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  • 151. Edsbagge, Mikael
    et al.
    Andreasson, Ulf
    Ambarki, Khalid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Wikkelsø, Carsten
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Blennow, Kaj
    Zetterberg, Henrik
    Tullberg, Mats
    Alzheimer's Disease-Associated Cerebrospinal Fluid (CSF) Biomarkers do not Correlate with CSF Volumes or CSF Production Rate2017In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 58, no 3, p. 821-828Article in journal (Refereed)
    Abstract [en]

    Background: Neuropathologically, Alzheimer's disease (AD) is characterized by accumulation of a 42 amino acid peptide called amyloid-beta (A beta(42)) in extracellular senile plaques together with intraneuronal inclusions of hyperphosphorylated tau protein in neurofibrillary tangles and neuronal degeneration. These changes are reflected in the cerebrospinal fluid (CSF), the volumes and production rates of which vary considerably between individuals, by reduced concentration of A beta(42), increased concentration of phosphorylated tau (P-tau) protein, and increased concentration of total tau (T-tau) protein, respectively. Objective: To examine the outstanding question if CSF concentrations of AD associated biomarkers are influenced by variations in CSF volumes, CSF production rate, and intracranial pressure in healthy individuals. Methods: CSF concentrations of A beta(42), P-tau, and T-tau, as well as a number of other AD-related CSF biomarkers were analyzed together with intracranial subarachnoid, ventricular, and spinal CSF volumes, as assessed by magnetic resonance imaging volumetric measurements, and CSF production rate in 19 cognitively normal healthy subjects (mean age 70.6, SD 3.6 years). Results: Negative correlations were seen between the concentrations of three CSF biomarkers (albumin ratio, A beta(38), and A beta(40)), and ventricular CSF volume, but apart from this finding, no significant correlations were observed. Conclusion: These results speak against inter-individual variations in CSF volume and production rate as important confounds in the AD biomarker research field.

  • 152.
    Edvardsson, David
    et al.
    Umeå University, Faculty of Medicine, Department of Nursing. Australian Centre for Evidence-Based Aged Care (ACEBAC), La Trobe University, Australia.
    Winblad, Bengt
    Sandman, Per-Olof
    Umeå University, Faculty of Medicine, Department of Nursing.
    Person-centred care of people with severe Alzheimer's disease: current status and ways forward2008In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 7, no 4, p. 362-367Article in journal (Refereed)
    Abstract [en]

    When caring for people with severe Alzheimer's disease (AD), the concept of the person being central is increasingly advocated in clinical practice and academia as an approach to deliver high-quality care. The aim of person-centred care, which emanates from phenomological perspectives on AD, is to acknowledge the personhood of people with AD in all aspects of their care. It generally includes the recognition that the personality of the person with AD is increasingly concealed rather than lost; personalisation of the person's care and their environment; offering shared decision-making; interpretation of behaviour from the viewpoint of the person; and prioritising the relationship as much as the care tasks. However, questions remain about how to provide, measure, and explore clinical outcomes of person-centred care. In this Review, we summarise the current knowledge about person-centred care for people with severe AD and highlight the areas in need of further research.

  • 153. Ekblad, Laura L.
    et al.
    Johansson, Jarkko
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Turku PET Centre, University of Turku, Finland.
    Helin, Semi
    Viitanen, Matti
    Laine, Hanna
    Puukka, Pauli
    Jula, Antti
    Rinne, Juha O.
    Midlife insulin resistance, APOE genotype, and late-life brain amyloid accumulation2018In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 90, no 13, p. e1150-e1157Article in journal (Refereed)
    Abstract [en]

    Objective To examine whether midlife insulin resistance is an independent risk factor for brain amyloid accumulation in vivo after 15 years, and whether this risk is modulated by APOE epsilon 4 genotype. Methods This observational study examined 60 elderly volunteers without dementia (mean age at baseline 55.4 and at follow-up 70.9 years, 55.5% women) from the Finnish population-based, nationwide Health2000 study with [C-11]Pittsburgh compound B-PET imaging in 2014-2016. The participants were recruited according to their homeostatic model assessment of insulin resistance (HOMA-IR) values in the year 2000, and their APOE epsilon 4 genotype. The exposure group (IR+, n = 30) consisted of individuals with HOMA-IR > 2.17 at baseline (highest tertile of the Health2000 study population), and the control group (IR-, n = 30) consisted of individuals with HOMA-IR < 1.25 at baseline (lowest tertile). The groups were enriched for APOE epsilon 4 carriers, resulting in 50% (n = 15) APOE epsilon 4 carriers in both groups. Analyses were performed with multivariate logistic and linear regression. Results An amyloid-positive PET scan was found in 33.3% of the IR-group and 60.0% of the IR+ group (odds ratio 3.0, 95% confidence interval 1.1-8.9, p = 0.04). The increased risk was seen in carriers and noncarriers of APOE epsilon 4 genotype. Higher midlife, but not late-life continuous HOMA-IR was associated with a greater brain amyloid burden at follow-up after multivariate adjustments for other cognitive and metabolic risk factors (ss = 0.11, 95% confidence interval 0.002-0.22, p = 0.04). Conclusions These results indicate that midlife insulin resistance is an independent risk factor for brain amyloid accumulation in elderly individuals without dementia.

  • 154.
    Ekhtiari Bidhendi, Elaheh
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    SOD1 prions transmit templated aggregation and fatal ALS-like disease2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal neurodegenerative disease characterized by a progressive degeneration of the upper and lower motor neurons. The resulting paresis begins focally, usually in one muscle, and spreads contiguously, leading to muscle wasting, progressive paralysis and eventually death. 90% of all ALS cases are sporadic, with no genetic background (sALS), while 10% are hereditary or familial (fALS). The first identified cause of ALS was mutations in the gene encoding the enzyme superoxide dismutase 1 (SOD1), which are found in 3-6% of the ALS patients. Mutations in SOD1 confer a cytotoxic gain of function on the enzyme. Cytosolic inclusions containing aggregated SOD1 in motor neurons are a hallmark of ALS, both in patients and transgenic (Tg) mice carrying mutant human SOD1s (hSOD1). These inclusions have also been reported in sporadic and familial ALS cases without SOD1 mutations, suggesting a broader role of this protein in the ALS pathology. However, the mechanism of SOD1 misfolding and aggregation, and their contribution to the disease pathogenesis, is unclear.

    Our research group has recently identified two structurally different strains of hSOD1 aggregates (denoted A and B) in the central nervous system of Tg murine models expressing full-length hSOD1 variants.

    The aim of this thesis is to investigate if the SOD1 aggregation is a collateral byproduct in the process of the disease, or if it drives ALS pathogenesis. In addition, this work investigates the spreading characteristic of the disease in vivo.

    Human SOD1 A and B seeds were prepared from spinal cords of terminally ill hSOD1 Tg mice by ultracentrifugation through a density gradient. Minute amounts of the aggregate seeds were micro-inoculated into the lumbar spinal cord of asymptomatic recipient Tg mice, overexpressing G85R mutant hSOD1 (hSOD1G85R). Mice inoculated with A or B aggregates developed early-onset fatal ALS-like disease, becoming terminally ill around 100 days after inoculation. This is nearly 200 days earlier than hSOD1G85R Tg mice inoculated with a control preparation or non-inoculated mice. Concomitantly, exponentially growing templated hSOD1 aggregation developed in the recipient mice, spreading all along the neuraxis. The pathology provoked by the A and B strains differed in aggregation growth rates, disease progression rates, aggregate distribution along the neuraxis, rates of weight loss, end-stage amounts of aggregates, and histopathology.

    Next, we explored the existence of mutant hSOD1 aggregates with prion-like properties in the spinal cord of ALS patients.  To this end, aggregate seeds were prepared from the spinal cord of the autopsy material of an ALS patient carrying the hSOD1G127X truncation mutation, as well as from mice transgenic for the same mutation. The aggregates showed a strain A-like core structure. Inoculation of both the murine and human derived seeds into the lumbar spinal cord of hSOD1 expressing mice efficiently transmitted strain A aggregation, propagating rostrally throughout the neuraxis and causing premature fatal ALS-like disease. The inoculation of human or murine control seeds had no effect. The potency of the ALS patient-derived seed was exceedingly high, and the disease was initiated under conditions plausible to exist also in the human motor system. These results demonstrate for the first time, the presence of hSOD1 aggregates with prion-like properties in human ALS.

    We extended the exploration of hSOD1 prion mechanisms by inoculating another recipient mouse line, with wild-type-like stability and essentially normal SOD activity. Mice that are hemizygous for the hSOD1D90A transgene insertion do not develop ALS pathology and have normal murine lifespans (>700 days). Homozygous mice develop ALS-like disease around 400 days-of-age. Interestingly, inoculations of both strain A and B seeds into the lumbar spinal cord of hemizygous hSOD1D90A mice induced progressive hSOD1 aggregations and premature fatal ALS-like disease after around 250 and 350 days, respectively. In contrast, hemizygous hSOD1D90A mice inoculated with a mouse control seed died from senescence-related causes at ages beyond 700 days.

    Altogether, data in this thesis shows that the hSOD1 aggregate strains are ALS transmitting prions, suggesting that prion-like growth and spread of hSOD1 aggregation is the core pathogenic mechanism of SOD1-induced ALS.

  • 155.
    Ekhtiari Bidhendi, Elaheh
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Bergh, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis-like disease2016In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 126, no 6, p. 2249-2253Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is an adult-onset degeneration of motor neurons that is commonly caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Both patients and Tg mice expressing mutant human SOD1 (hSOD1) develop aggregates of unknown importance. In Tg mice, 2 different strains of hSOD1 aggregates (denoted A and B) can arise; however, the role of these aggregates in disease pathogenesis has not been fully characterized. Here, minute amounts of strain A and B hSOD1 aggregate seeds that were prepared by centrifugation through a density cushion were inoculated into lumbar spinal cords of 100-day-old mice carrying a human SOD1 Tg. Mice seeded with A or B aggregates developed premature signs of ALS and became terminally ill after approximately 100 days, which is 200 days earlier than for mice that had not been inoculated or were given a control preparation. Concomitantly, exponentially growing strain A and B hSOD1 aggregations propagated rostrally throughout the spinal cord and brainstem. The phenotypes provoked by the A and B strains differed regarding progression rates, distribution, end-stage aggregate levels, and histopathology. Together, our data indicate that the aggregate strains are prions that transmit a templated, spreading aggregation of hSOD1, resulting in a fatal ALS-like disease.

  • 156.
    Ekhtiari Bidhendi, Elaheh
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pakkenberg, Bente
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis2018In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 136, no 6, p. 939-953Article in journal (Refereed)
    Abstract [en]

    Motor neurons containing aggregates of superoxide dismutase 1 (SOD1) are hallmarks of amyotrophic lateral sclerosis (ALS) caused by mutations in the gene encoding SOD1. We have previously reported that two strains of mutant human (h) SOD1 aggregates (denoted A and B) can arise in hSOD1-transgenic models for ALS and that inoculation of such aggregates into the lumbar spinal cord of mice results in rostrally spreading, templated hSOD1 aggregation and premature fatal ALS-like disease. Here, we explored whether mutant hSOD1 aggregates with prion-like properties also exist in human ALS. Aggregate seeds were prepared from spinal cords from an ALS patient carrying the hSOD1G127Gfs*7 truncation mutation and from mice transgenic for the same mutation. To separate from mono-, di- or any oligomeric hSOD1 species, the seed preparation protocol included ultracentrifugation through a density cushion. The core structure of hSOD1G127Gfs*7 aggregates present in mice was strain A-like. Inoculation of the patient- or mouse-derived seeds into lumbar spinal cord of adult hSOD1-expressing mice induced strain A aggregation propagating along the neuraxis and premature fatal ALS-like disease (p < 0.0001). Inoculation of human or murine control seeds had no effect. The potencies of the ALS patient-derived seed preparations were high and disease was initiated in the transgenic mice by levels of hSOD1G127Gfs*7 aggregates much lower than those found in the motor system of patients carrying the mutation. The results suggest that prion-like growth and spread of hSOD1 aggregation could be the primary pathogenic mechanism, not only in hSOD1 transgenic rodent models, but also in human ALS.

  • 157.
    Ekhtiari Bidhendi, Elaheh
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Marklund, SL
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Superoxide dismutase prions transmit fatal ALS to transgenic mice which do not spontaneously develop symptomsManuscript (preprint) (Other academic)
  • 158.
    Ekman, Urban
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Functional brain imaging of cognitive status in Parkinson's disease2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Parkinson’s disease (PD) is next to Alzheimer’s disease (AD) the second most common neurodegenerative disease. PD has traditionally been characterised as a motor disorder, but more recent research has revealed that cognitive impairments are frequent. Cognitive impairments in executive functions, attention, and working memory with reliance on dopaminergic transmission, are often described as dominating the cognitive profile in early-phase PD. However, although knowledge about the neuropathology that underlies the cognitive impairments in PD has increased, its features are complex and knowledge remains insufficient. Therefore, the aim of the current thesis was to improve the understanding of how task-evoked brain responses relate to cognitive status in patients with PD, with and without mild cognitive impairment (MCI), and to evaluate the predictive value of PD-MCI in respect of prodromal Parkinson’s disease dementia (PDD). This was conducted within the “new Parkinsonism in Umeå” (NYPUM) project, which is a prospective cohort study. Patients with idiopathic PD were included in this thesis, and the patients were examined with a comprehensive neuropsychological battery and with a functional MRI (fMRI) working memory protocol. During scanning, patients conducted a verbal two-back task in which they needed to maintain and actively update relevant information, and the primary outcome measure was blood-oxygen-level-dependent (BOLD) signal. This thesis shows that patients with PD-MCI had significantly lower BOLD signal responses than patients without MCI in frontal (anterior cingulate cortex) and striatal (right caudate) regions (Study I). The altered BOLD response in the right caudate was associated with altered presynaptic dopamine binding. The fronto-striatal alterations persisted across time but without any additional change. However, decreased posterior cortical (right fusiform gyrus) BOLD signal responses were observed in patients with PD-MCI relative to patients without MCI across time (Study II). Finally, PD-MCI at baseline examination is highly predictive for prodromal PDD with a six-fold increased risk. Cognitive tests with a posterior cortical basis, to a greater extent, are predictive for prodromal PDD than tests with a fronto-striatal basis. The observed working memory related alterations in patients with PD-MCI suggest that early cognitive impairments in PD are linked to fronto-striatal dopaminergic dysfunction. The longitudinal development of cognitive impairment in PD reflects additional posterior cortical dysfunction. This might reflect a dual syndrome, with dopamine-depleted fronto-striatal alterations that characterise PD-MCI in general, whereas additional posterior cortical cognitive alterations with a non-dopaminergic basis to a greater extent characterise prodromal PDD. If, and how, the two potential syndromes interact, is still unclear. Thus, this thesis provides information on cognitive neuropathological changes in PD that might contribute to more relevant choices of pharmacotherapy and diagnostic accuracy in respect of PDD. However, additional large-scale longitudinal imaging studies are needed to further clarify the neuropatholgogical features of PD-MCI in respect of prodromal PDD.

  • 159.
    Ekman, Urban
    et al.
    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), Physiology. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Domellöf, Magdalena
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Elgh, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Lundquist, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Longitudinal changes in task-evoked brain responses in Parkinson's disease patients with and without mild cognitive impairment2014In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 8, article id 207Article in journal (Refereed)
    Abstract [en]

    Cognitive deficits are common in Parkinson's disease. Previous cross-sectional research has demonstrated a link between cognitive impairments and fronto-striatal dopaminergic dysmodulation. However, longitudinal studies that link disease progression with altered task-evoked brain activity are lacking. Therefore, our objective was to longitudinally evaluate working-memory related brain activity changes in Parkinson's disease patients with and without mild cognitive impairment (MCI). Patients were recruited within a longitudinal cohort study of incident patients with idiopathic parkinsonism. We longitudinally (at baseline examination and at 12-months follow-up) compared 28 patients with Parkinson's disease without MCI with 11 patients with Parkinson's disease and MCI. Functional MRI blood oxygen level dependent signal was measured during a verbal two-back working-memory task. Patients with MCI under-recruited bilateral medial prefrontal cortex at both time-points (main effect of group: p < 0.001, uncorrected). Critically, a significant group-by-time interaction effect (p < 0.001, uncorrected) was found in the right fusiform gyrus, indicating that working-memory related activity decreased for patients with Parkinson's disease and MCI between baseline and follow-up, while patients without MCI were stable across time-points. The functional connectivity between right fusiform gyrus and bilateral caudate nucleus was stronger for patients without MCI relative to patients with MCI. Our findings support the view that deficits in working-memory updating are related to persistent fronto-striatal under-recruitments in patients with early phase Parkinson's disease and MCI. The longitudinal evolution of MCI in Parkinson's disease translates into additional task-evoked posterior cortical changes.

  • 160.
    Ekman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. 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 Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Jakobson Mo, Susanna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    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).
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Functional brain activity and presynaptic dopamine uptake in patients with Parkinson's disease and mild cognitive impairment: a cross-sectional study2012In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 11, no 8, p. 679-687Article in journal (Refereed)
    Abstract [en]

    Background: Many patients with Parkinson's disease have mild cognitive impairment (MCI). Deficits in executive functions and working memory suggest dysfunctional frontostriatal brain circuitry. We aimed to assess brain responses during a working memory task in a cohort of newly diagnosed drug-naive patients with Parkinson's disease with and without MCI.

    Methods: Participants were recruited within a prospective cohort study of incident patients with idiopathic parkinsonism, including Parkinson's disease. Between Jan 1, 2004, and April 30, 2009, all physicians in the Umea catchment area were requested to refer all individuals with suspected parkinsonism to the Department of Neurology at lima University. Included patients fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria for Parkinson's disease. Control individuals were matched on the basis of age and sex with the first 50 patients included in the study. Participants who scored 1.5 SDs or more below the population mean on at least two cognitive measures were diagnosed with MCI. The primary outcome measures were functional MRI blood-oxygen-level-dependent signal and SPECT presynaptic uptake. Functional MRI was done during a verbal two-back working memory task. Presynaptic dopamine SPECT was done to assess presynaptic striatal dopaminergic system integrity. Event-related transient analyses of functional MRI data were done for the whole brain and for frontostriatal regions of interest, and semi-quantitative SPECT analyses were done for striatal regions of interest.

    Findings: Compared with controls (n=24), patients with Parkinson's disease (n=77) had under-recruitment in an extensive brain network including bilateral striatal and frontal regions (p<0.001). Within the Parkinson's disease group, patients with Parkinson's disease and MCI (n=30) had additional under-recruitment in the right dorsal caudate nucleus (p=0.005) and the bilateral anterior cingulate cortex (p<0.001) compared with patients with Parkinson's disease without MCI (n=26). In patients with Parkinson's disease and MCI, SPECT uptake in the right caudate was lower than in patients with Parkinson's disease without MCI (p=0.008) and correlated with striatal functional MRI blood-oxygen-level-dependent signal (r=0.32, p=0.031).

    Interpretation: These altered brain responses in patients with Parkinson's disease and MCI suggest that cognitive impairment is linked to frontostriatal dysfunction.

  • 161. Ekström, Ingrid
    et al.
    Josefsson, Maria
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Larsson, Maria
    Rönnlund, Michael
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Nordin, Steven
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Olofsson, Jonas K.
    Subjective olfactory loss in older adults concurs with long-term odor identification decline2019In: Chemical Senses, ISSN 0379-864X, E-ISSN 1464-3553, Vol. 44, no 2, p. 105-112Article in journal (Refereed)
    Abstract [en]

    Olfactory impairments may provide early indications of future health outcomes in older adults. Thus, an important question concerns whether these impairments can be self-assessed. Previous findings of cross-sectional studies indicate low correlations between self-reported olfactory function and objective olfactory performance. On the other hand, subjective olfactory impairments predict future dementia and mortality in longitudinal settings. No previous study has assessed the relationship between subjectively and objectively measured decline in olfaction over time. Based on data for 903 older adults derived from the Betula Study, a Swedish population-based prospective study, we tested whether rate-of-change in odor identification could be predicted from subjective olfactory decline over a time span of 10 years during which subjective and objective odor functions were assessed on 2 or 3 test occasions. Indeed, we found that participants who experienced subjective olfactory decline over the study period also had significantly steeper rates of decline in odor identification, even after adjusting for demographic, cognitive, and genetic factors that previously have been associated with performance in odor identification. This association was, however, not present in a subsample with baseline cognitive impairment. We interpret these results as evidence that when asked about whether they have an olfactory impairment or not, older persons are assessing intraindividual olfactory changes, rather than interindividual differences. Our results indicate that subjective olfactory loss reflects objective olfactory decline in cognitively intact older adults. This association might be harnessed to predict health outcomes and highlights the need to develop effective olfactory self-assessments.

  • 162.
    Elgh, Eva
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Nyberg, Lars
    Umeå University, Faculty of Social Sciences, Department of Psychology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Altered prefrontal brain activity in persons at risk for Alzheimer's disease: an f-MRI study2003In: International psychogeriatrics, ISSN 1041-6102, E-ISSN 1741-203X, Vol. 15, no 2, p. 121-133Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Early diagnosis of Alzheimer's disease (AD) is critical for adequate treatment and care. Recently it has been shown that functional magnetic resonance imaging (fMRI) can be important in preclinical detection of AD. The purpose of this study was to examine possible differences in memory-related brain activation between persons with high versus low risk for AD. This was achieved by combining a validated neurocognitive screening battery (the 7-minutes test) with memory assessment and fMRI. METHODS: One hundred two healthy community-living persons with subjective memory complaints were recruited through advertisement and tested with the 7-minutes test. Based on their test performance they were classified as having either high (n = 8) or low risk (n = 94) for AD. Six high-risk individuals and six age-, sex-, and education-matched low-risk individuals were investigated with fMRI while engaged in episodic memory tasks. RESULTS: The high-risk individuals performed worse than low-risk individuals on tests of episodic memory. Patterns of brain activity during episodic encoding and retrieval showed significant group differences (p < .05 corrected). During both encoding and retrieval, the low-risk persons showed increased activity relative to a baseline condition in prefrontal brain regions that previously have been implicated in episodic memory. By contrast, the high-risk persons did not significantly activate any prefrontal regions, but instead showed increased activity in visual occipito-temporal regions. CONCLUSION: Patterns of prefrontal brain activity related to episodic memory differ between persons with high versus low risk for AD, and lowered prefrontal activity may predict subsequent disease.

  • 163. Endo, Satoshi
    et al.
    Takada, Sayaka
    Honda, Ryo P.
    Müller, Kathrin
    Weishaupt, Jochen H.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Ludolph, Albert C.
    Kamatari, Yuji O.
    Matsunaga, Toshiyuki
    Kuwata, Kazuo
    El-Kabbani, Ossama
    Ikari, Akira
    Instability of C154Y variant of aldo-keto reductase 1C32017In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 276, p. 194-202Article in journal (Refereed)
    Abstract [en]

    Aldo-keto reductase (AKR) 1C3 is a cytosolic enzyme that metabolizes steroids, prostaglandins, toxic aldehydes and drugs. Recently, some nonsynonymous single nucleotide polymorphisms of AKR1C3 have been suggested to impact steroid and drug metabolism. In this study, we examined the effects of C154Y and L159V variants of AKR1C3 on stability and function of the enzyme. Both variants had been detected in patients with the neurodegenerative disease amyotrophic lateral sclerosis. Recombinant wild-type (WT), C154Y and L159V enzymes were similar in specific activity, but C154Y displayed much lower thermostability than WT and L159V. C154Y was inactivated by 10-min incubation at >25 °C, and about 90% of its activity was lost at 40 °C. Differential scanning fluorimetry revealed that Tm (thermal denaturation midpoint) of C154Y was lower than that of WT. In order to study the cause of thermosensitivity of C154Y, we prepared C154F and C154S mutant AKR1C3s. Like C154Y, C154F was highly sensitive to thermal inactivation, whereas C154S showed almost the same thermostability as WT. The C154F and C154Y variants induced secondary and tertiary structural changes in AKR1C3 at 40 °C as reflected by their altered circular dichroism and 8-anilinonaphthalene-1-sulfonate fluorescence characteristics. These results suggest that the replacement of C154 with a residue possessing a bulky aromatic side-chain impairs the folding of the α-helix containing C154 and its neighboring secondary structures, leading to low thermostability of AKR1C3. AKR1C3 metabolizes cytotoxic 4-oxo-2-nonenal into a less toxic metabolite, and overexpression of WT in HEK293 cells alleviated the 4-oxo-2-nonenal-induced cytotoxicity. In contrast, the overexpression of C154Y in the cells did not show such a significant protective effect, suggesting that C154Y is unstable in cells.

  • 164. Engström, Christer
    et al.
    Brändström, Sven
    Sigvardsson, Sören
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Social medicine.
    Cloninger, C Robert
    Nylander, Per-Olof
    Bipolar disorder. III: harm avoidance a risk factor for suicide attempts2004In: Bipolar Disorders, ISSN 1398-5647, E-ISSN 1399-5618, Vol. 6, no 2, p. 130-138Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of the study was to examine whether personality, i.e. temperament and character influence suicide attempts in bipolar patients.

    Methods: Bipolar patients were recruited from lithium dispensaries. Temperament and character inventory (TCI) was administered to 100 euthymic bipolar patients and 100 controls.

    Results: Age of onset was significantly lower in patients with suicide attempts in the total bipolar group (I and II) and bipolar I patients compared with patients without suicide attempts. Bipolar (I and II) and bipolar I patients with suicide attempts were significantly higher in harm avoidance (HA) and reward dependence compared with patients without suicide attempts. Patients (I and II) with suicide attempts had significantly more anticipatory worry, fatigability and asthenia than patients without suicide attempts. Bipolar I patients with suicide attempts had significantly more fatigability and asthenia and were more dependent than patients without suicide attempts. HA was lowest in patients with no suicide attempts and no family history of suicide, higher in patients with family history of suicide or patients with suicide attempts, and significantly highest in patients with suicide attempts and family history of suicide. Patients with suicide attempts and family history of suicide had more anticipatory worry, fatigability and asthenia. Bipolar disorder was significantly correlated to HA and suicide attempts to HA and PS. Family history of suicide and gender were significantly correlated to suicide attempts.

    Conclusions: Age of onset, HA, PS, gender and family history of suicide had a moderate to very strong effect on suicide attempts in bipolar patients.

  • 165. Engström, Christer
    et al.
    Brändström, Sven
    Sigvardsson, Sören
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Social medicine.
    Cloninger, Robert
    Nylander, Per-Olof
    Bipolar disorder I. Temperament and character2004In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 82, no 1, p. 131-134Article in journal (Refereed)
    Abstract [en]

    Background: The nature of the relationship between personality and bipolar affective disorders is an important but unanswered question. Methods: We have studied personality in bipolar patients by using the Temperament and Character Inventory (TCI). TCI were administered to 100 euthymic bipolar patients and 100 controls from the normal population.

    Results: Bipolar patients were significantly higher in harm avoidance (HA) and lower in reward dependence (RD), self-directedness (SD), and cooperativeness (CO) than controls. Bipolar patients are more fatigable, less sentimental, more independent, less purposeful, less resourceful, less empathic, less helpful, less pure-hearted, and have less impulse control than controls. Bipolar II patients are more impulsive, more fatigable, less resourceful, and have less impulse control than bipolar I patients.

    Limitations: Our results are limited to euthymic bipolar patients and cannot be generalized to affective disorders.

    Conclusions: Even when clinically euthymic on lithium maintenance, bipolar patients continue to have a characteristic cognitive deficit. This is in agreement with cognitive theories about cognitive deficits in depression that are regarded as important vulnerability factors in mood disorders.

  • 166.
    Erba, P
    et al.
    University of Manchester, University Hospital of Basel.
    Mantovani, Cristina
    University of Manchester.
    Kalbermatten, Daniel F
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pierer, G
    University Hospital of Basel.
    Terenghi, Giorgio
    University of Manchester.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Regeneration potential and survival of transplanted undifferentiated adipose tissue-derived stem cells in peripheral nerve conduits2010In: Journal of plastic, reconstructive & aesthetic surgery : JPRAS, ISSN 1878-0539, Vol. 63, no 12, p. e811-e817Article in journal (Refereed)
    Abstract [en]

    Adipose tissue-derived stem cells (ADSCs) have shown potential for the treatment of nerve injuries. Most previous efforts have aimed at stimulating regeneration by using neural-differentiation protocols, but the potential of undifferentiated ADSCs to enhance axonal growth as well as their ability to transdifferentiate in situ have been poorly investigated. In this study, using a rat sciatic nerve model we show that ADSCs, transplanted in an artificial nerve conduit, stimulate axonal outgrowth from the proximal nerve stump and evoke greater Schwann cell (SC) proliferation/intrusion in the distal stump. To track the fate of the transplanted cells, we used green fluorescent protein (GFP)-labelling and polymerase chain reaction (PCR) for the detection of the sex determining region Y (SRY) gene in the donor male cells. Both methods indicated a lack of significant quantities of viable cells 14 days after transplantation. These results suggest that any regenerative effect of transplanted ADSCs is more likely to be mediated by an initial boost of released growth factors and/or by an indirect effect on endogenous SCs activity. Future studies need to address long-term cell survival in tissue-engineered nerve conduits to improve the neuroregenerative potential of ADSCs.

  • 167.
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Activity in part of the neural correlates of consciousness reflects integration2017In: Consciousness and Cognition, ISSN 1053-8100, E-ISSN 1090-2376, Vol. 55, p. 26-34Article in journal (Refereed)
    Abstract [en]

    Integration is commonly viewed as a key process for generating conscious experiences. Accordingly, there should be increased activity within the neural correlates of consciousness when demands on integration increase. We used fMRI and "informational masking" to isolate the neural correlates of consciousness and measured how the associated brain activity changed as a function of required integration. Integration was manipulated by comparing the experience of hearing simple reoccurring tones to hearing harmonic tone triplets. The neural correlates of auditory consciousness included superior temporal gyrus, lateral and medial frontal regions, cerebellum, and also parietal cortex. Critically, only activity in left parietal cortex increased significantly as a function of increasing demands on integration. We conclude that integration can explain part of the neural activity associated with the generation conscious experiences, but that much of associated brain activity apparently reflects other processes.

  • 168.
    Eriksson, Johan
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    The conscious brain: Empirical investigations of the neural correlates of perceptual awareness2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Although consciousness has been studied since ancient time, how the brain implements consciousness is still considered a great mystery by most. This thesis investigates the neural correlates of consciousness by measuring brain activity with functional magnetic resonance imaging (fMRI) while specific contents of consciousness are defined and maintained in various experimental settings. Study 1 showed that the brain works differently when creating a new conscious percept compared to when maintaining the same percept over time. Specifically, sensory and fronto-parietal regions were activated for both conditions but with different activation patterns within these regions. This distinction between creating and maintaining a conscious percept was further supported by Study 2, which in addition showed that there are both differences and similarities in how the brain works when defining a visual compared to an auditory percept. In particular, frontal cortex was commonly activated while posterior cortical activity was modality specific. Study 3 showed that task difficulty influenced the degree of frontal and parietal cortex involvement, such that fronto-parietal activity decreased as a function of ease of identification. This is interpreted as evidence of the non-necessity of these regions for conscious perception in situations where the stimuli are distinct and apparent. Based on these results a model is proposed where sensory regions interact with controlling regions to enable conscious perception. The amount and type of required interaction depend on stimuli and task characteristics, to the extent that higher-order cortical involvement may not be required at all for easily recognizable stimuli.

  • 169.
    Eriksson, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Kalpouzos, Grégoria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Rewiring the brain with repeated retrieval: A parametric fMRI study of the testing effect2011In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 505, no 1, p. 36-40Article in journal (Refereed)
    Abstract [en]

    The "testing effect" refers to the beneficial effects on memory performance from being tested, a phenomenon of potentially substantial implications in educational settings. While the effect itself is firmly established in previous research, little is known of related brain changes. Here we used fMRI and a parametric design to show that repeated successful retrieval during a memory acquisition phase leads to higher brain activity in the anterior cingulate cortex (ACC) at a subsequent test phase. The extent of ACC activity increase correlated across individuals with memory performance 5 months later. In relation to recent research that associates the ACC with memory consolidation processes, the present results suggest that the testing effect may operate at the systems level by enhancing consolidation of memory representations.

  • 170.
    Eriksson, Johan
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Riklund Åhlström, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    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).
    Similar frontal and distinct posterior cortical regions mediate visual and auditory perceptual awareness2007In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 17, no 4, p. 760-765Article in journal (Refereed)
    Abstract [en]

    Activity in ventral visual cortex is a consistent neural correlate of visual consciousness. However, activity in this area seems insufficient to produce awareness without additional involvement of frontoparietal regions. To test the generality of the frontoparietal response, neural correlates of auditory awareness were investigated in a paradigm that previously has revealed frontoparietal activity during conscious visual perception. A within-experiment comparison showed that frontal regions were related to both visual and auditory awareness, whereas parietal activity was correlated with visual awareness and superior temporal activity with auditory awareness. These results indicate that frontal regions interact with specific posterior regions to produce awareness in different sensory modalities.

  • 171.
    Eriksson, Johan
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Riklund Åhlström, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nyberg, Lars
    Umeå University, Faculty of Social Sciences, Department of Psychology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Visual consciousness: dissociating the neural correlates of perceptual transitions from sustained perception with fMRI2004In: Consciousness and Cognition, ISSN 1053-8100, E-ISSN 1090-2376, Vol. 13, no 1, p. 61-72Article in journal (Refereed)
    Abstract [en]

    To investigate the possible dichotomy between the neurophysiological bases of perceptual transitions versus sustaining a particular percept over time, an fMRI study was conducted with subjects viewing fragmented pictures. Unlike most other perceptually unstable stimuli, fragmented pictures give rise to only one perceptual transition and a continuous period of sustained perception. Earlier research is inconclusive on the subject of which anatomical regions should be attributed to what temporal aspect of perception, and the aim of the present study was to shed more light on the subject. In this study occipitotemporal and fronto-parietal regions were found to be activated for both aspects. However, regions in the medial-temporal lobe were activated specifically for transitions, whereas medial and dorsolateral prefrontal regions were activated specifically for sustained perception. These results provide further support for the theory that the initial creation of perceptual awareness and upholding perceptual awareness over time are separate processes involving different brain regions.

  • 172.
    Eriksson, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Stiernstedt, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Öhlund, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Changing Zaire to Congo: The fate of no-longer relevant mnemonic information.2014In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 101, p. 1-7Article in journal (Refereed)
    Abstract [en]

    In an ever-changing world there is constant pressure on revising long-term memory, such when people or countries change name. What happens to the old, pre-existing information? One possibility is that old associations gradually are weakened and eventually lost. Alternatively, old and no longer relevant information may still be an integral part of memory traces. To test the hypothesis that old mnemonic information still becomes activated when people correctly retrieve new, currently relevant information, brain activity was measured with fMRI while participants performed a cued-retrieval task. Paired associates (symbol-sound and symbol-face pairs) were first learned during two days. Half of the associations were then updated during the next two days, followed by fMRI scanning on day 5 and also 18months later. As expected, retrieval reactivated sensory cortex related to the most recently learned association (visual cortex for symbol-face pairs, auditory cortex for symbol-sound pairs). Critically, retrieval also reactivated sensory cortex related to the no-longer relevant associate. Eighteen months later, only non-updated symbol-face associations were intact. Intriguingly, a subset of the updated associations was now treated as though the original association had taken over, in that memory performance was significantly worse than chance and that activity in sensory cortex for the original but not the updated associate correlated (negatively) with performance. Moreover, the degree of "residual" reactivation during day 5 inversely predicted memory performance 18months later. Thus, updating of long-term memory involves adding new information to already existing networks, in which old information can stay resilient for a long time.

  • 173.
    Eriksson, M
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Bergenheim, A. Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Sandström, M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    TREATMENT OF GLIOBLASTOMA: IMPROVEMENTS OVER TWO DECADES AT A SINGLE CENTRE2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, p. 236-236Article in journal (Other academic)
    Abstract [en]

    Glioblastoma (GBM) is a rapidly progressing tumour with a short overall survival. The treatment of GBM has evolved over the last decades and is today multimodal including surgery with maximal tumour resection followed by radiotherapy and chemotherapy for patients in good performance status. The aim of this study was to evaluate the development of treatment and the outcome for GBM patients at a single centre. PATIENTS AND METHODS: 244 patients treated for GBM 2005 - 2015 has been included in a tissue bank with tumour tissue and/or blood samples. A clinical database has been set up with basic patient characteristics and details on surgery and non-surgical treatment. Survival was also studied for all 571 patients in our region diagnosed with GBM between 1995 and 2015. RESULTS: The overall median survival for all patients from 1995 to 2015 was 9.3 months. There was a stepwise improvement from 6.9 to 10.3 months for patients diagnosed 1995–1996 and 2010–2015, respectively (p<0.05). The two-year survival for the same time periods improved from 7.4% to 17.8% (p<0.01). After the introduction of postoperative radiochemotherapy for patients in good performance status in 2005 an increased survival was noted. The implementation of intraoperative 5-aminolevulinic acid did, in patients that underwent tumour resection, increase the number of total tumour resections (≥95%) from 32.6% to 54.1% (p<0.001). Positive prognostic factors were young age, good performance status, absence of diabetes or metabolic disease, total tumour resection and completion of postoperative radiochemotherapy. CONCLUSIONS: The results of this study are in line with earlier results regarding survival and prognostic factors. Despite the improvements made, the prognosis is still dismal and the need for further research on GBM treatment is great.

  • 174.
    Fernandes, Carla Patricia Duarte
    et al.
    K.G. Jebsen Centre for Psychosis Research, Norwegian Centre for Mental Disorders Research (NORMENT), Department of Clinical Science, University of Bergen, Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
    Westlye, Lars Tjelta
    K.G. Jebsen Centre for Psychosis Research, Norwegian Centre For Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, Department of Psychology, University of Oslo, Oslo N-0317, Norway.
    Giddaluru, Sudheer
    K.G. Jebsen Centre for Psychosis Research, Norwegian Centre for Mental Disorders Research (NORMENT), Department of Clinical Science, University of Bergen, Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
    Christoforou, Andrea
    K.G. Jebsen Centre for Psychosis Research, Norwegian Centre for Mental Disorders Research (NORMENT), Department of Clinical Science, University of Bergen, Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nilsson, Lars-Göran
    Department of Psychology, Stockholm University and Stockholm Brain Institute, Uppsala, Sweden.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Lundervold, Astri Johansen
    Department of Biological and Medical Psychology, K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, Kavli Research Centre for Aging and Dementia, Haraldsplass Deaconess Hospital.
    Reinvang, Ivar
    Department of Psychology, University of Oslo, Oslo N-0317, Norway.
    Steen, Vidar Martin
    K.G. Jebsen Centre for Psychosis Research, Norwegian Centre for Mental Disorders Research (NORMENT), Department of Clinical Science, University of Bergen, Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
    Le Hellard, Stéphanie
    K.G. Jebsen Centre for Psychosis Research, Norwegian Centre for Mental Disorders Research (NORMENT), Department of Clinical Science, University of Bergen, Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
    Espeseth, Thomas
    K.G. Jebsen Centre for Psychosis Research, Norwegian Centre For Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, Department of Psychology, University of Oslo, Oslo N-0317, Norway.
    Lack of association of the rs1344706 ZNF804A variant with cognitive functions and DTI indices of white matter microstructure in two independent healthy populations2014In: Psychiatry Research: Neuroimaging, ISSN 0925-4927, E-ISSN 1872-7506, Vol. 222, no 1-2, p. 60-66Article in journal (Refereed)
    Abstract [en]

    The rs1344706 single nucleotide polymorphism within intron 2 of the ZNF804A gene is strongly associated with schizophrenia and bipolar disorder. This variant has also been associated in some studies with a range of cognitive and neuroimaging phenotypes, but several studies have reported no effect on the same phenotypes in other samples. Here, we genotyped 670 healthy adult Norwegian subjects and 1753 healthy adult Swedish subjects for rs1344706, and tested for associations with cognitive phenotypes including general intellectual abilities, memory functions and cognitive inhibition. We also tested whether rs1344706 is associated with white matter microstructural properties using diffusion tensor imaging (DTI) data from 250 to 340 of the Norwegian and Swedish subjects, respectively. Whole-brain voxel-wise statistical modeling of the effect of the ZNF804A variant on two DTI indices, fractional anisotropy (FA) and radial diffusivity (RD), was performed using tract-based spatial statistics (TBSS), and commonly reported effect sizes were calculated within several large-scale white matter pathways based on neuroanatomical atlases. No significant associations were found between rs1344706 and the cognitive traits or white matter microstructure. We conclude that the rs1344706 SNP has no significant effect on these phenotypes in our two reasonably powered samples.

  • 175. Fisher, Robert S.
    et al.
    Acevedo, Carlos
    Arzimanoglou, Alexis
    Bogacz, Alicia
    Cross, J. Helen
    Elger, Christian E.
    Engel, Jerome, Jr.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    French, Jacqueline A.
    Glynn, Mike
    Hesdorffer, Dale C.
    Lee, B. I.
    Mathern, Gary W.
    Moshe, Solomon L.
    Perucca, Emilio
    Scheffer, Ingrid E.
    Tomson, Torbjorn
    Watanabe, Masako
    Wiebe, Samuel
    ILAE official report: a practical clinical definition of epilepsy2014In: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 55, no 4, p. 475-482Article in journal (Refereed)
    Abstract [en]

    Epilepsy was defined conceptually in 2005 as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. This definition is usually practically applied as having two unprovoked seizures >24h apart. The International League Against Epilepsy (ILAE) accepted recommendations of a task force altering the practical definition for special circumstances that do not meet the two unprovoked seizures criteria. The task force proposed that epilepsy be considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals who either had an age-dependent epilepsy syndrome but are now past the applicable age or who have remained seizure-free for the last 10years and off antiseizure medicines for at least the last 5years. "Resolved" is not necessarily identical to the conventional view of "remission or "cure." Different practical definitions may be formed and used for various specific purposes. This revised definition of epilepsy brings the term in concordance with common use. A PowerPoint slide summarizing this article is available for download in the Supporting Information section.

  • 176. Fisher, Robert S.
    et al.
    Acevedo, Carlos
    Arzimanoglou, Alexis
    Bogacz, Alicia
    Cross, J. Helen
    Elger, Christian E.
    Engel, Jerome, Jr.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    French, Jacqueline A.
    Hesdorffer, Dale C.
    Lee, Byung-In
    Mathern, Gary W.
    Moshe, Solomon L.
    Perucca, Emilio
    Scheffer, Ingrid E.
    Tomson, Torbjorn
    Watanabe, Masako
    Wiebe, Samuel
    How long for epilepsy remission in the ILAE definition?2017In: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 58, no 8, p. 1486-1487Article in journal (Refereed)
  • 177.
    Fjellman-Wiklund, Anncristine
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Grip, Helena
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Karlsson, J Stefan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Sundelin, Gunnevi
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    EMG trapezius muscle activity pattern in string players: Part I - Is there variability in the playing technique?2004In: International Journal of Industrial Ergonomics, ISSN 0169-8141, E-ISSN 1872-8219, Vol. 33, no 4, p. 347-356Article in journal (Refereed)
  • 178.
    Flanagan, J Randall
    et al.
    Department of Psychology, Queen's University, Kingston, Ontario, Canada, Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.
    Rotman, Gerben
    Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.
    Reichelt, Andreas F
    Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    The role of observers' gaze behaviour when watching object manipulation tasks: predicting and evaluating the consequences of action2013In: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, E-ISSN 1471-2970, Vol. 368, no 1628, p. 20130063-Article in journal (Refereed)
    Abstract [en]

    When watching an actor manipulate objects, observers, like the actor, naturally direct their gaze to each object as the hand approaches and typically maintain gaze on the object until the hand departs. Here, we probed the function of observers' eye movements, focusing on two possibilities: (i) that observers' gaze behaviour arises from processes involved in the prediction of the target object of the actor's reaching movement and (ii) that this gaze behaviour supports the evaluation of mechanical events that arise from interactions between the actor's hand and objects. Observers watched an actor reach for and lift one of two presented objects. The observers' task was either to predict the target object or judge its weight. Proactive gaze behaviour, similar to that seen in self-guided action-observation, was seen in the weight judgement task, which requires evaluating mechanical events associated with lifting, but not in the target prediction task. We submit that an important function of gaze behaviour in self-guided action observation is the evaluation of mechanical events associated with interactions between the hand and object. By comparing predicted and actual mechanical events, observers, like actors, can gain knowledge about the world, including information about objects they may subsequently act upon.

  • 179.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Misfolded superoxide dismutase-1 in sporadic and familial Amyotrophic Lateral Sclerosis2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative syndrome of unknown etiology that most commonly affects people in middle and high age. The hallmark of ALS is a progressive and simultaneous loss of upper and lower motor neurons in the central nervous system that leads to a progressive muscle atrophy, paralysis and death usually by respiratory failure. ALS is not a pure motor neuronal syndrome; it extends beyond the motor system and affects extramotor areas of the brain as well. The majority of the patients suffer from a sporadic ALS disease (SALS) while in at least ten percent the disease appears in a familial form (FALS). Mutations in the gene encoding the antioxidant enzyme superoxide dismutase-1 (SOD1) are the most common cause of FALS. More than 165 SOD1 mutations have been described, and these confer the enzyme a cytotoxic gain of function. Evidence suggests that the toxicity results from structural instability which makes the mutated enzyme prone to misfold and form aggregates in the spinal cord and brain motor neurons. Recent studies indicate that the wild-type human SOD1 protein (wt-hSOD1) has the propensity to develop neurotoxic features.

    The aim of the present study was to investigate if wt-hSOD1 is involved in the pathogenesis of SALS and FALS patients lacking SOD1 mutations and to evaluate the neurotoxic effect of misfolded wt-hSOD1 protein in vivo by generating a transgenic wt-hSOD1 mice model. We produced specific SOD1-peptide-generated antibodies that could discriminate between the misfolded and native form of the enzyme and optimized a staining protocol for detection of misfolded wt-hSOD1 by immunohistochemistry and confocal microscopy of brain and spinal cord tissue. We discovered that aggregates of misfolded wt-hSOD1 were constitutively present in the cytoplasm of motor neurons in all investigated SALS patients and in FALS patients lacking SOD1 gene mutations. Interestingly, the misfolded wt-hSOD1 aggregates were also found in some motor neuron nuclei and in the nuclei of the surrounding glial cells, mainly astrocytes but also microglia and oligodendrocytes, indicating that misfolded wt-hSOD1 protein aggregates may exert intranuclear toxicity. We compared our findings to FALS with SOD1 mutations by investigating brain and spinal cord tissue from patients homozygous for the D90A SOD1 mutation, a common SOD1 mutation that encodes a stable SOD1 protein with a wild-type-like enzyme activity. We observed a similar morphology with a profound loss of motor neurons and aggregates of misfolded SOD1 in the remaining motor neuron. Interestingly, we found gliosis and microvacuolar degeneration in the superficial lamina of the frontal and temporal lobe, indicating a possible frontotemporal lobar dementia in addition to the ALS disorder.

    Our morphological and biochemical findings were tested in vivo by generating homozygous transgenic mice that over expressed wt-hSOD1. These mice developed a fatal ALS-like disease, mimicking the one seen in mice expressing mutated hSOD1. The wt-hSOD1 mice showed a slower weight gain compared to non-transgenic mice and developed a progressive ALS-like hind-leg paresis. Aggregates of misfolded wt-hSOD1 were found in the brain and spinal cord neurons similar to those in humans accompanied by a loss of 41 % of motor neurons compared to non-transgenic litter mates.

    In conclusion, we found misfolded wt-hSOD1 aggregates in the cytoplasm and nuclei of motor neurons and glial cells in all patients suffering from ALS syndrome. Notable is the fact that misfolded wt-hSOD1 aggregates were also detected in FALS patients lacking SOD1 mutations indicating a role for SOD1 even when other genetic mutations are present. The neurotoxicity of misfolded wt-hSOD1 protein was confirmed in vivo by wt-hSOD1 transgenic mice that developed a fatal ALS-like disease. Taken together, our results support the notion that misfolded wt-hSOD1 could be generally involved and play a decisive role in the pathogenesis of all forms of ALS.

  • 180.
    Forsberg, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Glial nuclear aggregates of superoxide dismutase-1 are regularly present in patients with amyotrophic lateral sclerosis2011In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 121, no 5, p. 623-634Article in journal (Refereed)
    Abstract [en]

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

  • 181.
    Forsberg, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Graffmo, Karin S
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Bergh, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High expression of wild-type human superoxide dismutase-1 gives a model of sporadic ALSManuscript (preprint) (Other academic)
  • 182.
    Forsberg, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Graffmo, Karin Sixtensdotter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Pakkenberg, Bente
    Weber, Markus
    Nielsen, Martin
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Munch Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Misfolded SOD1 inclusions in patients with mutations in C9orf72 and other ALS/FTD-associated genes2019In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 90, no 8, p. 861-869Article in journal (Refereed)
    Abstract [en]

    Objective: A hallmark of amyotrophic lateral sclerosis (ALS) caused by mutations in superoxide dismutase-1 (SOD1) are inclusions containing SOD1 in motor neurons. Here, we searched for SOD1-positive inclusions in 29 patients carrying ALS-linked mutations in six other genes.

    Methods: A panel of antibodies that specifically recognise misfolded SOD1 species were used for immunohistochemical investigations of autopsy tissue.

    Results: The 18 patients with hexanucleotide-repeat-expansions in C9orf72 had inclusions of misfolded wild type (WT) SOD1(WT) in spinal motor neurons. Similar inclusions were occasionally observed in medulla oblongata and in the motor cortex and frontal lobe. Patients with mutations in FUS, KIF5A, NEK1, ALSIN or VAPB, carried similar SOD1(WT) inclusions. Minute amounts of misSOD1(WT) inclusions were detected in 2 of 20 patients deceased from non-neurological causes and in 4 of 10 patients with other neurodegenerative diseases. Comparison was made with 17 patients with 9 different SOD1 mutations. Morphologically, the inclusions in patients with mutations in C9orf72HRE, FUS, KIF5A, NEK1, VAPB and ALSIN resembled inclusions in patients carrying the wildtype-like SOD1(D90A) mutation, whereas patients carrying unstable SOD1 mutations (A4V, V5M, D76Y, D83G, D101G, G114A, G127X, L144F) had larger skein-like SOD1-positive inclusions.

    Conclusions and relevance Abundant inclusions containing misfolded SOD1(WT) are found in spinal and cortical motor neurons in patients carrying mutations in six ALS-causing genes other than SOD1. This suggests that misfolding of SOD1(WT) can be part of a common downstream event that may be pathogenic. The new anti-SOD1 therapeutics in development may have applications for a broader range of patients.

  • 183. Forsberg, L.
    et al.
    Johansson, S.
    Nordin, N.
    Hillert, J.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lycke, J.
    Burman, J.
    Landtblom, A. -M
    Walentin, F.
    Martin, C.
    Nilsson, P.
    Dahle, C.
    Piehl, F.
    Olsson, T.
    A Swedish nationwide pharmaco-epidemiological and genetic study (IMSE) of the long-term safety and efficacy of dimethyl fumarate2015In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 21, p. 286-287Article in journal (Other academic)
  • 184.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    An enigmatic neuropathy at the Swedish House of Parliament in the early 20th century2012In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, p. 841-841Article in journal (Other academic)
  • 185.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    The potential of inhibitors of endocannabinoid metabolism as anxiolytic and antidepressive drugs-A practical view2015In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 25, no 6, p. 749-762Article, review/survey (Refereed)
    Abstract [en]

    The endocannabinoid system, comprising cannabinoid CB1 and CB2 receptors, their endogenous ligands anandamide and 2-arachidonoylglyerol, and their synthetic and metabolic enzymes, are involved in many biological processes in the body, ranging from appetite to bone turnover. Compounds inhibiting the breakdown of anandamide and 2-arachidonoylglycerol increase brain levels of these lipids and thus modulate endocannabinoid signalling. In the present review, the preclinical evidence that these enzymes are good targets for development of novel therapies for anxiety and depression are discussed from a practical, rather than mechanistic, point of view. It is concluded that the preclinical data are promising, albeit tempered by problems of tolerance as well as effects upon learning and memory for irreversible monoacylglycerol lipase inhibitors, and limited by a focus upon male rodents alone. Clinical data so far has been restricted to safety studies with inhibitors of anandamide hydrolysis and a hitherto unpublished study on such a compound in elderly patients with major depressive disorders, but under the dose regimes used, they are well tolerated and show no signs of "cannabis-like" behaviours.

  • 186. Freischmidt, Axel
    et al.
    Müller, Kathrin
    Ludolph, Albert C.
    Weishaupt, Jochen H.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Neurology, Ulm University, Ulm, Germany.
    Association of Mutations in TBK1 With Sporadic and Familial Amyotrophic Lateral Sclerosis and Frontotemporal Dementia2017In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 74, no 1, p. 110-113Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative syndromes that occur sporadically or have been associated with mostly dominant inheritance of mutations in more than 30 genes. A critical issue is whether all reported mutations are disease causing or are coincidental findings. In this review we analyze the pathogenicity of nonsynonymous variants in the newly discovered gene encoding TANK-binding kinase 1 (TBK1). The available data suggest that mutations in TBK1 that cause a 50% reduction of TBK1 protein levels are pathogenic. In most cases, the almost complete loss of expression of the mutated TBK1 allele is due to loss-of-function mutations creating a premature termination codon and the degradation of the mutated messenger RNA by nonsense-mediated messenger RNA decay. In addition, TBK1 protein levels reduced by 50% have been proven for specific in-frame deletions of 1 or several amino acids, probably due to increased degradation of the mutated protein. Evaluation of many of the TBK1 missense mutations found in patients with ALS or FTD is prevented by missing data demonstrating cosegregation of the variants and incomplete knowledge about the TBK1 functions relevant for neurodegeneration. These findings suggest that haploinsufficiency of TBK1 is causative for ALS and FTD regardless of the type of mutation. Evaluation of TBK1 variants that do not cause haploinsufficiency is not possible without data demonstrating cosegregation.

  • 187. Freischmidt, Axel
    et al.
    Wieland, Thomas
    Richter, Benjamin
    Ruf, Wolfgang
    Schaeffer, Veronique
    Mueller, Kathrin
    Marroquin, Nicolai
    Nordin, Frida
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Huebers, Annemarie
    Weydt, Patrick
    Pinto, Susana
    Press, Rayomond
    Millecamps, Stephanie
    Molko, Nicolas
    Bernard, Emilien
    Desnuelle, Claude
    Soriani, Marie-Helene
    Dorst, Johannes
    Graf, Elisabeth
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Feiler, Marisa S.
    Putz, Stefan
    Boeckers, Tobias M.
    Meyer, Thomas
    Winkler, Andrea S.
    Winkelman, Juliane
    de Carvalho, Mamede
    Thal, Dietmar R.
    Otto, Markus
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Volk, Alexander E.
    Kursula, Petri
    Danzer, Karin M.
    Lichtner, Peter
    Dikic, Ivan
    Meitinger, Thomas
    Ludolph, Albert C.
    Strom, Tim M.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Weishaupt, Jochen H.
    Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia2015In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 18, no 5, p. 631-+Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.

  • 188. Gallo, Valentina
    et al.
    Brayne, Carol
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Barker, Roger A
    Petersson, Jesper
    Hansson, Oskar
    Lindqvist, Daniel
    Ruffmann, Claudio
    Ishihara, Lianna
    Luben, Robert
    Arriola, Larraitz
    Bergareche, Alberto
    Gavrila, Diana
    Erro, Maria Elena
    Vanacore, Nicola
    Sacerdote, Carlotta
    Bueno-De-Mesquita, Bas
    Vermeulen, Roel
    Seelen, Meinie
    Sieri, Sabina
    Masala, Giovanna
    Ramat, Silvia
    Kyrozis, Andreas
    Thricopolou, Antonia
    Panico, Salvatore
    Mattiello, Amalia
    Kaaks, Rudolf
    Teucher, Birgit
    Katzke, Verena
    Kloss, Manja
    Curry, Lisa
    Calboli, Federico
    Riboli, Elio
    Vineis, Paolo
    Middleton, Lefkos
    Parkinson's Disease Case Ascertainment in the EPIC Cohort: The NeuroEPIC4PD Study2015In: Neurodegenerative Diseases, ISSN 1660-2854, E-ISSN 1660-2862, Vol. 15, no 6, p. 331-338Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Large epidemiological prospective studies represent an important opportunity for investigating risk factors for rare diseases such as Parkinson's disease (PD). Here we describe the procedures we used for ascertaining PD cases in the EPIC (European Prospective Investigation into Cancer and Nutrition) study. Methods: The following three-phase procedure was used: (1) elaboration of a NeuroEPIC4PD template for clinical data collection, (2) identification of all potential PD cases via record linkage and (3) validation of the diagnosis through clinical record revision, in a population of 220,494 subjects recruited in 7 European countries. All cases were labelled with the NeuroEPIC4PD diagnoses of 'definite', 'very likely', 'probable', or 'possible' PD. Results: A total of 881 PD cases were identified, with over 2,741,780 person-years of follow-up (199 definite, 275 very likely, 146 probable, and 261 possible). Of these, 734 were incident cases. The mean age at diagnosis was 67.9 years (SD 9.2) and 458 patients (52.0%) were men. Bradykinesia was the most frequent presenting motor sign (76.5%). Tremor-dominant and akinetic rigid forms of PD were the most common types of PD. A total of 289 patients (32.8%) were dead at the time of the last follow-up. Conclusions: This exercise proved that it is feasible to ascertain PD in large population-based cohort studies and offers a potential framework to be replicated in similar studies.

  • 189. Gallo, Valentina
    et al.
    Vanacore, Nicola
    Bueno-de-Mesquita, H. Bas
    Vermeulen, Roel
    Brayne, Carol
    Pearce, Neil
    Wark, Petra A.
    Ward, Heather A.
    Ferrari, Pietro
    Jenab, Mazda
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wennberg, Patrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Wareham, Nicholas
    Katzke, Verena
    Kaaks, Rudolf
    Weiderpass, Elisabete
    Peeters, Petra H.
    Mattiello, Amalia
    Pala, Valeria
    Barricante, Aurelio
    Chirlaque, Maria-Dolores
    Travier, Noemie
    Travis, Ruth C.
    Sanchez, Maria-Jose
    Pessah-Rasmussen, Helene
    Petersson, Jesper
    Tjønneland, Anne
    Tumino, Rosario
    Ramon Quiros, Jose
    Trichopoulou, Antonia
    Kyrozis, Andreas
    Oikonomidou, Despoina
    Masala, Giovanna
    Sacerdote, Carlotta
    Arriola, Larraitz
    Boeing, Heiner
    Vigl, Matthaeus
    Claver-Chapelon, Francoise
    Middleton, Lefkos
    Riboli, Elio
    Vineis, Paolo
    Physical activity and risk of Amyotrophic Lateral Sclerosis in a prospective cohort study2016In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 31, no 3, p. 255-266Article in journal (Refereed)
    Abstract [en]

    Previous case-control studies have suggested a possible increased risk of Amyotrophic Lateral Sclerosis (ALS) with physical activity (PA), but this association has never been studied in prospective cohort studies. We therefore assessed the association between PA and risk of death from ALS in the European Prospective Investigation into Cancer and Nutrition. A total of 472,100 individuals were included in the analysis, yielding 219 ALS deaths. At recruitment, information on PA was collected through standardised questionnaires. Total PA was expressed by the Cambridge Physical Activity Index (CPAI) and analysed in relation to ALS mortality, using Cox hazard models. Interactions with age, sex, and anthropometric measures were assessed. Total PA was weakly inversely associated with ALS mortality with a borderline statistically significant trend across categories (p = 0.042), with those physically active being 33 % less likely to die from ALS compared to those inactive: HR = 0.67 (95 % CI 0.42-1.06). Anthropometric measures, sex, and age did not modify the association with CPAI. The present study shows a slightly decreased-not increased like in case-control studies-risk of dying from ALS in those with high levels of total PA at enrolment. This association does not appear confounded by age, gender, anthropometry, smoking, and education. Ours was the first prospective cohort study on ALS and physical activity.

  • 190.
    Gharibyan, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Narayana, Vinod
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ankarcrona, Maria
    Karolinska Institute.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Morozova-Roche, Ludmilla
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Emerging role of inflammatory S100A9 in Alzheimer’s disease amyloid growth and neurodegenerationManuscript (preprint) (Other academic)
  • 191.
    Ghasimi, Soma
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Haapasalo, H.
    Eray, M.
    Korhonen, K.
    Brannstrom, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Immunohistochemical analysis of LRIG proteins in meningiomas: correlation between estrogen receptor status and LRIG expression2012In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 14, no Suppl 3, p. 69-69Article in journal (Other academic)
  • 192. Giddaluru, Sudheer
    et al.
    Espeseth, Thomas
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Aging Research Center, Karolinska Institutet and Stockholm University, 11330 Stockholm, Sweden.
    Westlye, Lars T
    Lundquist, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Christoforou, Andrea
    Cichon, Sven
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Steen, Vidar M
    Reinvang, Ivar
    Nilsson, Lars Göran
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). ARC, Karolinska Institutet, Stockholm, Sweden.
    Le Hellard, Stéphanie
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Genetics of structural connectivity and information processing in the brain2016In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 221, no 9, p. 4643-4661Article in journal (Refereed)
    Abstract [en]

    Understanding the genetic factors underlying brain structural connectivity is a major challenge in imaging genetics. Here, we present results from genome-wide association studies (GWASs) of whole-brain white matter (WM) fractional anisotropy (FA), an index of microstructural coherence measured using diffusion tensor imaging. Data from independent GWASs of 355 Swedish and 250 Norwegian healthy adults were integrated by meta-analysis to enhance power. Complementary GWASs on behavioral data reflecting processing speed, which is related to microstructural properties of WM pathways, were performed and integrated with WM FA results via multimodal analysis to identify shared genetic associations. One locus on chromosome 17 (rs145994492) showed genome-wide significant association with WM FA (meta P value = 1.87 × 10(-08)). Suggestive associations (Meta P value <1 × 10(-06)) were observed for 12 loci, including one containing ZFPM2 (lowest meta P value = 7.44 × 10(-08)). This locus was also implicated in multimodal analysis of WM FA and processing speed (lowest Fisher P value = 8.56 × 10(-07)). ZFPM2 is relevant in specification of corticothalamic neurons during brain development. Analysis of SNPs associated with processing speed revealed association with a locus that included SSPO (lowest meta P value = 4.37 × 10(-08)), which has been linked to commissural axon growth. An intergenic SNP (rs183854424) 14 kb downstream of CSMD1, which is implicated in schizophrenia, showed suggestive evidence of association in the WM FA meta-analysis (meta P value = 1.43 × 10(-07)) and the multimodal analysis (Fisher P value = 1 × 10(-07)). These findings provide novel data on the genetics of WM pathways and processing speed, and highlight a role of ZFPM2 and CSMD1 in information processing in the brain.

  • 193.
    Gilthorpe, Jonathan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Oozeer, Fazal
    Nash, Julia
    Calvo, Margarita
    Bennett, David Lh
    Lumsden, Andrew
    Pini, Adrian
    Extracellular histone H1 is neurotoxic and drives a pro-inflammatory response in microglia.2013In: F1000Research, ISSN 2046-1402, Vol. 2, no 148Article in journal (Refereed)
    Abstract [en]

    In neurodegenerative conditions and following brain trauma it is not understood why neurons die while astrocytes and microglia survive and adopt pro-inflammatory phenotypes. We show here that the damaged adult brain releases diffusible factors that can kill cortical neurons and we have identified histone H1 as a major extracellular candidate that causes neurotoxicity and activation of the innate immune system. Extracellular core histones H2A, H2B H3 and H4 were not neurotoxic. Innate immunity in the central nervous system is mediated through microglial cells and we show here for the first time that histone H1 promotes their survival, up-regulates MHC class II antigen expression and is a powerful microglial chemoattractant. We propose that when the central nervous system is degenerating, histone H1 drives a positive feedback loop that drives further degeneration and activation of immune defences which can themselves be damaging. We suggest that histone H1 acts as an antimicrobial peptide and kills neurons through mitochondrial damage and apoptosis.

  • 194. Gislason, Thorarinn
    et al.
    Bertelsen, Randi J
    Real, Francisco Gomez
    Sigsgaard, Torben
    Franklin, Karl A
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lindberg, Eva
    Janson, Christer
    Arnardottir, Erna Sif
    Hellgren, Johan
    Benediktsdottir, Bryndis
    Forsberg, Bertil
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Johannessen, Ane
    Self-reported exposure to traffic pollution in relation to daytime sleepiness and habitual snoring: a questionnaire study in seven North-European cities2016In: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 24, p. 93-99Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE/BACKGROUND: Little is known about associations between traffic exposure and sleep disturbances. We examined if self-reported exposure to traffic is associated with habitual snoring and daytime sleepiness in a general population.

    METHODS: In the RHINE III study, 12184 adults answered questions on sleep disturbances and traffic exposure. We analysed bedrooms near roads with traffic, bedrooms with traffic noise, and travelling regularly along busy roads as proxies for traffic exposures, using logistic regression. Adjustment factors were study centre, gender, age, smoking habits, educational level, body mass index, physical activity, obstructive sleep apnoea, and sleep duration.

    RESULTS: One in ten lived near a busy road, 6% slept in a bedroom with traffic noise, and 11% travelled regularly along busy roads. Habitual snoring affected 25% and daytime sleepiness 21%. More men reported snoring and more women reported daytime sleepiness. Having a bedroom with traffic noise was associated with snoring (adjusted OR 1.29, [95% CI 1.12, 1.48]). For daytime sleepiness, on the other hand, bedroom with traffic noise and high exposure to traffic pollution have significant risk factors (adjusted ORs 1.46 [1.11, 1.92] and 1.65 [1.11, 2.45]). Results were consistent across study centres.

    CONCLUSIONS: Daytime sleepiness is associated with traffic pollution and traffic noise, while habitual snoring is only associated with traffic noise. Self-reported traffic exposure should be taken into account when diagnosing and planning treatment for patients with sleep disturbances, because reducing noise and pollution exposure in the bedroom may have a beneficial effect.

  • 195. Glasø de Lange, Ann-Marie
    et al.
    Sjøli Bråthen, Anne Cecilie
    Grydeland, Håkon
    Sexton, Claire
    Johansen-Berg, Heidi
    Andersson, Jesper L. R.
    Rohani, Darius A.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Fjell, Anders M.
    Walhovd, Kristine B.
    White matter integrity as a marker for cognitive plasticity in aging2016In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 47, p. 74-82Article in journal (Refereed)
    Abstract [en]

    Age-related differences in white matter (WM) integrity are substantial, but it is unknown whether between subject variability in WM integrity influences the capacity for cognitive improvement. We investigated the effects of memory training related to active and passive control conditions in older adults and tested whether WM integrity at baseline was predictive of training benefits. We hypothesized that (1) memory improvement would be restricted to the training group, (2) widespread areas would show greater mean diffusivity (MD) and lower fractional anisotropy in older adults relative to young adults, and (3) within these areas, variability in WM microstructure in the older group would be predictive of training gains. The results showed that only the group receiving training improved their memory. Significant age differences in MD and fractional anisotropy were found in widespread areas. Within these areas, voxelwise analyses showed a negative relationship between MD and memory improvement in 3 clusters, indicating that WM integrity could serve as a marker for the ability to adapt in response to cognitive challenges in aging. 

  • 196. Godbolt, Alison
    et al.
    Nygren-DeBoussard, Catharina
    Stenberg, Maud
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine.
    Ulfarsson, Trandur
    Lindgren, Marie
    Karlsdottir, Gudrun
    Borg, Jorgen
    Cognitive recovery in the first 3 months after severe traumatic brain injury: preliminary data from "PROBRAIN'' study2012In: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 26, no 4-5, p. 639-639Article in journal (Other academic)
  • 197.
    Gorbach, Tetiana
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    de Luna, Xavier
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden; .
    A Hierarchical Bayesian Mixture Modeling Approach for Analysis of Resting-State Functional Brain Connectivity: An Alternative to ThresholdingManuscript (preprint) (Other academic)
  • 198.
    Gorbach, Tetiana
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    de Luna, Xavier
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden..
    Bayesian mixture modeling for longitudinal fMRI connectivity studies with dropoutManuscript (preprint) (Other academic)
  • 199.
    Gorbach, Tetiana
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Pudas, Sara
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Orädd, Greger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Josefsson, Maria
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    de Luna, Xavier
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Longitudinal association between hippocampus atrophy and episodic-memory decline2017In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 51, p. 167-176Article in journal (Refereed)
    Abstract [en]

    There is marked variability in both onset and rate of episodic-memory decline in aging. Structural magnetic resonance imaging studies have revealed that the extent of age-related brain changes varies markedly across individuals. Past studies of whether regional atrophy accounts for episodic-memory decline in aging have yielded inconclusive findings. Here we related 15-year changes in episodic memory to 4-year changes in cortical and subcortical gray matter volume and in white-matter connectivity and lesions. In addition, changes in word fluency, fluid IQ (Block Design), and processing speed were estimated and related to structural brain changes. Significant negative change over time was observed for all cognitive and brain measures. A robust brain-cognition change-change association was observed for episodic-memory decline and atrophy in the hippocampus. This association was significant for older (65-80 years) but not middle-aged (55-60 years) participants and not sensitive to the assumption of ignorable attrition. Thus, these longitudinal findings highlight medial-temporal lobe system integrity as particularly crucial for maintaining episodic-memory functioning in older age. 

  • 200.
    Graffmo, Karin S.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Expression of wild-type human superoxide dismutase-1 in mice causes amyotrophic lateral sclerosis2013In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 22, no 1, p. 51-60Article in journal (Refereed)
    Abstract [en]

    A common cause of amyotrophic lateral sclerosis (ALS) is mutations in the gene encoding superoxide dismutase-1. There is evolving circumstantial evidence that the wild-type protein can also be neurotoxic and that it may more generally be involved in the pathogenesis of ALS. To test this proposition more directly, we generated mice that express wild-type human superoxide dismutase-1 at a rate close to that of mutant superoxide dismutase-1 in the commonly studied G93A transgenic model. These mice developed an ALS-like syndrome and became terminally ill after around 370 days. The loss of spinal ventral neurons was similar to that in the G93A and other mutant superoxide dismutase-1 models, and large amounts of aggregated superoxide dismutase-1 were found in spinal cords, but also in the brain. The findings show that wild-type human superoxide dismutase-1 has the ability to cause ALS in mice, and they support the hypothesis of a more general involvement of the protein in the disease in humans.

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