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  • 101.
    Blomstedt, Patric
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Hariz, Marwan I
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Tisch, Stephen
    Holmberg, Monica
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Bergenheim, Tommy A
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    A family with a hereditary form of torsion dystonia from northern Sweden treated with bilateral pallidal deep brain stimulation2009Inngår i: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 24, nr 16, s. 2415-2419Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 102.
    Blomstedt, Patric
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Jabre, Mazen
    Bejjani, Boulos-Paul
    Koskinen, Lars-Owe
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Electromagnetic environmental influences on implanted deep brain stimulators2006Inngår i: Neuromodulation (Malden, Mass.), ISSN 1094-7159, E-ISSN 1525-1403, Vol. 9, nr 4, s. 262-269Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective.  The objective of this study was to report our observations on the external electromagnetic field influences on deep brain stimulation (DBS) in our patient population and how these influences affected our patients’ lives and other healthcare-related conditions.

    Materials and Methods.  We have retrospectively analyzed data concerning the effects of external electromagnetic fields on 172 of our patients implanted with DBS.

    Results.  Identifiable electromagnetic sources turned the implantable pulse generator (IPG) off in 20 patients. In two patients, these episodes necessitated replacement of the Itrel II IPG (Medtronic Inc., Minneapolis, MN, USA) with the magnetically shielded Kinetra IPG (Medtronic Inc.). Six patients received cardiac pacemakers, leading, in two patients, to interference between the systems. Our experience concerning magnetic resonance imaging, electrocardiogram (ECG), heart defibrillation, electro-cautery, and other sources of electromagnetic interference also is described.

    Conclusions.  External electromagnetic interference may, in rare cases, constitute a severe threat to the well-being of the patient implanted with a DBS system. Also, malfunction of a DBS system may constitute a medical emergency. Nevertheless, in spite of these external electromagnetic influences, we consider DBS to be a safe method, provided safety protocols are followed, and provided that provider awareness about potential hazards is present.

  • 103.
    Blomstedt, Patric
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Lindvall, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Linder, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Olivecrona, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Hariz, Marwan I.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Reoperation after failed deep brain stimulation for essential tremor2012Inngår i: World Neurosurgery, ISSN 1878-8750, Vol. 78, nr 5, s. 554.e1-554.e5Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: To evaluate the effects of reoperation with deep brain stimulation (DBS) in the caudal zona incerta (cZi) in patients with failed DBS in the ventral intermediate (Vim) nucleus of the thalamus for essential tremor. METHODS: The results of reoperation with cZi DBS in five patients with failed Vim DBS were retrospectively analyzed. RESULTS: Two patients had early failure of Vim DBS, and three after several years of good effect. The mean deviation from the atlas Vim target point was 1.4 mm. Before the reoperation Vim DBS improved hand function and tremor in the treated hand at 25 %, whereas cZi DBS achieved an improvement of 57%. Although cZi was more efficient than Vim DBS, also in the patients with late failure of Vim DBS, they still exhibited a considerable residual tremor on cZi DBS. CONCLUSIONS: The effect on tremor was, in this small sample population, improved by implanting an electrode in the cZi. The effect was modest in those patients suffering a deterioration years after the initial operation.

  • 104.
    Blomstedt, Patric
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Olivecrona, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Sailer, Alexandra
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurofysiologi.
    Hariz, Marwan I
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Dittmar and the history of stereotaxy: or rats, rabbits, and references2007Inngår i: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 60, nr 1, s. 198-201Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    The renaissance of stereotactic functional neurosurgery has resulted in increased interest in its origins. Twenty articles concerning this field trace the history back to a paper published in 1873 by Dittmar: “Über die Lage des sogenannten Gefaesszentrums in der Medulla oblongata” [On the location of the so-called vasomotor center in the medulla oblongata]. Few facts are presented. But, taken together, the impression given by the secondary sources is that Dittmar, in 1873, presented a guiding device for localization of intracranial structures for the positioning of electrodes/blades in the medulla oblongata in rats. Of the publications that cite Dittmar's original article as their only quoted source, half did not specify the inserted object and the animal of the experiment. The remaining articles reported either that the introduced object was an electrode or that the experiments were performed on rats. Dittmar's original article, however, did not report use of his apparatus for insertion of electrodes, nor did he use rats. All experiments were performed by making incisions in the medulla oblongata in rabbits. Dittmar's apparatus was constructed to allow more precision when performing incisions in the medulla oblongata than could be obtained performing incisions freehand. The incision point was chosen and the blade introduced with direct visual guidance. This has been described as “spatial localization of intracranial structures,” “a special targeting instrument,” or simply, “a guiding device.” In our opinion, it can most properly be classified as a supportive arm.

  • 105.
    Blomstedt, Patric
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Sandvik, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Fytagoridis, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Tisch, Stephen
    Department of Neurology, St Vincent's Hospital, University of New South Wales, Sydney, Australia.
    The posterior subthalamic area in the treatment of movement disorders: past, present, and future2009Inngår i: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 64, nr 6, s. 1029-1038Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The introduction of thalamotomy in 1954 led naturally to exploration of the underlying subthalamic area, with the development of such procedures as campotomy and subthalamotomy in the posterior subthalamic area. The most popular of these procedures was the subthalamotomy, which was performed in thousands of patients for various movement disorders. Today, in the deep brain stimulation (DBS) era, subthalamic nucleus DBS is the treatment of choice for Parkinson's disease, whereas thalamic and pallidal DBS are mainly used for nonparkinsonian tremor and dystonia, respectively. The interest in DBS in the posterior subthalamic area has been quite limited, however, with a total of 95 patients presented in 14 articles. During recent years, interest has increased, and promising results have been published concerning both Parkinson's disease and nonparkinsonian tremor. We reviewed the literature to investigate the development of surgery in the posterior subthalamic area from the lesional era to the present.

  • 106.
    Blomstedt, Patric
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Sandvik, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Hariz, Marwan
    UCL Insitute of Neurology, Queen Square, London, Uk.
    Fytagoridis, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Hariz, Gun-Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Arbetsterapi.
    Koskinen, Lars-Owe
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Influence of age, gender and severity of tremor on outcome after thalamic and subthalamic DBS for essential tremor2011Inngår i: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 17, nr 8, s. 617-620Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Deep brain stimulation (DBS) is an established treatment for essential tremor (ET). The nucleus ventralis intermedius thalami (Vim) is the target of choice, but promising results have been presented regarding DBS in the posterior subthalamic area (PSA). The aim of this study was to evaluate the possible influence of gender, age and severity of disease on the outcome of these procedures. Sixty eight patients (34 Vim, 34 PSA) with ET were included in this non-randomised study. Evaluation using the Essential Tremor Rating Scale (ETRS) was performed before, and one year after surgery concerning PSA DBS, and at a mean of 28 ± 24 months concerning Vim DBS. Items 5/6 and 11-14 (hand tremor and hand function) were selected for analysis of tremor outcome. The efficacy of DBS on essential tremor was not related to age or gender. Nor was it associated with the severity of tremor when the percentual reduction of tremor on stimulation was taken into account. However, patients with a more severe tremor at baseline had a higher degree of residual tremor on stimulation. Tremor in the treated hand and hand function were improved with 70% in the Vim group and 89% in the PSA group.

  • 107.
    Blomstedt, Patric
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Sandvik, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Linder, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Fredricks, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Hariz, Marwan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Deep brain stimulation of the subthalamic nucleus versus the zona incerta in the treatment of essential tremor2011Inngår i: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 153, nr 12, s. 2329-2335Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

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

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

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

  • 108.
    Blomstedt, Patric
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Sandvik, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Tisch, Stephen
    Deep brain stimulation in the posterior subthalamic area in the treatment of essential tremor2010Inngår i: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 25, nr 10, s. 1350-1356Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To evaluate the posterior subthalamic area (PSA) as a target for deep brain stimulation (DBS) in the treatment of essential tremor (ET). The ventral intermediate nucleus of the thalamus is the traditional target for DBS in the treatment of ET. Recent studies have presented beneficial effects of DBS in the PSA in the treatment of tremor. Twenty-one patients with ET were included in this study. All patients were evaluated before and 1 year after surgery, on and off stimulation, using the essential tremor rating scale (ETRS). A marked microlesional effect was noticed in 83%, in some cases obviating the need for electrical stimulation for many months. The total ETRS was reduced from 46.2 at baseline to 18.7 (60%). Item 5/6 (tremor of the upper extremity) was improved from 6.2 to 0.3 (95%), and items 11 to 14 (hand function) from 9.7 to 1.3 (87%) concerning the contralateral hand. Activities of daily living were improved by 66%. No severe complication occurred. Eight patients presented a postoperative mild dysphasia that regressed within days to weeks. DBS in the PSA resulted in a marked reduction of tremor.

  • 109.
    Blomstedt, Patric
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Sjöberg, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Hansson, Maja
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Bodlund, Owe
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Hariz, Marwan I
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Deep brain stimulation in the treatment of depression2011Inngår i: Acta Psychiatrica Scandinavica, ISSN 0001-690X, E-ISSN 1600-0447, Vol. 123, nr 1, s. 4-11Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective:  To present the technique of deep brain stimulation (DBS) and to evaluate the studies conducted on DBS in the treatment of therapy-refractory major depressive disorder (MDD).

    Method:  A review of the literature on DBS in the treatment of MDD was conducted.

    Results:  The results of DBS in MDD have been presented in 2 case reports and 3 studies of 47 patients operated upon in 5 different target areas. Positive effects have been presented in all studies and side effects have been minor. DBS in the nucleus accumbens resulted in a mean reduction of Hamilton depression rating scale (HDRS) of 36% after 1 year and 30% of the 10 patients achieved remission. DBS in the internal capsule/ventral striatum resulted in a reduction of 44% after 1 year, and at the last evaluation after in mean 2 years, 40% of the 15 patients were in remission. The 20 patients with subcallosal cingulated gyrus DBS had a reduction of HDRS of 52% after 1 year, and 35% were within 1 point from remission or in remission.

    Conclusion:  DBS is a promising treatment for therapy-refractory MDD. The published experience is, however, limited, and the method is at present an experimental therapy.

  • 110.
    Blomstedt, Patric
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Sjöberg, Rickard L
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Hansson, Maja
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Bodlund, Owe
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Hariz, Marwan I
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Deep brain stimulation in the treatment of obsessive-compulsive disorder2013Inngår i: World Neurosurgery, ISSN 1878-8750, E-ISSN 1878-8769, Vol. 80, nr 6, s. e245-e253Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Deep brain stimulation (DBS) has emerged as a treatment for severe cases of therapy-refractory obsessive-compulsive disorder (OCD), and promising results have been reported. The literature might, however, be somewhat unclear, considering the different targets used, and due to repeated inclusion of individual patients in multiple publications. The aim of this report was to review the literature on DBS for OCD.

    METHODS: The modern literature concerning studies conducted on DBS in the treatment of OCD was reviewed.

    RESULTS: The results of DBS in OCD have been presented in 25 reports with 130 patients, of which, however, only 90 contained individual patients. Five of these reports included at least 5 individual patients not presented elsewhere. Sixty-eight of these patients underwent implantation in the region of the internal capsule/ventral striatum, including the nucleus accumbens. The target in this region has varied between groups and over time, but the latest results from bilateral procedures in this area have shown a 50% reduction of OCD scores, depression, and anxiety. The subthalamic nucleus has been suggested as an alternative target. Although beneficial effects have been demonstrated, the efficacy of this procedure cannot be decided, because only results after 3 months of active stimulation have been presented so far.

    CONCLUSIONS: DBS is a promising treatment for therapy-refractory OCD, but the published experience is limited and the method is at present an experimental therapy.

  • 111.
    Blomstedt, Patric
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Stenmark Persson, Rasmus
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Hariz, Gun-Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Arbetsterapi. Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Linder, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Fredricks, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Häggström, Björn
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Philipsson, Johanna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Hariz, Marwan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap. Unit of Functional Neurosurgery, UCL Institute of Neurology, London, UK.
    Deep brain stimulation in the caudal zona incerta versus best medical treatment in patients with Parkinson's disease: a randomised blinded evaluation2018Inngår i: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 89, nr 7, s. 710-716Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Several open-label studies have shown good effect of deep brain stimulation (DBS) in the caudal zona incerta (cZi) on tremor, including parkinsonian tremor, and in some cases also a benefit on akinesia and axial symptoms. The aim of this study was to evaluate objectively the effect of cZi DBS in patients with Parkinson's disease (PD).

    Method: 25 patients with PD were randomised to either cZi DBS or best medical treatment. The primary outcomes were differences between the groups in the motor scores of the Unified Parkinson's Disease Rating Scale (UPDRS-III) rated single-blindly at 6 months and differences in the Parkinson's Disease Questionnaire 39 items (PDQ-39). 19 patients, 10 in the medical arm and 9 in the DBS arm, fulfilled the study.

    Results: The DBS group had 41% better UPDRS-III scores off-medication on-stimulation compared with baseline, whereas the scores of the non-surgical patients off-medication were unchanged. In the on-medication condition, there were no differences between the groups, neither at baseline nor at 6 months. Subitems of the UPDRS-III showed a robust effect of cZi DBS on tremor. The PDQ-39 domains 'stigma' and 'ADL' improved only in the DBS group. The PDQ-39 summary index improved in both groups.

    Conclusion: This is the first randomised blinded evaluation of cZi DBS showing its efficacy on PD symptoms. The most striking effect was on tremor; however, the doses of dopaminergic medications could not be decreased. cZi DBS in PD may be an addition to existing established targets, enabling tailoring the surgery to the needs of the individual patient.

  • 112.
    Blomstedt, Patric
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Taira, Takaomi
    Hariz, Marwan
    Rescue pallidotomy for dystonia through implanted deep brain stimulation electrode2016Inngår i: Surgical Neurology International, ISSN 2152-7806, E-ISSN 2152-7806, Vol. 7, s. S815-S817Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Some patients with deep brain stimulation (DBS), where removal of implants is indicated due to hardware related infections, are not candidates for later re-implantation. In these patients a rescue lesion through the DBS electrode has been suggested as an option. In this case report we present a patient where a pallidotomy was performed using the DBS electrode.

    CASE DESCRIPTION: An elderly woman with bilateral Gpi DBS suffered an infection around the left burr hole involving the DBS electrode. A unilateral lesion was performed through the DBS electrode before it was removed. No side effects were encountered. Burke-Fahn-Marsden (BFM) dystonia movement scale score was 39 before DBS. With DBS before lesioning BFM score was 2.5 points. The replacement of the left sided stimulation with a pallidotomy resulted in only a minor deterioration of the score to 5 points.

    CONCLUSIONS: In the case presented here a small pallidotomy performed with the DBS electrode provided a satisfactory effect on the patient's dystonic symptoms. Thus, rescue lesions through the DBS electrodes, although off-label, might be considered in patients with Gpi DBS for dystonia when indicated.

  • 113. Blumen, Sergiu C
    et al.
    Inzelberg, Rivka
    Nisipeanu, Puiu
    Carasso, Ralph L
    Oved, Daniel
    Aizenstein, Orna
    Drory, Vivian E
    Bergstrom, Christina
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Aggressive familial ALS with unusual brain MRI and a SOD1 gene mutation.2010Inngår i: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders, ISSN 1466-0822, E-ISSN 1743-4483, Vol. 11, nr 1-2, s. 228-231Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 114.
    Bobinski, Lukas
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    On evolution of intracranial changes after severe traumatic brain injury and its impact on clinical outcome2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Severe traumatic brain injury (sTBI) is a cause of death and disability worldwide and requires treatment at specialized neuro-intensive care units (NICU) with a multimodal monitoring approach. The CT scan imaging supports the monitoring and diagnostics. The level of S100B and neuron specific enolase (NSE) reflects the severity of the injury. The therapy resistant intracranial hypertension requires decompressive craniectomy (DC). After DC, the cranium must be reconstructed to recreate the normal intracranial physiology as well as to address cosmetic issues. The evolution of the pathological intracranial changes was analyzed in accordance with the three CT classifications: Marshall, Rotterdam and Morris-Marshall. The Rotterdam scale was best in describing the dynamics of the pathological evolution. Both the Rotterdam score and Morris- Marshall classification showed strong correlation with the clinical outcome, a finding that suggests that they could be used for prognostication. We demonstrated a clear correlation between the CT classifications and concentrations of S100B and NSE. The results revealed a concomitant correlation between NSE and S100B and clinical outcome. We found that the interaction between the ICP, Rotterdam CT classification, and concentrations of biochemical biomarkers are all associated with DC. We found a high percentage of complications following cranioplasty. Our results call into question whether custom-made allograft should be considered the best material for cranioplasty. It is concluded that both the Rotterdam and Morris-Marshall classification contribute to clinical evaluation of intracranial dynamics after sTBI, and might be used in combination with biochemical biomarkers for better assessment. The decision to perform DC should include a re-assesment of ICP evolution, CT scan images and concentration of the biochemical biomarkers. Furthermore, when determining whether DC treatment should be used, surgeon should also consider the risks of the following cranioplasty.

  • 115.
    Bobinski, Lukas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Koskinen, Lars-Owe D.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Lindvall, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Complications following cranioplasty using autologous bone or polymethylmethacrylate-Retrospective experience from a single center2013Inngår i: Clinical neurology and neurosurgery (Dutch-Flemish ed. Print), ISSN 0303-8467, E-ISSN 1872-6968, Vol. 115, nr 9, s. 1788-1791Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: A decompressive hemicraniectomy is a potentially life-saving intervention following head trauma. Once performed patients are obliged to undergo a second procedure with cranioplasty. Two of the most commonly used materials are autologous bone and polymethylmethacrylate (PMMA). We have now evaluated complications following a cranioplasty using these materials. Materials and methods: During a 7-year period (2002-2008) 49 patients were operated with a decompressive craniectomy following head trauma. Patients received a cranioplasty consisting of autologous bone (30 patients, 61.2%) or PMMA (19 patients, 38.8%) and were followed at least 24 months. Patient data were collected retrospectively. Results: Twenty patients (20/49, 40.8%) experienced a complication that prompted a re-operation. There was a significantly higher rate of complications leading to a re-operation (53.3% vs. 21.1%, p = 0.03) and a shorter survival time of the cranioplasty (mean 48.1 +/- 7.8 vs. 79.5 +/- 9.0 months, p = 0.035) in patients with autologous bone compared to PMMA. Bone resorption and the presence of postoperative hematomas were significantly more common in patients with autologous bone. The material used for cranioplasty was the only variable that significantly correlated to the rate of complications. Conclusions: In our series we had a high percentage of patients needing re-operation due to complications following a cranioplasty. Though generally considered a straightforward procedure, complications and associated morbidity in patients undergoing cranioplasty should not be underestimated. 

  • 116.
    Bobinski, Lukas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Olivecrona, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Koskinen, Lars-Owe D.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Rotterdam score, ICP, CPP, S-100B, NSE and their association with Decompressive Craniectomy in severe Traumatic Brain InjuryArtikkel i tidsskrift (Annet vitenskapelig)
  • 117. Bogaert, Elke
    et al.
    Goris, An
    Van Damme, Philip
    Geelen, Veerle
    Lemmens, Robin
    van Es, Michael A
    van den Berg, Leonard H
    Sleegers, Kristel
    Verpoorten, Nathalie
    Timmerman, Vincent
    Jonghe, Peter De
    Van Broeckhoven, Christine
    Traynor, Bryan J
    Landers, John E
    Brown, Robert H
    Glass, Jonathan D
    Al-Chalabi, Ammar
    Shaw, Christopher E
    Birve, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Slowik, Agnieszka
    Tomik, Barbara
    Melki, Judith
    Robberecht, Wim
    Van Den Bosch, Ludo
    Polymorphisms in the GluR2 gene are not associated with amyotrophic lateral sclerosis2012Inngår i: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, nr 2, s. 418-420Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Excitotoxicity is thought to play a pathogenic role in amyotrophic lateral sclerosis (ALS). Excitotoxic motor neuron death is mediated through the Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type of glutamate receptors and Ca(2+) permeability is determined by the GluR2 subunit. We investigated whether polymorphisms or mutations in the GluR2 gene (GRIA2) predispose patients to ALS. Upon sequencing 24 patients and 24 controls no nonsynonymous coding variants were observed but 24 polymorphisms were identified, 9 of which were novel. In a screening set of 310 Belgian ALS cases and 794 healthy controls and a replication set of 3157 cases and 5397 controls from 6 additional populations no association with susceptibility, age at onset, or disease duration was observed. We conclude that polymorphisms in the GluR2 gene (GRIA2) are not a major contributory factor in the pathogenesis of ALS.

  • 118. Bolin, Kristian
    et al.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    The Cost Effectiveness of Newer Epilepsy Treatments A Review of the Literature on Partial-Onset Seizures2012Inngår i: PharmacoEconomics (Auckland), ISSN 1170-7690, E-ISSN 1179-2027, Vol. 30, nr 10, s. 903-923Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Background and Objective: Epilepsy is one of the most common neurological disorders, affecting more than 3 million people in Europe. This paper reviews the published evidence regarding the cost effectiveness of second-generation antiepileptic drugs (AEDs). Methods: A systematic literature search was performed, using the databases Academic Search Complete, Econlit, EMBASE and MEDLINE. Health economic evaluations of newer (second-generation) AEDs, published as full-length journal articles, were searched for. We focused on evaluations of newer AEDs as treatment for partial-onset seizures. 470 studies were initially identified and 19 were finally included. Information regarding (i) AEDs studied, (ii) cost effectiveness, and (iii) a variety of health economic modelling specifics was extracted from each study. Then, the included studies were summarized and a quality assessment was performed, according to the British Medical Journal's guidelines for economic studies. Results: The results were as follows: (i) the cost per additional QALY for newer AEDs used as adjunctive treatment, compared with standard therapy, ranged between $US19 139 (levetiracetam) and $US57 210 (pregabalin) [year 2010 values]; no cost-effectiveness evidence was identified for felbamate, eslicarbazepine, oxcarbazepine or tiagabine; and (ii) all studies met at least 60% of the British Medical Journal's guidelines criteria, and seven studies were found to satisfy more than 80% of the criteria. Guidelines criteria not met involve inadequate reporting of input data and modelling details, including validation and availability of models used for cost-effectiveness calculations. Conclusions: Although failure to meet good practice guidelines influences the reliability of the presented evidence adversely, a sufficient number of the included studies were found to comply enough with the guidelines in order for the qualitative content of the cost-effectiveness results that some of the newer AEDs are cost effective to be reliable. In fact, this conclusion is likely to be relatively robust, since the effect of improved seizure control on labour market performance was not included in the base-case results in any of the included studies and improved seizure control need only to have a moderate effect on sickness absenteeism in order for the corresponding treatment to be cost effective even when willingness to pay for an additional QALY is low. However, the cost effectiveness of newer AEDs has only been studied for a small number of settings, and hence future studies incorporating additional settings are needed.

  • 119. Bondy, Melissa
    et al.
    Bainbridge, Matthew
    Jhangiani, Shalini
    Jalali, Ali
    Plon, Sharon E.
    Armstrong, Georgina
    Bernstein, Jonine
    Claus, Elizabeth
    Davis, Faith
    Houlston, Richard
    Il'yasova, Dora
    Jenkins, Robert
    Johansen, Christoffer
    Lachance, Daniel
    Lai, Rose
    Lau, Ching
    Merrell, Ryan
    Olson, Sara
    Sadetzki, Siegal
    Schildkraut, Joellen
    Shete, Sanjay
    Barnholtz-Sloan, Jill
    Wrensch, Margaret
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Gibbs, Richard A.
    POT1 GERMLINE MUTATIONS MAY EXPLAIN A SUBSET OF FAMILIAL GLIOMA: A REPORT FROM THE GLIOGENE CONSORTIUM2013Inngår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 15, nr Supplement: 3, s. 89-89Artikkel i tidsskrift (Annet vitenskapelig)
  • 120.
    Boremalm, Malin
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Natalizumab, rituximab and fingolimod as escalation therapy in multiple sclerosis2018Independent thesis Basic level (professional degree), 20 poäng / 30 hpOppgave
  • 121.
    Boremalm, Malin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Juto, A.
    Axelsson, M.
    Novakova, L.
    Frisell, T.
    Svenningsson, A.
    Lycke, J.
    Piehl, F.
    Salzer, Jonatan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Natalizumab, rituximab and fingolimod as escalation therapy in multiple sclerosis2019Inngår i: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 26, nr 8, s. 1060-1067Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and purpose: Breakthrough disease on first-line injectables in relapsing-remitting multiple sclerosis (RRMS) is a common clinical situation where comparative studies between different escalation therapies are lacking. The aim of this study was to compare the efficacy, safety and medication persistence of natalizumab (NTZ), rituximab (RTX) and fingolimod (FGL) as escalation therapy in RRMS.

    Methods: Patients switching from interferon or glatiramer acetate to NTZ, RTX or FGL due to breakthrough disease were identified through the Swedish multiple sclerosis (MS) registry at four large MS centers in this retrospective observational study. Data were collected from the MS registry and medical charts. Hazard ratios (HRs) for relapses, adverse events and drug discontinuation with 95% confidence interval (CI) were calculated using multivariable confounder-adjusted Cox proportional hazard models.

    Results: A total of 241 patients were included. The annualized relapse rates were 0.02 for NTZ, 0.03 for RTX and 0.07 for FGL. Compared with NTZ, the adjusted HR for relapse was 1.0 (95% CI, 0.2-5.6) for RTX and 3.4 (95% CI, 1.3-9.2) for FGL. The annualized drug discontinuation rates were 0.15, 0.01 and 0.15 for NTZ, RTX and FGL, respectively. The adjusted HR for drug discontinuation was 0.05 (95% CI, 0.01-0.38) for RTX and 1.0 (95% CI, 0.6-1.7) for FGL vs. NTZ.

    Conclusions: In patients with RRMS on interferon/glatiramer acetate with breakthrough disease, switching to NTZ or RTX was associated with less disease activity compared with FGL. RTX displayed superior medication persistence compared with both NTZ and FGL.

  • 122.
    Brammås, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Jakobsson, Stina
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Ulvenstam, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Internal Medicine, Section of Cardiology, Östersund Hospital, Sweden.
    Mooe, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Mortality After Ischemic Stroke in Patients With Acute Myocardial Infarction Predictors and Trends Over Time in Sweden2013Inngår i: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 44, nr 11, s. 3050-3055Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and Purpose Acute myocardial infarction (AMI) increases the risk of ischemic stroke, and mortality among these patients is high. Here, we aimed to estimate the 1-year mortality reliably after AMI complicated by ischemic stroke. We also aimed to identify trends over time for mortality during 1998-2008, as well as factors that predicted increased or decreased mortality. Methods Data for 173 233 unselected patients with AMI were collected from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admissions registry for 1998-2008. Specifically, we analyzed 1-year follow-up and mortality data for patients with AMI with and without ischemic stroke. Kaplan-Meyer analysis was used to analyze mortality trends over time, and Cox regression analysis was used to identify uni- and multivariate predictors of mortality. Results The 1-year mortality was 36.5% for AMI complicated by ischemic stroke and 18.3% for AMI without stroke. Mortality decreased over time in patients with and without ischemic stroke. The absolute decreases in mortality were 9.4% and 7.5%, respectively. Reperfusion and secondary preventive therapies were associated with a decreased mortality rate. Conclusions Mortality after AMI complicated by an ischemic stroke is very high but decreased from 1998 to 2008. The increased use of evidence-based therapies explains the improved prognosis.

  • 123. Brenner, David
    et al.
    Mueller, Kathrin
    Wieland, Thomas
    Weydt, Patrick
    Boehm, Sarah
    Lule, Dorothee
    Huebers, Annemarie
    Neuwirth, Christoph
    Weber, Markus
    Borck, Guntram
    Wahlqvist, Magnus
    Danzer, Karin M.
    Volk, Alexander E.
    Meitinger, Thomas
    Strom, Tim M.
    Otto, Markus
    Kassubek, Jan
    Ludolph, Albert C.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap. Neurology Department, Ulm University, Ulm, Germany.
    Weishaupt, Jochen H.
    NEK1 mutations in familial amyotrophic lateral sclerosis2016Inngår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 139, s. CP14-CP17Artikkel i tidsskrift (Fagfellevurdert)
  • 124. Brenner, P.
    et al.
    Burkill, S.
    Jokinen, Jussi
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Moore, A.
    Geissbuehler, Y.
    Hillert, J.
    Bahmanyar, S.
    Montgomery, S.
    Multiple sclerosis and risk of completed and attempted suicide - a national cohort study2015Inngår i: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 21, s. 23-24Artikkel i tidsskrift (Annet vitenskapelig)
  • 125. Brenner, Philip
    et al.
    Granqvist, Mathias
    Königsson, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Al Nimer, Faiez
    Piehl, Fredrik
    Jokinen, Jussi
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Division of Psychiatry, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Depression and fatigue in multiple sclerosis: Relation to exposure to violence and cerebrospinal fluid immunomarkers2018Inngår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 89, s. 53-58Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Multiple sclerosis (MS) is a neuroinflammatory condition characterized by chronic dysregulation of immune responses leading to repeated episodes of inflammation in the central nervous system. Depression and fatigue are common among MS patients, even in early disease phases, and the disease course can be negatively affected by stressful events. IL-6 and IL-8 have been associated with depression and stressful life events in non-MS patients. The aim of this study was to examine the relationships between depression, fatigue, and exposure to violence, with IL-6 and IL-8 levels in the cerebrospinal fluid (CSF) of MS patients. Levels of IL-6 and -8 were analyzed in the CSF of 47 patients with relapsing-remitting MS. Correlations between IL-6 and IL-8 levels and self-rated depression and fatigue symptoms, as well as clinician-rated history of being exposed to interpersonal violence, were analyzed with correction for age, sex and MS disability status. IL-6 correlated significantly (p < 0.05) with depressive symptoms (adjusted Spearman’s ρ = 0.39), fatigue (ρ = 0.39), and exposure to violence in adult life (ρ = 0.35). Depression correlated with both fatigue and being exposed to violence. Associations were not present among patients exposed to disease modifying drugs. In exploratory analyses, the relationship between exposure to violence and IL-6 was non-significant when controlled for depression. Further research should focus on replication of these results, as well as exploring the impact of stressful life events on immune regulation and the clinical characteristics and prognosis of MS patients.

  • 126. Broom, Wendy J
    et al.
    Johnson, D V
    Auwarter, K E
    Iafrate, A J
    Russ, C
    Al-Chalabi, A
    Sapp, P C
    McKenna-Yasek, D
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Brown, R H
    SOD1A4V-mediated ALS: absence of a closely linked modifier gene and origination in Asia2008Inngår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 430, nr 3, s. 241-245Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS. Approximately 20% of cases are due to mutations in the Cu/Zn superoxide dismutase gene (SOD1). In North America, SOD1(A4V) is the most common SOD1 mutation. Carriers of the SOD1(A4V) mutation share a common phenotype with rapid disease progression and death on average occurring at 1.4 years (versus 3-5 years with other dominant SOD1 mutations). Previous studies of SOD1(A4V) carriers identified a common haplotype around the SOD1 locus, suggesting a common founder for most SOD1(A4V) patients. In the current study we sequenced the entire common haplotypic region around SOD1 to test the hypothesis that polymorphisms in either previously undescribed coding regions or non-coding regions around SOD1 are responsible for the more aggressive phenotype in SOD1(A4V)-mediated ALS. We narrowed the conserved region around the SOD1 gene in SOD1(A4V) ALS to 2.8Kb and identified five novel SNPs therein. None of these variants was specifically found in all SOD1(A4V) patients. It therefore appears likely that the aggressive nature of the SOD1(A4V) mutation is not a result of a modifying factor within the region around the SOD1 gene. Founder analysis estimates that the A4V mutation occurred 540 generations (approximately 12,000 years) ago (95% CI 480-700). The conserved minimal haplotype is statistically more similar to Asian than European population DNA sets, suggesting that the A4V mutation arose in native Asian-Americans who reached the Americas through the Bering Strait.

  • 127. Broom, Wendy J
    et al.
    Johnson, Daniel V
    Garber, Manuel
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Lennon, Niall
    Landers, John
    Nusbaum, Chad
    Russ, Carsten
    Brown, Robert H
    DNA sequence analysis of the conserved region around the SOD1 gene locus in recessively inherited ALS2009Inngår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 463, nr 1, s. 64-69Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 128.
    Brynolfsson, Joel
    et al.
    Swedish Defence Research Agency (FOI).
    Högberg, Johanna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för datavetenskap.
    Kaati, Lisa
    Swedish Defence Research Agency (FOI).
    Mårtensson, Christian
    Swedish Defence Research Agency (FOI).
    Svenson, Pontus
    Swedish Defence Research Agency (FOI).
    Abstraction techniques for social networks2010Inngår i: Proceedings of the 2010 International Conference on Advances in Social Networks Analysis and Mining, IEEE, 2010Konferansepaper (Fagfellevurdert)
  • 129. Brys, Ivani
    et al.
    Halje, Par
    Scheffer-Teixeira, Robson
    Varney, Mark
    Newman-Tancredi, Adrian
    Petersson, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Integrative Neurophysiology and Neurotechnology, Neuronano Research Center, Department of Experimental Medical Sciences, Lund University, Sweden.
    Neurophysiological effects in cortico-basal ganglia-thalamic circuits of antidyskinetic treatment with 5-HT1A receptor biased agonists2018Inngår i: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 302, s. 155-168Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recently, the biased and highly selective 5-HT1A agonists, NLX-112, F13714 and F15599, have been shown to alleviate dyskinesia in rodent and primate models of Parkinson's disease, while marginally interfering with antiparkinsonian effects of levodopa. To provide more detailed information on the processes underlying the alleviation of dyskinesia, we have here investigated changes in the spectral contents of local field potentials in cortico-basal ganglia-thalamic circuits following treatment with this novel group of 5-HT1A agonists or the prototypical agonist, 8-OH-DPAT. Dyskinetic symptoms were consistently associated with 80 Hz oscillations, which were efficaciously suppressed by all 5-HT1A agonists and reappeared upon co-administration of the antagonist, WAY100635. At the same time, the peak-frequency of fast 130 Hz gamma oscillations and their cross-frequency coupling to low-frequency delta oscillations were modified to a different extent by each of the 5-HT1A agonists. These findings suggest that the common antidyskinetic effects of these drugs may be chiefly attributable to a reversal of the brain state characterized by 80 Hz gamma oscillations, whereas the differential effects on fast gamma oscillations may reflect differences in pharmacological properties that might be of potential relevance for non-motor symptoms.

  • 130.
    Brännström, Thomas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Bergh, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Ekhtiari Bidhendi, Elaheh
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Marklund, Stefan M.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Mutant SOD1 aggregates from human ventral horn transmit templated aggregation and fatal ALS-like disease2019Inngår i: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 29, s. 90-90Artikkel i tidsskrift (Annet vitenskapelig)
  • 131.
    Bråndal, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin. Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Fysioterapi.
    Eriksson, Marie
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Glader, Eva-Lotta
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Wester, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin. Department of Clinical Sciences, Karolinska Institute, Danderyd hospital, Stockholm, Sweden.
    Effect of early supported discharge after stroke on patient reported outcome based on the Swedish Riksstroke registry2019Inngår i: BMC Neurology, ISSN 1471-2377, E-ISSN 1471-2377, Vol. 19, artikkel-id 40Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The efficacy of early supported discharge (ESD) has not been tested in current stroke care setting, which provide relatively short hospital stays, access to hyper-acute therapies and early carotid stenosis interventions. This study aimed to compare patient-reported outcome measures (PROM) among patients with stroke that received modern stroke unit care with or without ESD.

    Methods: Observational study of 30,232 patients with first-ever stroke registered in the Riksstroke registry in Sweden, between 1 January 2010 and 31 December 2013. Patient characteristics were collected from the Riksstroke and Statistics Sweden databases. The primary outcome was satisfaction with the rehabilitation at 3 months after discharge. Secondary outcome were information about stroke provided, tiredness/fatigue, pain, dysthymia/ depression, general health status and dependence in activities of daily living (mobility, toileting and dressing) at 3 months after the stroke. We used separate multivariable logistic regression models for each PROM variable to analyze associations between PROMs and ESD/no ESD.

    Results: The ESD group comprised 1495 participants: the control group comprised 28,737 participants. Multivariable logistic regression models of PROMs showed that, compared to controls, the ESD group was more satisfied with rehabilitation after discharge (OR: 1.78, 95% CI: 1.17–2.49), experienced less dysthymia/depression (OR: 0.68, 95% 0.55–0.84) and showed more independence in mobility (OR: 1.50, 95% CI: 1.17–1.92), toileting (OR: 1.30, 95%CI: 1.05–1.61), and dressing (OR: 1.23, 95%CI: 1.02–1.48).

    Conclusion: In the setting of modern stroke unit care, ESD appeared to have positive effects on stroke rehabilitation, in the subacute phase.

  • 132. Burgunder, J-M
    et al.
    Schöls, L
    Baets, J
    Andersen, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Gasser, T
    Szolnoki, Z
    Fontaine, B
    Van Broeckhoven, C
    Di Donato, S
    De Jonghe, P
    Lynch, T
    Mariotti, C
    Spinazzola, A
    Tabrizi, S J
    Tallaksen, C
    Zeviani, M
    Harbo, H F
    Finsterer, J
    EFNS guidelines for the molecular diagnosis of neurogenetic disorders: motoneuron, peripheral nerve and muscle disorders2011Inngår i: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 18, nr 2, s. 207-E20Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 133. Burkhardt, Christian
    et al.
    Neuwirth, Christoph
    Sommacal, Andreas
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Weber, Markus
    Is survival improved by the use of NIV and PEG in amyotrophic lateral sclerosis (ALS)?: A post-mortem study of 80 ALS patients2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 5, artikkel-id e0177555Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Non-invasive ventilation (NIV) and percutaneous gastrostomy (PEG) are guideline-recommended interventions for symptom management in amyotrophic lateral sclerosis (ALS). Their effect on survival is controversial and the impact on causes of death is unknown.

    Objective: To investigate the effect of NIV and PEG on survival and causes of death in ALS patients.

    Methods: Eighty deceased ALS patients underwent a complete post mortem analysis for causes of death between 2003 and 2015. Forty-two of these patients consented for genetic testing. Effects of NIV and PEG on survival and causes of death were analyzed in a multivariable Cox proportional hazard regression.

    Results: Six patients, who requested assisted suicide causing drug-induced hypoxia, were excluded from final analysis. Respiratory failure was the main cause of death in 72 out of 74 patients. Fifteen out of 74 died of aspiration pneumonia 23/74 of bronchopneumonia and 8/74 of a combination of aspiration pneumonia and bronchopneumonia. Twenty died of hypoxia without concomitant infection, and six patients had pulmonary embolism alone or in combination with pneumonia. NIV (p = 0.01) and PEG (p<0.01) had a significant impact on survival. In patients using NIV bronchopneumonia was significantly more frequent (p <0.04) compared to non-NIV patients. This effect was even more pronounced in limb onset patients (p<0.002). Patients with C9orf72 hexanucleotide repeat expansions showed faster disease progression and shorter survival (p = 0.01).

    Conclusion: The use of NIV and PEG prolongs survival in ALS. This study supports current AAN and EFNS guidelines which recommend NIV and PEG as a treatment option in ALS. The risk of bronchopneumonia as cause of death may be increased by NIV.

  • 134. Burman, Joachim
    et al.
    Iacobaeus, Ellen
    Svenningsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Lycke, Jan
    Gunnarsson, Martin
    Nilsson, Petra
    Vrethem, Magnus
    Fredrikson, Sten
    Martin, Claes
    Sandstedt, Anna
    Uggla, Bertil
    Lenhoff, Stig
    Johansson, Jan-Erik
    Isaksson, Cecilia
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Hägglund, Hans
    Carlson, Kristina
    Fagius, Jan
    Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience2014Inngår i: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 85, nr 10, s. 1116-1121Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive multiple sclerosis (MS). No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated patients constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish patients treated with HSCT for MS. METHODS: Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two patients were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 patients had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 patients (83%) had relapsing-remitting MS, and mean follow-up time was 47 months. RESULTS: At 5 years, relapse-free survival was 87%; MRI event-free survival 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%). CONCLUSIONS: HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres.

  • 135. Burman, Joachim
    et al.
    Svenningsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Cerebrospinal fluid concentration of Galectin-9 is increased in secondary progressive multiple sclerosis2016Inngår i: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 292, s. 40-44Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Galectin-9 is produced by activated astrocytes, induces a pro -inflammatory response in microglia and maybe important to the pathogenesis of secondary progressive MS. In this study, Galectin-9 concentrations in CSF samples from healthy controls and two independent patient cohorts of MS patients were determined by ELISA. Patients from one of the cohorts underwent MRI as well. Galectin-9 concentrations in CSF were higher in SPMS patients than healthy controls and RRMS patients in both cohorts. Galectin-9 concentrations correlated with the number of lesions on Tl-weighted images, but not with gadolinium enhancing lesions, IgG index or CSF cell count.

  • 136.
    Bäckman, Lars
    et al.
    Aging Research Center, Karolinska Institutet, Gävlegatan 16, SE-113 30 Stockholm, Sweden.
    Karlsson, Sari
    Aging Research Center, Karolinska Institutet, Gävlegatan 16, SE-113 30 Stockholm, Sweden.
    Fischer, Håkan
    Aging Research Center, Karolinska Institutet, Gävlegatan 16, SE-113 30 Stockholm, Sweden.
    Karlsson, Per
    Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden.
    Brehmer, Yvonne
    Aging Research Center, Karolinska Institutet, Gävlegatan 16, SE-113 30 Stockholm, Sweden.
    Rieckmann, Anna
    Aging Research Center, Karolinska Institutet, Gävlegatan 16, SE-113 30 Stockholm, Sweden.
    Macdonald, Stuart WS
    Aging Research Center, Karolinska Institutet, Gävlegatan 16, SE-113 30 Stockholm, Sweden; Department of Psychology, University of Victoria, Canada .
    Farde, Lars
    Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden.
    Nyberg, Lars
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Dopamine D(1) receptors and age differences in brain activation during working memory2011Inngår i: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 32, nr 10, s. 1849-1856Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In an fMRI study, 20 younger and 20 healthy older adults were scanned while performing a spatial working-memory task under two levels of load. On a separate occasion, the same subjects underwent PET measurements using the radioligand [(11)C] SCH23390 to determine dopamine D(1) receptor binding potential (BP) in caudate nucleus and dorsolateral prefrontal cortex (DLPFC). The fMRI study revealed a significant load modulation of brain activity (higher load>lower load) in frontal and parietal regions for younger, but not older, adults. The PET measurements showed marked age-related reductions of D(1) BP in caudate and DLPFC. Statistical control of caudate and DLPFC D(1) binding eliminated the age-related reduction in load-dependent BOLD signal in left frontal cortex, and attenuated greatly the reduction in right frontal and left parietal cortex. These findings suggest that age-related alterations in dopaminergic neurotransmission may contribute to underrecruitment of task-relevant brain regions during working-memory performance in old age.

  • 137.
    Bäckström, David C
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Eriksson Domellöf, Magdalena
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Linder, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Olsson, Bob
    Öhrfelt, Annika
    Trupp, Miles
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Zetterberg, Henrik
    Blennow, Kaj
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Cerebrospinal Fluid Patterns and the Risk of Future Dementia in Early, Incident Parkinson Disease2015Inngår i: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 72, nr 10, s. 1175-1182Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 138.
    Bäckström, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Eriksson Domellöf, Magdalena
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Granåsen, Gabriel
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Linder, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Mayans, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Elgh, Eva
    Umeå universitet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Jakobson Mo, Susanna
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    PITX3 genotype and risk of dementia in Parkinson's disease: A population-based study2017Inngår i: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 381, s. 278-284Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dementia is a devastating manifestation of Parkinson's disease (PD). This study investigates whether a common polymorphism in the PITX3 gene (rs2281983), which is of importance for the function of dopaminergic neurons, affects the risk of developing dementia in PD and whether it affects dopamine transporter (DAT) uptake. We PITX3 genotyped 133 patients with new-onset, idiopathic PD, participating in a population-based study in Sweden. Patients were followed prospectively during 6-11 years with extensive investigations, including neuropsychology and DAT-imaging with I-123 FP-CIT. The primary outcome was the incidence of PD dementia (PDD), diagnosed according to published criteria, studied by the Kaplan-Meier method and Cox proportional hazards. Performance in individual cognitive domains, the incidence of visual hallucinations, disease progression and striatal DAT uptake on imaging was also investigated. PD patients carrying the PITX3 C allele had an increased risk of developing PDD (hazard ratio: 2.87, 95% CI: 1.42-5.81, p = 0.003), compared to the PD patients homozygous for the T-allele. Furthermore, the PITX3 C allele carriers with PD had a poorer cognitive performance in the visuospatial domain (p < 0.001) and a higher incidence of visual hallucinations. A trend towards a lower striatal DAT uptake in the PITX3 C allele carriers was suggested, but could not be confirmed. Our results show that a common polymorphism in the PITX3 gene affects the risk of developing PDD and visuospatial dysfunction in idiopathic PD. If validated, these findings can provide new insights into the neurobiology and genetics of non-motor symptoms in PD.

  • 139.
    Bäckström, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Eriksson Domellöf, Magdalena
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Granåsen, Gabriel
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Linder, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Mayans, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Elgh, Eva
    Umeå universitet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Zetterberg, H.
    Blennow, K.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Polymorphisms in dopamine-associated genes and cognitive decline in Parkinson's disease2018Inngår i: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 137, nr 1, s. 91-98Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: Cognitive decline is common in Parkinson's disease (PD), but the underlying mechanisms for this complication are incompletely understood. Genotypes affecting dopamine transmission may be of importance. This study investigates whether genotypes associated with reduced prefrontal dopaminergic tone and/or reduced dopamine D2-receptor availability (Catechol-O-methyltransferase [COMT] Val(158)Met genotype and DRD2 (CT)-T-957 genotype) affect the development of cognitive deficits in PD.

    Materials and methods: One hundred and 34 patients with idiopathic PD, participating in a regional, population-based study of incident parkinsonism, underwent genotyping. After extensive baseline investigations (including imaging and biomarker analyses), the patients were followed prospectively during 6-10 years with neuropsychological evaluations, covering six cognitive domains. Cognitive decline (defined as the incidence of either Parkinson's disease mild cognitive impairment [PD-MCI] or dementia [PDD], diagnosed according to published criteria and blinded to genotype) was studied as the primary outcome.

    Results: Both genotypes affected cognition, as shown by Cox proportional hazards models. While the COMT(158)Val/Val genotype conferred an increased risk of mild cognitive impairment in patients with normal cognition at baseline (hazard ratio: 2.13, P=.023), the DRD2(957)T/T genotype conferred an overall increased risk of PD dementia (hazard ratio: 3.22, P<.001). The poorer cognitive performance in DRD2(957)T/T carriers with PD occurred mainly in episodic memory and attention.

    Conclusions: The results favor the hypothesis that dopamine deficiency in PD not only relate to mild cognitive deficits in frontostriatal functions, but also to a decline in memory and attention. This could indicate that dopamine deficiency impairs a wide network of brain areas.

  • 140.
    Bäckström, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Granåsen, Gabriel
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Eriksson Domellöf, Magdalenax
    Umeå universitet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi. Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Linder, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Jakobson Mo, Susanna
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi. Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI).
    Riklund, Katrine
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi. Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI).
    Zetterberg, Henrik
    Blennow, Kaj
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Early predictors of mortality in parkinsonism and Parkinson disease: A population-based study2018Inngår i: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 91, nr 22, s. E2045-E2056Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective To examine mortality and associated risk factors, including possible effects of mild cognitive impairment, imaging, and CSF abnormalities, in a community-based population with incident parkinsonism and Parkinson disease. Methods One hundred eighty-two patients with new-onset, idiopathic parkinsonism were diagnosed from January 2004 through April 2009, in a catchment area of 142,000 inhabitants in Sweden. Patients were comprehensively investigated according to a multimodal research protocol and followed prospectively for up to 13.5 years. A total of 109 patients died. Mortality rates in the general Swedish population were used to calculate standardized mortality ratio and expected survival, and Cox proportional hazard models were used to investigate independent predictors of mortality. Results The standardized mortality ratio for all patients was 1.84 (95% confidence interval 1.50-2.22, p < 0.001). Patients with atypical parkinsonism (multiple system atrophy or progressive supranuclear palsy) had the highest mortality. In early Parkinson disease, a mild cognitive impairment diagnosis, freezing of gait, hyposmia, reduced dopamine transporter activity in the caudate, and elevated leukocytes in the CSF were significantly associated with shorter survival. Conclusion Although patients presenting with idiopathic parkinsonism have reduced survival, the survival is highly dependent on the type and characteristics of the parkinsonian disorder. Patients with Parkinson disease presenting with normal cognitive function seem to have a largely normal life expectancy. The finding of a subtle CSF leukocytosis in patients with Parkinson disease with short survival may have clinical implications.

  • 141.
    Bäckström, Torbjörn
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Bixo, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Nyberg, Sigrid
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Savic, Ivanka
    Increased neurosteroid sensitivity - An explanation to symptoms associated with chronic work related stress in women?2013Inngår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 38, nr 7, s. 1078-1089Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Work related psychosocial stress can be accompanied by so called burnout syndrome with symptoms of mental exhaustion, physical fatigue, and cognitive dysfunction. Underlying mechanisms for acquiring burnout syndrome are not clear. Animal studies show that chronic stress is associated with altered release of GABA-A receptor modulating steroids (GAMS), altered composition of the GABA-A receptor and altered sensitivity to GAMS. In the present study we investigated if such changes occur in women with burnout syndrome. We further asked whether flumazenil (a benzodiazepine antagonist, but with positive modulating effects on GABA-A receptors with altered subunit composition) can block the effect of the GAMS allopregnanolone. Ten women with occupational psychosocial stress and burnout syndrome were compared with twelve healthy controls in an experimental setting. Saccadic eye velocity (SEV) was measured after an injection of allopregnanolone, followed by an injection of flumazenil and a second injection of allopregnanolone. The sensitivity to allopregnanolone was significantly higher in the patients compared to controls after the first injection (p = 0.04) and the difference increased when the response per allopregnanolone concentration unit was compared ( p = 0.006). Following the flumazenil injection the burnout patients (p= 0.016), but not controls, showed a decrease in SEV and flumazenil acted like a positive modulator that is agonistic. There was no significant difference between the groups after second allopregnanolone injection. In conclusion, patients with work related psychosocial stress and burnout syndrome show a different response to GABA-A receptor modulators than controls suggesting a changed GABA-A receptor function in these patients. More precisely we hypothesize that the alpha 4 and delta subunits are up-regulated elevating the responsiveness to allopregnanolone and change the effect of flumazenil, which provides a potential explanation to the burnout syndrome. Flumazenil does not block the effect of allopregnanolone.

  • 142.
    Bäckström, Torbjörn
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Haage, D.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Löfgren, Mats
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Johansson, I. M.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Strömberg, J.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Nyberg, S.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Andreen, Lotta
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Ossewaarde, L.
    van Wingen, G. A.
    Turkmen, Sahruh
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Bengtsson, S. K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons2011Inngår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 191, nr Special issue, s. 46-54Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

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

  • 143. Cadilhac, Dominique A.
    et al.
    Amatya, Bhasker
    Lalor, Erin
    Rudd, Anthony
    Lindsay, Patrice
    Asplund, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Is There Evidence That Performance Measurement in Stroke Has Influenced Health Policy and Changes to Health Systems?2012Inngår i: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 43, nr 12, s. 3413-3420Artikkel, forskningsoversikt (Fagfellevurdert)
  • 144. Cantoni, Claudia
    et al.
    Bollman, Bryan
    Licastro, Danilo
    Xie, Mingqiang
    Mikesell, Robert
    Schmidt, Robert
    Yuede, Carla M.
    Galimberti, Daniela
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Klein, Robyn S.
    Cross, Anne H.
    Otero, Karel
    Piccio, Laura
    TREM2 regulates microglial cell activation in response to demyelination in vivo2015Inngår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 129, nr 3, s. 429-447Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage.

  • 145. Capelle, Hans-Holger
    et al.
    Blahak, Christian
    Schrader, Christoph
    Baezner, Hansjoerg
    Hariz, Marwan I.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Bergenheim, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Krauss, Joachim K.
    Bilateral deep brain stimulation for cervical dystonia in patients with previous peripheral surgery2012Inngår i: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 27, nr 2, s. 301-304Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: There are no data available concerning whether patients with cervical dystonia who have recurrent or new symptoms after peripheral denervation surgery benefit similarly from pallidal deep brain stimulation compared with patients who receive primarily pallidal stimulation. Methods: Data on 7 cervical dystonia patients with recurrent or progressive dystonia after peripheral denervation who underwent pallidal stimulation were prospectively collected. Deep brain stimulation was performed in Mannheim/ Hannover, Germany, or in Umea, Sweden. To the subgroup from Mannheim/Hannover, a second group of patients without previous peripheral surgery was matched. Assessments included the Toronto Western Spasmodic Torticollis Rating Scale and the Burke-FahnMarsden dystonia rating scale, as well as the Tsui scale in the Swedish patients. Results: The 4 patients from Mannheim/Hannover experienced sustained improvement from pallidal stimulation by a mean of 57.5% according to the Toronto Western Spasmodic Torticollis Rating Scale (P <.05) and by a mean of 69.5% according to the Burke-FahnMarsden dystonia rating scale (P <.05) at long-term follow-up of 40.5 months. The patients from Umea had a mean Tsui score of 7 prior to surgery and a mean score of 3 at the mean follow-up of 8 months (62.5%). In the matched group the Toronto Western Spasmodic Torticollis Rating Scale improved by 58.8% and the Burke-Fahn-Marsden dystonia rating scale by 67% (P <.05) at long-term follow-up (mean, 41.5 months). Conclusions: Patients who had prior peripheral surgery for cervical dystonia experience improvement from subsequent pallidal stimulation that is comparable to that of de novo patients. (C) 2011 Movement Disorder Society

  • 146. Carew, J. D.
    et al.
    Nair, G.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Wuu, J.
    Gronka, S.
    Hu, X.
    Benatar, M.
    Presymptomatic spinal cord neurometabolic findings in SOD1-positive people at risk for familial ALS2011Inngår i: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 77, nr 14, s. 1370-1375Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

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

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

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

  • 147.
    Carlsson, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Nylander, P-O
    Hellman, Urban
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Forsman-Semb, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Holmgren, Gösta
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Holmberg, Monica
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Identification of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1.2002Inngår i: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 59, nr 11, s. 1804-1807Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Migraine is the most common type of chronic episodic headache. To find novel susceptibility genes for familial migraine with and without aura, a genomewide screen was performed in a large family from northern Sweden. Evidence of linkage was obtained on chromosome 6p12.2-p21.1, with a maximum two-point lod score of 5.41 for marker D6S452. The patients with migraine shared a common haplotype of 10 Mb between markers D6S1650 and D6S1960.

  • 148.
    Carlsson, Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Yu, Ji-Guo
    Department of Natural and Environmental Physiology, Mid Sweden University.
    Moza, Monica
    Department of Pathology and Neuroscience Program, Biomedicum Helsinki, University of Helsinki and University Central Hospital, Finland.
    Carpén, Olli
    Department of Pathology, University of Turku and Turku University Central Hospital, Finland.
    Thornell, Lars-Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Myotilin: a prominent marker of myofibrillar remodelling2007Inngår i: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 17, nr 1, s. 61-68Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Myofibrillar remodelling with insertion of sarcomeres is a typical feature of biopsies taken from persons suffering of exercise-induced delayed onset muscle soreness. Here we studied the presence of the sarcomeric protein myotilin in eccentric exercise related lesions. Myotilin is a component of sarcomeric Z-discs and it binds several other Z-disc proteins, i.e. alpha-actinin, filamin C, F-actin and FATZ. Myotilin has previously been shown to be present in nemaline rods and central cores and to be mutated in limb girdle muscular dystrophy 1A (LGMD1A) and in a subset of myofibrillar myopathies, indicating an important role in Z-disc maintenance. Our findings on non-diseased muscle affected by eccentric exercise give new information on how myotilin is associated to myofibrillar components upon remodelling. We show that myotilin was present in increased amount in lesions related to Z-disc streaming and events leading to insertion of new sarcomeres in pre-existing myofibrils and can therefore be used as a marker for myofibrillar remodelling. Interestingly, myotilin is preferentially associated with F-actin rather than with the core Z-disc protein alpha-actinin during these events. This suggests that myotilin has a key role in the dynamic molecular events mediating myofibrillar assembly in normal and diseased skeletal muscle.

  • 149. Cenci, M. Angela
    et al.
    Jörntell, Henrik
    Petersson, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). The Group for Integrative Neurophysiology and Neurotechnology, Neuronano Research Centre, Department Experimental Medical Science, Lund University, Lund, Sweden.
    On the neuronal circuitry mediating l-DOPA-induced dyskinesia2018Inngår i: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 125, nr 8, s. 1157-1169Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

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

  • 150. Ceulemans, Shana
    et al.
    De Zutter, Sonia
    Heyrman, Lien
    Norrback, Karl-Fredrik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Nordin, Annelie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Nilsson, Lars-Goran
    Adolfsson, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Del-Favero, Jurgen
    Claes, Stephan
    Evidence for the involvement of the glucocorticoid receptor gene in bipolar disorder in an isolated northern Swedish population2011Inngår i: Bipolar Disorders, ISSN 1398-5647, E-ISSN 1399-5618, Vol. 13, nr 7-8, s. 614-623Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

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

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

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

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