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  • 1.
    Alping, Peter
    et al.
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Askling, Johan
    Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Burman, Joachim
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Fink, Katharina
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden.
    Fogdell-Hahn, Anna
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Gunnarsson, Martin
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Neurology.
    Hillert, Jan
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Langer-Gould, Annette
    Clinical and Translational Neuroscience, Southern California Permanente Medical Group, Kaiser Permanente, Pasadena, CA, USA.
    Lycke, Jan
    Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, Sweden.
    Nilsson, Petra
    Department of Clinical Sciences/Neurology, Lund University, Lund, Sweden.
    Salzer, Jonatan
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Svenningsson, Anders
    Department of Clinical Sciences, Karolinska Institute, Danderyd Hospital, Stockholm, Sweden.
    Vrethem, Magnus
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Olsson, Tomas
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden.
    Piehl, Fredrik
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden.
    Frisell, Thomas
    Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Cancer Risk for Fingolimod, Natalizumab, and Rituximab in Multiple Sclerosis Patients2020Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Novel, highly effective disease-modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking.

    METHODS: In this nationwide register-based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national health care and census registers. We included 4,187 first-ever initiations of rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, and location to 37,801 non-MS general population subjects. Primary outcome was time to first invasive cancer.

    RESULTS: We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate [IR] per 10,000 person-years = 34.4, 95% confidence interval [CI] = 23.7-48.3), fingolimod 28 (IR = 44.0, 95% CI = 29.2-63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1-41.6). The general population IR was 31.0 (95% CI = 27.8-34.4). Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly higher risk with fingolimod compared to the general population (hazard ratio [HR] = 1.53, 95% CI = 0.98-2.38) and rituximab (HR = 1.68, 95% CI = 1.00-2.84).

    INTERPRETATION: In this first large comparative study of 3 highly effective MS disease-modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline-significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer, and further studies are warranted to validate these findings.

  • 2. Alping, Peter
    et al.
    Frisell, Thomas
    Novakova, Lenka
    Islam-Jakobsson, Protik
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Salzer, Jonatan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Björck, Anna
    Axelsson, Markus
    Malmeström, Clas
    Fink, Katharina
    Lycke, Jan
    Svenningsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap. Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Piehl, Fredrik
    Rituximab versus Fingolimod after Natalizumab in Multiple Sclerosis Patients2016Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 79, nr 6, s. 950-958Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Many JC virus antibody-positive relapsing-remitting multiple sclerosis (RRMS) patients who are stable on natalizumab switch to other therapies to avoid progressive multifocal leukoencephalopathy.

    Methods: We compared outcomes for all RRMS patients switching from natalizumab due to JC virus antibody positivity at 3 Swedish multiple sclerosis centers with different preferential use of rituximab and fingolimod (Stockholm, n = 156, fingolimod 51%; Gothenburg, n = 64, fingolimod 88%; Umea, n = 36, fingolimod 19%), yielding a total cohort of N = 256 (fingolimod 55%).

    Results: Within 1.5 years of cessation of natalizumab, 1.8% (rituximab) and 17.6% (fingolimod) of patients experienced a clinical relapse (hazard ratio for rituximab = 0.10, 95% confidence interval [CI] = 0.02-0.43). The hazard ratio (favoring rituximab) for adverse events (5.3% vs 21.1%) and treatment discontinuation (1.8% vs 28.2%) were 0.25 (95% CI = 0.10-0.59) and 0.07 (95% CI = 0.02-0.30), respectively. Furthermore, contrast-enhancing lesions were found in 1.4% (rituximab) versus 24.2% (fingolimod) of magnetic resonance imaging examinations (odds ratio = 0.05, 95% CI = 0.00-0.22). Differences remained when adjusting for possible confounders (age, sex, disability status, time on natalizumab, washout time, follow-up time, and study center).

    Interpretation: Our findings suggest an improved effectiveness and tolerability of rituximab compared with fingolimod in stable RRMS patients who switch from natalizumab due to JC virus antibody positivity. Although residual confounding factors cannot be ruled out, the shared reason for switching from natalizumab and the preferential use of either rituximab or fingolimod in 2 of the centers mitigates these concerns.

  • 3. Autti, Taina
    et al.
    Muttilainen, M.
    Raininko, Raili
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Heiskala, H.
    Puranen, J.
    Häkkinen, A-M.
    Tienari, P.
    Santavuori, Pirkko
    Suominen, P.
    Somer, M.
    Extensive cerebral white matter abnormality without clinical symptoms: a new hereditary condition?1999Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 45, nr 6, s. 801-5Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    30-year-old father and his 2 sons with slight hyperkinesia and mildly dysmorphic features and their close relatives were examined clinically and with computed tomography (CT) and magnetic resonance imaging (MRI). Neurophysiological and biochemical examinations were normal; however, brain MRI of the father and sons revealed extensive cerebral white matter changes. No radiological progression could be detected at a 13-year follow-up examination of the father, and proton magnetic resonance spectroscopy (MRS) of the father at the age of 30 years was normal. MRI findings in the relatives were normal, suggesting an autosomal dominant syndrome due to a new mutation in the father.

  • 4.
    Benatar, Michael
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Wuu, Joanne
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Lombardi, Vittoria
    Malaspina, Andrea
    Neurofilament light: a candidate biomarker of presymptomatic amyotrophic lateral sclerosis and phenoconversion2018Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 84, nr 1, s. 130-139Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To evaluate neurofilament light (NfL) as a biomarker of the presymptomatic phase of amyotrophic lateral sclerosis (ALS).

    Methods: The study population includes 84 individuals at risk for developing ALS, 34 controls, 17 ALS patients, and 10 phenoconverters (at-risk individuals observed both before and after the emergence of clinically manifest disease). At-risk individuals are enrolled through Pre-Symptomatic Familial ALS (Pre-fALS), a longitudinal natural history and biomarker study of individuals who are carriers of any ALS-associated gene mutation (in SOD1, C9orf72, TARDBP, FUS, VCP, etc), but who, at the time of enrollment, demonstrated no clinical symptoms or signs (including electromyographic evidence) of manifest disease. NfL in serum and cerebrospinal fluid (CSF) were quantified using an electrochemiluminescence immunoassay.

    Results: Serum and CSF NfL are substantially higher in ALS patients compared to controls and at-risk individuals and remain relatively stable over time. Among phenoconverters, however, NfL levels were elevated (ie, above the range observed in controls) as far back as approximate to 12 months preceding the emergence of the earliest clinical symptoms or signs of disease.

    Interpretation: Serum (and CSF) NfL are informative biomarkers of presymptomatic ALS, providing a new tool to quantify presymptomatic disease progression and to potentially predict the timing of clinical phenoconversion. As such, quantification of NfL may aid the design and implementation of early therapeutic intervention for affected individuals and/or disease prevention trials for individuals at short-term risk of developing ALS. 

  • 5. Cossee, Mireille
    et al.
    Durr, Alexandra
    Schmitt, Michèle
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Trouillas, Paul
    Allinson, Patricia
    Kostrzewa, Markus
    Nivelon-Chevallier, Annie
    Gustavson, Karl-Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Kohlschutter, Alfried
    Müller, Ulrich
    Mandel, Jean-Louis
    Brice, Alexis
    Koenig, Michel
    Cavalcanti, Francesca
    Tammaro, Angela
    De Michele, Giuseppe
    Filla, Alessandro
    Cocozza, Sergio
    Labuda, Malgorzata
    Montermini, Laura
    Poirier, Josée
    Pandolfo, Massimo
    Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes1999Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 45, nr 2, s. 200-206Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Friedreich's ataxia is the most common inherited ataxia. Ninety-six percent of patients are homozygous for GAA trinucleotide repeat expansions in the first intron of the frataxin gene. The remaining cases are compound heterozygotes for a GAA expansion and a frataxin point mutation. We report here the identification of 10 novel frataxin point mutations, and the detection of a previously described mutation (G130V) in two additional families. Most truncating mutations were in exon 1. All missense mutations were in the last three exons coding for the mature frataxin protein. The clinical features of 25 patients with identified frataxin point mutations were compared with those of 196 patients homozygous for the GAA expansion. A similar phenotype resulted from truncating mutations and from missense mutations in the carboxy-terminal half of mature frataxin, suggesting that they cause a comparable loss of function. In contrast, the only two missense mutations located in the amino-terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early-onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function. The incidence of optic disk pallor was higher in compound heterozygotes than in expansion homozygotes, which might correlate with a very low residual level of normal frataxin produced from the expanded allele.

  • 6.
    Dekhtyar, Serhiy
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Marseglia, Anna
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Xu, Weili
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Darin-Mattsson, Alexander
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Wang, Hui-Xin
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Stressforskningsinstitutet.
    Fratiglioni, Laura
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI). Stockholm Gerontology Research Center, Sweden.
    Genetic risk of dementia mitigated by cognitive reserve: A cohort study2019Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 86, nr 1, s. 68-78Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective We investigated whether cognitive reserve modifies the risk of dementia attributable to apolipoprotein epsilon 4 (APOE-epsilon 4), a well-known genetic risk factor for dementia. Methods We followed 2,556 cognitively intact participants aged >= 60 years from the ongoing prospective community-based Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). Dementia was ascertained through clinical and neuropsychological assessments and diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria. Structural equation modeling was used to generate a cognitive reserve indicator from 4 previously validated contributors: early life education, midlife substantive work complexity, late life leisure activities, and late life social networks. Cox proportional hazard models estimated dementia risk in relation to cognitive reserve indicator. The interaction between the cognitive reserve indicator and APOE-epsilon 4 was assessed on multiplicative and additive scales. Results After an average of 6.3 years (range = 2.1-10.7) of follow-up, 232 dementia cases were ascertained. Relative to individuals in the lowest tertile of cognitive reserve indicator, those with moderate and high reserve were at a reduced risk of dementia. There was no multiplicative interaction between APOE-epsilon 4 status and cognitive reserve indicator (p = 0.113). Additive interaction was statistically significant. Relative to APOE-epsilon 4 carriers with low cognitive reserve, epsilon 4 carriers with high reserve had a reduced risk of dementia (hazard ratio [HR] = 0.28, 95% confidence interval [CI] = 0.13-0.59). The magnitude of risk reduction was similar in epsilon 4 noncarriers with a high cognitive reserve indicator (HR = 0.24, 95% CI = 0.15-0.40). Interpretation Lifelong engagement in reserve-enhancing activities attenuates the risk of dementia attributable to APOE-epsilon 4. Promoting cognitive reserve might be especially effective in subpopulations with high genetic risk of dementia. ANN NEUROL 2019

  • 7. Diekstra, Frank P.
    et al.
    Van Deerlin, Vivianna M.
    van Swieten, John C.
    Al-Chalabi, Ammar
    Ludolph, Albert C.
    Weishaupt, Jochen H.
    Hardiman, Orla
    Landers, John E.
    Brown, Robert H., Jr.
    van Es, Michael A.
    Pasterkamp, R. Jeroen
    Koppers, Max
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Estrada, Karol
    Rivadeneira, Fernando
    Hofman, Albert
    Uitterlinden, Andre G.
    van Damme, Philip
    Melki, Judith
    Meininger, Vincent
    Shatunov, Aleksey
    Shaw, Christopher E.
    Leigh, P. Nigel
    Shaw, Pamela J.
    Morrison, Karen E.
    Fogh, Isabella
    Chio, Adriano
    Traynor, Bryan J.
    Czell, David
    Weber, Markus
    Heutink, Peter
    de Bakker, Paul I. W.
    Silani, Vincenzo
    Robberecht, Wim
    van den Berg, Leonard H.
    Veldink, Jan H.
    C9orf72 and UNC13A Are Shared Risk Loci for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: A Genome-Wide Meta-Analysis2014Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 76, nr 1, s. 120-133Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD. Methods: We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes. Results: Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 x 10(-12)) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 x 10(-11)) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 x 10(-7)) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 x 10(-7)). Interpretation: We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP.

  • 8.
    Eklund, Anders
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Centrum för medicinsk teknik och fysik (CMTF).
    Jóhannesson, Gauti
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Johansson, Elias
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Holmlund, Petter
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Qvarlander, Sara
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Ambarki, Khalid
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Wåhlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper. Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI).
    Koskinen, Lars-Owe D.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Malm, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    The Pressure Difference between Eye and Brain Changes with Posture2016Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 80, nr 2, s. 269-276Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: The discovery of a posture-dependent effect on the difference between intraocular pressure (IOP) and intracranial pressure (ICP) at the level of lamina cribrosa could have important implications for understanding glaucoma and idiopathic intracranial hypertension and could help explain visual impairments in astronauts exposed to microgravity. The aim of this study was to determine the postural influence on the difference between simultaneously measured ICP and IOP.

    Methods: Eleven healthy adult volunteers (age = 46 ± 10 years) were investigated with simultaneous ICP, assessed through lumbar puncture, and IOP measurements when supine, sitting, and in 9° head-down tilt (HDT). The trans–lamina cribrosa pressure difference (TLCPD) was calculated as the difference between the IOP and ICP. To estimate the pressures at the lamina cribrosa, geometrical distances were estimated from magnetic resonance imaging and used to adjust for hydrostatic effects.

    Results: The TLCPD (in millimeters of mercury) between IOP and ICP was 12.3 ± 2.2 for supine, 19.8 ± 4.6 for sitting, and 6.6 ± 2.5 for HDT. The expected 24-hour average TLCPD on earth—assuming 8 hours supine and 16 hours upright—was estimated to be 17.3mmHg. By removing the hydrostatic effects on pressure, a corresponding 24-hour average TLCPD in microgravity environment was simulated to be 6.7mmHg.

    Interpretation: We provide a possible physiological explanation for how microgravity can cause symptoms similar to those seen in patients with elevated ICP. The observed posture dependency of TLCPD also implies that assessment of the difference between IOP and ICP in upright position may offer new understanding of the pathophysiology of idiopathic intracranial hypertension and glaucoma. 

  • 9.
    Finnsson, Johannes
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Sundblom, Jimmy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Melberg, Atle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Raininko, Raili
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course2015Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 78, nr 3, s. 412-25Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Duplication of the LMNB1 gene encoding lamin B1 causes adult-onset autosomal-dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia. Magnetic resonance imaging (MRI) of the brain reveals characteristic findings. This is the first longitudinal study on this disease. Our objective is to describe the natural clinical and radiological course of LMNB1-related ADLD.

    METHODS: Twenty-three subjects in two families with LMNB1 duplications were studied over two decades with clinical assessment and MRI of the brain and spinal cord. They were 29 to 70 years old at their first MRI. Repeated MRIs were performed in 14 subjects over a time period of up to 17 years.

    RESULTS: Pathological MRI findings were found in the brain and spinal cord in all examinations (i.e., even preceding clinical symptoms). MRI changes and clinical symptoms progressed in a definite order. Autonomic dysfunction appeared in the fifth to sixth decade, preceding or together with gait and coordination difficulties. Motor signs developed ascending from spastic paraplegia to tetraplegia and pseudobulbar palsy in the seventh decade. There were clinical, radiological, and neurophysiological signs of myelopathy. Survival lasted more than two decades after clinical onset.

    INTERPRETATION: LMNB1-related ADLD is a slowly progressive neurological disease. MRI abnormalities of the brain and spinal cord can precede clinical symptoms by more than a decade and are extensive in all symptomatic patients. Spinal cord involvement is a likely contributing factor to early autonomic symptoms and spastic paraplegia. Ann Neurol 2015;78:412-425.

  • 10. Gallo, Valentina
    et al.
    Bueno-De-Mesquita, H Bas
    Vermeulen, Roel
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Kyrozis, Andreas
    Linseisen, Jakob
    Kaaks, Rudolph
    Allen, Naomi E
    Roddam, Andrew W
    Boshuizen, Hendriek C
    Peeters, Petra H
    Palli, Domenico
    Mattiello, Amalia
    Sieri, Sabina
    Tumino, Rosario
    Jiménez-Martín, Juan-Manuel
    Díaz, María José Tormo
    Suarez, Laudina Rodriguez
    Trichopoulou, Antonia
    Agudo, Antonio
    Arriola, Larraitz
    Barricante-Gurrea, Aurelio
    Bingham, Sheila
    Khaw, Kay-Tee
    Manjer, Jonas
    Lindkvist, Björn
    Overvad, Kim
    Bach, Flemming W
    Tjønneland, Anne
    Olsen, Anja
    Bergmann, Manuela M
    Boeing, Heiner
    Clavel-Chapelon, Francoise
    Lund, Eiliv
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Middleton, Lefkos
    Vineis, Paolo
    Riboli, Elio
    Smoking and risk for amyotrophic lateral sclerosis: analysis of the EPIC cohort2009Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 65, nr 4, s. 378-385Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Cigarette smoking has been reported as "probable" risk factor for Amyotrophic Lateral Sclerosis (ALS), a poorly understood disease in terms of aetiology. The extensive longitudinal data of the European Prospective Investigation into Cancer and Nutrition (EPIC) were used to evaluate age-specific mortality rates from ALS and the role of cigarette smoking on the risk of dying from ALS.

    Methods: A total of 517,890 healthy subjects were included, resulting in 4,591,325 person-years. ALS cases were ascertained through death certificates. Cox hazard models were built to investigate the role of smoking on the risk of ALS, using packs/years and smoking duration to study dose-response.

    Results: A total of 118 subjects died from ALS, resulting in a crude mortality rate of 2.69 per 100,000/year. Current smokers at recruitment had an almost two-fold increased risk of dying from ALS compared to never smokers (HR = 1.89, 95% C.I. 1.14-3.14), while former smokers at the time of enrollment had a 50% increased risk (HR = 1.48, 95% C.I. 0.94-2.32). The number of years spent smoking increased the risk of ALS (p for trend = 0.002). Those who smoked more than 33 years had more than a two-fold increased risk of ALS compared with never smokers (HR = 2.16, 95% C.I. 1.33-3.53). Conversely, the number of years since quitting smoking was associated with a decreased risk of ALS compared with continuing smoking.

    Interpretation: These results strongly support the hypothesis of a role of cigarette smoking in aetiology of ALS. We hypothesize that this could occur through lipid peroxidation via formaldehyde exposure.

  • 11. Gunnarsson, Martin
    et al.
    Malmestrom, Clas
    Rosengren, Lars
    Lycke, Jan
    Svenningsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    The Neurofilament Light Chain is Not Stable in Vitro Reply2011Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 69, nr 6, s. 1066-1067Artikkel i tidsskrift (Fagfellevurdert)
  • 12. Gunnarsson, Martin
    et al.
    Malmeström, Clas
    Axelsson, Markus
    Sundström, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Dahle, Charlotte
    Vrethem, Magnus
    Olsson, Tomas
    Piehl, Fredrik
    Norgren, Niklas
    Rosengren, Lars
    Svenningsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Lycke, Jan
    Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab2011Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 69, nr 1, s. 83-89Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Our data demonstrate that natalizumab treatment reduces the accumulation of nerve injury in relapsing forms of MS. It is anticipated that highly effective anti-inflammatory treatment can reduce axonal loss, thereby preventing development of permanent neurological disability.

  • 13.
    Gustavsson, Anna-Märta
    et al.
    Lund University, Malmö, Sweden; Skåne University Hospital, Malmö, Sweden.
    van Westen, Danielle
    Lund University, Lund, Sweden.
    Stomrud, Erik
    Lund University, Malmö, Sweden; Skåne University Hospital, Malmö, Sweden.
    Engström, Gunnar
    Lund University, Malmö, Sweden.
    Nägga, Katarina
    Region Östergötland, Närsjukvården i centrala Östergötland, Medicinska och geriatriska akutkliniken. Lund University, Malmö, Sweden.
    Hansson, Oskar
    Lund University, Malmö, Sweden; Skåne University Hospital, Malmö, Sweden.
    Midlife Atherosclerosis and Development of Alzheimer or Vascular Dementia2020Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 87, nr 1, s. 52-62Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: To investigate whether midlife atherosclerosis is associated with different dementia subtypes and related underlying pathologies.

    METHODS: Participants comprised the cardiovascular cohort of the Swedish prospective population-based Malmö Diet and Cancer Study (N = 6,103). Carotid plaques and intima media thickness (IMT) were measured at baseline (1991-1994). Dementia incidence until 2014 was obtained from national registers. Diagnoses were reviewed and validated in medical records. In a cognitively unimpaired subcohort (n = 330), β-amyloid42 and tau were quantified in cerebrospinal fluid (CSF), and white matter hyperintensity volume, lacunar infarcts, and cerebral microbleeds were estimated on magnetic resonance imaging (2009-2015).

    RESULTS: During 20 years of follow-up, 462 individuals developed dementia (mean age at baseline = 57.5 ± 5.9 years, 58% women). Higher IMT in midlife was associated with an increased hazard ratio (HR) of all-cause dementia (adjusted HR = 1.14 [95% confidence interval (CI) = 1.03-1.26]) and vascular dementia (adjusted HR = 1.32 [95% CI = 1.10-1.57]) but not Alzheimer disease (AD) dementia (adjusted HR = 0.95 [95% CI = 0.77-1.17]). Carotid plaques were associated with vascular dementia when assessed as a 3-graded score (adjusted HR = 1.90 [95% CI = 1.07-3.38]). In the cognitively unimpaired subcohort (53.8 ± 4.6 years at baseline, 60% women), higher IMT in midlife was associated with development of small vessel disease (adjusted odds ratio [OR] = 1.47 [95% CI = 1.05-2.06]) but not significantly with abnormal CSF AD biomarkers (adjusted OR = 1.28 [95% CI = 0.87-1.90] for Aβ42 and 1.35 [95% CI = 0.86-2.13] for Aβ42 /p-tau). Carotid plaques revealed no significant association with any of the underlying brain pathologies.

    INTERPRETATION: Our findings support an association between midlife atherosclerosis and development of vascular dementia and cerebral small vessel disease but not between atherosclerosis and subsequent AD dementia or AD pathology. ANN NEUROL 2019.

  • 14. Hedström, Anna Karin
    et al.
    Åkerstedt, Torbjörn
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Stressforskningsinstitutet.
    Hillert, Jan
    Olsson, Tomas
    Alfredsson, Lars
    Shift work at young age is associated with increased risk for multiple sclerosis2011Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 70, nr 5, s. 733-41Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Environmental factors play a prominent role in multiple sclerosis (MS) etiology. The aim of this study was to investigate the potential association between shift work and MS risk, which has previously never been investigated.

    METHODS: This report is based on 2 population-based, case-control studies, 1 with incident cases (1,343 cases, 2,900 controls) and 1 with prevalent cases (5,129 cases, 4,509 controls). Using logistic regression, the occurrence of MS among subjects who have been exposed to shift work at various ages was compared with that of those who have never been exposed by calculating the odds ratio (OR) with a 95% confidence interval (CI).

    RESULTS: In both studies, there was a significant association between working shift at a young age and occurrence of MS (OR, 1.6; 95% CI, 1.2-2.1 in the incidence study and OR, 1.3; 95% CI, 1.0-1.6 in the prevalence study). In the incident study, the OR of developing MS was 2.0 (95% CI, 1.2-3.6) among those who had worked shifts for 3 years or longer before age 20 years, compared with those who had never worked shifts. The OR for the corresponding comparison in the prevalent study was 2.1 (95% CI, 1.3-3.4).

    INTERPRETATION: The observed association between shift work at a young age and occurrence of MS in 2 independent studies strengthens the notion of a true relationship. Consequences of shift work such as circadian disruption and sleep restriction are associated with disturbed melatonin secretion and enhanced proinflammatory responses and may thus be part of the mechanism behind the association.

  • 15.
    Hopp, Sarah
    et al.
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany.;Univ Hosp Wurzburg, Dept Neurosurg, D-97080 Wurzburg, Germany..
    Albert-Weissenberger, Christiane
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany.;Univ Hosp Wurzburg, Dept Neurosurg, D-97080 Wurzburg, Germany..
    Mencl, Stine
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany..
    Bieber, Michael
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany.;Univ Hosp Wurzburg, Comprehens Heart Failure Ctr DZHI, D-97080 Wurzburg, Germany..
    Schuhmann, Michael K.
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany..
    Stetter, Christian
    Univ Hosp Wurzburg, Dept Neurosurg, D-97080 Wurzburg, Germany..
    Nieswandt, Bernhard
    Univ Wurzburg, Rudolf Virchow Ctr, German Res Soc, Res Ctr Expt Biomed, D-97070 Wurzburg, Germany..
    Schmidt, Peter M.
    CSL Ltd, Mol Sci & Biotechnol Inst Bio21, Parkville, Vic, Australia..
    Monoranu, Camelia-Maria
    Univ Wurzburg, Comprehens Canc Ctr Mainfranken, Inst Pathol, Dept Neuropathol, D-97070 Wurzburg, Germany..
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Marklund, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Nolte, Marc W.
    CSL Behring, Marburg, Germany..
    Siren, Anna-Leena
    Univ Hosp Wurzburg, Dept Neurosurg, D-97080 Wurzburg, Germany..
    Kleinschnitz, Christoph
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany..
    Targeting Coagulation Factor XII as a Novel Therapeutic Option in Brain Trauma2016Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 79, nr 6, s. 970-982Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury.

    Methods: We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury.

    Results: Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage.

    Interpretation: The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies.

  • 16.
    Jonas, Robin
    et al.
    Heidelberg Univ, Med Fac Mannheim, Dept Expt Pain Res, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany;Stanford Univ, Dept Anesthesiol, Stanford, CA 94305 USA.
    Namer, Barbara
    Friedrich Alexander Univ Erlangen Nuremberg, Dept Physiol 1, Nurnberg, Germany.
    Stockinger, Lenka
    Swiss Parapleg Ctr, Ctr Pain Med, Nottwil, Switzerland.
    Chisholm, Kim
    Kings Coll London, London Pain Consortium, Neurorestorat Grp, London, England.
    Schnakenberg, Mark
    Heidelberg Univ, Med Fac Mannheim, Dept Expt Pain Res, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany.
    Landmann, Gunther
    Swiss Parapleg Ctr, Ctr Pain Med, Nottwil, Switzerland.
    Kucharczyk, Mateusz
    Kings Coll London, London Pain Consortium, Neurorestorat Grp, London, England.
    Konrad, Christoph
    Kantonsspital Lucerne, Dept Anaesthesiol, Luzern, Switzerland.
    Schmidt, Roland
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Carr, Richard
    Heidelberg Univ, Med Fac Mannheim, Dept Expt Pain Res, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany.
    McMahon, Stephen
    Kings Coll London, London Pain Consortium, Neurorestorat Grp, London, England.
    Schmelz, Martin
    Heidelberg Univ, Med Fac Mannheim, Dept Expt Pain Res, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany.
    Rukwied, Roman
    Heidelberg Univ, Med Fac Mannheim, Dept Expt Pain Res, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany.
    Tuning in C-nociceptors to reveal mechanisms in chronic neuropathic pain2018Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 83, nr 5, s. 945-957Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective

    Develop and validate a low‐intensity sinusoidal electrical stimulation paradigm to preferentially activate C‐fibers in human skin.

    Methods

    Sinusoidal transcutaneous stimulation (4Hz) was assessed psychophysically in healthy volunteers (n = 14) and neuropathic pain patients (n = 9). Pursuing laser Doppler imaging and single nociceptor recordings in vivo in humans (microneurography) and pigs confirmed the activation of “silent” C‐nociceptors. Synchronized C‐fiber compound action potentials were evoked in isolated human nerve fascicles in vitro. Live cell imaging of L4 dorsal root ganglia in anesthetized mice verified the recruitment of small‐diameter neurons during transcutaneous 4‐Hz stimulation of the hindpaw (0.4mA).

    Results

    Transcutaneous sinusoidal current (0.05–0.4mA, 4Hz) activated “polymodal” C‐fibers (50% at ∼0.03mA) and “silent” nociceptors (50% at ∼0.04mA), intensities substantially lower than that required with transcutaneous 1‐ms rectangular pulses (“polymodal” ∼3mA, “silent” ∼50mA). The stimulation induced delayed burning (nonpulsating) pain and a pronounced axon‐reflex erythema, both indicative of C‐nociceptor activation. Pain ratings to repetitive stimulation (1 minute, 4Hz) adapted in healthy volunteers by Numeric Rating Scale (NRS) –3 and nonpainful skin sites of neuropathic pain patients by NRS –0.5, whereas pain even increased in painful neuropathic skin by approximately NRS +2.

    Interpretation

    Sinusoidal electrical stimulation at 4Hz enables preferential activation of C‐nociceptors in pig and human skin that accommodates during ongoing (1‐minute) stimulation. Absence of such accommodation in neuropathic pain patients suggest axonal hyperexcitability that could be predictive of alterations in peripheral nociceptor encoding and offer a potential therapeutic entry point for topical analgesic treatment.

  • 17.
    Jonsson, P Andreas
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi. Klinisk kemi.
    Bergemalm, Daniel
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi. Klinisk kemi.
    Andersen, Peter M
    Umeå universitet, Medicinsk fakultet, Farmakologi och klinisk neurovetenskap, Neurologi. Neurologi.
    Gredal, Ole
    Brännström, Thomas
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi. Patologi.
    Marklund, Stefan L
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi. Klinisk kemi.
    Inclusions of amyotrophic lateral sclerosis-linked superoxide dismutase in ventral horns, liver, and kidney2008Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 63, nr 5, s. 671-675Artikkel i tidsskrift (Fagfellevurdert)
  • 18. Järvelä, I.
    et al.
    Autti, Taina
    Lamminranta, S.
    Aberg, P.
    Raininko, Raili
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Santavuori, P.
    Clinical and magnetic resonance imaging findings in Batten disease: Analysis of the major mutation (1.02-kb deletion)1997Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 42, nr 5, s. 799-802Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A total of 36 patients with Batten disease (juvenile-onset neuronal ceroid lipofuscinosis), homozygous or heterozygous for the major mutation, a 1.02-kb deletion, in the CLN3 gene, were studied to relate their genotype to their clinical phenotype. The onset of visual failure and epilepsy was highly concordant in both groups. Great inter- and intrafamilial heterogeneity was demonstrated in the development of mental and physical handicap and in magnetic resonance imaging findings among both homozygous and heterozygous patients. The 1.02-kb deletion in homozygous form was always associated with mental and physical handicap, whereas the heterozygous phenotype could be extremely benign without affecting the intellectual level of the patient. Our data suggest that genetic background, modifying genes, and environmental factors all influence the final phenotype of Batten disease.

  • 19. Kadir, Ahmadul
    et al.
    Andreasen, Niels
    Almkvist, Ove
    Wall, Anders
    Forsberg, Anton
    Engler, Henry
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Hagman, Göran
    Lärksäter, Marie
    Winblad, Bengt
    Zetterberg, Henrik
    Blennow, Kaj
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Nordberg, Agneta
    Effect of phenserine treatment on brain functional activity and amyloid in Alzheimer's disease2008Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 63, nr 5, s. 621-631Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: The effects of (-)-phenserine (phenserine) and placebo/donepezil treatment on regional cerebral metabolic rate for glucose (rCMRglc) and brain amyloid load were investigated by positron emission tomography in 20 patients with mild Alzheimer's disease in relation to cerebrospinal fluid (CSF) and plasma biomarkers, and cognitive function. Methods: The first 3 months of the study was a randomized, double-blind, placebo-controlled phase, during which 10 patients received phenserine (30mg/day) and 10 patients the placebo. Three to 6 months was an open-label extension phase, during which the placebo group received donepezil (5mg/day) and the phenserine group remained on phenserine. After 6 months, all patients received phenserine treatment up to 12 months. The patients underwent positron emission tomography examinations to measure rCMR91c (F-18-FDG) and amyloid load (C-11-PIB) at baseline and after 3 and 6 months of the treatment. Neuropsychological and biomarker data were collected at the three times of positron emission tomography imaging. Results: Statistically significant effects on a composite neuropsychological test score were observed in the phenserine-treated group compared with the placebo and donepezil group at 3 and 6 months, respectively. Values of rCMRglc were significantly increased in several cortical regions after 3 months of phenserine treatment, compared with baseline, and correlated positively with cognitive function and CSF beta-amyloid 40 (A beta 40). Cortical Pittsburgh Compound B retention correlated negatively with CSF A beta 40 levels and the ratio A beta/beta-secretase-cleaved amyloid precursor protein. In CSF, A beta 40 correlated positively with the attention domain of cognition. Interpretation: Phenserine treatment was associated with an improvement in cognition and an increase in rCMRglc.

  • 20. Kadir, Ahmadul
    et al.
    Andreasen, Niels
    Almkvist, Ove
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen.
    Wall, Anders
    Forsberg, Anton
    Engler, Henry
    Hagman, Göran
    Lärksäter, Marie
    Winblad, Bengt
    Zetterberg, Henrik
    Blennow, Kaj
    Långström, Bengt
    Nordberg, Agneta
    Effect of phenserine treatment on brain functional activity and amyloid in Alzheimer's disease2008Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 63, nr 5, s. 621-631Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: The effects of (-)-phenserine (phenserine) and placebo/donepezil treatment on regional cerebral metabolic rate for glucose (rCMRglc) and brain amyloid load were investigated by positron emission tomography in 20 patients with mild Alzheimer's disease in relation to cerebrospinal fluid (CSF) and plasma biomarkers, and cognitive function.

    METHODS: The first 3 months of the study was a randomized, double-blind, placebo-controlled phase, during which 10 patients received phenserine (30 mg/day) and 10 patients the placebo. Three to 6 months was an open-label extension phase, during which the placebo group received donepezil (5 mg/day) and the phenserine group remained on phenserine. After 6 months, all patients received phenserine treatment up to 12 months. The patients underwent positron emission tomography examinations to measure rCMRglc (8F-FDG) and amyloid load (11C-PIB) at baseline and after 3 and 6 months of the treatment. Neuropsychological and biomarker data were collected at the three times of positron emission tomography imaging.

    RESULTS: Statistically significant effects on a composite neuropsychological test score were observed in the phenserine-treated group compared with the placebo and donepezil group at 3 and 6 months, respectively. Values of rCMRglc were significantly increased in several cortical regions after 3 months of phenserine treatment, compared with baseline, and correlated positively with cognitive function and CSF beta-amyloid 40 (Abeta40). Cortical Pittsburgh Compound B retention correlated negatively with CSF Abeta40 levels and the ratio Abeta/beta-secretase-cleaved amyloid precursor protein. In CSF, Abeta40 correlated positively with the attention domain of cognition.

    INTERPRETATION: Phenserine treatment was associated with an improvement in cognition and an increase in rCMRglc.

  • 21.
    Kai, Lehtimaki
    et al.
    Tampere Univ Hosp, Dept Neurosci & Rehabil, POB 2000,Teiskontie 35,Bldg A, Tampere 33521, Finland..
    Jaakko, W. Langsjo
    Tampere Univ Hosp, Intens Care Unit, Tampere, Finland..
    Jyrki, Ollikainen
    Tampere Univ Hosp, Dept Neurosci & Rehabil, POB 2000,Teiskontie 35,Bldg A, Tampere 33521, Finland..
    Hanna, Heinonen
    Tampere Univ Hosp, Dept Clin Neurophysiol, Tampere, Finland..
    Timo, Mottonen
    Tampere Univ Hosp, Dept Neurosci & Rehabil, POB 2000,Teiskontie 35,Bldg A, Tampere 33521, Finland..
    Timo, Tahtinen
    Tampere Univ Hosp, Dept Neurosci & Rehabil, POB 2000,Teiskontie 35,Bldg A, Tampere 33521, Finland..
    Joonas, Haapasalo
    Tampere Univ Hosp, Dept Neurosci & Rehabil, POB 2000,Teiskontie 35,Bldg A, Tampere 33521, Finland..
    Tenhunen, Jyrki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Jani, Katisko
    Oulu Univ Hosp, Dept Neurosurg, Oulu, Finland..
    Juha, Ohman
    Tampere Univ Hosp, Dept Neurosci & Rehabil, POB 2000,Teiskontie 35,Bldg A, Tampere 33521, Finland..
    Jukka, Peltola
    Tampere Univ Hosp, Dept Neurosci & Rehabil, POB 2000,Teiskontie 35,Bldg A, Tampere 33521, Finland..
    Successful management of super-refractory status epilepticus with thalamic deep brain stimulation2017Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 81, nr 1, s. 142-146Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Super-refractory status epilepticus is a condition characterized by recurrence of status epilepticus despite use of deep general anesthesia, and it has high morbidity and mortality rates. We report a case of a 17-year-old boy with a prolonged super-refractory status epilepticus that eventually resolved after commencing deep brain stimulation of the centromedian nucleus of the thalamus. Later attempt to reduce stimulation parameters resulted in immediate relapse of status epilepticus, suggesting a pivotal role of deep brain stimulation in the treatment response. Deep brain stimulation may be a treatment option in super-refractory status epilepticus when other treatment options have failed. ANN NEUROL 2017;81:142-146

  • 22. Killestein, Joep
    et al.
    Olsson, Tomas
    Wallström, Erik
    Svenningsson, Anders
    Khademi, Mohsen
    Blumhardt, Lance D
    Fagius, Jan
    Hillert, Jan
    Landtblom, Anne-Marie
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Neurologiska kliniken.
    Hedenius, Charlotte
    Årfors, Leopold
    Barkhof, Frederik
    Polman, Chris H
    Antibody-Mediated suppression of Vbeta5.2/5.3+ T Cells in Multiple Sclerosis: Results from an MRI-Monitored Phase II Clinical Trial2002Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 51, nr 4, s. 467-474Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The objective of this study was to evaluate the safety and efficacy of the humanized antibody ATM-027 in a baseline versus treatment magnetic resonance imaging-monitored study. Expansion of Vß5.2/5.3+ T cells has been demonstrated in the peripheral blood, cerebrospinal fluid, and brain lesions of MS patients. In a phase I study, ATM-027 depleted these cells in peripheral blood and, in parallel, T-cell MBP reactivity and IFN-? expression were reduced. We studied 59 patients with relapsing-remitting MS (47 on ATM-027 and 12 on placebo) stratified for HLA-DR2 status. Monthly intravenous injections were given for 6 months. Individual dose titration was employed to obtain depletion of the target T-cell level and downregulation of antigen receptor density as monitored by flow cytometry. Five monthly magnetic resonance imaging scans were performed before treatment to establish baseline activity, six during treatment, and three during follow-up. Additional immunological assessments were performed to elucidate the mechanism of action of ATM-027. The treatment was safe and well tolerated, inducing consistent suppression of the target cell population. During run-in, active lesions were found in 78.7% (37/47) of patients treated with ATM-027. During treatment, the median number of lesions was reduced by 33% (p = 0.13) independent of DR2 status. The corresponding volume of enhancement was 221 mm3 at baseline, with a reduction of 10% during treatment. Decreased numbers of cells expressing interferon-? messenger RNA, and decreased T-cell reactivity to several myelin antigens were found in ATM-027 treated patients. In conclusion, consistent suppression of Vß 5.2/5.3+ T cells was achieved. However, the effect size on magnetic resonance imaging was considerably less than the targeted 60%.

  • 23. Lange, Dale J.
    et al.
    Shahbazi, Mona
    Silani, Vincenzo
    Ludolph, Albert C.
    Weishaupt, Jochen H.
    Ajroud-Driss, Senda
    Fields, Kara G.
    Remanan, Rahul
    Appel, Stanley H.
    Morelli, Claudia
    Doretti, Alberto
    Maderna, Luca
    Messina, Stefano
    Weiland, Ulrike
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap. Department of Neurology, Ulm University, Ulm, Germany.
    Pyrimethamine Significantly Lowers Cerebrospinal Fluid Cu/Zn Superoxide Dismutase in Amyotrophic Lateral Sclerosis Patients with SOD1 Mutations2017Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 81, nr 6, s. 837-848Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Cu/Zn superoxide dismutase (SOD1) reduction prolongs survival in SOD1-transgenic animal models. Pyrimethamine produces dose-dependent SOD1 reduction in cell culture systems. A previous phase 1 trial showed pyrimethamine lowers SOD1 levels in leukocytes in patients with SOD1 mutations. This study investigated whether pyrimethamine lowered SOD1 levels in the cerebrospinal fluid (CSF) in patients carrying SOD1 mutations linked to familial amyotrophic lateral sclerosis (fALS/SOD1). Methods: A multicenter (5 sites), open-label, 9-month-duration, dose-ranging study was undertaken to determine the safety and efficacy of pyrimethamine to lower SOD1 levels in the CSF in fALS/SOD1. All participants underwent 3 lumbar punctures, blood draw, clinical assessment of strength, motor function, quality of life, and adverse effect assessments. SOD1 levels were measured in erythrocytes and CSF. Pyrimethamine was measured in plasma and CSF. Appel ALS score, ALS Functional Rating Scale-Revised, and McGill Quality of Life Single-Item Scale were measured at screening, visit 6, and visit 9. Results: We enrolled 32 patients; 24 completed 6 visits (18 weeks), and 21 completed all study visits. A linear mixed effects model showed a significant reduction in CSF SOD1 at visit 6 (p<0.001) with a mean reduction of 13.5% (95% confidence interval [CI] 58.4-18.5) and at visit 9 (p<0.001) with a mean reduction of 10.5% (95% CI55.2-15.8). Interpretation: Pyrimethamine is safe and well tolerated in ALS. Pyrimethamine is capable of producing a significant reduction in total CSF SOD1 protein content in patients with ALS caused by different SOD1 mutations. Further long-term studies are warranted to assess clinical efficacy.

  • 24.
    Larsson, Susanna C.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, S-17177 Stockholm, Sweden.
    Burgess, Stephen
    Univ Cambridge, Med Res Council, Biostat Unit, Cambridge, England;Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Smoking and stroke: A mendelian randomization study2019Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 86, nr 3, s. 468-471Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We used the Mendelian randomization design to explore the potential causal association of smoking with ischemic stroke and intracerebral hemorrhage using summary statistics data for 34,217 ischemic stroke cases and 404,630 noncases, and 1,545 cases of intracerebral hemorrhage and 1,481 noncases. Genetic predisposition to smoking initiation (ever smoking regularly), based on up to 372 single-nucleotide polymorphisms, was statistically significantly positively associated with any ischemic stroke, large artery stroke, and small vessel stroke but not cardioembolic stroke or intracerebral hemorrhage. This study provides genetic support for a causal association of smoking with ischemic stroke, particularly large artery and small vessel stroke. ANN NEUROL 2019;86:468-471

  • 25.
    Larsson, Susanna C.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Nobels Vag 13, Stockholm, Sweden.
    Traylor, Matthew
    Univ Cambridge, Dept Clin Neurosci, Stroke Res Grp, Cambridge, England.
    Markus, Hugh S.
    Univ Cambridge, Dept Clin Neurosci, Stroke Res Grp, Cambridge, England.
    Homocysteine and small vessel stroke: A mendelian randomization analysis2019Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 85, nr 4, s. 495-501Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective

    Trials of B vitamin therapy to lower blood total homocysteine (tHcy) levels for prevention of stroke are inconclusive. Secondary analyses of trial data and epidemiological studies suggest that tHcy levels may be particularly associated with small vessel stroke (SVS). We assessed whether circulating tHcy and B vitamin levels are selectively associated with SVS, but not other stroke subtypes, using Mendelian randomization.

    Methods

    We used summary statistics data for single-nucleotide polymorphisms (SNPs) associated with tHcy (n = 18), folate (n = 3), vitamin B-6 (n = 1), and vitamin B-12 (n = 14) levels, and the corresponding data for stroke from the MEGASTROKE consortium (n = 16,952 subtyped ischemic stroke cases and 404,630 noncases).

    Results

    Genetically predicted tHcy was associated with SVS, with an odds ratio of 1.34 (95% confidence interval [CI], 1.13-1.58; p = 6.7 x 10(-4)) per 1 standard deviation (SD) increase in genetically predicted tHcy levels, but was not associated with large artery or cardioembolic stroke. The association was mainly driven by SNPs at or near the MTHFR and MUT genes. The odds ratios of SVS per 1 SD increase in genetically predicted folate and vitamin B-6 levels were 0.49 (95% CI, 0.34-0.71; p = 1.3 x 10(-4)) and 0.70 (95% CI, 0.52-0.94; p = 0.02), respectively. Genetically higher vitamin B-12 levels were not associated with any stroke subtype.

    Interpretation

    These findings suggest that any effect of homocysteine-lowering treatment in preventing stroke will be confined to the SVS subtype. Whether genetic variants at or near the MTHFR and MUT genes influence SVS risk through pathways other than homocysteine levels and downstream effects require further investigation. Ann Neurol 2019;85:495-501

  • 26. Leinonen, Ville
    et al.
    Koivisto, Anne M.
    Savolainen, Sakari
    Rummukainen, Jaana
    Tamminen, Juuso N.
    Tillgren, Tomi
    Vainikka, Sannakaisa
    Pyykko, Okko T.
    Molsa, Juhani
    Fraunberg, Mikael
    Pirttila, Tuula
    Jaaskelainen, Juha E.
    Soininen, Hilkka
    Rinne, Jaakko
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Amyloid and Tau Proteins in Cortical Brain Biopsy and Alzheimer's Disease2010Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 68, nr 4, s. 446-453Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Amyloid-beta(A beta) aggregates are presumed to be found in the brain at an early stage of Alzheimer's disease (AD) but have seldom been assessed by brain biopsy during life in often elderly patients.

    Methods: Between 1991 and 2006 we evaluated 468 patients with suspected normal pressure hydrocephalus with intraventricular pressure monitoring and a right frontal cortical biopsy sample immunostained for A beta and hyperphosphorylated tau (HP tau). Adequate samples and the clinical follow-up data until death or the end of 2008, available in 433 cases, were reviewed for the clinical signs of dementia, including AD. Logistic regression analysis was used to analyze whether A beta and/or HP tau in the biopsy samples obtained during life predicted development of cognitive impairment, in particular, AD.

    Results: Of the 433 frontal cortical samples, 42 (10%) displayed both A beta and HP tau, 144 (33%) A beta only, and 247 (57%) neither A beta nor HP tau. In a median follow-up time of 4.4 years, 94 patients (22%) developed clinical AD. The presence of both A beta and HP tau was strongly associated (odds ratio [OR], 68.2; 95% confidence interval [Cl], 22.1-210) and A beta alone significantly associated (OR, 10.8; 95% Cl, 4.9-23.8) with the clinical diagnosis of AD.

    Interpretation: This is the largest follow-up study of patients assessed for the presence of A beta and HP tau in frontal cortical brain biopsy samples. 1) The presence of A beta and HP tau spoke strongly for the presence or later development of clinical AD; 2) A beta alone was suggestive of AD; and 3) the absence of A beta and HP tau spoke against a later clinical diagnosis of AD.

  • 27.
    Lindqvist, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Levy, Yotam
    Kings Coll London, Fac Life Sci & Med, Ctr Human & Aerosp Physiol Sci, Guys Campus,Shepherds House,Room 3-3, London SE1 1UL, England..
    Pati-Alam, Alisha
    Kings Coll London, Fac Life Sci & Med, Ctr Human & Aerosp Physiol Sci, Guys Campus,Shepherds House,Room 3-3, London SE1 1UL, England..
    Hardeman, Edna C.
    Univ New S Wales, Sch Med Sci, Neuromuscular & Regenerat Med Unit, Sydney, NSW, Australia..
    Gregorevic, Paul
    Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia.;Monash Univ, Dept Biochem & Mol Biol, Melbourne, Vic 3004, Australia.;Univ Melbourne, Dept Physiol, Melbourne, Vic, Australia.;Univ Washington, Sch Med, Dept Neurol, Seattle, WA 98195 USA..
    Ochala, Julien
    Kings Coll London, Fac Life Sci & Med, Ctr Human & Aerosp Physiol Sci, Guys Campus,Shepherds House,Room 3-3, London SE1 1UL, England..
    Modulating Myosin Restores Muscle Function in a Mouse Model of Nemaline Myopathy2016Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 79, nr 5, s. 717-725Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Nemaline myopathy, one of the most common congenital myopathies, is associated with mutations in various genes including ACTA1. This disease is also characterized by various forms/degrees of muscle weakness, with most cases being severe and resulting in death in infancy. Recent findings have provided valuable insight into the underlying pathophysiological mechanisms. Mutations in ACTA1 directly disrupt binding interactions between actin and myosin, and consequently the intrinsic force-generating capacity of muscle fibers. ACTA1 mutations are also associated with variations in myofiber size, the mechanisms of which have been unclear. In the present study, we sought to test the hypotheses that the compromised functional and morphological attributes of skeletal muscles bearing ACTA1 mutations (1) would be directly due to the inefficient actomyosin complex and (2) could be restored by manipulating myosin expression.

    Methods: We used a knockin mouse model expressing the ACTA1 His40Tyr actin mutation found in human patients. We then performed in vivo intramuscular injections of recombinant adeno-associated viral vectors harboring a myosin transgene known to facilitate muscle contraction.

    Results: We observed that in the presence of the transgene, the intrinsic force-generating capacity was restored and myofiber size was normal.

    Interpretation: This demonstrates a direct link between disrupted attachment of myosin molecules to actin monomers and muscle fiber atrophy. These data also suggest that further therapeutic interventions should primarily target myosin dysfunction to alleviate the pathology of ACTA1-related nemaline myopathy.

  • 28.
    Margolis, Russell L
    et al.
    USA.
    Holmes, Susan E
    Rosenblatt, Adam
    Gourley, Lisa
    O'Hearn, Elizabeth
    Ross, Christopher A
    Seltzer, William K
    Walker, Ruth H
    Ashizawa, Tetsuo
    Rasmussen, Astrid
    Hayden, Michael
    Almqvist, Elisabeth W
    Harris, Juliette
    Fahn, Stanley
    MacDonald, Marcy E
    Mysore, Jayalakshmi
    Shimohata, Takayoshi
    Tsuji, Shoji
    Potter, Nicholas
    Nakaso, Kazuhiro
    Adachi, Yoshiki
    Nakashima, Kenji
    Bird, Thomas
    Krause, Amanda
    Greenstein, Penny
    Huntington's Disease-like 2 (HDL2) in North America and Japan.2004Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 56, nr 5, s. 670-4Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Huntington's Disease-like 2 (HDL2) is a progressive, autosomal dominant, neurodegenerative disorder with marked clinical and pathological similarities to Huntington's disease (HD). The causal mutation is a CTG/CAG expansion mutation on chromosome 16q24.3, in a variably spliced exon of junctophilin-3. The frequency of HDL2 was determined in nine independent series of patients referred for HD testing or selected for the presence of an HD-like phenotype in North America or Japan. The repeat length, ancestry, and age of onset of all North American HDL2 cases were determined. The results show that HDL2 is very rare, with a frequency of 0 to 15% among patients in the nine case series with an HD-like presentation who do not have the HD mutation. HDL2 is predominantly, and perhaps exclusively, found in individuals of African ancestry. Repeat expansions ranged from 44 to 57 triplets, with length instability in maternal transmission detected in a repeat of r2=0.29, p=0.0098). The results further support the evidence that the repeat expansion at the chromosome 16q24.3 locus is the direct cause of HDL2 and provide preliminary guidelines for the genetic testing of patients with an HD-like phenotype.

  • 29.
    Mefford, Heather C
    et al.
    Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA.
    Yendle, Simone C
    Epilepsy Research Center and Department of Medicine, University of Melbourne, Austin Health, Australia.
    Hsu, Cynthia
    Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA.
    Cook, Joseph
    Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA.
    Geraghty, Eileen
    Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA.
    McMahon, Jacinta M
    Epilepsy Research Center and Department of Medicine, University of Melbourne, Austin Health, Australia.
    Eeg-Olofsson, Orvar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Sadleir, Lynette G
    Departments of Paediatrics, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand.
    Gill, Deepak
    T.Y. Nelson Department of Neurology, the Children's Hospital at Westmead, University of Sydney, Westmead, Australia.
    Ben-Zeev, Bruria
    Pediatric Neurology Unit, Edmond and Lilly Safra Pediatric Hospital, Sheba Med Center, Tel Aviv University, Tel-Aviv, Israel.
    Lerman-Sagie, Tally
    Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel.
    Mackay, Mark
    Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Australia.
    Freeman, Jeremy L
    Department of Neurology, Royal Children's Hospital, Australia.
    Andermann, Eva
    Departments of Neurology and Neurosurgery and Human Genetics, McGill University, Montreal Quebec, Canada.
    Pelakanos, James T
    Department of Paediatric Neurology, Royal Children's Hospital, Brisbane, Australia.
    Andrews, Ian
    Department of Neurology, Sydney Children's Hospital, Sydney, Australia.
    Wallace, Geoffrey
    Department of Paediatric Neurology, Mater Medical Centre and Royal Children's Hospital, South Brisbane, Australia.
    Eichler, Evan E
    Department of Genome Sciences, University of Washington, Seattle, WA.
    Berkovic, Samuel F
    Epilepsy Research Center and Department of Medicine, University of Melbourne, Austin Health, Australia.
    Scheffer, Ingrid E
    Epilepsy Research Center and Department of Medicine, University of Melbourne, Austin Health, Australia.
    Rare copy number variants are an important cause of epileptic encephalopathies2011Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 70, nr 6, s. 974-985Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    Rare copy number variants (CNVs)-deletions and duplications-have recently been established as important risk factors for both generalized and focal epilepsies. A systematic assessment of the role of CNVs in epileptic encephalopathies, the most devastating and often etiologically obscure group of epilepsies, has not been performed.

    METHODS:

    We evaluated 315 patients with epileptic encephalopathies characterized by epilepsy and progressive cognitive impairment for rare CNVs using a high-density, exon-focused, whole-genome oligonucleotide array.

    RESULTS:

    We found that 25 of 315 (7.9%) of our patients carried rare CNVs that may contribute to their phenotype, with at least one-half being clearly or likely pathogenic. We identified 2 patients with overlapping deletions at 7q21 and 2 patients with identical duplications of 16p11.2. In our cohort, large deletions were enriched in affected individuals compared to controls, and 4 patients harbored 2 rare CNVs. We screened 2 novel candidate genes found within the rare CNVs in our cohort but found no mutations in our patients with epileptic encephalopathies. We highlight several additional novel candidate genes located in CNV regions.

    INTERPRETATION:

    Our data highlight the significance of rare CNVs in the epileptic encephalopathies, and we suggest that CNV analysis should be considered in the genetic evaluation of these patients. Our findings also highlight novel candidate genes for further study.

  • 30.
    Montgomery, Scott
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Clinical Epidemiology Unit, Department of Medicine, Karolinska Institute Solna, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, United Kingdom.
    Hiyoshi, Ayako
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län.
    Burkill, Sarah
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Institute Solna, Stockholm, Sweden; Center for Pharmacoepidemiology, Department of Medicine, Karolinska Institute Solna, Stockholm, Sweden.
    Alfredsson, Lars
    Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden; Center for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
    Bahmanyar, Shahram
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Institute Solna, Stockholm, Sweden; Center for Pharmacoepidemiology, Department of Medicine, Karolinska Institute Solna, Stockholm, Sweden.
    Olsson, Tomas
    Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Concussion in adolescence and risk of multiple sclerosis2017Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 82, nr 4, s. 554-561Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To assess whether concussion in childhood or adolescence is associated with subsequent multiple sclerosis (MS) risk. Previous research suggests an association, but methodological limitations included retrospective data collection and small study populations.

    Methods: The national Swedish Patient Register (hospital diagnoses) and MS Register were used to identify all MS diagnoses up to 2012 among people born since 1964, when the Patient Register was established. The 7,292 patients with MS were matched individually with 10 people without MS by sex, year of birth, age/vital status at MS diagnosis, and region of residence (county), resulting in a study population of 80,212. Diagnoses of concussion and control diagnoses of broken limb bones were identified using the Patient Register from birth to age 10 years or from age 11 to 20 years. Conditional logistic regression was used to examine associations with MS.

    Results: Concussion in adolescence was associated with a raised risk of MS, producing adjusted odds ratios (95% confidence intervals) of 1.22 (1.05-1.42, p=0.008) and 2.33 (1.35-4.04, p=0.002) for 1 diagnosis of concussion and >1 diagnosis of concussion, respectively, compared with none. No notable association with MS was observed for concussion in childhood, or broken limb bones in childhood and adolescence.

    Interpretation: Head trauma in adolescence, particularly if repeated, is associated with a raised risk of future MS, possibly due to initiation of an autoimmune process in the central nervous system. This further emphasizes the importance of protecting young people from head injuries. Ann Neurol 2017;82:554-561

  • 31.
    Montgomery, Scott
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet Solna, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, United Kingdom.
    Hiyoshi, Ayako
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Burkill, Sarah
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet Solna, Stockholm, Sweden; Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institutet Solna, Stockholm, Sweden.
    Alfredsson, Lars
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
    Bahmanyar, Shahram
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet Solna, Stockholm, Sweden; Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institutet Solna, Stockholm, Sweden.
    Olsson, Tomas
    Department of Clinical Neuroscience, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Reply to "concussion may not cause multiple sclerosis".2017Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 82, nr 4, s. 652-653Artikkel i tidsskrift (Fagfellevurdert)
  • 32.
    Morbelli, Silvia
    et al.
    IRCCS Osped Policlin San Martino, Italy; Univ Genoa, Italy.
    Chincarini, Andrea
    Natl Inst Nucl Phys INFN, Italy.
    Brendel, Matthias
    Ludwig Maximilians Univ Munchen, Germany.
    Rominger, Axel
    Ludwig Maximilians Univ Munchen, Germany; Univ Hosp Bern, Switzerland.
    Bruffaerts, Rose
    Katholieke Univ Leuven, Belgium; Univ Hosp Leuven, Belgium.
    Vandenberghe, Rik
    Katholieke Univ Leuven, Belgium; Univ Hosp Leuven, Belgium.
    Kramberger, Milica G.
    Univ Med Ctr, Slovenia.
    Trost, Maja
    Univ Med Ctr, Slovenia; Univ Ljubljana, Slovenia.
    Garibotto, Valentina
    Geneva Univ Hosp, Switzerland; Univ Geneva, Switzerland.
    Nicastro, Nicolas
    Geneva Univ Hosp, Switzerland; Univ Cambridge, England.
    Frisoni, Giovanni B.
    Geneva Univ Hosp, Switzerland.
    Lemstra, Afina W.
    Vrije Univ Amsterdam Med Ctr, Netherlands.
    van der Zande, Jessica
    Vrije Univ Amsterdam Med Ctr, Netherlands.
    Pilotto, Andrea
    Univ Brescia, Italy; FERB ONLUS S Isidoro Hosp, Italy.
    Padovani, Alessandro
    Univ Brescia, Italy.
    Garcia-Ptacek, Sara
    Karolinska Inst, Sweden.
    Savitcheva, Irina
    Karolinska Inst, Sweden.
    Ochoa-Figueroa, Miguel A.
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Fysiologiska kliniken US. Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Södersjukhuset, Sweden.
    Davidsson, Anette
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Fysiologiska kliniken US.
    Camacho, Valle
    Univ Autonoma Barcelona, Spain.
    Peira, Enrico
    Univ Genoa, Italy.
    Arnaldi, Dario
    Univ Genoa, Italy.
    Bauckneht, Matteo
    IRCCS Osped Policlin San Martino, Italy; Univ Genoa, Italy.
    Pardini, Matteo
    IRCCS Osped Policlin San Martino, Italy; Univ Genoa, Italy.
    Sambuceti, Gianmario
    IRCCS Osped Policlin San Martino, Italy; Univ Genoa, Italy.
    Aarsland, Dag
    Stavanger Univ Hosp, Norway; Kings Coll London, England.
    Nobili, Flavio
    IRCCS Osped Policlin San Martino, Italy; Univ Genoa, Italy.
    Metabolic patterns across core features in dementia with lewy bodies2019Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 85, nr 5, s. 715-725Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective

    To identify brain regions whose metabolic impairment contributes to dementia with Lewy bodies (DLB) clinical core features expression and to assess the influence of severity of global cognitive impairment on the DLB hypometabolic pattern.

    Methods

    Brain fluorodeoxyglucose positron emission tomography and information on core features were available in 171 patients belonging to the imaging repository of the European DLB Consortium. Principal component analysis was applied to identify brain regions relevant to the local data variance. A linear regression model was applied to generate core‐feature–specific patterns controlling for the main confounding variables (Mini‐Mental State Examination [MMSE], age, education, gender, and center). Regression analysis to the locally normalized intensities was performed to generate an MMSE‐sensitive map.

    Results

    Parkinsonism negatively covaried with bilateral parietal, precuneus, and anterior cingulate metabolism; visual hallucinations (VH) with bilateral dorsolateral–frontal cortex, posterior cingulate, and parietal metabolism; and rapid eye movement sleep behavior disorder (RBD) with bilateral parieto‐occipital cortex, precuneus, and ventrolateral–frontal metabolism. VH and RBD shared a positive covariance with metabolism in the medial temporal lobe, cerebellum, brainstem, basal ganglia, thalami, and orbitofrontal and sensorimotor cortex. Cognitive fluctuations negatively covaried with occipital metabolism and positively with parietal lobe metabolism. MMSE positively covaried with metabolism in the left superior frontal gyrus, bilateral–parietal cortex, and left precuneus, and negatively with metabolism in the insula, medial frontal gyrus, hippocampus in the left hemisphere, and right cerebellum.

    Interpretation

    Regions of more preserved metabolism are relatively consistent across the variegate DLB spectrum. By contrast, core features were associated with more prominent hypometabolism in specific regions, thus suggesting a close clinical–imaging correlation, reflecting the interplay between topography of neurodegeneration and clinical presentation in DLB patients. Ann Neurol 2019;85:715–725

  • 33. Nordstrom, Peter
    et al.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Gustafson, Yngve
    Nordström, Anna
    Traumatic brain injury and young onset dementia: a nationwide cohort study2014Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 75, nr 3, s. 374-381Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective

    To investigate the association between traumatic brain injuries (TBIs) and the risk of young onset dementia (YOD), that is, dementia before 65 years of age.

    Methods

    The study cohort comprised 811,622 Swedish men (mean age = 18 years) conscripted for military service between 1969 and 1986. TBIs, dementia, and covariates were extracted from national registers. Time-dependent exposures using Cox proportional hazard regression models were evaluated.

    Results

    During a median follow-up period of 33 years, there were 45,249 men with at least 1 TBI in the cohort. After adjustment for covariates, 1 mild TBI (hazard ratio [HR] = 1.0, 95% confidence interval [CI] = 0.5-2.0), at least 2 mild TBIs (HR = 2.5, 95% CI = 0.8-8.1), or 1 severe TBI (HR = 0.7, 95% CI = 0.1-5.2) were not associated with Alzheimer dementia (AD). Other types of dementia were strongly associated with the risk of 1 mild TBI (HR = 3.8, 95% CI = 2.8-5.2), at least 2 mild TBIs (HR = 10.4, 95% CI = 6.3-17.2), and 1 severe TBI (HR = 11.4, 95% CI = 7.4-17.5) in age-adjusted analysis. However, these associations were largely attenuated after adjustment for covariates (1 mild TBI: HR = 1.7; at least 2 mild TBIs: HR = 1.7; 1 severe TBI: HR = 2.6; p < 0.05 for all).

    Interpretation

    In the present study, we found strong associations between YOD of non-AD forms and TBIs of different severity. These associations were, however, markedly attenuated after multivariate adjustment. Ann Neurol 2014;75:374-381

  • 34.
    Nordström, Peter
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Michaelsson, Karl
    Gustafson, Yngve
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Nordström, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Traumatic brain injury and young onset dementia: a nationwide cohort study2014Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 75, nr 3, s. 374-381Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective To investigate the association between traumatic brain injuries (TBIs) and the risk of young onset dementia (YOD), that is, dementia before 65 years of age. Methods The study cohort comprised 811,622 Swedish men (mean age = 18 years) conscripted for military service between 1969 and 1986. TBIs, dementia, and covariates were extracted from national registers. Time-dependent exposures using Cox proportional hazard regression models were evaluated. Results During a median follow-up period of 33 years, there were 45,249 men with at least 1 TBI in the cohort. After adjustment for covariates, 1 mild TBI (hazard ratio [HR] = 1.0, 95% confidence interval [CI] = 0.5-2.0), at least 2 mild TBIs (HR = 2.5, 95% CI = 0.8-8.1), or 1 severe TBI (HR = 0.7, 95% CI = 0.1-5.2) were not associated with Alzheimer dementia (AD). Other types of dementia were strongly associated with the risk of 1 mild TBI (HR = 3.8, 95% CI = 2.8-5.2), at least 2 mild TBIs (HR = 10.4, 95% CI = 6.3-17.2), and 1 severe TBI (HR = 11.4, 95% CI = 7.4-17.5) in age-adjusted analysis. However, these associations were largely attenuated after adjustment for covariates (1 mild TBI: HR = 1.7; at least 2 mild TBIs: HR = 1.7; 1 severe TBI: HR = 2.6; p < 0.05 for all). Interpretation In the present study, we found strong associations between YOD of non-AD forms and TBIs of different severity. These associations were, however, markedly attenuated after multivariate adjustment.

  • 35. Nordström, Peter
    et al.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Gustafson, Yngve
    Nordström, Anna
    Traumatic brain injury and young onset dementia: a nationwide cohort study2014Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 75, nr 3, s. 374-381Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: To investigate the association between traumatic brain injuries (TBIs) and the risk of young onset dementia (YOD), that is, dementia before 65 years of age.

    METHODS: The study cohort comprised 811,622 Swedish men (mean age 5 18 years) conscripted for military service between 1969 and 1986. TBIs, dementia, and covariates were extracted from national registers. Time-dependent exposures using Cox proportional hazard regression models were evaluated.

    RESULTS: During a median follow-up period of 33 years, there were 45,249 men with at least 1 TBI in the cohort. After adjustment for covariates, 1 mild TBI (hazard ratio [HR] 5 1.0, 95% confidence interval [CI] 5 0.5–2.0), at least 2 mild TBIs (HR 5 2.5, 95% CI 5 0.8–8.1), or 1 severe TBI (HR 5 0.7, 95% CI 5 0.1–5.2) were not associated with Alzheimer dementia (AD). Other types of dementia were strongly associated with the risk of 1 mild TBI (HR 5 3.8, 95% CI 5 2.8–5.2), at least 2 mild TBIs (HR 5 10.4, 95% CI 5 6.3–17.2), and 1 severe TBI (HR 5 11.4, 95% CI 5 7.4–17.5) in age-adjusted analysis. However, these associations were largely attenuated after adjustment for covariates (1 mild TBI: HR 5 1.7; at least 2 mild TBIs: HR 5 1.7; 1 severe TBI: HR 5 2.6; p < 0.05 for all).

    INTERPRETATION: In the present study, we found strong associations between YOD of non-AD forms and TBIs of different severity. These associations were, however, markedly attenuated after multivariate adjustment.

  • 36.
    Nyholm, Dag
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Askmark, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Aquilonius, Sten-Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Stalevo reduction in dyskinesia evaluation in Parkinson's disease results were expected from a pharmacokinetic viewpoint2011Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 69, nr 2, s. 424-424Artikkel i tidsskrift (Fagfellevurdert)
  • 37. Pedersen, Nancy L
    et al.
    Gatz, Margret
    Berg, Stig
    Högskolan i Jönköping, Hälsohögskolan, HHJ, Institutet för gerontologi. Högskolan i Jönköping, Hälsohögskolan, HHJ. Åldrande - livsvillkor och hälsa.
    Johansson, Boo
    How heritable is Alzheimer's Disease in late in llife?: Findings from Swedish twins2004Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 55, nr 2, s. 180-185Artikkel i tidsskrift (Fagfellevurdert)
  • 38. Peuralinna, Terhi
    et al.
    Oinas, Minna
    Polvikoski, Tuomo
    Paetau, Anders
    Sulkava, Raimo
    Niinistö, Leena
    Kalimo, Hannu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Hernandez, Dena
    Hardy, John
    Singleton, Andrew
    Tienari, Pentti J.
    Myllykangas, Liisa
    Neurofibrillary tau pathology modulated by genetic variation of alpha-synuclein2008Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 64, nr 3, s. 348-352Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We analyzed whether genetic variation of alpha-synuclein modulates the extent of neuropathological changes in a population-based autopsied sample of 272 elderly Finns. None of the 11 markers was associated with the extent of neocortical beta-amyloid pathology. The intron 4 marker rs2572324 was associated with the extent of neurofibrillary pathology (p = 0.0006, permuted p = 0.004; Braak stages IV-VI vs 0-II). The same variant also showed a trend for association with neocortical Lewy-related pathology. These results suggest for the first time that variation of alpha-synuclein modulates neurofibrillary tau pathology and support the recent observations of an interaction of alpha-synuclein and tau in neurodegeneration.

  • 39.
    Piccini, P
    et al.
    England.
    Lindvall, O
    Lund University.
    Björklund, A
    Brundin, P
    Lund University.
    Hagell, Peter
    Lund University.
    Ceravolo, R
    England.
    Oertel, W
    Tyskland.
    Quinn, N
    England.
    Samuel, M
    England.
    Rehncrona, S
    Lund University.
    Widner, H
    Lund University.
    Brooks, D J
    England.
    Delayed recovery of movement-related cortical function in Parkinson's disease after striatal dopaminergic grafts2000Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 48, nr 5, s. 689-695Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Intrastriatal transplantation of dopaminergic neurones aims to repair the selective loss of nigrostriatal projections and the consequent dysfunction of striatocortical circuitries in Parkinson's disease (PD). Here, we have studied the effects of bilateral human embryonic dopaminergic grafts on the movement-related activation of frontal cortical areas in 4 PD patients using H2 15O positron emission tomography and a joystick movement task. At 6.5 months after transplantation, mean striatal dopamine storage capacity as measured by 18F-dopa positron emission tomography was already significantly elevated in these patients. This was associated with a modest clinical improvement on the Unified Parkinson's Disease Rating Scale, whereas the impaired cortical activation was unchanged. At 18 months after surgery, there was further significant clinical improvement in the absence of any additional increase in striatal 18F-dopa uptake. Rostral supplementary motor and dorsal prefrontal cortical activation during performance of joystick movements had significantly improved, however. Our data suggest that the function of the graft goes beyond that of a simple dopamine delivery system and that functional integration of the grafted neurones within the host brain is necessary to produce substantial clinical recovery in PD.

  • 40. Pittock, Sean J
    et al.
    Lucchinetti, Claudia F
    Parisi, Jospeh E
    Benarroch, Eduardo E
    Mokri, Bahram
    Stephan, Christina L
    Kim, Kwang-Kuk
    Kilimann, Manfred W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Lennon, Vanda A
    Amphiphysin autoimmunity: paraneoplastic accompaniments2005Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 58, nr 1, s. 96-107Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amphiphysin-IgG was identified in 71 patients among 120,000 evaluated serologically for paraneoplastic autoantibodies. Clinical information was available for 63 patients. Cancer was detected in 50 (mostly limited), proven histologically in 46, and was imaged intrathoracically in 4 patients (lung, small-cell [27] and non-small cell [1]), breast [16] and melanoma [2]). Neurological accompaniments included (decreasing frequency): neuropathy, encephalopathy, myelopathy, stiff-man phenomena, and cerebellar syndrome. In a case examined neuropathologically, parenchymal T-lymphocyte infiltration (predominantly CD8(+)) was prominent in lower brainstem, spinal cord, and dorsal root ganglion. Coexisting paraneoplastic autoantibodies, identified in 74% of patients, predicted a common neoplasm and indicated other neuronal autoantigen targets that plausibly explained several neurological manifestations; for example, P/Q-type Ca(2+)-channel antibody with Lambert-Eaton syndrome (n = 5), anti-neuronal nuclear antibody type 1 with sensory neuronopathy (n = 7), K(+)-channel antibody with limbic encephalitis (n = 1) or neuromyotonia (n = 1), and collapsin response-mediator protein-5-IgG with optic neuritis (n = 3). Patients with isolated amphiphysin-IgG (n = 19) were more likely to be women (with breast cancer, p < 0.05) and to have myelopathy or stiff-man phenomena (p < 0.01). Overall, a minority of women (39%) and men (12%) had stiff-man phenomena. Only 10% of women (some with lung carcinoma) and 4% of men fulfilled diagnostic criteria for stiff-man syndrome.

  • 41.
    Qiu, Chengxuan
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Centrum för forskning om äldre och åldrande (ARC), (tills m KI).
    Sigurdsson, Sigurdur
    Zhang, Qian
    Jonsdottir, Maria K.
    Kjartansson, Olafur
    Eiriksdottir, Gudny
    Garcia, Melissa E.
    Harris, Tamara B.
    van Buchem, Mark A.
    Gudnason, Vilmundur
    Launer, Lenore J.
    Diabetes, Markers of Brain Pathology and Cognitive Function: The Age, Gene/Environment Susceptibility-Reykjavik Study2014Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 75, nr 1, s. 138-146Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: We investigated whether, and the extent to which, vascular and degenerative lesions in the brain mediate the association of diabetes with poor cognitive performance. Methods: This cross-sectional study included 4,206 participants (age>65 years; 57.8% women) of the Age, Gene/Environment Susceptibility-Reykjavik Study. Data were collected through interview, clinical examination, psychological testing, and laboratory tests. The composite scores on memory, information-processing speed, and executive function were derived from a cognitive test battery. Markers of cerebral macrovascular (cortical infarcts), microvascular (subcortical infarcts, cerebral microbleeds, and higher white matter lesion volume), and neurodegenerative (lower gray matter, normal white matter, and total brain tissue volumes) processes were assessed on magnetic resonance images. Mediation models were employed to test the mediating effect of brain lesions on the association of diabetes with cognitive performance controlling for potential confounders. Results: There were 462 (11.0%) persons with diabetes. Diabetes was significantly associated with lower scores on processing speed and executive function, but not with memory function. Diabetes was significantly associated with all markers of brain pathology. All of these markers were significantly associated with lower scores on memory, processing speed, and executive function. Formal mediation tests suggested that markers of cerebrovascular and degenerative pathology significantly mediated the associations of diabetes with processing speed and executive function. Interpretation: Diabetes is associated with poor performance on cognitive tests of information-processing speed and executive function. The association is largely mediated by markers of both neurodegeneration and cerebrovascular disease. Older people with diabetes should be monitored for cognitive problems and brain lesions.

  • 42.
    Sundström, Peter
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Wåhlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik.
    Ambarki, Khalid
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik.
    Birgander, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi.
    Eklund, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik.
    Malm, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Venous and cerebrospinal fluid flow in multiple sclerosis. A case-control study.2010Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 68, nr 2, s. 255-259Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The prevailing view on multiple sclerosis etiopathogenesis has been challenged by the suggested new entity chronic cerebrospinal venous insufficiency. To test this hypothesis, we studied 21 relapsing-remitting multiple sclerosis cases and 20 healthy controls with phase-contrast magnetic resonance imaging. In addition, in multiple sclerosis cases we performed contrast-enhanced magnetic resonance angiography. We found no differences regarding internal jugular venous outflow, aqueductal cerebrospinal fluid flow, or the presence of internal jugular blood reflux. Three of 21 cases had internal jugular vein stenoses. In conclusion, we found no evidence confirming the suggested vascular multiple sclerosis hypothesis.

  • 43.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Göteborg University, Sahlgrenska Hospital, Göteborg, Sweden.
    Pilon, Marc
    Chalmers University, Lundberg Laboratory, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Göteborg University, Sahlgrenska Hospital, Göteborg, Sweden.
    A Caenorhabditis elegans model of the myosin heavy chain IIa E706K [corrected] mutation2005Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 58, nr 3, s. 442-448Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mutations in myosin heavy chain (MyHC) genes recently have been shown to be associated with various forms of congenital myopathies: myosin myopathies. The MyHC IIa E706K mutation is associated with congenital joint contractures, early-onset muscle weakness, and progressive course with moderate to severe muscle weakness later in life. To study the pathogenicity of this MyHC mutation, we investigated the effect of the corresponding mutation (E710K) in the major MyHC isoform (MyHC B) of the body wall muscle of the nematode Caenorhabditis elegans. Worms with null mutations in the MyHC B gene (unc-54) are severely paralyzed and depleted of thick filaments in the body wall muscle sarcomeres. unc-54 null mutants with extrachromosomal arrays of a gene construct including the entire wild-type unc-54 gene were partially rescued as determined by a motility assay and by morphological analysis of the body wall muscle. Analysis of unc-54 null mutants with extrachromosomal arrays of the unc-54 gene with the E710K mutation were severely paralyzed but showed formation of thick filaments in the body wall muscle. We conclude that the MyHC E706K (E710K in C. elegans) mutation is pathogenic and that the effect is primarily functional rather than structural because thick filaments are formed. The C. elegans model may be useful to study suspected pathogenic mutations in MyHC genes associated with human muscle diseases.

  • 44.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Thornell, Lars-Eric
    Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå.
    Lindberg, Christopher
    Department of Neurology, Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Lindvall, Björn
    Neuromuscular Unit, University Hospital, Linköping, Sweden.
    Henriksson, Karl-Gösta
    Neuromuscular Unit, University Hospital, Linköping, Sweden.
    Oldfors, Anders
    Department of Pathology, Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Myosin storage myopathy associated with a heterozygous missense mutation in MYH72003Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 54, nr 4, s. 494-500Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Myosin constitutes the major part of the thick filaments in the contractile apparatus of striated muscle. MYH7 encodes the slow/beta-cardiac myosin heavy chain (MyHC), which is the main MyHC isoform in slow, oxidative, type 1 muscle fibers of skeletal muscle. It is also the major MyHC isoform of cardiac ventricles. Numerous missense mutations in the globular head of slow/beta-cardiac MyHC are associated with familial hypertrophic cardiomyopathy. We identified a missense mutation, Arg1845Trp, in the rod region of slow/beta-cardiac MyHC in patients with a skeletal myopathy from two different families. The myopathy was characterized by muscle weakness and wasting with onset in childhood and slow progression, but no overt cardiomyopathy. Slow, oxidative, type 1 muscle fibers showed large inclusions consisting of slow/beta-cardiac MyHC. The features were similar to a previously described entity: hyaline body myopathy. Our findings indicate that the mutated residue of slow/beta-cardiac MyHC is essential for the assembly of thick filaments in skeletal muscle. We propose the term myosin storage myopathy for this disease.

  • 45.
    Tajsharghi, Homa
    et al.
    Sahlgrenska University Hospital.
    Thornell, Lars-Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Lindberg, Christopher
    Sahlgrenska University Hospital.
    Lindvall, Björn
    University Hospital, Linköping.
    Henriksson, Karl-Gösta
    University Hospital, Linköping.
    Oldfors, Anders
    Sahlgrenska University Hospital.
    Myosin storage myopathy associated with a heterozygous missense mutation in MYH72003Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 54, nr 4, s. 494-500Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Myosin constitutes the major part of the thick filaments in the contractile apparatus of striated muscle. MYH7 encodes the slow/beta-cardiac myosin heavy chain (MyHC), which is the main MyHC isoform in slow, oxidative, type 1 muscle fibers of skeletal muscle. It is also the major MyHC isoform of cardiac ventricles. Numerous missense mutations in the globular head of slow/beta-cardiac MyHC are associated with familial hypertrophic cardiomyopathy. We identified a missense mutation, Arg1845Trp, in the rod region of slow/beta-cardiac MyHC in patients with a skeletal myopathy from two different families. The myopathy was characterized by muscle weakness and wasting with onset in childhood and slow progression, but no overt cardiomyopathy. Slow, oxidative, type 1 muscle fibers showed large inclusions consisting of slow/beta-cardiac MyHC. The features were similar to a previously described entity: hyaline body myopathy. Our findings indicate that the mutated residue of slow/beta-cardiac MyHC is essential for the assembly of thick filaments in skeletal muscle. We propose the term myosin storage myopathy for this disease.

  • 46.
    Tajshargi, Homa
    et al.
    Göteborg.
    Thornell, L-E
    Umeå.
    Lindberg, Christopher
    Göteborg.
    Lindvall, Björn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Neurologiska kliniken.
    Henriksson, Karl-Gösta
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Neurologiska kliniken.
    Oldfors, Anders
    Göteborg.
    Myosin storage myopathy associated with a heterozygous missense mutation in MYH72003Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 54, nr 4, s. 494-500Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Myosin constitutes the major part of the thick filaments in the contractile apparatus of striated muscle. MYH7 encodes the slow/▀-cardiac myosin heavy chain (MyHC), which is the main MyHC isoform in slow, oxidative, type 1 muscle fibers of skeletal muscle. It is also the major MyHC isoform of cardiac ventricles. Numerous missense mutations in the globular head of slow/▀-cardiac MyHC are associated with familial hypertrophic cardiomyopathy. We identified a missense mutation, Arg1845Trp, in the rod region of slow/▀-cardiac MyHC in patients with a skeletal myopathy from two different families. The myopathy was characterized by muscle weakness and wasting with onset in childhood and slow progression, but no overt cardiomyopathy. Slow, oxidative, type 1 muscle fibers showed large inclusions consisting of slow/▀-caxdiac MyHC. The features were similar to a previously described entity: hyaline body myopathy. Our findings indicate that the mutated residue of slow/▀-cardiac MyHC is essential for the assembly of thick filaments in skeletal muscle. We propose the term myosin storage myopathy for this disease.

  • 47.
    Tågerud, Sven
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Libelius, Rolf
    Magnusson, Caroline
    Muscle Nogo-A: a marker for amyotrophic lateral sclerosis or for denervation?2007Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 62Artikkel i tidsskrift (Annet vitenskapelig)
  • 48.
    Uusimaa, J.
    et al.
    Department of Paediatrics, University of Oulu, Oulu, Finland, Clinical Research Center, Oulu University Hospital, Oulu, Finland.
    Moilanen, J.S.
    Department of Clinical Genetics, University of Oulu, Oulu, Finland, Institute of Medical Technology, University of Tampere, Tampere, Finland.
    Vainionpaa, L.
    Vainionpää, L., Department of Paediatrics, University of Oulu, Oulu, Finland.
    Tapanainen, P.
    Department of Paediatrics, University of Oulu, Oulu, Finland.
    Lindholm, P.
    Department of Otorhinolaryngology, University of Oulu, Oulu, Finland, Department of Child Psychiatry, University of Oulu, Oulu, Finland.
    Nuutinen, M.
    Department of Paediatrics, University of Oulu, Oulu, Finland.
    Lopponen, T.
    Löppönen, T., Department of Clinical Genetics, University of Oulu, Oulu, Finland, Department of Paediatrics, University of Kuopio, Kuopio, Finland.
    Maki-Torkko, E.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi.
    Rantala, H.
    Department of Paediatrics, University of Oulu, Oulu, Finland.
    Majamaa, K.
    Clinical Research Center, Oulu University Hospital, Oulu, Finland, Department of Neurology, University of Oulu, Oulu, Finland, Department of Neurology, University of Turku, Turku, Finland, Department of Neurology, University of Turku, FIN-20014 Turku, Finland.
    Prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children2007Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 62, nr 3, s. 278-287Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: We studied the prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children in a defined population in Notthern Ostrobothnia, Finland. Methods: Children with diagnoses commonly associated with mitochondrial diseases were ascertained. Blood DNA from 522 selected children was analyzed for 3243A>G. Children with the mutation were clinically examined. Information on health history before the age of 18 years was collected from previously identified adult patients with 3243A>G. Mutation segregation analysis in buccal epithelial cells was performed in mothers with 3243A>G and their children whose samples were analyzed anonymously. Results: Eighteen children were found to harbor 3243A>G in a population of 97,609. A minimum estimate for the prevalence of 3243A>G was 18.4 in 100,000 (95% confidence interval, 10.9-29.1/100,000). Information on health in childhood was obtained from 37 adult patients with 3243A>G. The first clinical manifestations appearing in childhood were sensorineural hearing impairment, short stature or delayed maturation, migraine, learning difficulties, and exercise intolerance. Mutation analysis from 13 mothers with 3243A>G and their 41 children gave a segregation rate of 0.80. The mothers with hetetoplasmy greater than 50% tended to have offspring with lower or equal heteroplasmy, whereas the opposite was true for mothers with heteroplasmy less than or equal to 50% (p = 0.0016). Interpretation: The prevalence of 3243A>G is relatively high in the pediatric population, but the morbidity in children is relatively low. The random genetic drift model may be inappropriate for the transmission of the 3243A>G mutation. © 2007 American Neurological Association.

  • 49.
    Uusimaa, Johanna
    et al.
    Department of Paediatrics, University of Oulu, Oulu; Clinical Research Center, Oulu University Hospital, Oulu.
    Moilanen, Jukka S
    Department of Clinical Genetics, University of Oulu, Oulu; Institute of Medical Technology, University of Tampere, Tampere.
    Vainionpää, Leena
    Department of Paediatrics, University of Oulu, Oulu.
    Tapanainen, Päivi
    Department of Paediatrics, University of Oulu, Oulu.
    Lindholm, Päivi
    Department of Otorhinolaryngology, University of Oulu, Oulu; Department of Child Psychiatry, University of Oulu, Oulu.
    Nuutinen, Matti
    Department of Paediatrics, University of Oulu, Oulu.
    Löppönen, Tuija
    Department of Clinical Genetics, University of Oulu, Oulu; Department of Paediatrics, University of Kuopio, Kuopio, Finland.
    Mäki-Torkko, Elina
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Otorhinolaryngology, University of Oulu, Oulu; Department of Otorhinolaryngology, Linköping University Hospital, Linköping, Sweden.
    Rantala, Heikki
    Department of Paediatrics, University of Oulu, Oulu.
    Majamaa, Kari
    Clinical Research Center, Oulu University Hospital, Oulu; Department of Neurology, University of Oulu, Oulu; Department of Neurology, University of Turku, Turku, Finland.
    Prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children2007Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 62, nr 3, s. 278-287Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: We studied the prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children in a defined population in Northern Ostrobothnia, Finland.

    METHODS: Children with diagnoses commonly associated with mitochondrial diseases were ascertained. Blood DNA from 522 selected children was analyzed for 3243A>G. Children with the mutation were clinically examined. Information on health history before the age of 18 years was collected from previously identified adult patients with 3243A>G. Mutation segregation analysis in buccal epithelial cells was performed in mothers with 3243A>G and their children whose samples were analyzed anonymously.

    RESULTS: Eighteen children were found to harbor 3243A>G in a population of 97,609. A minimum estimate for the prevalence of 3243A>G was 18.4 in 100,000 (95% confidence interval, 10.9-29.1/100,000). Information on health in childhood was obtained from 37 adult patients with 3243A>G. The first clinical manifestations appearing in childhood were sensorineural hearing impairment, short stature or delayed maturation, migraine, learning difficulties, and exercise intolerance. Mutation analysis from 13 mothers with 3243A>G and their 41 children gave a segregation rate of 0.80. The mothers with heteroplasmy greater than 50% tended to have offspring with lower or equal heteroplasmy, whereas the opposite was true for mothers with heteroplasmy less than or equal to 50% (p = 0.0016).

    INTERPRETATION: The prevalence of 3243A>G is relatively high in the pediatric population, but the morbidity in children is relatively low. The random genetic drift model may be inappropriate for the transmission of the 3243A>G mutation.

  • 50.
    Uusimaa, Johanna
    et al.
    University of Oulu and Oulu University Hospital, Finland.
    Moilanen, Jukka
    University of Oulu and University of Tampere, Finland.
    Vainionpää, Leena
    University of Oulu, Finland.
    Tapanainen, Päivi
    University of Oulu, Finland.
    Lindholm, Päivi
    University of Oulu, Finland.
    Nuutinen, Matti
    University of Oulu, Finland.
    Löppönen, Tuija
    University of Oulu and University of Kuopio, Finland.
    Mäki-Torkko, Elina
    Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US. University of Oulu, Finland .
    Rantala, Heikki
    University of Oulu, Finland.
    Majamaa, Kari
    Oulu University Hospital and University of Oulu and University of Turku, Finland.
    Prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children2007Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 62, nr 3, s. 278-287Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    We studied the prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children in a defined population in Northern Ostrobothnia, Finland.

    METHODS:

    Children with diagnoses commonly associated with mitochondrial diseases were ascertained. Blood DNA from 522 selected children was analyzed for 3243A>G. Children with the mutation were clinically examined. Information on health history before the age of 18 years was collected from previously identified adult patients with 3243A>G. Mutation segregation analysis in buccal epithelial cells was performed in mothers with 3243A>G and their children whose samples were analyzed anonymously.

    RESULTS:

    Eighteen children were found to harbor 3243A>G in a population of 97,609. A minimum estimate for the prevalence of 3243A>G was 18.4 in 100,000 (95% confidence interval, 10.9-29.1/100,000). Information on health in childhood was obtained from 37 adult patients with 3243A>G. The first clinical manifestations appearing in childhood were sensorineural hearing impairment, short stature or delayed maturation, migraine, learning difficulties, and exercise intolerance. Mutation analysis from 13 mothers with 3243A>G and their 41 children gave a segregation rate of 0.80. The mothers with heteroplasmy greater than 50% tended to have offspring with lower or equal heteroplasmy, whereas the opposite was true for mothers with heteroplasmy less than or equal to 50% (p = 0.0016).

    INTERPRETATION:

    The prevalence of 3243A>G is relatively high in the pediatric population, but the morbidity in children is relatively low. The random genetic drift model may be inappropriate for the transmission of the 3243A>G mutation.

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