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  • 1.
    Bäckström, David C
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Eriksson Domellöf, Magdalena
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Olsson, Bob
    Öhrfelt, Annika
    Trupp, Miles
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Zetterberg, Henrik
    Blennow, Kaj
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Cerebrospinal Fluid Patterns and the Risk of Future Dementia in Early, Incident Parkinson Disease2015In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 72, no 10, p. 1175-1182Article in journal (Refereed)
    Abstract [en]

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

  • 2. Fogh, Isabella
    et al.
    Lin, Kuang
    Tiloca, Cinzia
    Rooney, James
    Gellera, Cinzia
    Diekstra, Frank P.
    Ratti, Antonia
    Shatunov, Aleksey
    van Es, Michael A.
    Proitsi, Petroula
    Jones, Ashley
    Sproviero, William
    Chio, Adriano
    McLaughlin, Russell Lewis
    Soraru, Gianni
    Corrado, Lucia
    Stahl, Daniel
    Del Bo, Roberto
    Cereda, Cristina
    Castellotti, Barbara
    Glass, Jonathan D.
    Newhouse, Steven
    Dobson, Richard
    Smith, Bradley N.
    Topp, Simon
    van Rheenen, Wouter
    Meininger, Vincent
    Melki, Judith
    Morrison, Karen E.
    Shaw, Pamela J.
    Leigh, P. Nigel
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Kiel University, Institute of Clinical Molecular Biology, Kiel, Germany.
    Comi, Giacomo P.
    Ticozzi, Nicola
    Mazzini, Letizia
    D'Alfonso, Sandra
    Traynor, Bryan J.
    Van Damme, Philip
    Robberecht, Wim
    Brown, Robert H.
    Landers, John E.
    Hardiman, Orla
    Lewis, Cathryn M.
    van den Berg, Leonard H.
    Shaw, Christopher E.
    Veldink, Jan H.
    Silani, Vincenzo
    Al-Chalabi, Ammar
    Powell, John
    Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis2016In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 73, no 7, p. 812-820Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset. OBJECTIVE To identify gene variants influencing survival in ALS. DESIGN, SETTING, AND PARTICIPANTS This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7 174 392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015. MAIN OUTCOMES AND MEASURES Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed bymeta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis. RESULTS Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 [12] years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P = 1.87 x 10(-9)) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 x 10(-8)). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38-1.89; P = 1.87 x 10(-9)), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208 CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11-1.24; P = 3.53 x 10(-8)), corresponding to a 4-month reduction in survival compared with TT carriers. CONCLUSIONS AND RELEVANCE This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not feasible, treatment that modifies survival is the most realistic strategy. Therefore, identification of modifier genes that might influence ALS survival could improve the understanding of the biology of the disease and suggest biological targets for pharmaceutical intervention. In addition, genetic risk scores for survival could be used as an adjunct to clinical trials to account for the genetic contribution to survival.

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

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

  • 4.
    Granqvist, Mathias
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Boremalm, Malin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Poorghobad, Amyar
    Svenningsson, Anders
    Salzer, Jonatan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Frisell, Thomas
    Piehl, Fredrik
    Comparative Effectiveness of Rituximab and Other Initial Treatment Choices for Multiple Sclerosis2018In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 75, no 3, p. 320-327Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Comparative real-world effectiveness studies of initial disease-modifying treatment (DMT) choices for relapsing-remitting multiple sclerosis (RRMS) that include rituximab are lacking.

    OBJECTIVE To assess the effectiveness and drug discontinuation rates of rituximab among patients with newly diagnosed RRMS compared with injectable DMTs, dimethyl fumarate, fingolimod, or natalizumab.

    DESIGN, SETTING, AND PATIENTS This retrospective cohort study used prospectively collected data to examine specialized care of 2 Swedish county-based community samples of patients with RRMS. Patients with RRMS who received diagnoses from January 1, 2012, to October 31, 2015, who resided in Stockholm or Vasterbotten Counties were identified from a Swedish multiple sclerosis registry.

    MAIN OUTCOMES AND MEASURES All reasons for drug discontinuation of initial treatment choice (main outcome) and specific reasons for switching (secondary outcomes) were analyzed with multivariable Cox regression, including propensity scores.

    RESULTS Among 494 patients (median [interquartile range] age, 34.4 [27.4-43.4] years; 158 men [32.0%]), 215 received an injectable DMT (43.5%); 86 (17.4%), dimethyl fumarate; 17 (3.4%), fingolimod; 50 (10.1%), natalizumab; 120 (24.3%), rituximab; and 6 (1.2%), other DMT. Regional preferences were pronounced, with 42 of 52 (81%) and 78 of 442 (18%) receiving rituximab in Vasterbotten and Stockholm, respectively. The annual discontinuation rate for rituximab, injectable DMTs, dimethyl fumarate, fingolimod, and natalizumab were 0.03, 0.53, 0.32, 0.38, and 0.29, respectively. Continued disease activity was the main reason for discontinuation of injectable DMTs, dimethyl fumarate, and fingolimod; positive John Cunningham virus serology results were the main reason for discontinuation of natalizumab. Rate of clinical relapses and/or neuroradiologic disease activity were significantly lower for rituximab compared with injectable DMTs and dimethyl fumarate, with a tendency for lower relapse rates also compared with natalizumab and fingolimod. The annual discontinuation rate of initial treatment choice was significantly lower in Vasterbotten compared with Stockholm (0.09 and 0.37, respectively).

    CONCLUSIONS AND RELEVANCE Rituximab was superior to all other DMT in terms of drug discontinuation and displayed better clinical efficacy compared with injectable DMTs and dimethyl fumarate with borderline significance compared with natalizumab and fingolimod. The county where rituximab constituted the main initial treatment choice displayed better outcomes in most measured variables. Collectively, our findings suggest that rituximab performs better than other commonly used DMTs in patients with newly diagnosed RRMS.

  • 5. Martinez-Ramirez, Daniel
    et al.
    Jimenez-Shahed, Joohi
    Leckman, James Frederick
    Porta, Mauro
    Servello, Domenico
    Meng, Fan-Gang
    Kuhn, Jens
    Huys, Daniel
    Baldermann, Juan Carlos
    Foltynie, Thomas
    Hariz, Marwan I.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Sobell Department of Motor Neuroscience, University College London Institute of Neurology, London, United Kingdom.
    Joyce, Eileen M.
    Zrinzo, Ludvic
    Kefalopoulou, Zinovia
    Silburn, Peter
    Coyne, Terry
    Mogilner, Alon Y.
    Pourfar, Michael H.
    Khandhar, Suketu M.
    Auyeung, Man
    Ostrem, Jill Louise
    Visser-Vandewalle, Veerle
    Welter, Marie-Laure
    Mallet, Luc
    Karachi, Carine
    Houeto, Jean Luc
    Klassen, Bryan Timothy
    Ackermans, Linda
    Kaido, Takanobu
    Temel, Yasin
    Gross, Robert E.
    Walker, Harrison C.
    Lozano, Andres M.
    Walter, Benjamin L.
    Mari, Zoltan
    Anderson, William S.
    Changizi, Barbara Kelly
    Moro, Elena
    Zauber, Sarah Elizabeth
    Schrock, Lauren E.
    Zhang, Jian-Guo
    Hu, Wei
    Rizer, Kyle
    Monari, Erin H.
    Foote, Kelly D.
    Malaty, Irene A.
    Deeb, Wissam
    Gunduz, Aysegul
    Okun, Michael S.
    Efficacy and Safety of Deep Brain Stimulation in Tourette Syndrome: The International Tourette Syndrome Deep Brain Stimulation Public Database and Registry2018In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 75, no 3, p. 353-359Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Collective evidence has strongly suggested that deep brain stimulation (DBS) is a promising therapy for Tourette syndrome.

    OBJECTIVE To assess the efficacy and safety of DBS in a multinational cohort of patients with Tourette syndrome.

    DESIGN, SETTING, AND PARTICIPANTS The prospective International Deep Brain Stimulation Database and Registry included 185 patients with medically refractory Tourette syndrome who underwent DBS implantation from January 1, 2012, to December 31, 2016, at 31 institutions in 10 countries worldwide.

    EXPOSURES Patients with medically refractory symptoms received DBS implantation in the centromedian thalamic region (93 of 163 [57.1%]), the anterior globus pallidus internus (41 of 163 [25.2%]), the posterior globus pallidus internus (25 of 163 [15.3%]), and the anterior limb of the internal capsule (4 of 163 [2.5%]).

    MAIN OUTCOMES AND MEASURES Scores on the Yale Global Tic Severity Scale and adverse events.

    RESULTS The International Deep Brain Stimulation Database and Registry enrolled 185 patients (of 171 with available data, 37 females and 134 males; mean [SD] age at surgery, 29.1 [10.8] years [range, 13-58 years]). Symptoms of obsessive-compulsive disorder were present in 97 of 151 patients (64.2%) and 32 of 148 (21.6%) had a history of self-injurious behavior. The mean (SD) total Yale Global Tic Severity Scale score improved from 75.01 (18.36) at baseline to 41.19 (20.00) at 1 year after DBS implantation (P<.001). The mean (SD) motor tic subscore improved from 21.00 (3.72) at baseline to 12.91 (5.78) after 1 year (P <.001), and the mean (SD) phonic tic subscore improved from 16.82 (6.56) at baseline to 9.63 (6.99) at 1 year (P <.001). The overall adverse event rate was 35.4%(56 of 158 patients), with intracranial hemorrhage occurring in 2 patients (1.3%), infection in 4 patients with 5 events (3.2%), and lead explantation in 1 patient (0.6%). The most common stimulation-induced adverse effects were dysarthria (10 [6.3%]) and paresthesia (13 [8.2%]).

    CONCLUSIONS AND RELEVANCE Deep brain stimulationwas associated with symptomatic improvement in patients with Tourette syndrome but also with important adverse events. A publicly available website on outcomes of DBS in patients with Tourette syndrome has been provided.

  • 6. Solomon, Alina
    et al.
    Turunen, Heidi
    Ngandu, Tiia
    Peltonen, Markku
    Levälahti, Esko
    Helisalmi, Seppo
    Antikainen, Riitta
    Bäckman, Lars
    Hänninen, Tuomo
    Jula, Antti
    Laatikainen, Tiina
    Lehtisalo, Jenni
    Lindström, Jaana
    Paajanen, Teemu
    Pajala, Satu
    Stigsdotter-Neely, Anna
    Umeå University, Faculty of Social Sciences, Department of Psychology. Department of Social and Psychological Studies, Karlstad University, Karlstad, Sweden.
    Strandberg, Timo
    Tuomilehto, Jaakko
    Soininen, Hilkka
    Kivipelto, Miia
    Effect of the Apolipoprotein E Genotype on Cognitive Change During a Multidomain Lifestyle Intervention A Subgroup Analysis of a Randomized Clinical Trial2018In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 75, no 4, p. 462-470Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: The role of the apolipoprotein E (APOE) epsilon 4 allele as an effect modifier in lifestyle interventions to prevent cognitive impairment is still unclear. OBJECTIVE: To examine whether the APOE epsilon 4 allele modifies the previously reported significant cognitive benefits of a multidomain lifestyle intervention (prespecified subgroup analysis). DESIGN, SETTING, AND PARTICIPANTS: The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was a randomized clinical trial in 6 centers across Finland (screening and randomization performed from September 7, 2009, through November 24, 2011; intervention duration, 2 years). Data analysis was performed from August 1, 2015, to March 31, 2016. The study population was at-risk older individuals from the general population. Inclusion criteria were age of 60 to 77 years; Cardiovascular Risk Factors, Aging, and Dementia risk score of at least 6 points; and cognition at a mean level or slightly lower than expected for age. Individuals with dementia or substantial cognitive impairment and conditions that prevented cooperation or safe engagement in the intervention were excluded. APOE genotype data were available for 1175 of the 1260 participants. INTERVENTIONS: Participants were randomly assigned in a 1: 1 ratio to a multidomain intervention group (diet, exercise, cognitive training, and vascular risk management) or a control group (general health advice). Group allocation was not actively disclosed to participants, and outcome assessors were masked to group allocation. MAIN OUTCOMES AND MEASURES: Primary outcome was change in cognition measured through a comprehensive neuropsychological test battery. Analysis was based on modified intention to treat (participants with at least 1 postbaseline assessment). RESULTS: A total of 1109 participants (mean [SD] age, 69.3 [4.7] years; 514 [46.3%] female) were included in the analysis: 362 APOE epsilon 4 allele carriers (173 intervention and 189 control) and 747 noncarriers (380 intervention and 367 control). The APOE epsilon 4 carriers and noncarriers were not significantly different at baseline (except for serum cholesterol level). The difference between the intervention and control groups in annual neuropsychological test battery total score change was 0.037 (95% CI, 0.001 to 0.073) among carriers and 0.014 (95% CI, -0.011 to 0.039) among noncarriers. Intervention effect was not significantly different between carriers and noncarriers (0.023; 95% CI, -0.021 to 0.067). CONCLUSIONS AND RELEVANCE: Healthy lifestyle changesmay be beneficial for cognition in older at-risk individuals even in the presence of APOE-related genetic susceptibility to dementia. Whether such benefits are more pronounced in APOE epsilon 4 carriers compared with noncarriers should be further investigated. The findings also emphasize the importance of early prevention strategies that target multiple modifiable risk factors simultaneously.

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