    Abstract [en]

    Age constitutes a salient feature of a face and signals group membership. There is evidence of greater attention to and better memory for own-age than other-age faces. However, little is known about the neural and behavioral mechanisms underlying processing differences for own-age vs. other-age faces. Even less is known about the impact of emotion expressed in faces on such own-age effects. Using fMRI, the present study examined brain activity while young and older adult participants identified expressions of neutral, happy, and angry young and older faces. Across facial expressions, medial prefrontal cortex, insula, and (for older participants) amygdala showed greater activity to own-age than other-age faces. These own-age effects in ventral medial prefrontal cortex and insula held for neutral and happy faces, but not for angry faces. This novel and intriguing finding suggests that processing of negative facial emotions under some conditions overrides age-of-face effects.

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