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  • 51.
    Jakobson Mo, Susanna
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Cross-camera comparison of ROI-based semi-quantitative 123I-IBZM SPECT data in healthy volunteers using an anthropomorphic phantom for calibration2013In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 54, no 5, p. 549-556Article in journal (Refereed)
    Abstract [en]

    Background In (123)I-Iolopride (IBZM) SPECT reference values may diverge between camera systems. If multicenter pooling of normal material databases is needed, differences in measured semi-quantitative data due to equipment performance and reconstruction parameters have to be investigated in each instance to determine the comparability.

    Purpose To explore the differences in (123)I-IBZM measured uptake ratios between two different gamma cameras in healthy controls, the intra-rater reproducibility of the image evaluation method and the possibility to equalize uptake ratios by calibration through an anthropomorphic phantom.

    Material and Methods Differences in ROI-based semi-quantitative data from two different gamma camera systems, the three-headed brain dedicated Neurocam and the two-headed multipurpose hybrid system Infinia Hawkeye, were studied using image data from a group of healthy volunteers and an anthropomorphic brain-phantom scanned with both cameras. Several reconstruction methods and corrections were applied. To test the reliability of the ROI method, the intra-observer reproducibility was determined for the ROI method in this study.

    Results The ROI method had a high reliability. Differences in mean measured uptake (123)I-IBZM ratios in healthy controls varied between 2.9% and 6.5% depending on reconstruction and correction for attenuation and scatter. After calibration, the differences decreased. There were no statistically significant differences between corrected ratios from the two camera systems in the study when images were reconstructed with attenuation correction.

    Conclusion The conformity of uptake ratios in attenuation corrected (123)I-IBZM images derived from the two different cameras was improved by using an anthropomorphic phantom for calibration.

  • 52.
    Jakobson Mo, Susanna
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Edenbandt, Lars
    Göteborgs Universitet, Avdelningen för molekylär och klinisk medicin.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    123I-FP-Cit and 123I-IBZM SPECT uptake in a prospective normal material analysed with two different semi-quantitative image evaluation tools2013In: Nuclear medicine communications, ISSN 0143-3636, E-ISSN 1473-5628, Vol. 34, no 10, p. 978-989Article in journal (Refereed)
    Abstract [en]

    Objective: The need for age-adjusted and/or sex-adjusted reference values in dopamine transporter (DAT) and dopamine D2 receptor (D2R) imaging with single-photon emission computed tomography (SPECT) in a longitudinal study of parkinsonian diseases was investigated. We used two different image evaluation tools with a cross-sectional and longitudinal statistical approach.

    Materials and methods: Baseline DAT and/or D2R SPECT were performed in 51 healthy controls (HC), age-matched to patients in an ongoing prospective study on idiopathic parkinsonism. Twenty-four HC were re-examined after 3 years and 21 HC were examined again after 5 years. SPECT was performed with I-123-FP-Cit and I-123-IBZM on a two-headed hybrid gamma camera. Regions of interest and volumes of interest (VOIs) were used for image evaluation. A cross-sectional and longitudinal statistical analysis was carried out.

    Results: Fewer sex-based differences and less age dependency were seen in DAT SPECT uptake ratios compared with D2R SPECT uptake ratios and when comparing uptake ratios obtained with regions of interest against those with VOIs. In the cross-sectional analysis, a significant age-dependent decline was seen in women in both DAT and D2R uptakes with the VOI method but not in men with either evaluation method. In the longitudinal dataset, both a slight decline and increase over time were seen in DAT uptake; however, a general pattern of decrease was seen in both men and women in D2R uptake.

    Conclusion: The choice of the image evaluation method can influence the pattern of sex-based and age-related differences. The results speak for the use of age-stratified reference values for women, in particular when using a VOI method.

  • 53.
    Jakobson Mo, Susanna
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Granåsen, Gabriel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Unit of Functional Neurosurgery, UCL Institute of Neurology, London, UK.
    Long-term dopamine transporter imaging in Parkinson's disease treated with zona incerta stimulation2016In: Nuclear medicine communications, ISSN 0143-3636, E-ISSN 1473-5628, Vol. 37, no 5, p. 499-508Article in journal (Refereed)
    Abstract [en]

    Objective: The caudal zona incerta (cZI) is a promising, clinically beneficial target for deep brain stimulation (DBS) in Parkinson’s disease (PD). To assess whether DBS of the cZI affects the rate of dopamine terminal dysfunction, PD patients with and without DBS were followed prospectively with 123I FP-Cit single photon emission tomography from the first diagnosis and up to 8 years.

    Methods: Six patients underwent DBS of the cZI during the survey period. Twenty-two PD patients only on pharmacotherapy served as controls. 123I FP-Cit and clinical assessment were performed at baseline and after 1, 3 and 5 years in all patients. Ten patients also underwent a 123I FP-Cit after 8 years. Image data were evaluated semiquantitatively. Mixed-model analysis was used to assess the relative change in 123I FP-Cit uptake and comparison between surgically and conservatively treated PD patients.

    Results: The relative decrease in 123I FP-Cit uptake was more pronounced in DBS-treated patients than in controls in the more affected caudate (P=0.037) and putamen (P=0.013). The annual decrease rates were higher in the less affected than the more affected putamen, and were slightly greater in DBS-treated patients (4.8%, 95%confidence interval: 8.5–2.2%) than in controls (4.0%, 95% confidence interval: 5.1–3.1%).

    Conclusion: This long-term prospective study confirms that the underlying dopaminergic dysfunction continues despite clinical improvement in PD patients with DBS of the cZI. A slightly faster rate of decrease in 123I FP-Cit uptake in these patients compared with conservatively treated PD patients may reflect a more aggressive form of PD.

  • 54.
    Jakobson Mo, Susanna
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Holmberg, Henrik
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Pre- and postsynaptic dopamine SPECT in idiopathic parkinsonian diseases: a follow-up study2013In: BioMed Research International, ISSN 2314-6141, Vol. 2013, p. 143532-Article in journal (Refereed)
    Abstract [en]

    We prospectively evaluated the diagnostic contribution of 123I-FP-Cit (DAT) and 123I-IBZM (IBZM) SPECT in 29 patients with Parkinson’s disease (PD) (74.4 ± 4.2 years) and 28 patients with atypical parkinsonian diseases (APD) (74.3 ± 9.2 years). Twelve had multiple system atrophy (MSA) and 16 progressive supranuclear palsy (PSP). Sixteen age-matched healthy controls (HC) were included. DAT and IBZM SPECTs were made at baseline and after 1 year in all PD patients and in 20 (DAT) and 18 (IBZM) of the APD patients, and after 3 years in 22 (DAT) and 17 (IBZM) of the PD patients and in 10 (DAT) and 10 (IBZM) of the APD patients. The relative DAT uptake decrease was faster in PD and PSP than in HC and MSA. In PSP the DAT uptake was lower than in MSA after 1 year but not after 3 years. Baseline IBZM uptake was not significantly different between patients and HC or between PD and APD. One year after initiated dopaminergic treatment the mean IBZM uptake in the MSA patients remained high compared to PSP and after 3 years compared to PD, PSP, and HC.Thus, the pattern of uptake of these ligands over time may be of value in discriminating between these diagnoses.

  • 55.
    Jakobson Mo, Susanna
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Pre- and postsynaptic dopamine SPECT in the early phase of idiopathic parkinsonism: a population-based study2010In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 37, no 11, p. 2154-2164Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The aim of this study was to assess the diagnostic contribution of pre- and postsynaptic dopamine SPECT in drug-naïve patients with early idiopathic parkinsonism and to investigate possible differences between idiopathic Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) and possible differences in motor subtypes of parkinsonism.

    METHODS: A group of 128 newly diagnosed idiopathic parkinsonian patients and 48 healthy controls was studied. Presynaptic baseline SPECT with (123)I-FP-CIT was performed in all patients and in 120 patients also a baseline postsynaptic SPECT with (123)I-IBZM. Clinical diagnoses were reassessed after 12 months.

    RESULTS: Presynaptic uptake in the putamen and caudate was significantly reduced in patients compared to controls. Presynaptic uptake ratios were not different between PD patients and patients with APS, and postsynaptic uptake in APS was not significantly reduced compared to PD or controls. In half of the APS patients both pre- and postsynaptic uptake ratios were reduced on the same side in the striatum. Impaired motor performance was associated with decreased presynaptic uptake in the putamen in PD. The postural instability and gait difficulty (PIGD) subtype of PD had lower presynaptic uptake ratios than patients with tremor-dominated (TD) symptoms.

    CONCLUSION: Not only presynaptic putamen uptake ratios, but also caudate ratios were reduced in a majority of the patients in our study. At baseline scan, i.e. in an early stage of the disease, the accuracy of excluding APS in the whole study population was 85% using a combination of pre- and postsynaptic SPECT. Already at baseline, lower presynaptic SPECT ratios were seen in PD with PIGD at onset compared to those with TD subtype.

  • 56.
    Jakobson Mo, Susanna
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Accuracy of Visual Assessment of Dopamine Transporter Imaging in Early Parkinsonism2015In: Movement Disorders Clinical Practice, ISSN 2330-1619, Vol. 2, no 1, p. 17-23Article in journal (Refereed)
    Abstract [en]

    Dopamine transporter (DaT) imaging may be supportive in the initial clinical diagnostic workup in patients with suspected parkinsonian diseases, given that the method has the potential to detect dopaminergic degeneration. We investigated the diagnostic accuracy of visual assessment of the initial DaT single-photon emission CT (DaT-SPECT) with 123I-FP-CIT in a large group of early-stage parkinsonian patients. After inclusion in a long-term multidisciplinary population-based prospective study, a baseline DaT-SPECT was done in 171 incidental, L-dopa-naïve, parkinsonian patients (102 men and 69 women) and 37 healthy controls (19 men and 18 women). The results of the DaT-SPECTs were linked to criteria-based clinical diagnoses, which were set after a mean follow-up of 4.6 (±1.7) years. The outcome of the visual assessment was also compared with that of a semiquantitative evaluation method using regions of interest to measure uptake ratios in the caudate and putamen. We found that visual assessment of DaT-SPECT in clinically diagnosed incidental Parkinson's disease patients had a sensitivity of 94% and a specificity of 92%, rendering a positive likelihood ratio of 11.75 and a negative likelihood ratio of 0.07. The proportion of false positives was 1.4% and false negatives 4.8% at baseline. These figures were comparable to those of the semiquantitative method. This study demonstrates that visual interpretation of presynaptic dopamine imaging with 123I-FP-CIT offers reliable support in the diagnostic procedure of early parkinsonian diseases.

  • 57.
    Johansson, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Lindström, Britta
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Johansson, Gudrun M.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Balance and mobility in patients with newly diagnosed Parkinson's disease - a five-year follow-up of a cohort in northern Sweden2018In: Disability and Rehabilitation, ISSN 0963-8288, E-ISSN 1464-5165, p. 1-10Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The presence of early balance impairment in patients with Parkinson's disease has not been fully investigated.

    PURPOSE: The purpose of this study was to examine balance and mobility, self-perceived unsteadiness, self-reported falls, and effects of medication on balance among patients at their first visit to a neurological clinic and during the ensuing five years.

    MATERIALS AND METHODS: The participants were collected from a prospective longitudinal study. One hundred and forty-five patients with idiopathic Parkinson's disease and 31 healthy controls were included. The outcome measures were the Berg Balance Scale, the Timed Up and Go, the Postural Stability test and a questionnaire.

    RESULTS: At their first visit to the neurological clinic, the patients performed less well on the Berg Balance Scale (p < 0.001, r = 0.36), the Timed Up and Go (p < 0.001, r = 0.32), and the Postural Stability test (p < 0.001, r = 0.35) compared with the controls. In addition, a higher percentage of the patients reported self-perceived unsteadiness (p < 0.001, phi = 0.47). During the ensuing five years, balance and mobility worsened both with and without medication (p < 0.01, r = 0.24-0.37), although with small median differences.

    CONCLUSIONS: Further studies are needed to confirm that minor balance impairments exist even at the time of diagnosis and worsen during the ensuing five years. IMPLICATIONS FOR REHABILITATION Impairments in balance and mobility may occur early in Parkinson's disease, especially in the elderly patients, and seem to worsen during the first five years. There is a need to use sensitive outcome measures and to ask the patients about unsteadiness and falls to detect balance impairment in this cohort. Parkinsonian medication has a limited effect on balance and may preferably be complemented with balance exercises to target balance impairment early in Parkinson's disease.

  • 58. Khoo, Sok Kean
    et al.
    Petillo, David
    Kang, Un Jung
    Resau, James H.
    Berryhill, Brian
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Neuman, Leslie A.
    Tan, Aik Choon
    Plasma-Based Circulating MicroRNA Biomarkers for Parkinson's Disease2012In: Journal of Parkinson's Disease, ISSN 1877-7171, Vol. 2, no 4, p. 321-331Article in journal (Refereed)
    Abstract [en]

    Background: The current "gold-standard" for Parkinson's disease (PD) diagnosis is based primarily on subjective clinical rating scales related with motor features. Molecular biomarkers that are objective and quantifiable remain attractive as clinical tools to detect PD prior to its motor onsets.

    Objective: Here, we aimed to identify, develop, and validate plasma-based circulating microRNA (miRNAs) as biomarkers for PD.

    Methods: Global miRNA expressions were acquired from a discovery set of 32 PD/32 controls using microarrays. k-Top Scoring Pairs (k-TSP) algorithm and significance analysis of microarrays (SAM) were applied to obtain comprehensive panels of PD-predictive biomarkers. TaqMan miRNA-specific real-time PCR assays were performed to validate the microarray data and to evaluate the biomarker performance using a new replication set of 42 PD/30 controls. Data was analyzed in a paired PD-control fashion. The validation set was composed of 30 PD, 5 progressive supranuclear palsy, and 4 multiple system atrophy samples from a new clinical site.

    Results: We identified 9 pairs of PD-predictive classifiers using k-TSP analysis and 13 most differentially-expressed miRNAs by SAM. A combination of both data sets produced a panel of PD-predictive biomarkers: k-TSP1 (miR-1826/miR-450b-3p), miR-626, and miR-505, and achieved the highest predictive power of 91% sensitivity, 100% specificity, 100% positive predicted value, and 88% negative predicted value in the replication set. However, low predictive values were shown in the validation set.

    Conclusions: This proof-of-concept study demonstrates the feasibility of using plasma-based circulating miRNAs as biomarkers for neurodegenerative disorders such as PD and shows the challenges of molecular biomarker research using samples from multiple clinical sites.

  • 59. Kristian, B.
    et al.
    Wachtmeister, K.
    Stefan, F.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Retigabine as add-on treatment of refractory epilepsy a cost-utility study in a Swedish setting2013In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 127, no 6, p. 419-426Article in journal (Refereed)
    Abstract [en]

    Objectives To calculate comparative incremental cost-effectiveness ratios (cost per quality-adjusted life year, QALY) and net marginal benefits for retigabine as add-on treatment for patients with uncontrolled focal seizures as compared to add-on lacosamide treatment and no add-on treatment, respectively. Materials & Methods Calculations were performed using a validated decision-tree model. The study population consisted of adult patients with focal-onset epilepsy in published randomized placebo-controlled add-on trials of retigabine or lacosamide. Healthcare utilization and QALY for each treatment alternative were calculated. Probabilistic sensitivity analysis was performed using the specification of this model as a basis for Monte Carlo simulations. 2009 prices were used for all costs. Results Results were reported for a 2-year follow-up period. Retigabine add-on treatment was both more effective and less costly than lacosamide add-on treatment, and the cost per additional QALY for the retigabine no add-on (standard) therapy comparison was estimated at 2009Euro 15,753. Using a willingness-to-pay threshold for a QALY of Euro 50,000, the net marginal values were estimated at 2009Euro 605,874 for retigabine vs lacosamide and 2009Euro 2,114,203 for retigabine vs no add-on, per 1,000 patients. The probabilistic analyses showed that the likelihood that retigabine treatment is cost-effective is at least 70%. Conclusions The estimated cost per additional QALY, for the retigabine vs no add-on treatment comparison, is well within the range of newly published estimates of willingness to pay for an additional QALY. Thus, add-on retigabine treatment for people with focal-onset epilepsy with no/limited response to standard antiepileptic treatment appears to be cost-effective.

  • 60.
    Lenfeldt, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hansson, William
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Diffusion tensor imaging and correlations to Parkinson rating scales2013In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 260, no 11, p. 2823-2830Article in journal (Refereed)
    Abstract [en]

    The contribution of various brain areas to the overall progression of Parkinson's disease remains to be determined. In this study, we apply MRI diffusion tensor imaging to investigate how alterations in diffusion relate to phenotype and symptoms measured by clinical rating scales. Sixty-four patients were investigated at baseline and three follow-ups (1, 3 and 5 years). Thirty-six patients remained in the last follow-up. Regions of interests included frontal white matter, basal ganglia, thalamus, and cerebellum. Scoring on the Unified Parkinson's Disease Rating Scale (UPDRS) I, II, III, Hoehn and Yahr (HY) scale and the Schwab and England scale (SE) was determined. Mean, radial, and axial diffusion and fractional anisotropy were modeled with phenotype and clinical scales in a multivariate/univariate analysis correcting for other covariates. Significance was set at 0.05 Bonferroni corrected. All rating scales except UPDRS III significantly correlated to the diffusion measures, as did clinical phenotype. Specifically, putamen, globus pallidus, and thalamus demonstrated higher diffusion with worsening scores. Diffusion in thalamus was higher in the tremor dominant phenotype than in postural imbalance and gait disturbance. Decline in overall functionality (UPDRS II and SE scale), including mental status (UPDRS I) and stage of the disease (HY scale), in Parkinson's disease is related to altered diffusion in the lentiform nucleus and thalamus. Motor function is not mirrored in diffusion changes, possibly due to medication. Tremor dominant PD patients show diffusion alterations in the thalamus, but the significance of this for tremor generation remains to be determined.

  • 61.
    Lenfeldt, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Holmlund, Henny
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Frontal white matter injuries predestine gait difficulties in Parkinson's disease2016In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 134, no 3, p. 210-218Article in journal (Refereed)
    Abstract [en]

    Objectives: This study applies diffusion tensor imaging (DTI) to determine differences in neuronal integrity between motor phenotypes in Parkinson's disease. Material and Methods: One hundred and twenty-two patients (47 females, mean age = 70.3 years) were included at baseline. Forty patients were tremor dominant (TD), 64 had postural imbalance and gait difficulty (PIGD), and 18 patients were indeterminate. The DTI was repeated after one, three and 5 years, including reassessment of phenotype. DTI was quantified using fractional anisotropy (FA), and mean, radial and axial diffusion. Targeted white matter involved six regions of interests (ROIs) in prefrontal cortex (PFC), the entrance to the external capsule (EEC) and lateral to the horn of the anterior ventricle (LVAH). Grey matter involved the basal ganglia. Data were analysed using mixed linear models with P < 0.05 (Bonferroni corrected) as significance threshold. Results: PIGD and Indeterminate had reduced FA and axial diffusion in PFC, EEC and LVAH compared to Tremor dominant (P < 0.05). Basal ganglia showed no differences. Post hoc analysis showed that FA correlated negatively, and mean and radial diffusion positively, to PIGD symptoms in EEC, LVAH and four ROIs in PFC (P < 0.05). Tremor symptoms showed no correlations. Patients converting to PIGD and Indeterminate had lower FA, and higher mean and radial diffusion, at baseline in EEC, LVAH and four areas in PFC compared to non-converting patients (P < 0.05). Conclusion: Degeneration in frontal white matter is connected to PIGD symptoms in Parkinson's disease and if present at an early stage, the risk for conversion to the PIGD phenotype increases.

  • 62.
    Lenfeldt, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Diffusion measures in early stage parkinsonism: controversial findings including hemispheric lateralisation2013In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 19, no 4, p. 469-471Article in journal (Refereed)
  • 63.
    Lenfeldt, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Fractional anisotropy in the substantia nigra in Parkinson's disease: a complex picture2015In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 22, no 10, p. 1410-1416Article in journal (Refereed)
    Abstract [en]

    Background and purpose: This study employs magnetic resonance imaging (MRI) diffusion tensor imaging to compare diffusion measures in the brains of patients with Parkinson's disease (PD) with healthy controls using longitudinal data. Methods: One-hundred and twenty-two patients and 34 controls were included at baseline. The MRI investigations were repeated after 1, 3 and 5 years. The diffusion measures were quantified using fractional anisotropy and mean, radial and axial diffusion (FA, MD, RD, AD). Regions of interest included the anterior, middle and posterior substantia nigra (SN), but also other areas. Linear models were used to test for the effect of disease and hemispheric lateralization. The P value was set at 0.05 (Bonferroni corrected). Results: Fractional anisotropy and AD were increased in the three nigral subareas in PD (P < 0.01), but MD and RD were unaltered. The right SN had higher FA than the left in all subareas (P < 0.01). MD and AD were increased in the right anterior part (P < 0.04), whereas MD and RD were decreased in the right middle and posterior parts (P < 0.001). The left middle cerebellar peduncle had increased FA and AD (P < 0.001) and decreased MD and RD (P < 0.01) compared to the right. Diffusion measures did not progress over time and side differences were not related to disease or lateralization of symptoms. Conclusions: Increased FA in the SN in PD indicates gliosis and inflammation in the nuclei, but possibly also intrusion of surrounding fibres into the shrinking structure. The hemispheric side differences of diffusion might reflect natural lateralization of connectivity, but their relation to PD must be studied further.

  • 64.
    Lenfeldt, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Åström, Björn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Jakobson Mo, Susanna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Fractional Anisotropy and Mean Diffusion as Measures of Dopaminergic Function in Parkinson's Disease: Challenging Results2017In: Journal of Parkinson's Disease, ISSN 1877-7171, E-ISSN 1877-718X, Vol. 7, no 1, p. 129-142Article in journal (Refereed)
    Abstract [en]

    Background: Diffusion tensor imaging (DTI) has been purported as an imaging technique to assess dopaminergic degeneration in Parkinson’s disease.

    Objective: To test if fractional anisotropy (FA) and mean diffusion (MD) in the basal ganglia as measured by DTI correlates with dopaminergic function as measured by dopamine transporter (DAT) and dopamine D2-receptor (D2R) SPECT.

    Methods: One-hundred and eleven patients with Parkinson’s disease (71±10 years) and thirty-one controls (68±7 years) performed DTI, DAT and D2R SPECT at baseline and four follow-ups (1-year: 89 patients/zero controls; 3-year: 72/11; 5-year: 48/17; and 8-year: 13/13). Four equipment combinations of MRI scanners/SPECT gamma cameras were used during the study. Data from each combination were analyzed separately. Regions-of-interest were outlined in the substantia nigra (three subareas, DTI only) and in the striatum (putamen and caudate). Side differences and bilateral averages were correlated using linear regression. The significance threshold was set at P < 0.001 and 0.001 < P< 0.05 was defined as a trend towards significance.

    Results: For side differences, no significant correlations were observed, but in patients, there was a trend towards a negative correlation between MD in the middle nigra and putaminal DAT uptake in two combinations (P = 0.04 and P = 0.03). For averages, in patients, striatal MD correlated negatively with striatal DAT uptake in one combination (P = 0.0005) and trended towards negative correlations with striatal D2R uptake (one combination, P = 0.03) and with the sum of striatal DAT and D2R uptake (two combinations P = 0.002 and P = 0.03). FA showed no correlations in patients, and no correlations were found in controls.

    Conclusions: The poor correlations between MD and dopamine activity –and absent correlations for FA – imply that additional diffusion measures must be developed to reliably assess the dopaminergic degeneration in Parkinson’s disease.

  • 65. Lill, Christina M.
    et al.
    Rengmark, Aina
    Pihlstrom, Lasse
    Fogh, Isabella
    Shatunov, Aleksey
    Sleiman, Patrick M.
    Wang, Li-San
    Liu, Tian
    Lassen, Christina F.
    Meissner, Esther
    Alexopoulos, Panos
    Calvo, Andrea
    Chio, Adriano
    Dizdar, Nil
    Faltraco, Frank
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Kirchheiner, Julia
    Kurz, Alexander
    Larsen, Jan P.
    Liebsch, Maria
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Morrison, Karen E.
    Nissbrandt, Hans
    Otto, Markus
    Pahnke, Jens
    Partch, Amanda
    Restagno, Gabriella
    Rujescu, Dan
    Schnack, Cathrin
    Shaw, Christopher E.
    Shaw, Pamela J.
    Tumani, Hayrettin
    Tysnes, Ole-Bjorn
    Valladares, Otto
    Silani, Vincenzo
    van den Berg, Leonard H.
    van Rheenen, Wouter
    Veldink, Jan H.
    Lindenberger, Ulman
    Steinhagen-Thiessen, Elisabeth
    Teipel, Stefan
    Perneczky, Robert
    Hakonarson, Hakon
    Hampel, Harald
    von Arnim, Christine A. F.
    Olsen, Jorgen H.
    Van Deerlin, Vivianna M.
    Al-Chalabi, Ammar
    Toft, Mathias
    Ritz, Beate
    Bertram, Lars
    The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease2015In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 11, no 12, p. 1407-1416Article in journal (Refereed)
    Abstract [en]

    A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Ab42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 x 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR 5 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR 5 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Ab42 suggesting that TREM2's role in AD may involve tau dysfunction. (C) 2015 The Alzheimer's Association.

  • 66.
    Linder, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Olsson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Larsson, Ann-Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Edström, Mona
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Degenerative changes were common in brain magnetic resonance imaging in patients with newly diagnosed Parkinson's disease in a population-based cohort2009In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 256, no 10, p. 1671-1680Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate newly diagnosed patients with Parkinson's disease (PD) with structural magnetic resonance imaging (MRI), to compare them with healthy controls, to relate the findings to clinical subtypes - tremor dominant (TD) or postural instability and gait difficulty (PIGD) - and to investigate the relationship between both the duration from onset of symptoms to diagnosis and the severity of symptoms and the MRI findings. Patients with a definite PD diagnosis were compared to patients with a probable PD diagnosis. We hypothesized that the PIGD subtype, the probable PD group, a greater symptom severity and a longer symptom duration would all be associated with more frequent pathological findings. Sixty-six PD patients were included and examined with MRI, 35 with the PIGD subtype and 23 with the TD subtype. Fifty-three had definite PD and 13 probable PD. Thirty healthy individuals, matched for age and sex, served as controls. Degenerative changes in the cerebellar cortex and the superior cerebellar peduncle were significantly more common in the probable PD group than in the controls, suggesting the possibility of an emerging atypical parkinsonian disorder. No significant MRI differences were found between definite PD and controls, between definite PD and probable PD, nor between PIGD and TD. No significant associations were found between duration to diagnosis and MRI results, nor between severity of symptoms and MRI results. Thus, although pathological MRI findings were common they can not be used to separate subgroups of PD in newly diagnosed patients.

  • 67.
    Linder, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Libelius, Rolf
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Holmberg, Björn
    Institute of Neuroscience and Physiology/Neurology Göteborg University, Göteborg, Sweden..
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Anal sphincter electromyography in patients with newly diagnosed idiopathic parkinsonism2012In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 126, no 4, p. 248-255Article in journal (Refereed)
    Abstract [en]

    Objectives The differential diagnosis of patients with idiopathic parkinsonism is difficult, especially early in the course of the disease. External anal sphincter electromyography has been reported to be of value in the differential diagnosis between Parkinson’s disease and multiple system atrophy. Patients with multiple system atrophy are reported to have pathological external anal sphincter electromyography and patients with Parkinson’s disease are reported to have significantly less pathological external anal sphincter electromyography results. Comparisons between patients with parkinsonian disorders have usually been made many years into the disease, and thus it is largely unknown if the results of external anal sphincter electromyography can be used to distinguish the different diagnoses in the early phase of the disease.

    Material and methods We investigated 148 newly diagnosed patients with idiopathic parkinsonism from a population-based incidence cohort (100 definite Parkinson’s disease, 21 probable Parkinson’s disease, 16 multiple system atrophy, eleven progressive supranuclear palsy, and 40 controls) with external anal sphincter electromyography within three months of their first visit and, in the majority of patients, before start of treatment with dopaminergic drugs. The clinical diagnoses were made using established clinical diagnostic criteria after a median follow-up of three years.

    Results All patient groups had more pathological external anal sphincter electromyography results than controls. No external anal sphincter electromyography differences were found between the patient groups, especially not between Parkinson’s disease and multiple system atrophy.

    Conclusions External anal sphincter electromyography examination cannot separate the different parkinsonian subgroups from each other in early course of the diseases.

  • 68.
    Linder, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Incidence of Parkinson's disease and parkinsonism in northern Sweden: a population-based study2010In: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 25, no 3, p. 341-348Article in journal (Refereed)
    Abstract [en]

    The differential diagnosis of parkinsonian disorders is difficult, especially early in the course of the diseases. The clinical subtypes of Parkinson's disease (PD) have not so far been described in newly diagnosed patients. We present a prospective incidence cohort study of patients with idiopathic parkinsonian syndromes in the Umeå region in northern Sweden identified over a 4-year period. The clinical diagnoses were re-evaluated at follow-up visits at 12 months. We found 138 patients with parkinsonism: 112 PD, 12 multiple system atrophy with predominant parkinsonism (MSA-P), six progressive supranuclear palsy (PSP) and eight unclassifiable patients. The crude incidences for all age ranges per 100,000 were: PD 19.7 (95% confidence interval 16.1-23.3); MSA-P 2.1 (1.1-3.7); PSP 1.1 (0.4-2.4); idiopathic parkinsonism 24.3 (20.2-28.4). Age-standardized to the average Swedish population 2004-2007: PD 22.5 (18.3-26.7); MSA-P 2.4 (1.2-4.2); PSP 1.2 (0.4-2.6); idiopathic parkinsonism 27.5 (22.9-32.1). The crude annual incidence rate for PD, with exclusion of patients with normal dopamine receptor uptake (FP-CIT-SPECT), was 18.8 per 100,000 (95% confidence interval 15.2-22.4), age-adjusted to the average Swedish population 2004 to 2007: 21.5 (17.4-25.6). The incidence rates did not differ significantly between men and women. The cumulative incidence of PD up to 89 years of age was for men 3.4%, for women 2.6%, and for both sexes combined 2.9%. The annual incidence rates found for PD, idiopathic parkinsonism, MSA-P and PSP are among the highest reported.

  • 69.
    Linder, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wenngren, Britt-Inger
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Impaired oculomotor function in a community-based patient population with newly diagnosed idiopathic parkinsonism2012In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 259, no 6, p. 1206-1214Article in journal (Refereed)
    Abstract [en]

    The differential diagnosis of idiopathic parkinsonism can be very challenging, especially early in the course of the disease. Oculomotor function has been reported to differ between the diseases constituting idiopathic parkinsonism. A detailed examination of the oculomotor functions could thus possibly be useful in the early differential diagnostic procedure. Oculomotor function could also differ between subgroups of patients with Parkinson's disease (PD). We examined the oculomotor function in a population-based incidence cohort with newly diagnosed idiopathic parkinsonism and 38 controls. We examined 135 patients with parkinsonism 105 PD, 11 progressive supranuclear palsy (PSP), and 19 multiple system atrophy with predominant parkinsonism (MSA-P)] within 3 months of their first visit to our clinic and before initiation of dopaminergic medication. The oculomotor measurements were repeated after 12 months. The clinical diagnosis was that of the latest clinical follow-up (median follow-up was 3 years). All patients were examined with (123)I-N-(omega)-fluoropropyl-2-β-carbomethoxy-3-β-(4-iodophenyl) nortropane single-photon emission computed tomography (FP-CIT SPECT), and only patients with pathological uptake of the ligand were included. Pathological changes in the oculomotor function were found in all patient groups compared to controls at the baseline examination. In PD, there were correlations between total axial motor scores and vertical saccade velocity and precision, horizontal saccade velocity and precision, and smooth pursuit gain at 20 and 30°/s. Oculomotor test results could not separate the different forms of idiopathic parkinsonism in the early phase from each other. Few changes in the oculomotor functions were observed between the baseline and the 12-month follow-up examinations. No correlations were found between the oculomotor measurements and disease severity or duration.

  • 70.
    Lunde, Kristin Aaser
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Chung, Janete
    Dalen, Ingvild
    Pedersen, Kenn Freddy
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Domellöf, Magdalena E.
    Umeå University, Faculty of Social Sciences, Department of Psychology. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Elgh, Eva
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Macleod, Agnus D
    Tzoulis, Charalampos
    Larsen, Jan-Petter
    Tysnen, Ole-Bjørn
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Counsell, Carl E.
    Alves, Guido
    Maple-Grødem, Jodi
    Association of glucocerebrosidase polymorphisms and mutations with dementia in incident Parkinson's disease2018In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, ISSN 1552-5260, Vol. 14, no 10, p. 1293-1301Article in journal (Refereed)
    Abstract [en]

    Introduction

    Both polymorphisms and mutations in glucocerebrosidase (GBA) may influence the development of dementia in patients with Parkinson's disease.

    Methods

    Four hundred forty-two patients and 419 controls were followed for 7 years. Dementia was diagnosed using established criteria. Participants were analyzed for GBA genetic variants, including E326K, T369M, and L444P. Associations between GBA carrier status and dementia were assessed with Cox survival analysis.

    Results

    A total of 12.0% of patients with Parkinson's disease carried a GBA variant, and nearly half (22/53) of them progressed to dementia during follow-up. Carriers of deleterious GBA mutations (adjusted hazard ratio 3.81, 95% confidence interval 1.35 to 10.72; P = .011) or polymorphisms (adjusted hazard ratio 1.79; 95% confidence interval 1.07 to 3.00; P = .028) progressed to dementia more rapidly than noncarriers.

    Discussion

    GBA variants are of great clinical relevance for the development of dementia in Parkinson's disease, especially due to the relatively higher frequency of these alleles compared with other risk alleles.

  • 71. Machaczka, Maciej
    et al.
    Paucar, Martin
    Kämpe Björkvall, Cecilia
    Smith, Nicholas J. C.
    Cox, Timothy M.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Svenningsson, Per
    Novel hyperkinetic dystonia-like manifestation and neurological disease course of Swedish Gaucher patients2018In: Blood Cells, Molecules & Diseases, ISSN 1079-9796, E-ISSN 1096-0961, Vol. 68, no S1, p. 86-92Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Neuronopathic Gaucher disease type 3 (GD3) is frequent in northern Sweden, whereas GD1 is found throughout the country. In a nation-wide study, we examined neurological manifestations and clinical course in 12 patients with GD3 and 13 patients with GD1.

    METHODS: The patients were evaluated by standardized neurological assessments. Every sixth month, the GD3 patients were rated with the modified Severity Scoring Tool. At baseline and at the 3years follow-up, patients underwent University of Pennsylvania Smell Identification Test, Montreal Cognitive Assessment and Hospital Anxiety and Depression Scale. When clinical signs were present, additional examinations were undertaken.

    RESULTS: Marked clinical heterogeneity was evident in both GD3 and GD1 groups. Several GD3 patients had a hitherto unreported rapid and repetitive dystonia-like hyperkinetic movement disorder. Most patients with GD3 have abnormalities of horizontal gaze, ataxia and focal epilepsy, some also had cognitive impairment, anxiety and hyposmia. Six GD3 patients, all homoallelic for L444P GBA1 mutations, have lived beyond 40years of age; and none has developed Parkinsonism. Two of the GD1 patients suffer from Parkinsonism; mild to complete hyposmia was present in six GD3 and five GD1 patients. Neither the group of GD3 nor GD1 patients had detectable progression of their neurological manifestations.

    CONCLUSIONS: These middle-aged and older Swedish GD3 or GD1 patients are clinically stable over time. However, we have identified unusual clinical features, discordant phenotypes and a hyperkinetic dystonia-like movement disorder which appears unique to this Swedish disease variant and expands the phenotype for GD.

  • 72.
    Marklund, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Franklin, Karl A
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Oral Appliance Therapy in Patients With Daytime Sleepiness and Snoring or Mild to Moderate Sleep Apnea: A Randomized Clinical Trial2015In: JAMA Internal Medicine, ISSN 2168-6106, E-ISSN 2168-6114, Vol. 175, no 8, p. 1278-1285Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: Oral appliances that move the mandible forward during sleep are suggested as treatment for mild to moderate obstructive sleep apnea.

    OBJECTIVE: To test whether an adjustable, custom-made oral appliance improves daytime sleepiness and quality of life in patients with daytime sleepiness and snoring or mild to moderate obstructive sleep apnea.

    DESIGN, SETTING, AND PARTICIPANTS: Ninety-six patients with daytime sleepiness and an apnea-hypopnea index (AHI) lower than 30 were included in a randomized, placebo-controlled, parallel trial in Umeå, Sweden, from May 2007 through August 2011.

    INTERVENTIONS: Four months' intervention with an oral appliance or a placebo device.

    MAIN OUTCOMES AND MEASURES: Daytime sleepiness was measured with the Epworth Sleepiness Scale, the Karolinska Sleepiness Scale, and the Oxford Sleep Resistance (OSLER) test. Quality of life was assessed with the Short-Form 36-Item Health Survey (SF-36) and the Functional Outcomes of Sleep Questionnaire (FOSQ). Secondary outcomes included the apnea-hypopnea index, headaches, symptoms of restless legs, and insomnia.

    RESULTS: Oral appliance therapy was not associated with improvements in daytime sleepiness from baseline to 4-month follow-up when compared with the placebo device; Epworth score >10: 53% at baseline to 24% at follow-up for the oral appliance group vs 54% at baseline to 40% at follow-up for the placebo device group, P = .11; median (IQR) for Karolinska score ≥7/wk: 10 (8 to 14) at baseline to 7 (4 to 9) at follow-up for the oral appliance group vs 12 (6 to 15) at baseline to 8 (5 to 12) at follow-up for the placebo device group, P = .11; mean between-group difference in OSLER test, -2.4 min (95% CI, -6.3 to 1.4). The mean between-group difference for the total FOSQ score was insignificant (-1.2 [95% CI, -2.5 to 0.1]). No domain of the SF-36 differed significantly between the groups. The AHI was below 5 in 49% of patients using the active appliance and in 11% using placebo, with an odds ratio of 7.8 (95% CI, 2.6-23.5) and a number needed to treat of 3. Snoring (P < .001) and symptoms of restless legs (P = .02) were less frequent when using the oral appliance vs placebo, but this did not apply to headache or insomnia.

    CONCLUSIONS AND RELEVANCE: A custom-made, adjustable oral appliance reduces obstructive sleep apnea, snoring, and possibly restless legs without effects on daytime sleepiness and quality of life among patients with daytime sleepiness and snoring or mild to moderate sleep apnea.

    TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00477009.

  • 73.
    Morozova-Roche, Ludmilla
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Davis, Jason
    Institutionen för kemi, Oxford universitet, Storbritannien.
    Ny snabbanalys för diagnos av Parkinsons sjukdom2012In: Neurologi i Sverige, ISSN 2000-8538, no 4, p. 74-78Article, review/survey (Other academic)
  • 74. Nilsson, Maria H
    et al.
    Hariz, Gun-Marie
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wictorin, Klas
    Miller, Michael
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hagell, Peter
    Development and testing of a self administered version of the freezing of gait questionnaire2010In: BMC Neurology, ISSN 1471-2377, E-ISSN 1471-2377, Vol. 10, no 85Article in journal (Refereed)
    Abstract [en]

    Background

    The Freezing of Gait Questionnaire (FOGQ) was developed in response to the difficulties of observing and quantifying freezing of gait (FOG) clinically as well as in laboratory settings. However, as the FOGQ is a clinician-administered patient-reported rating scale it cannot be used in postal surveys. Here we report the development and measurement properties of a self-administered version of the FOGQ (FOGQsa).

    Methods

    A clinical sample and a postal survey sample of non-demented people with Parkinson's disease (PD; total n = 225) completed the FOGQsa and questionnaires concerning physical functioning (PF) and fall-related self efficacy (FES). Additional questions (No/Yes) regarded previous falls and whether they were afraid of falling. The clinical sample was also assessed with the Unified PD Rating Scale (UPDRS). Thirty-five participants completed FOGQsa and were also assessed with the original version (FOGQ) in a clinical interview.

    Results

    There were no differences (P = 0.12) between FOGQ (median, 10; q1-q3, 2-14) and FOGQsa (median, 8; 2-14) scores. The Spearman (rs) and intra-class correlations between the two were 0.92 and 0.91 (95% CI, 0.82-0.95), respectively. For FOGQsa, corrected item-total correlations ranged between 0.68-0.89. Reliability was 0.93 (95% CI, 0.91-0.94). FOGQsa scores correlated strongest with UPDRS Item 14 (Freezing; rs, 0.76) and with FES (rs, -0.74). The weakest correlation was found with age (rs, 0.14). Fallers scored significantly (p < 0.001) higher on FOGQsa compared to non-fallers, median scores 8 (q1-q3, 4-14) versus 2 (0-7). Those expressing a fear of falling scored higher (p < 0.001) than those who did not, median scores 2 (0-7) versus 6 (2-14).

    Conclusions

    The present findings indicate that the FOGQsa is as reliable and valid as the original interview administered FOGQ version. This has important clinical implications when investigating FOG in large scale studies.

  • 75.
    Norberg, Anna
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Exclusion of the juvenile myoclonic epilepsy gene EFHC1 as the cause of migraine on chromosome 6, but association to two rare polymorphisms in MEP1A and RHAG.2006In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 396, no 2, p. 137-142Article in journal (Refereed)
  • 76.
    Norgren, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mattson, Emma
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    A high-penetrance form of late-onset torsion dystonia maps to a novel locus (DYT21) on chromosome 2q14.3-q21.32011In: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753, Vol. 12, no 2, p. 137-143Article in journal (Refereed)
    Abstract [en]

    The primary dystonias are a genetically heterogeneous group of disorders that can be subdivided in pure dystonias, dystonia-plus syndromes, and paroxymal dystonia. Four pure autosomal dominant dystonia loci have been mapped to date, DYT1, 6, 7, and 13, with varying penetrance. We report the mapping of a novel locus for a late-onset form of pure torsion dystonia in a family from northern Sweden. The disease is inherited in an autosomal dominant manner with a penetrance that may be as high as 90%. The torsion dystonia locus in this family was mapped to chromosome 2q14.3-q21.3 using an Illumina linkage panel. We also confirmed the linkage, using ten tightly linked microsatellite markers in the region, giving a maximum LOD score of 5.59 for marker D2S1260. The disease-critical region is 3.6-8.9 Mb depending on the disease status of one individual carrying a centromeric recombination. Mutational analysis was performed on 22 genes in the disease-critical region, including all known and hypothetical genes in the smaller, 3.6-Mb region, but no disease-specific mutations were identified. Copy number variation analysis of the region did not reveal any deletions or duplications. In order to increase the chances of finding the disease gene, fine-mapping may be necessary to decrease the region of interest. This report will hopefully result in the identification of additional dystonia families with linkage to the same locus, and thereby, refinement of the disease critical region.

  • 77.
    Nyberg, Lars
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Andersson, Micael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Jakobson Mo, Susanna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Larsson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Marklund, Petter
    Nilsson, Lars-Göran
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Bäckman, Lars
    Striatal dopamine D2 binding is related to frontal BOLD response during updating of long-term memory representations.2009In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 46, no 4, p. 1194-1199Article in journal (Refereed)
    Abstract [en]

    Multi-modal brain imaging was used to examine the relation between individual differences in resting-state striatal dopamine D2 binding and the magnitude of prefrontal BOLD activation during updating of long-term memory (LTM) representations. Increased activity in the left prefrontal cortex was observed when LTM updating was required, and there was a positive correlation between striatal D2 activity and the magnitude of left prefrontal activity during updating. These findings support predictions from neurocomputational models of a relation of dopaminergic neurotransmission to transient cognitive operations and related brain activity.

  • 78. Paslawski, Wojciech
    et al.
    Zareba-Paslawska, Justyna
    Zhang, Xiaoqun
    Holzl, Katharina
    Wadensten, Henrik
    Shariatgorji, Mohammadreza
    Janelidze, Shorena
    Hansson, Oskar
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Andren, Per E.
    Svenningsson, Per
    alpha-synuclein-lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson's disease patients2019In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 30, p. 15226-15235Article in journal (Refereed)
    Abstract [en]

    The progressive accumulation, aggregation, and spread of alpha-synuclein (alpha SN) are common hallmarks of Parkinson's disease (PD) pathology. Moreover, numerous proteins interact with alpha SN species, influencing its toxicity in the brain. In the present study, we extended analyses of alpha SN-interacting proteins to cerebrospinal fluid (CSF). Using coimmunoprecipitation, followed by mass spectrometry, we found that alpha SN colocalize with apolipoproteins on lipoprotein vesicles. We confirmed these interactions using several methods, including the enrichment of lipoproteins with a recombinant alpha SN, and the subsequent uptake of prepared vesicles by human dopaminergic neuronal-like cells. Further, we report an increased level of ApoE in CSF from early PD patients compared with matched controls in 3 independent cohorts. Moreover, in contrast to controls, we observed the presence of ApoE-positive neuromelanin-containing dopaminergic neurons in substantia nigra of PD patients. In conclusion, the cooccurrence of alpha SN on lipoprotein vesicles, and their uptake by dopaminergic neurons along with an increase of ApoE in early PD, proposes a mechanism(s) for alpha SN spreading in the extracellular milieu of PD.

  • 79. Patil, Ketan S.
    et al.
    Basak, Indranil
    Dalen, Ingvild
    Hoedt, Esthelle
    Lange, Johannes
    Lunde, Kristin A.
    Liu, Ying
    Tysnes, Ole-Bjørn
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Aarsland, Dag
    Neubert, Thomas A.
    Larsen, Jan Petter
    Alves, Guido
    Møller, Simon Geir
    Combinatory microRNA serum signatures as classifiers of Parkinson's disease2019In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 64, p. 202-210Article in journal (Refereed)
    Abstract [en]

    Introduction: As current clinical diagnostic protocols for Parkinson's disease (PD) may be prone to inaccuracies there is a need to identify and validate molecular biomarkers, such as circulating microRNAs, which will complement current practices and increase diagnostic accuracy. This study identifies, verifies and validates combinatory serum microRNA signatures as diagnostic classifiers of PD across different patient cohorts. Methods: 370 PD (drug naive) and control serum samples from the Norwegian ParkWest study were used for identification and verification of differential microRNA levels in PD which were validated in a blind study using 64 NY Parkinsonism in UMea (NYPUM) study serum samples and tested for specificity in 48 Dementia Study of Western Norway (DemWest) study Alzheimer's disease (AD) serum samples using miRNA-microarrays, and quantitative (q) RT-PCR. Proteomic approaches identified potential molecular targets for these microRNAs. Results: Using Affymetrix GeneChip (R) miRNA 4.0 arrays and qRT-PCR we comprehensively analyzed serum microRNA levels and found that the microRNA (PARKmiR)-combinations, hsa-miR-335-5p/hsa-miR-3613-3p (95% CI, 0.87-0.94), hsa-miR-335-5p/hsa-miR-6865-3p (95% CI, 0.87-0.93), and miR-335-5p/miR-3613-3p/miR-6865-3p (95% CI, 0.87-0.94) show a high degree of discriminatory accuracy (AUC 0.9-1.0). The PARKmiR signatures were validated in an independent PD cohort (AUC <= 0.71) and analysis in AD serum samples showed PARKmiR signature specificity to PD. Proteomic analyses showed that the PAFtKmiRs regulate key PD-associated proteins, including alpha-synuclein and Leucine Rich Repeat Kinase 2. Conclusions: Our study has identified and validated unique miRNA serum signatures that represent PD classifiers, which may complement and increase the accuracy of current diagnostic protocols.

  • 80. Petillo, David
    et al.
    Orey, Stephen
    Tan, Aik Choon
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Khoo, Sok Kean
    Parkinson's Disease-related Circulating microRNA Biomarkers: a Validation Study2015In: AIMS Medical Science, ISSN 2375-1576, Vol. 2, no 1, p. 7-14Article in journal (Refereed)
    Abstract [en]

    Parkinson's disease (PD) is the second most common neurodegenerative disease. One of the major challenges in studying this progressive neurological disorder is to identify and develop biomarkers for early detection. Recently, several blood-based microRNA (miRNA) biomarkers for PD have been reported. However, follow-up studies with new, independent cohorts have been rare. Previously, we identified a panel of four circulating miRNA biomarkers for PD (miR-1826, miR-450b-3p, miR-505, and miR-626) with biomarker performance of 91% sensitivity and 100% specificity. However, the expression of miR-450b-3p could not be detected in a new, independent validation set. In our current study, we improved the detection power by including a non-biased pre-amplification step in quantitative real-time PCR (qRT-PCR) and reevaluated the biomarker performance. We found the panel of four PD-related miRNAs achieved the predictive power of 83% sensitivity and 75% specificity in our validation set. This is the first biomarker validation study of PD which showed reproducibility and robustness of plasma-based circulating miRNAs as molecular biomarkers and qRT-PCR as potential diagnostic assay.

  • 81. Pihlstrom, L.
    et al.
    Bjornara, K. -A
    Dizdar, N.
    Fardell, C.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Holmberg, B.
    Larsen, J. P.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nissbrandt, H.
    Tysnes, O. -B
    Dietrichs, E.
    Toft, M.
    A Scandinavian multi-centre study replicates 11 susceptibility loci from genome-wide association studies in Parkinson's disease2012In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, p. 40-40Article in journal (Other academic)
  • 82. Pihlstrom, Lasse
    et al.
    Axelsson, Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Bjornara, Kari Anne
    Dizdar, Nil
    Fardell, Camilla
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Holmberg, Björn
    Larsen, Jan Petter
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nissbrandt, Hans
    Tysnes, Ole-Bjorn
    Öhman, Eilert
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Dietrichs, Espen
    Toft, Mathias
    Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease2013In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, no 6, p. 1708.e7-1708.e13Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have identified a number of susceptibility loci in sporadic Parkinson's disease (PD). Recent larger studies and meta-analyses have greatly expanded the list of proposed association signals. We performed a case-control replication study in a Scandinavian population, analyzing samples from 1345 unrelated PD patients and 1225 control subjects collected by collaborating centers in Norway and Sweden. Single-nucleotide polymorphisms representing 18 loci previously reported at genome-wide significance levels were genotyped, as well as 4 near-significant, suggestive, loci. We replicated 11 association signals at p < 0.05 (SNCA, STK39, MAPT, GPNMB, CCDC62/HIP1R, SYT11, GAK, STX1B, MCCC1/LAMP3, ACMSD, and FGF20). The more recently nominated susceptibility loci were well represented among our positive findings, including 3 which have not previously been validated in independent studies. Conversely, some of the more well-established loci failed to replicate. While future meta-analyses should corroborate disease associations further on the level of common markers, efforts to pinpoint functional variants and understand the biological implications of each risk locus in PD are also warranted. (C) 2013 Elsevier Inc. All rights reserved.

  • 83. Pihlstrøm, Lasse
    et al.
    Rengmark, Aina
    Bjørnarå, Kari Anne
    Dizdar, Nil
    Fardell, Camilla
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Holmberg, Björn
    Larsen, Jan Petter
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nissbrandt, Hans
    Tysnes, Ole-Bjørn
    Dietrichs, Espen
    Toft, Mathias
    Fine mapping and resequencing of the PARK16 locus in Parkinson's disease2015In: Journal of Human Genetics, ISSN 1434-5161, E-ISSN 1435-232X, Vol. 60, no 7, p. 357-362Article in journal (Refereed)
    Abstract [en]

    The PARK16 locus, spanning five genes on chromosome 1, was among the first genetic regions to show genome-wide association in Parkinson's disease (PD). Subsequent investigations have found variability in PARK16 top-hits and association patterns across populations, and the implicated genes and mechanisms are currently unclear. In the present study, we aimed to explore the contribution of PARK16 variability to PD risk in a Scandinavian population. We genotyped 17 single-nucleotide polymorphisms in a case-control sample set of 2570 individuals from Norway and Sweden to fine map the locus. Targeted resequencing of the full coding regions of SLC45A3, NUCKS1, RAB7L1, SLC41A1 and PM20D1 was performed in DNA pools from a subset of 387 patient samples. We find evidence for an association with PD for rs1775143 as well as a haplotype located around the 5' region of RAB7L1, implicating variants which are not in high linkage disequilibrium with the strongest signal from a recent large meta-analysis in Caucasians. We also provide suggestive support for epistasis between RAB7L1 and LRRK2 as previously hypothesized by others. Comparing our results with previous work, allelic heterogeneity at PARK16 appears likely, and further studies are warranted to disentangle the complex patterns of association and pinpoint the functionally relevant variants.

  • 84. Pugliatti, Maura
    et al.
    Beghi, Ettore
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Ekman, Mattias
    Sobocki, Patrik
    Estimating the cost of epilepsy in Europe: a review with economic modeling.2007In: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 48, no 12, p. 2224-2233Article in journal (Other academic)
  • 85. Puschmann, Andreas
    et al.
    Jimenez-Ferrer, Itzia
    Lundblad-Andersson, Elin
    Martensson, Emma
    Hansson, Oskar
    Odin, Per
    Widner, Håkan
    Brolin, Kajsa
    Mzezewa, Ropafadzo
    Kristensen, Jonas
    Soller, Maria
    Ygland Rödström, Emil
    Ross, Owen A.
    Toft, Mathias
    Breedveld, Guido J.
    Bonifati, Vincenzo
    Brodin, Lovisa
    Zettergren, Anna
    Sydow, Olof
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Wirdefeldt, Karin
    Svenningsson, Per
    Nissbrandt, Hans
    Belin, Andrea Carmine
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Swanberg, Maria
    Low prevalence of known pathogenic mutations in dominant PD genes: A Swedish multicenter study2019In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 66, p. 158-165Article in journal (Refereed)
    Abstract [en]

    Objective: To determine the frequency of mutations known to cause autosomal dominant Parkinson disease (PD) in a series with more than 10% of Sweden's estimated number of PD patients.

    Methods: The Swedish Parkinson Disease Genetics Network was formed as a national multicenter consortium of clinical researchers who together have access to DNA from a total of 2,206 PD patients; 85.4% were from population-based studies. Samples were analyzed centrally for known pathogenic mutations in SNCA (duplications/triplications, p.Ala30Pro, p.Ala53Thr) and LRRK2 (p.Asn1437His, p.Arg1441His, p.Tyr1699Cys, p.Gly2019Ser, p.Ile2020Thr). We compared the frequency of these mutations in Swedish patients with published PD series and the gnomAD database.

    Results: A family history of PD in first- and/or second-degree relatives was reported by 21.6% of participants. Twelve patients (0.54%) carried LRRK2 p.(Gly2019Ser) mutations, one patient (0.045%) an SNCA duplication. The frequency of LRRK2 p.(Gly2019Ser) carriers was 0.11% in a matched Swedish control cohort and a similar 0.098% in total gnomAD, but there was a marked difference between ethnicities in gnomAD, with 42-fold higher frequency among Ashkenazi Jews than all others combined.

    Conclusions: In relative terms, the LRRK2 p.(Gly2019Ser) variant is the most frequent mutation among Swedish or international PD patients, and in gnomAD. SNCA duplications were the second.most common of the mutations examined. In absolute terms, however, these known pathogenic variants in dominant PD genes are generally very rare and can only explain a minute fraction of familial aggregation of PD. Additional genetic and environmental mechanisms may explain the frequent co-occurrence of PD in close relatives.

  • 86. Ran, Caroline
    et al.
    Brodin, Lovisa
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Westerlund, Marie
    Ramezani, Mehrafarin
    Gellhaar, Sandra
    Xiang, Fengqing
    Fardell, Camilla
    Nissbrandt, Hans
    Söderkvist, Peter
    Puschmann, Andreas
    Ygland, Emil
    Olson, Lars
    Willows, Thomas
    Johansson, Anders
    Sydow, Olof
    Wirdefeldt, Karin
    Galter, Dagmar
    Svenningsson, Per
    Belin, Andrea Carmine
    Strong association between glucocerebrosidase mutations and Parkinson's disease in Sweden2016In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 45, article id 212.e5Article in journal (Refereed)
    Abstract [en]

    Several genetic studies have demonstrated an association between mutations in glucocerebrosidase (GBA), originally implicated in Gaucher's disease, and an increased risk of Parkinson's disease (PD). We have investigated the possible involvement of genetic GBA variations in PD in the Swedish population. Three GBA variants, E326K, N370S, and L444P were screened in the largest Swedish Parkinson cohort reported to date; 1625 cases and 2025 control individuals. We found a significant association with high effect size of the rare variant L444P with PD (odds ratio 8.17; 95% confidence interval: 2.51-26.23; p-value = 0.0020) and a significant association of the common variant E326K (odds ratio 1.60; 95% confidence interval: 1.16-2.22; p-value = 0.026). The rare variant N370S showed a trend for association. Most L444P carriers (68%) were found to reside in northern Sweden, which is consistent with a higher prevalence of Gaucher's disease in this part of the country. Our findings support the role of GBA mutations as risk factors for PD and point to lysosomal dysfunction as a mechanism contributing to PD etiology.

  • 87. Rengmark, Aina
    et al.
    Pihlstrom, Lasse
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Toft, Mathias
    Low frequency of GCH1 and TH mutations in Parkinson's disease2016In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 29, p. 109-111Article in journal (Refereed)
    Abstract [en]

    Background: The causes of Parkinson's disease (PD) are unknown in the majority of patients. TheGCH1 gene encodes GTP-cyclohydrolase I, an important enzyme in dopaminesynthesis. Co-occurrence of dopa-responsive dystonia (DRD) and a PD phenotype has been reported in families with GCH1 mutations. Recently, rare coding variants in GCH1were found to be enriched in PD patients, indicating a role for the enzyme in theneurodegenerative process.

    Methods: To further elucidate the contribution of GCH1 mutations to sporadic PD, we examined its coding exons in a targeted deep sequencing study of 509 PD patients (mean age at onset 56.7 ± 12.0 years) and 230 controls. We further included the tyrosine hydroxylasegene TH, also known to cause DRD. Gene dose assessments were performed to screen for large copy number variants in a subset of 48 patients with early-onset PD.

    Results: No putatively pathogenic GCH1 mutations were found. The frequency of rare heterozygous variants in the TH gene was 0.69% (7/1018) in the patient group and 0.22% (1/460) in the control group (p = 0.45).

    Conclusions: Previous studies have found that coding variants in the GCH1 gene may be considered a risk factor for PD. Our study indicates that mutations in GCH1 are rare in late-onset PD. Several patients carried heterozygous variants in the TH gene that may affect protein function. Our study was not designed to determine with certainty if any of these variants play a role as risk factors for late-onset PD.

  • 88. Riso, Lukas
    et al.
    Kaaks, Rudolf
    Kuehn, Tilman
    Sookthai, Disorn
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Trupp, Miles
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Trichopoulou, Antonia
    La Vecchia, Carlo
    Karakatsani, Anna
    Gavrila, Diana
    Ferrari, Pietro
    Freisling, Heinz
    Petersson, Jesper
    Lewan, Susanne
    Vemeulen, Roel Ch.
    Panico, Salvatore
    Masala, Giovanna
    Ardanaz, Eva
    Krogh, Vittorio
    Perneczky, Robert
    Middleton, Lefkos T.
    Mokoroa, Olatz
    Sacerdote, Carlotta
    Sieri, Sabrina
    Hayat, Shabina A.
    Brayne, Carol
    Riboli, Elio
    Vineis, Paolo
    Gallo, Valentina
    Katzke, Verena A.
    General and abdominal adiposity and the risk of Parkinson's disease: A prospective cohort study2019In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 62, p. 98-104Article in journal (Refereed)
    Abstract [en]

    Introduction: Due to demographic change, an increase in the frequency of Parkinson's disease (PD) patients is expected in the future and, thus, the identification of modifiable risk factors is urgently needed. We aimed to examine the associations of body mass index (BMI) and waist circumference (WC) with incident PD. Methods: In 13 of the 23 centers of the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a total of 734 incident cases of PD were identified between 1992 and 2012 with a mean follow-up of 12 years. Cox proportional hazards regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI). We modelled anthropometric variables as continuous and categorical exposures and performed subgroup analyses by potential effect modifiers including sex and smoking. Results: We found no association between BMI, WC and incident PD, neither among men nor among women. Among never and former smokers, BMI and waist circumference were also not associated with PD risk. For male smokers, however, we observed a statistically significant inverse association between BMI and PD risk (HR 0.51, 95%CI: 0.30, 0.84) and the opposite for women, i.e. a significant direct association of BMI (HR 1.79, 95%CI: 1.04, 3.08) and waist circumference (HR 1.64, 95%CI: 1.03, 2.61) with risk of PD. Conclusion: Our data revealed no association between excess weight and PD risk but a possible interaction between anthropometry, sex and smoking.

  • 89.
    Sperens, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Georgiev, Dejan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Department of Neurology, University Medical Centre Ljubljana, Slovenia; Faculty of Computer Sciences and Informatics, University of Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Slovenia.
    Eriksson Domellöf, Magdalena
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hamberg, Katarina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Hariz, Gun-Marie
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Activities of daily living in men and women with Parkinson’s disease: eight-year prospective longitudinal studyManuscript (preprint) (Other academic)
  • 90.
    Ström, Anna-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    A role for both wild-type and expanded ataxin-7 in transcriptional regulation2005In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 20, no 3, p. 646-655Article in journal (Refereed)
    Abstract [en]

    Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease primarily affecting the brainstem, retina and Purkinje cells of the cerebellum. The disease is caused by a polyglutamine expansion in ataxin-7, a protein found in two complexes TFTC and STAGA, involved in transcriptional regulation. Transcriptional dysregulation has been implicated in the pathology of several polyglutamine diseases. In this paper, we analyzed the effect of both wild-type and expanded ataxin-7 on transcription driven by the co-activator CBP and the Purkinje cell expressed nuclear receptor RORα1. We could show that transcription mediated by both CBP and RORα1 was repressed by expanded ataxin-7. Interestingly, repression of transcription could also be observed with wild-type full-length ataxin-7, not only on CBP- and RORα1-mediated transcription, but also on basal transcription. The repression could be counteracted by inhibition of deacetylation, suggesting that ataxin-7 may act as a repressor of transcription by inhibiting the acetylation activity of TFTC and STAGA.

  • 91.
    Ström, Anna-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Identification and characterization of Spinocerebellar Ataxia Type 7 (SCA7) isoform SCA7b in mice2005In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1731, no 3, p. 149-153Article in journal (Refereed)
    Abstract [en]

    Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease primarily affecting the cerebellum, brainstem and retina. The disease is caused by a polyglutamine expansion in ataxin-7, a protein with largely unknown function. To improve our knowledge of the expression and function of wild-type and expanded ataxin-7, we looked for alternative SCA7 transcripts in mice. We identified a murine SCA7 isoform (SCA7b) containing an uncharacterized exon homologous to the newly identified human exon 12b. Northern blot analysis revealed three exon 12b containing transcripts with molecular sizes of 7.5, 4.4 and 3.0 kb in mice. This contrasted with the situation in humans, where only one exon 12b-containing transcript was observed. Furthermore, Northern blot of the human 4.4 kb SCA7b isoform predominantly showed expression in the brain, while expression of both the murine 7.5-kb and the 4.4-kb transcripts were observed in several tissues including brain, heart, liver, kidney and testis. Quantitative real-time RT-PCR analysis revealed that in muscle and heart SCA7b is the predominant SCA7 isoform, while in brain equal levels of SCA7a and SCA7b was observed. Insertion of exon 12b into the murine SCA7 ORF resulted in a frame-shift that gave rise to an alternative ataxin-7 protein (ataxin-7b). The novel 58-amino acid C-terminus in ataxin-7b directed the protein to a more cytoplasmic location.

  • 92.
    Sundström, P
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology. Neurologi.
    Juto, P
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Wadell, G
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Svenningsson, A
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology. Neurologi.
    Nyström, Lennarth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences. Epidemiologi och folkhälsovetenskap.
    Dillner, Joakim
    Forsgren, L
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology. Neurologi.
    An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study.2004In: Neurology, ISSN 1526-632X, Vol. 62, no 12, p. 2277-82Article in journal (Refereed)
  • 93.
    Sundström, P
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Svenningsson, A
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Nyström, Lennarth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Forsgren, L
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Clinical characteristics of multiple sclerosis in Västerbotten County in northern Sweden.2004In: J Neurol Neurosurg Psychiatry, ISSN 0022-3050, Vol. 75, no 5, p. 711-6Article in journal (Refereed)
  • 94. Tomson, Torbjörn
    et al.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Life expectancy in epilepsy.2005In: Lancet, ISSN 1474-547X, Vol. 365, no 9459, p. 557-8Article in journal (Refereed)
  • 95. Tomson, Torbjörn
    et al.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Blom, Sigfrid
    Westerberg, Carl-Einar
    Epilepsi2006In: Neurologi, Liber AB Stockholm , 2006, p. 297-336Chapter in book (Other (popular science, discussion, etc.))
  • 96.
    Trupp, Miles
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Öhrfelt, Annika
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Mölndal, Sweden.
    Zetterberg, Henrik
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Molndal, Sweden; UCL Inst Neurol, London, England.
    Obudulu, Ogonna
    Swedish Agr Univ, Dept Plant Physiol & Forest Genet, Swedish Metabol Ctr, Umea, Sweden.
    Malm, Linus
    Swedish Agr Univ, Dept Plant Physiol & Forest Genet, Swedish Metabol Ctr, Umea, Sweden.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Moritz, Thomas
    Swedish Agr Univ, Dept Plant Physiol & Forest Genet, Swedish Metabol Ctr, Umea, Sweden.
    Blennow, Kaj
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Molndal, Sweden.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Metabolite and peptide levels in plasma and CSF differentiating healthy controls from patients with newly diagnosed Parkinson's disease2014In: Journal of Parkinson's Disease, ISSN 1877-7171, E-ISSN 1877-718X, Vol. 4, no 3, p. 549-560Article in journal (Refereed)
    Abstract [en]

    Background: Parkinson's disease (PD) is a progressive, multi-focal neurodegenerative disease for which there is no effective disease modifying treatment. A critical requirement for designing successful clinical trials is the development of robust and reproducible biomarkers identifying PD in preclinical stages. Objective: To investigate the potential for a cluster of biomarkers visualized with multiple analytical platforms to provide a clinically useful tool. Methods: Gas Chromatography-Mass Spectrometry (GC-TOFMS) based metabolomics and immunoassay-based protein/peptide analyses on samples from patients with PD diagnosed in Northern Sweden. Low molecular weight compounds from both plasma and cerebrospinal fluid (CSF) from 20 healthy subjects (controls) and 20 PD patients at the time of diagnosis (baseline) were analyzed. Results: In plasma, we found a significant increase in several amino acids and a decrease in C16-C18 saturated and unsaturated fatty acids in patients as compared to control subjects. We also observed an increase in plasma levels of pyroglutamate and 2-oxoisocaproate (ketoleucine) that may be indicative of increased metabolic stress in patients. In CSF, there was a generally lower level of metabolites in PD as compared to controls, with a specific decrease in 3-hydroxyisovaleric acid, tryptophan and creatinine. Multivariate analysis and modeling of metabolites indicates that while the PD samples can be separated from control samples, the list of detected compounds will need to be expanded in order to define a robust predictive model. CSF biomarker immunoassays of candidate peptide/protein biomarkers revealed a significant decrease in the levels of A beta-38 and A beta-42, and an increase in soluble APP alpha in CSF of patients. Furthermore, these peptides showed significant correlations to each other, and positive correlations to the CSF levels of several 5- and 6-carbon sugars. However, combining these metabolites and proteins/peptides into a single model did not significantly improve the statistical analysis. Conclusions: Together, this metabolomics study has detected significant alterations in plasma and CSF levels of a cluster of amino acids, fatty acids and sugars based on clinical diagnosis and levels of known protein and peptide biomarkers.

  • 97. Valadas, A.
    et al.
    Contarino, M-F
    Albanese, A.
    Bhatia, K. P.
    Falup-Pecurariu, C.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Friedman, A.
    Giladi, N.
    Hutchinson, M.
    Kostic, V. S.
    Krauss, J. K.
    Lokkegaard, A.
    Marti, M. J.
    Milanov, I.
    Pirtosek, Z.
    Relja, M.
    Skorvanek, M.
    Stamelou, M.
    Stepens, A.
    Tamas, G.
    Taravari, A.
    Tzoulis, C.
    Vandenberghe, W.
    Vidailhet, M.
    Ferreira, J. J.
    Tijssen, M. A.
    Management of dystonia in Europe: a survey of the European network for the study of the dystonia syndromes2016In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 23, no 4, p. 772-779Article in journal (Refereed)
    Abstract [en]

    Background and purposeDystonia is difficult to recognize due to its large phenomenological complexity. Thus, the use of experts in dystonia is essential for better recognition and management of dystonia syndromes (DS). Our aim was to document managing strategies, facilities and expertise available in various European countries in order to identify which measures should be implemented to improve the management of DS. MethodsA survey was conducted, funded by the Cooperation in Science and Technology, via the management committee of the European network for the study of DS, which is formed from representatives of the 24 countries involved. ResultsLack of specific training in dystonia by general neurologists, general practitioners as well as other allied health professionals was universal in all countries surveyed. Genetic testing for rare dystonia mutations is not readily available in a significant number of countries and neurophysiological studies are difficult to perform due to a lack of experts in this field of movement disorders. Tetrabenazine is only readily available for treatment of dystonia in half of the surveyed countries. Deep brain stimulation is available in three-quarters of the countries, but other surgical procedures are only available in one-quarter of countries. ConclusionsInternationally, collaboration in training, advanced diagnosis, treatment and research of DS and, locally, in each country the creation of multidisciplinary teams for the management of dystonia patients could provide the basis for improving all aspects of dystonia management across Europe.

  • 98.
    Vikdahl, M.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Backman, L.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Håglin, Lena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Cardiovascular risk factors and the risk of Parkinson's disease2015In: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 69, no 6, p. 729-733Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/OBJECTIVES: The objective of this study was to investigate whether serum triglycerides (S-TG), cholesterol, blood pressure and waist/height ratio are risk factors for Parkinson's disease (PD).

    SUBJECTS AND METHODS: A population-based sample within the Northern Sweden Health and Disease Study (NSHDS) was used in this study (n = 101 790 subjects). Cases with PD were identified prospectively in a community-based study of idiopathic Parkinsonism in the period 2004-2009 in the county of Vasterbotten in northern Sweden. The case database obtained was crosslinked to the NSHDS. Eighty-four of 147 patients with PD had visited the primary health care 2-8 years before diagnosis for participation in the NSHDS. For each case, four referents from the NSHDS population were selected, matched for sex, age, year of health survey, subcohort and geographic area.

    RESULTS: Cases had lower mean S-TG levels (P = 0.007). After stratification for sex, the lower S-TG remained significant for men (P = 0.006) but not for women (P = 0.450), and these were confirmed by the conditional logistic regression for all cases, none adjusted (hazard ratio (HR): 0.65; 95% confidence interval (CI): 0.42, 0.99) and after adjusting for age, body mass index (BMI) and physical activity (HR: 0.61; 95% CI: 0.39, 0.96). Systolic blood pressure (SBP) was negatively associated with PD risk after adjustments for age, BMI and physical activity (HR: 0.98; 95% CI: 0.97-0.99). Smoking and former smoking were associated with a reduced risk for PD.

    CONCLUSIONS: We found lower S-TG and SBP 2-8 years before a diagnosis of PD. Smoking was confirmed to be negatively associated with PD, whereas recreational activity indicates a risk for women.

  • 99.
    Vikdahl, Magdalena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Carlsson, Maine
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Håglin, Lena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Weight gain and increased central obesity in the early phase of Parkinson's disease2014In: Clinical Nutrition, ISSN 0261-5614, E-ISSN 1532-1983, Vol. 33, no 6, p. 1132-1139Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: Weight loss is strongly associated with Parkinson's disease (PD) and impacts symptoms and disease progression. The aim of this study was to describe changes in body composition and to explore how body weight (BW), relates to disease progression and medication in the early phase of PD.

    METHODS: Participants in a prospective community-based case-control study of PD were followed-up three years after initial diagnosis. Anthropometric and bioelectrical impedance spectroscopy (BIS) measurements were used together with Mini Nutritional Assessment (MNA), a 24-h recall (24-HR) and a 3-day food registration (3-DFR) to complete the evaluation of nutritional status. Disease severity was assessed using the Mini Mental State Examination (MMSE), the Unified Parkinson's Disease Rating Scale motor score (UPDRS III), and the Hoehn and Yahr rating.

    RESULTS: The PD patients' BW gained 1.62 kg (±4.60, P = 0.009), an increase that significantly correlated with fat mass (FM) (r = 0.74), waist size (r = 0.65), waist/height ratio (r = 0.64), and total skin fold (r = 0.77). Linear regression showed an association between change in BW and physical activity level (PAL) (B = -8.554; P = 0.025) confirmed by the multiple linear regression. Linear regression also revealed an association between change in FM and MMSE (B = 0.654; P = 0.027).

    CONCLUSION: In early PD, weight gain was revealed over three years accompanied by an increase in FM and waist circumference. An inverse relation was revealed between change in BW and PAL. The MMSE, UPDRS III, and Hoehn and Yahr rating were unchanged. Medication and swallowing difficulties were not associated with change in BW.

  • 100.
    Vikdahl, Magdalena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Domellöf, Magdalena E.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Håglin, Lena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Olfactory function, eating ability, and visceral obesity associated with MMSE three years after Parkinson's disease diagnosis2015In: The Journal of Nutrition, Health & Aging, ISSN 1279-7707, E-ISSN 1760-4788, Vol. 19, no 9, p. 894-900Article in journal (Refereed)
    Abstract [en]

    This study examines whether risk factors for poor nutrition are associated with global cognitive function three years after confirmed Parkinson's disease (PD) diagnosis. The follow-up investigations for this prospective community-based study were conducted three years after PD diagnosis. The study participants lived in Vasterbotten County, a region in northern Sweden with 142,000 inhabitants. This study population consisted of 118 PD outpatients from the study of Newly Diagnosed PD in UmeAyen (NYPUM). Global cognition was assessed with the Mini Mental State Examination (MMSE) at baseline and at follow-up. Anthropometry, nutrition (Mini Nutritional Assessment, MNA, 3-day food registration, 3-FDR), olfactory function (Brief Smell Identification Test, B-SIT), and swallowing, cutting food, and salivation (single questions from the Unified Parkinson's Disease Rating Scale, UPDRS) were used as markers for nutritional status. The MMSE score decreased over three years (-1.06 +/- 3.38, p=0.001). Olfactory function at baseline was associated to MMSE at three years (B=0.365, p=0.004). Changes in waist/hip ratio (B=113.29, p=0.017), swallowing (B=1.18, P=0.033), and cutting food (B=-1.80, p=0.000) were associated with MMSE at follow-up. This study indicates that olfactory function, cutting food, swallowing, and visceral obesity are associated with MMSE three years after PD diagnosis.

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