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  • 1.
    Bloniecki, Victor
    et al.
    Department of Neurobiology, Caring Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institute, Stockholm, Sweden.
    Aarsland, Dag
    Department of Neurobiology, Caring Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institute, Stockholm, Sweden; Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden; Center for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
    Blennow, Kaj
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Cummings, Jeffrey
    Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.
    Falahati, Farshad
    Department of Neurobiology, Caring Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institute, Stockholm, Sweden.
    Winblad, Bengt
    Department of Neurobiology, Caring Sciences and Society (NVS), Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institute, Huddinge, Sweden.
    Freund-Levi, Yvonne
    Department of Neurobiology, Caring Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institute, Stockholm, Sweden; Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Effects of Risperidone and Galantamine Treatment on Alzheimer's Disease Biomarker Levels in Cerebrospinal Fluid2017In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 57, no 2, p. 387-393Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Treatment for neuropsychiatric symptoms (NPS) in dementia is insufficient. Antipsychotics and acetylcholinesterase inhibitors are used generating symptomatic improvements in behavior and cognition, but few studies have investigated their effect on Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF).

    OBJECTIVE: This is a secondary analysis based on an earlier clinical trial comparing the treatment effects on NPS. The aim of this study was to examine whether treatment with risperidone and galantamine affect levels of the biomarkers T-Tau, P-Tau, Aβ1-42, and Aβ42/40-ratio in CSF. The secondary aim was to test if baseline levels of these biomarkers are associated with the clinical course of NPS.

    METHODS: 83 patients (mean + SD 77.9.6±7.7 years) with dementia and NPS were randomized to galantamine (n = 44) or risperidone (n = 39) treatment. CSF samples were collected at baseline and after 12 weeks.

    RESULTS: Changes in levels of biomarkers between the two treatment groups did not differ significantly. Low baseline levels of Aβ1 - 42 was significantly associated with reduction of irritability at follow up. Low baseline levels of Aβ1-42, Aβ42/40, and P-Tau were significant correlates of reduction in appetite and eating disorders. CSF Aβ1-42 levels in patients treated with risperidone were significantly decreased at follow up, showing an 8% (40 pg/mL) reduction as compared with baseline (p = 0.03).

    CONCLUSIONS: Our results suggest that risperidone may affect the CSF profile of AD biomarkers indicating more amyloid pathology. Treatment with galantamine did not affect the CSF biomarkers in any direction. The AD CSF biomarkers displayed correlations with specific NPS suggesting potential research questions to be pursued.

  • 2.
    Bloniecki, Victor
    et al.
    Division of Clinical Geriatrics, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Aarsland, Dag
    Center for Alzheimer Research, Division for Neurogeriatrics, Department of Neurobiology, Caring Sciences and Society (NVS), Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; Center for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
    Cummings, Jeffrey
    Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, Nev., USA.
    Blennow, Kaj
    Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska University Hospital, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
    Freund-Levi, Yvonne
    Division of Clinical Geriatrics, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Agitation in dementia: relation to core cerebrospinal fluid biomarker levels2014In: Dementia and geriatric cognitive disorders extra, E-ISSN 1664-5464, Vol. 4, no 2, p. 335-43Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The objective of this study was to examine the associations of agitation with the cerebrospinal fluid dementia biomarkers total-tau (T-tau), phosphorylated-tau (P-tau) and Aβ1-42.

    METHODS: One hundred patients (mean age ± SD, 78.6 ± 7.5 years) with dementia and neuropsychiatric symptoms, of whom 67% were female, were included. Agitation was measured using the Cohen-Mansfield Agitation Inventory (CMAI; 46.5 ± 11.8 points).

    RESULTS: Total CMAI correlated with T-tau [rs (31) = 0.36, p = 0.04] and P-tau [rs (31) = 0.35, p = 0.05] in patients with Alzheimer's disease (AD; n = 33) but not in the total dementia population (n = 95).

    CONCLUSIONS: Our results suggest that tau-mediated pathology including neurofibrillary tangles and the intensity of the disease process might be associated with agitation in AD.

  • 3.
    Bos, Isabelle
    et al.
    Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, The Netherlands.
    Verhey, Frans R.
    Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, The Netherlands.
    Ramakers, Inez H. G. B.
    Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, The Netherlands.
    Jacobs, Heidi I. L.
    Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, The Netherlands.
    Soininen, Hilkka
    Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland; Neurocenter & Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
    Freund-Levi, Yvonne
    Department of Neurobiology, Caring Sciences and Society (NVS), Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Hampel, Harald
    AXA Research Fund and UPMC Chair, Sorbonne Universités, Université Pierre et Marie Curie (UPMC), Paris, France; Institut du cerveau et de la moelle (ICM), Hôpital Pitié-Salpêtrière, Paris, France.
    Tsolaki, Magda
    Aristotle University of Thessaloniki, Memory and Dementia Center, 3rd Department of Neurology, “G Papanicolau” General Hospital, Thessaloniki, Greece.
    Wallin, Åsa K.
    Department of Clinical Sciences Malmö, Clinical Memory Research Unit, Lund University, Lund, Sweden.
    van Buchem, Mark A.
    Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
    Oleksik, Ania
    Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
    Verbeek, Marcel M.
    Departments of Neurology and Laboratory Medicine, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen, The Netherlands.
    Olde Rikkert, Marcel
    Radboudumc Alzheimer Centre, Department of Geriatric Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
    van der Flier, Wiesje M.
    Department of Neurology, Alzheimer Centre, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands.
    Scheltens, Philip
    Department of Neurology, Alzheimer Centre, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands.
    Aalten, Pauline
    Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, The Netherlands.
    Visser, Pieter Jelle
    Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, The Netherlands; Department of Neurology, Alzheimer Centre, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands.
    Vos, Stephanie J. B.
    Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, The Netherlands.
    Cerebrovascular and amyloid pathology in predementia stages: the relationship with neurodegeneration and cognitive decline2017In: Alzheimer's Research & Therapy, E-ISSN 1758-9193, Vol. 9, no 1, article id 101Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cerebrovascular disease (CVD) and amyloid-β (Aβ) often coexist, but their influence on neurodegeneration and cognition in predementia stages remains unclear. We investigated the association between CVD and Aβ on neurodegenerative markers and cognition in patients without dementia.

    METHODS: We included 271 memory clinic patients with subjective or objective cognitive deficits but without dementia from the BioBank Alzheimer Center Limburg cohort (n = 99) and the LeARN (n = 50) and DESCRIPA (n = 122) multicenter studies. CSF Aβ1-42 and white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) scans were used as measures of Aβ and CVD, respectively. Individuals were classified into four groups based on the presence (+) or absence (-) of Aβ and WMH. We investigated differences in phosphorylated tau, total tau (t-tau), and medial temporal lobe atrophy (MTA) between groups using general linear models. We examined cognitive decline and progression to dementia using linear mixed models and Cox proportional hazards models. All analyses were adjusted for study and demographics.

    RESULTS: MTA and t-tau were elevated in the Aβ - WMH+, Aβ + WMH-, and Aβ + WMH+ groups. MTA was most severe in the Aβ + WMH+ group compared with the groups with a single pathology. Both WMH and Aβ were associated with cognitive decline, but having both pathologies simultaneously was not associated with faster decline.

    CONCLUSIONS: In the present study, we found an additive association of Aβ and CVD pathology with baseline MTA but not with cognitive decline. Because our findings may have implications for diagnosis and prognosis of memory clinic patients and for future scientific research, they should be validated in a larger sample with longer follow-up.

  • 4.
    Bos, Isabelle
    et al.
    Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience Maastricht University, Maastricht, Netherlands.
    Vos, Stephanie J. B.
    Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience Maastricht University, Maastricht, Netherlands.
    Jansen, Willemijn J.
    Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience Maastricht University, Maastricht, Netherlands.
    Vandenberghe, Rik
    University Hospital Leuven, Belgium; Laboratory for Cognitive Neurology, Department of Neurosciences KU Leuven, Leuven, Belgium.
    Gabel, Silvy
    Laboratory for Cognitive Neurology, Department of Neurosciences KU Leuven, Leuven, Belgium; Alzheimer Research Centre KU Leuven, Leuven, Belgium.
    Estanga, Ainara
    Center for Research and Advanced Therapies CITA-Alzheimer Foundation, San Sebastián, Spain.
    Ecay-Torres, Mirian
    Center for Research and Advanced Therapies CITA-Alzheimer Foundation, San Sebastián, Spain.
    Tomassen, Jori
    Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center VU University Amsterdam, Amsterdam, Netherlands.
    den Braber, Anouk
    Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center VU University Amsterdam, Amsterdam, Netherlands; Department of Biological Psychology VU University Amsterdam, Amsterdam, Netherlands.
    Lleó, Alberto
    Department of Neurology Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
    Sala, Isabel
    Department of Neurology Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
    Wallin, Anders
    Section for Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg Sahlgrenska Academy, Gothenburg, Sweden.
    Kettunen, Petronella
    Section for Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg Sahlgrenska Academy, Gothenburg, Sweden; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
    Molinuevo, José L.
    Alzheimer's Disease & Other Cognitive Disorders Unit, Hopsital Clínic Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; Barcelona Beta Brain Research Center, Unversitat Pompeu Fabra, Barcelona, Spain.
    Rami, Lorena
    Alzheimer's Disease & Other Cognitive Disorders Unit, Hopsital Clínic Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain.
    Chetelat, Gaël
    Institut National de la Santé et de la Recherche Médicale UMR-S U1237, Université de Caen-Normandie GIP Cyceron, Caen, France.
    de la Sayette, Vincent
    Institut National de la Santé et de la Recherche Médicale U1077, Université de Caen Normandie Ecole Pratique des Hautes Etudes, Caen, France; CHU de Caen Service de Neurologie, Caen, France.
    Tsolaki, Magda
    1st Department of Neurology, University General Hospital of Thessaloniki AHEPA, Thessaloniki, Greece.
    Freund-Levi, Yvonne
    Division of Clinical Geriatrics, Department of Neurobiology, Caring Sciences and Society (NVS), Karolinska Institutet, Stockholm, Sweden; Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry, Norrtälje Hospital Tiohundra, Norrtälje, Sweden.
    Johannsen, Peter
    Danish Dementia Research Centre, Rigshospitalet, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
    Novak, Gerald P.
    Janssen Pharmaceutical Research and Development, Titusville, NJ, United States.
    Ramakers, Inez
    Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience Maastricht University, Maastricht, Netherlands.
    Verhey, Frans R.
    Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience Maastricht University, Maastricht, Netherlands.
    Visser, Pieter Jelle
    Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience Maastricht University, Maastricht, Netherlands.
    Amyloid-β, Tau, and Cognition in Cognitively Normal Older Individuals: Examining the Necessity to Adjust for Biomarker Status in Normative Data.2018In: Frontiers in Aging Neuroscience, ISSN 1663-4365, E-ISSN 1663-4365, Vol. 10, article id 193Article in journal (Refereed)
    Abstract [en]

    We investigated whether amyloid-β (Aβ) and tau affected cognition in cognitively normal (CN) individuals, and whether norms for neuropsychological tests based on biomarker-negative individuals would improve early detection of dementia. We included 907 CN individuals from 8 European cohorts and from the Alzheimer's disease Neuroimaging Initiative. All individuals were aged above 40, had Aβ status and neuropsychological data available. Linear mixed models were used to assess the associations of Aβ and tau with five neuropsychological tests assessing memory (immediate and delayed recall of Auditory Verbal Learning Test, AVLT), verbal fluency (Verbal Fluency Test, VFT), attention and executive functioning (Trail Making Test, TMT, part A and B). All test except the VFT were associated with Aβ status and this influence was augmented by age. We found no influence of tau on any of the cognitive tests. For the AVLT Immediate and Delayed recall and the TMT part A and B, we calculated norms in individuals without Aβ pathology (Aβ- norms), which we validated in an independent memory-clinic cohort by comparing their predictive accuracy to published norms. For memory tests, the Aβ- norms rightfully identified an additional group of individuals at risk of dementia. For non-memory test we found no difference. We confirmed the relationship between Aβ and cognition in cognitively normal individuals. The Aβ- norms for memory tests in combination with published norms improve prognostic accuracy of dementia.

  • 5.
    Bos, Isabelle
    et al.
    Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, Netherlands.
    Vos, Stephanie J.
    Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, Netherlands.
    Frölich, Lutz
    Department of Geriatric Psychiatry, Zentralinstitut für Seelische Gesundheit, University of Heidelberg, Mannheim, Germany.
    Kornhuber, Johannes
    Department of Psychiatry and Psychotherapy, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
    Wiltfang, Jens
    Department of Psychiatry and Psychotherapy, University Medical Center (UMC), Georg-August-University, Göttingen, Germany.
    Maier, Wolfgang
    Department of Psychiatry and Psychotherapy, University of Bonn, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
    Peters, Oliver
    Department of Psychiatry and Psychotherapy, Charité Berlin, Berlin, Germany.
    Rüther, Eckhart
    Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany.
    Engelborghs, Sebastiaan
    Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium; Reference Center for Biological Markers of Dementia (BIODEM), University of Antwerp, Antwerp, Belgium.
    Niemantsverdriet, Ellis
    Reference Center for Biological Markers of Dementia (BIODEM), University of Antwerp, Antwerp, Belgium.
    De Roeck, Ellen Elisa
    Reference Center for Biological Markers of Dementia (BIODEM), University of Antwerp, Antwerp, Belgium; Department of Clinical and Lifespan Psychology, Vrije Universiteit Brussel, Brussels, Belgium.
    Tsolaki, Magda
    3rd Department of Neurology, Aristotle University of Thessaloniki, Memory and Dementia Center, “G Papanicolau” General Hospital, Thessaloniki, Greece.
    Freund-Levi, Yvonne
    Division of Clinical Geriatrics, Department of Neurobiology, Caring Sciences and Society (NVS), Karolinska Institutet, Huddinge, Sweden; Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Johannsen, Peter
    Danish Dementia Research Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    Vandenberghe, Rik
    Department of Neurology, University of Hospital Leuven, Leuven, Belgium; Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Belgium.
    Lleó, Alberto
    Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
    Alcolea, Daniel
    Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
    Frisoni, Giovanni B.
    Geneva Neuroscience Center, University Hospital and University of Geneva, Geneva, Switzerland; IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
    Galluzzi, Samantha
    IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
    Nobili, Flavio
    Clinical Neurology, Department of Neurosciences (DINOGMI), University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
    Morbelli, Silvia
    Nuclear Medicine, Department of Health Science (DISSAL), University of Genoa IRCCS AOU San Martino-IST, Genoa, Italy.
    Drzezga, Alexander
    Department of Nuclear Medicine, University of Cologne, Cologne, Germany.
    Didic, Mira
    AP-HM Hôpitaux de la Timone, Service de Neurologie et Neuropsychologie, Marseille, France; Aix-Marseille Université, INSERM, Institut de Neurosciences des Systèmes, Marseille, France.
    van Berckel, Bart N.
    Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
    Salmon, Eric
    Department of Neurology and Memory Clinic, CHU Liège, Liège, Belgium; GIGA-CRC in vivo Imaging, University of Liège, Liège, Belgium.
    Bastin, Christine
    GIGA-CRC in vivo Imaging, University of Liège, Liège, Belgium.
    Dauby, Solene
    Department of Neurology and Memory Clinic, CHU Liège, Liège, Belgium.
    Santana, Isabel
    Department of Neurology and Memory Clinic, CHU Liège, Liège, Belgium.
    Baldeiras, Inês
    Center for Neuroscience and Cell Biology, Faculty of Medicine, Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
    de Mendonça, Alexandre
    Institute of Molecular Medicine and Faculty of Medicine, University of Lisbon, Portugal.
    Silva, Dina
    Institute of Molecular Medicine and Faculty of Medicine, University of Lisbon, Portugal.
    Wallin, Anders
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Nordlund, Arto
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Coloma, Preciosa M.
    Real World Data Science (RWD-S) Neuroscience and Established Products, F. Hoffmann-La Roche Ltd. Pharmaceuticals Division, Basel, Switzerland.
    Wientzek, Angelika
    PDB RWD (Real World Data) Team, Roche Products Limited, Welwyn Garden City, UK; Epidemiologische Beratung und Literatur-Recherche “conepi”, Herrsching, Germany.
    Alexander, Myriam
    PDB RWD (Real World Data) Team, Roche Products Limited, Welwyn Garden City, UK.
    Novak, Gerald P.
    Janssen Pharmaceutical Research and Development, Titusville, NJ, USA.
    Gordon, Mark Forrest
    Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA.
    Wallin, Åsa K.
    Department of Clinical Sciences Malmö, Clinical Memory Research Unit, Lund University, Lund, Sweden.
    Hampel, Harald
    Sorbonne Universités, Université Pierre et Marie Curie, Paris 06, AXA Research Fund & UPMC Chair, Institut de la Mémoire et de la Maladie d’Alzheimer (IM2A), Paris, France; Institut du Cerveau et de la Moelle épinière (ICM), Département de Neurologie, Hôpital de la Pitié-Salpétrière, Paris, France.
    Soininen, Hilkka
    Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland; Neurocenter, Neurology, Kuopio University Hospital, Kuopio, Finland.
    Herukka, Sanna-Kaisa
    Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland; Neurocenter, Neurology, Kuopio University Hospital, Kuopio, Finland.
    Scheltens, Philip
    Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands.
    Verhey, Frans R.
    Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, Netherlands.
    Visser, Pieter Jelle
    Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, Netherlands; Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands.
    The frequency and influence of dementia risk factors in prodromal Alzheimer's disease2017In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 56, p. 33-40Article in journal (Refereed)
    Abstract [en]

    We investigated whether dementia risk factors were associated with prodromal Alzheimer's disease (AD) according to the International Working Group-2 and National Institute of Aging-Alzheimer's Association criteria, and with cognitive decline. A total of 1394 subjects with mild cognitive impairment from 14 different studies were classified according to these research criteria, based on cognitive performance and biomarkers. We compared the frequency of 10 risk factors between the subgroups, and used Cox-regression to examine the effect of risk factors on cognitive decline. Depression, obesity, and hypercholesterolemia occurred more often in individuals with low-AD-likelihood, compared with those with a high-AD-likelihood. Only alcohol use increased the risk of cognitive decline, regardless of AD pathology. These results suggest that traditional risk factors for AD are not associated with prodromal AD or with progression to dementia, among subjects with mild cognitive impairment. Future studies should validate these findings and determine whether risk factors might be of influence at an earlier stage (i.e., preclinical) of AD.

  • 6.
    Bos, Isabelle
    et al.
    Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands.
    Vos, Stephanie
    Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands.
    Verhey, Frans
    Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands.
    Scheltens, Philip
    Alzheimer Center, VU University Medical Center, Amsterdam, the Netherlands.
    Teunissen, Charlotte
    Neurochemistry Lab and Biobank, Department of Clinical Chemistry, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, the Netherlands.
    Engelborghs, Sebastiaan
    Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium; Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
    Sleegers, Kristel
    Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.
    Frisoni, Giovanni
    University of Geneva, Geneva, Switzerland; IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
    Blin, Olivier
    Mediterranean Institute of Cognitive Neuroscience, Aix Marseille University, Marseille, France.
    Richardson, Jill C.
    Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage, UK.
    Bordet, Régis
    University of Lille, Inserm, CHU Lille, Lille, France.
    Tsolaki, Magda
    1st Department of Neurology, AHEPA University Hospital, Makedonia, Thessaloniki, Greece.
    Popp, Julius
    Geriatric Psychiatry, Department of Mental Health and Psychiatry, Geneva University Hospitals, Geneva, Switzerland; Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
    Peyratout, Gwendoline
    Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
    Martinez-Lage, Pablo
    Department of Neurology, Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain.
    Tainta, Mikel
    Department of Neurology, Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain.
    Lleó, Alberto
    Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
    Johannsen, Peter
    Danish Dementia Research Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    Freund-Levi, Yvonne
    Department of Neurobiology, Caring Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden; Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Psychiatry Norrtälje Hospital Tiohundra, Norrtäije, Sweden.
    Frölich, Lutz
    Department of Geriatric Psychiatry, Zentralinstitut für Seelische Gesundheit, University of Heidelberg, Mannheim, Germany.
    Vandenberghe, Rik
    University Hospital Leuven, Leuven, Belgium.
    Westwood, Sarah
    University of Oxford, Oxford, United Kingdom.
    Dobricic, Valerija
    Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany.
    Barkhof, Frederik
    Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands; Institutes of Neurology and Healthcare Engineering, University College London, London, UK.
    Legido-Quigley, Cristina
    Steno Diabetes Center, Copenhagen, Denmark; King's College London, London, UK.
    Bertram, Lars
    Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany; School of Public Health, Imperial College London, London, UK; Department of Psychology, University of Oslo, Oslo, Norway.
    Lovestone, Simon
    University of Oxford, Oxford, United Kingdom.
    Streffer, Johannes
    Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Early Clinial Neurology, UCB Biopharma SPRL, Braine-l'Alleud, Belgium.
    Andreasson, Ulf
    Clinical Neurochemistry Lab, Institute of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Psychiatry and Neurochemistry, University of Gothenburg, Institute of Neuroscience and Physiology, Mölndal, Sweden.
    Blennow, Kaj
    Clinical Neurochemistry Lab, Institute of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Psychiatry and Neurochemistry, University of Gothenburg, Institute of Neuroscience and Physiology, Mölndal, Sweden.
    Zetterberg, Henrik
    Clinical Neurochemistry Lab, Institute of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Psychiatry and Neurochemistry, University of Gothenburg, Institute of Neuroscience and Physiology, Mölndal, Sweden; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; UK Dementia Research Institute, London, UK.
    Visser, Pieter Jelle
    Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands; Alzheimer Center, VU University Medical Center, Amsterdam, the Netherlands.
    Cerebrospinal fluid biomarkers of neurodegeneration, synaptic integrity, and astroglial activation across the clinical Alzheimer's disease spectrum2019In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 15, no 5, p. 644-654Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: We investigated relations between amyloid-β (Aβ) status, apolipoprotein E (APOE) ε4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total tau (T-tau).

    METHODS: We included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with Aβ status (Aβ- vs. Aβ+), clinical diagnosis APOE ε4 carriership, baseline cognition, and change in cognition.

    RESULTS: Ng and T-tau distinguished between Aβ+ from Aβ- individuals in each clinical group, whereas NFL and YKL-40 were associated with Aβ+ in nondemented individuals only. APOE ε4 carriership did not influence NFL, Ng, and YKL-40 in Aβ+ individuals. NFL was the best predictor of cognitive decline in Aβ+ individuals across the cognitive spectrum.

    DISCUSSION: Axonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker.

  • 7.
    Eriksdotter, Maria
    et al.
    Department of Neurobiology, Care Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Huddinge, Stockholm; Department of Geriatric Medicine, Karolinska University Hospital, Huddinge, Stockholm.
    Vedin, Inger
    Department of Medicine, Division of Hematology, Karolinska Institutet, Huddinge, Stockholm.
    Falahati, Farshad
    Department of Neurobiology, Care Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Huddinge, Stockholm.
    Freund-Levi, Yvonne
    Department of Neurobiology, Care Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Huddinge, Stockholm.
    Hjorth, Erik
    Department of Neurobiology, Care Sciences and Society (NVS), Division of Neurodegeneration, Karolinska Institutet, Huddinge, Stockholm.
    Faxen-Irving, Gerd
    Department of Neurobiology, Care Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Huddinge, Stockholm.
    Wahlund, Lars-Olof
    Department of Neurobiology, Care Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Huddinge, Stockholm; Department of Geriatric Medicine, Karolinska University Hospital, Huddinge, Stockholm.
    Schultzberg, Marianne
    Department of Neurobiology, Care Sciences and Society (NVS), Division of Neurodegeneration, Karolinska Institutet, Huddinge, Stockholm.
    Basun, Hans
    Division of Geriatrics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden; Department of Geriatric Medicine, Akademiska sjukhuset, Uppsala, Sweden.
    Cederholm, Tommy
    Division of Clinical Nutrition and Metabolism, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden; Department of Geriatric Medicine, Akademiska sjukhuset, Uppsala, Sweden.
    Palmblad, Jan
    Department of Medicine, Division of Hematology, Karolinska Institutet, Huddinge, Stockholm.
    Plasma Fatty Acid Profiles in Relation to Cognition and Gender in Alzheimer's Disease Patients During Oral Omega-3 Fatty Acid Supplementation: The OmegAD Study2015In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 48, no 3, p. 805-812Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: ω3 fatty acids (ω3 FAs) may slow the rate of decline in cognitive performance in mild forms of cognitive impairment and Alzheimer's disease (AD). However, the relationship between changes of plasma ω3 FA levels and cognitive performance, as well as effects of gender, are poorly known.

    OBJECTIVE: To study the effect of 6-month administration of DHA-rich ω3 FA supplementation on plasma FA profiles in patients with mild to moderate AD in relation to cognitive performance and gender. This investigation is part of the OmegAD Study.

    METHODS: 174 AD patients (74 ± 9 years) were randomized to a daily intake of 2.3 g ω3 FA or placebo for 6 months; subsequently all received the ω3 FA preparation for the next 6 months. Baseline as well as changes in plasma levels of the main ω3 FAs in 165 patients, while receiving ω3 FA supplementation for 6 months, were analyzed for association to cognitive performance (assessed by ADAS-cog and MMSE scores) as well as to gender.

    RESULTS: Preservation of cognitive functioning, assessed by ADAS-cog or its sub-items (but not MMSE) scores, was significantly associated to increasing plasma ω3 FA levels over time. Thus, the higher ω3 FA plasma levels rose, the lower was the rate of cognitive deterioration. This effect was not related to gender; since although females displayed higher ω3 FA plasma levels than did males after 6 months of supplementation, this difference disappeared when adjusted for body weight.

    CONCLUSIONS: Since our study suggests dose-response relationships between plasma levels of ω3 FA and preservation of cognition, future ω3 FA trials in patients with mild AD should consider exploring graded (and body weight adjusted) doses of ω3 FA.

  • 8.
    Faxen-Irving, Gerd
    et al.
    Department of Neurobiology, Care Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Huddinge, Sweden.
    Falahati, Farshad
    Department of Neurobiology, Care Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Huddinge, Sweden.
    Basun, Hans
    Department of Public Health and Caring Sciences, Division of Geriatrics, Uppsala University, Uppsala, Sweden.
    Eriksdotter, Maria
    Department of Neurobiology, Care Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Huddinge, Sweden; Department of Geriatrics, Karolinska University Hospital, Huddinge, Sweden.
    Vedin, Inger
    Department of Medicine, Division of Hematology, Department of NVS, Karolinska Institutet, Huddinge, Sweden.
    Wahlund, Lars-Olof
    Department of Neurobiology, Care Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Huddinge, Sweden; Department of Geriatrics, Karolinska University Hospital, Huddinge, Sweden.
    Schultzberg, Marianne
    Division of Neurodegeneration, Karolinska Institutet, Huddinge, Sweden.
    Hjorth, Erik
    Division of Neurodegeneration, Karolinska Institutet, Huddinge, Sweden.
    Palmblad, Jan
    Department of Medicine, Division of Hematology, Department of NVS, Karolinska Institutet, Huddinge, Sweden.
    Cederholm, Tommy
    Department of Public Health and Caring Sciences, Division of Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden; Department of Geriatric Medicine, Akademiska sjukhuset, Uppsala, Sweden.
    Freund-Levi, Yvonne
    Department of Neurobiology, Care Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Huddinge, Sweden; Department of Geriatrics, Karolinska University Hospital, Huddinge, Sweden.
    Does Fatty Acid Composition in Subcutaneous Adipose Tissue Differ between Patients with Alzheimer's Disease and Cohabiting Proxies?2018In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 61, no 2, p. 515-519Article in journal (Refereed)
    Abstract [en]

    Low tissue levels of the major marine ω3 fatty acids (FAs) DHA and EPA are found in Alzheimer's disease (AD). We investigated if healthy proxies to AD patients have higher levels of these ω3 FAs. We observed lower levels of EPA and DHA in subcutaneous adipose tissue biopsies from 64 AD patients compared with 16 cognitively healthy proxies. No significant difference was observed when pairwise comparisons were made between a subset of 16 AD patients and their co-habiting proxies. Larger studies are needed to replicate these findings and to determine if they could depend on FA intake or differences in metabolism.

  • 9.
    Faxén-Irving, Gerd
    et al.
    Department of NVS, Section of Clinical Nutrition, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Freund-Levi, Yvonne
    Department of NVS, Section of Clinical Geriatrics, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Eriksdotter-Jönhagen, Maria
    Department of NVS, Section of Clinical Geriatrics, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Basun, Hans
    Department of Public Health and Caring Sciences, Division of Geriatrics, Uppsala University Hospital, Uppsala, Sweden.
    Hjorth, Erik
    Department of NVS, Section of Clinical Nutrition, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Palmblad, Jan
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Vedin, Inger
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Cederholm, Tommy
    Department of Public Health and Caring Sciences, Division of Clinical Nutrition and Metabolism, Uppsala University Hospital, Uppsala, Sweden.
    Wahlund, Lars-Olof
    Department of NVS, Section of Clinical Geriatrics, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Effects on transthyretin in plasma and cerebrospinal fluid by DHA-rich n - 3 fatty acid supplementation in patients with Alzheimer's disease: the OmegAD study2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 36, no 1, p. 1-6Article in journal (Refereed)
    Abstract [en]

    Transthyretin (TTR) binds amyloid-β (Aβ) and may reduce brain Aβ, a pathological feature in Alzheimer's disease (AD). N - 3 fatty acids (FA), docosahexaenoic (DHA), and eicosapentaenoic acid (EPA) may increase TTR transcription in rat hippocampus. We studied effects of n - 3 FA supplementation on TTR-levels in patients with AD. Outpatients were randomized to receive 1.7 g DHA and 0.6 g EPA (n - 3/n - 3 group) or placebo (placebo/n - 3 group) during 6 months. After 6 months, all patients received n - 3 FA for another 6 months. TTR and FA were measured in plasma in all subjects, whereas TTR in cerebrospinal fluid (CSF) was measured in a subgroup. The study was completed by 89 patients in the n - 3/n - 3 group (75 y, 57% w) and 85 in the placebo/n - 3 group (75 y, 46% w). Baseline plasma-TTR was within normal range in both groups. After 6 months, plasma-TTR decreased in the placebo/n - 3 group (p < 0.001 within and p < 0.015 between the groups). No changes were observed in CSF TTR. From 6 to 12 months when both groups were supplemented, plasma-TTR increased significantly in both groups. Repeated measures ANOVA indicated an increase in TTR over time (p = 0.04) in those receiving n - 3 FA for 12 months. By linear regression analyses, n - 3 FA treatment was independently associated with increased plasma-TTR at 6 months (β = -0.172, p = 0.028). Thus, n - 3 FA treatment appeared to increase plasma-TTR in patients with AD. Since TTR may influence Aβ deposition in the brain, the results warrant further exploration.

  • 10.
    Forsberg, Anton
    et al.
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Juréus, Anders
    Neuroscience Research & Therapy Area, AstraZeneca Research & Development, Södertälje, Sweden.
    Cselényi, Zsolt
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; AstraZeneca Translational Sciences Centre, PET CoE, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden.
    Eriksdotter, Maria
    Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Freund-Levi, Yvonne
    Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; ; Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Jeppsson, Fredrik
    Neuroscience Research & Therapy Area, AstraZeneca Research & Development, Södertälje, Sweden; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
    Swahn, Britt-Marie
    Neuroscience Research & Therapy Area, AstraZeneca Research & Development, Södertälje, Sweden.
    Sandell, Johan
    Neuroscience Research & Therapy Area, AstraZeneca Research & Development, Södertälje, Sweden.
    Julin, Per
    Neuroscience Research & Therapy Area, AstraZeneca Research & Development, Södertälje, Sweden.
    Schou, Magnus
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; AstraZeneca Translational Sciences Centre, PET CoE, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden.
    Andersson, Jan
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Johnström, Peter
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; AstraZeneca Translational Sciences Centre, PET CoE, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden.
    Varnäs, Katarina
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Halldin, Christer
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Farde, Lars
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; AstraZeneca Translational Sciences Centre, PET CoE, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden.
    Svensson, Samuel
    Neuroscience Research & Therapy Area, AstraZeneca Research & Development, Södertälje, Sweden.
    Low background and high contrast PET imaging of amyloid-β with [11C]AZD2995 and [11C]AZD2184 in Alzheimer's disease patients2013In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 40, no 4, p. 580-593Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer's disease (AD).

    METHODS: In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [(11)C]AZD2995 and [(11)C]AZD2184 in three healthy control subjects and seven AD patients.

    RESULTS: AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [(3)H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [(11)C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [(11)C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus.

    CONCLUSION: Both AZD2995 and AZD2184 detect amyloid-β with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [(11)C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [(11)C]AZD2995. However, the very low nonspecific binding of [(11)C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-β. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy.

  • 11.
    Freund-Levi, Yvonne
    et al.
    Department of NVS, Section of Clinical Geriatrics, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Basun, Hans
    Division of Geriatrics, Department of Public Health and Caring Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Cederholm, Tommy
    Clinical Nutrition Research, Department of Public Health and Caring Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Faxén-Irving, Gerd
    Department of NVS, Section of Clinical Geriatrics, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Garlind, Anita
    Department of NVS, Section of Clinical Geriatrics, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Grut, Mikaela
    Department of Geriatrics, Danderyd Hospital, Stockholm, Sweden.
    Vedin, Inger
    Department of Medicine, Division of Hematology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Palmblad, Jan
    Department of Medicine, Division of Hematology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Wahlund, Lars-Olof
    Department of NVS, Section of Clinical Geriatrics, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Eriksdotter-Jönhagen, Maria
    Department of NVS, Section of Clinical Geriatrics, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Omega-3 supplementation in mild to moderate Alzheimer's disease: effects on neuropsychiatric symptoms2008In: International Journal of Geriatric Psychiatry, ISSN 0885-6230, E-ISSN 1099-1166, Vol. 23, no 2, p. 161-169Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Epidemiological and animal studies have suggested that dietary fish or fish oil rich in omega-3 fatty acids (omega3), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may have effects in psychiatric and behavioral symptoms in Alzheimer's disease (AD). An association with APOEomega4 carriers and neuropsychiatric symptoms in AD has also been suggested.

    OBJECTIVE: To determine effects of dietary omega3 supplementation to AD patients with mild to moderate disease on psychiatric and behavioral symptoms, daily functions and a possible relation to APOEgenotype.

    METHODS: Randomized, double-blind, placebo-controlled clinical trial where 204 AD patients (74+/-9 years) with acetylcholine esterase inhibitor treatment and a MMSE>15 points were randomized to daily intake of 1.7 g DHA and 0.6 g EPA (omega3 group) or placebo for 6 months. Then, all received the omega3 supplementation for 6 more months. Neuropsychiatric symptoms were measured with Neuropsychiatric Inventory (NPI) and Montgomery Asberg Depression Scale (MADRS). Caregivers burden and activities of daily living (Disability Assessment for Dementia, DAD) were also assessed.

    RESULTS: One hundred and seventy-four patients fulfilled the trial. 72% were APOEomega4 carriers. No significant overall treatment effects on neuropsychiatric symptoms, on activities of daily living or on caregiver's burden were found. However, significant positive treatment effects on the scores in the NPI agitation domain in APOEomega4 carriers (p=0.006) and in MADRS scores in non-APOEomega4 carriers (p=0.005) were found.

    CONCLUSIONS: Supplementation with omega3 in patients with mild to moderate AD did not result in marked effects on neuropsychiatric symptoms except for possible positive effects on depressive symptoms (assessed by MADRS) in non-APOEomega4 carriers and agitation symptoms (assessed by NPI) in APOEomega4 carriers. ClinicalTrials.gov identifier: NCT00211159

  • 12.
    Freund-Levi, Yvonne
    et al.
    Department of Neurobiology, Caring Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden; Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Bloniecki, Victor
    Department of Neurobiology, Caring Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.
    Auestad, Bjørn
    Research Department, Stavanger University Hospital, Stavanger, Norway; Department of Mathematics and Natural Sciences, University of Stavanger, Stavanger, Norway.
    Tysen Bäckström, Ann Christine
    Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Lärksäter, Marie
    Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Aarsland, Dag
    Department of Neurobiology, Caring Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden; Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Galantamine versus risperidone for agitation in people with dementia: a randomized, twelve-week, single-center study2014In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 38, no 3-4, p. 234-244Article in journal (Refereed)
    Abstract [en]

    AIMS: To examine the effects of galantamine and risperidone on agitation in patients with dementia.

    METHODS: A total of 100 patients with dementia and neuropsychiatric symptoms (mean age ± SD: 78.6 ± 7.5 years; 67% female) were included in this 12-week, randomized, parallel-group, controlled, single-center trial. The participants received galantamine (n = 50; target dose: 24 mg) or risperidone (n = 50; target dose: 1.5 mg) for 12 weeks.

    RESULTS: Both galantamine and risperidone treatment resulted in reduced agitation. However, risperidone showed a significant advantage over galantamine both at week 3 (mean difference in total Cohen-Mansfield Agitation Inventory score: 3.7 points; p = 0.03) and at week 12 (4.3 points; p = 0.01).

    CONCLUSIONS: Agitation improved in both groups, even if the treatment effects were more pronounced in the risperidone group; however, the effects on cognition and other aspects of tolerability were stronger with galantamine.

  • 13.
    Freund-Levi, Yvonne
    et al.
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Eriksdotter-Jönhagen, Maria
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Cederholm, Tommy
    Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University Hospital, Uppsala, Sweden.
    Basun, Hans
    Division of Geriatrics, Uppsala University Hospital, Uppsala, Sweden.
    Faxén-Irving, Gerd
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Garlind, Anita
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Vedin, Inger
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Vessby, Bengt
    Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University Hospital, Uppsala, Sweden.
    Wahlund, Lars-Olof
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Palmblad, Jan
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Medicine, M54, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study - A randomized double-blind trial2006In: Archives of Neurology, ISSN 0003-9942, E-ISSN 1538-3687, Vol. 63, no 10, p. 1402-1408Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Epidemiologic and animal studies have suggested that dietary fish or fish oil rich in omega-3 fatty acids, for example, docosahexaenoic acid and eicosapentaenoic acid, may prevent Alzheimer disease (AD).

    OBJECTIVE: To determine effects of dietary omega-3 fatty acid supplementation on cognitive functions in patients with mild to moderate AD.

    DESIGN: Randomized, double-blind, placebo-controlled clinical trial.

    PARTICIPANTS: Two hundred four patients with AD (age range [mean +/- SD], 74 +/- 9 years) whose conditions were stable while receiving acetylcholine esterase inhibitor treatment and who had a Mini-Mental State Examination (MMSE) score of 15 points or more were randomized to daily intake of 1.7 g of docosahexaenoic acid and 0.6 g of eicosapentaenoic acid (omega-3 fatty acid-treated group) or placebo for 6 months, after which all received omega-3 fatty acid supplementation for 6 months more.

    MAIN OUTCOME MEASURES: The primary outcome was cognition measured with the MMSE and the cognitive portion of the Alzheimer Disease Assessment Scale. The secondary outcome was global function as assessed with the Clinical Dementia Rating Scale; safety and tolerability of omega-3 fatty acid supplementation; and blood pressure determinations.

    RESULTS: One hundred seventy-four patients fulfilled the trial. At baseline, mean values for the Clinical Dementia Rating Scale, MMSE, and cognitive portion of the Alzheimer Disease Assessment Scale in the 2 randomized groups were similar. At 6 months, the decline in cognitive functions as assessed by the latter 2 scales did not differ between the groups. However, in a subgroup (n = 32) with very mild cognitive dysfunction (MMSE >27 points), a significant (P<.05) reduction in MMSE decline rate was observed in the omega-3 fatty acid-treated group compared with the placebo group. A similar arrest in decline rate was observed between 6 and 12 months in this placebo subgroup when receiving omega-3 fatty acid supplementation. The omega-3 fatty acid treatment was safe and well tolerated.

    CONCLUSIONS: Administration of omega-3 fatty acid in patients with mild to moderate AD did not delay the rate of cognitive decline according to the MMSE or the cognitive portion of the Alzheimer Disease Assessment Scale. However, positive effects were observed in a small group of patients with very mild AD (MMSE >27 points).

  • 14.
    Freund-Levi, Yvonne
    et al.
    Divisions of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Huddinge, Stockholm.
    Hjorth, Erik
    Divisions of Neurodegeneration, Department of Neurobiology, Care Sciences and Society (NVS), Huddinge, Stockholm.
    Lindberg, Catharina
    Divisions of Neurodegeneration, Department of Neurobiology, Care Sciences and Society (NVS), Huddinge, Stockholm.
    Cederholm, Tommy
    Clinical Nutrition and Metabolism, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
    Faxen-Irving, Gerd
    Clinical Nutrition, Department of Neurobiology, Care Sciences and Society (NVS), Huddinge, Stockholm.
    Vedin, Inger
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm.
    Palmblad, Jan
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm.
    Wahlund, Lars-Olof
    Divisions of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Huddinge, Stockholm.
    Schultzberg, Marianne
    Divisions of Neurodegeneration, Department of Neurobiology, Care Sciences and Society (NVS), Huddinge, Stockholm.
    Basun, Hans
    Geriatrics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
    Eriksdotter Jönhagen, Maria
    Divisions of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Huddinge, Stockholm.
    Effects of omega-3 fatty acids on inflammatory markers in cerebrospinal fluid and plasma in Alzheimer's disease: the OmegAD study2009In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 27, no 5, p. 481-490Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: omega-3 fatty acids (omega-3 FAs) found in dietary fish or fish oils are anti-inflammatory agents that may influence Alzheimer's disease (AD).

    OBJECTIVE: To study the effects of dietary omega-3 FA supplementation on inflammatory markers in cerebrospinal fluid (CSF) and plasma from patients with mild to moderate AD.

    METHODS: Thirty-five patients (70.3 +/- 8.2 years) were randomized to a daily intake of 2.3 g omega-3 FAs or placebo for 6 months. The inflammatory markers interleukin (IL)-6, tumour necrosis factor-alpha and soluble interleukin-1 receptor type II (sIL-1RII) were analysed in CSF and plasma at baseline and at 6 months. The AD markers tau-protein, hyperphosphorylated tau-protein and beta-amyloid (Abeta(1-42)) were assessed in CSF. High-sensitivity C-reactive protein was assessed in plasma. A possible relation to the APOE genotype was investigated.

    RESULTS: There was no significant treatment effect of omega-3 FAs on inflammatory and AD biomarkers in CSF or on inflammatory markers in plasma, nor was there any relation with APOE. A significant correlation was observed at baseline between sIL-1RII and Abeta(1-42) levels in CSF.

    CONCLUSIONS: Treatment of AD patients with omega-3 FAs for 6 months did not influence inflammatory or biomarkers in CSF or plasma. The correlation between sIL-1RII and Abeta(1-42) may reflect the reciprocal interactions between IL-1 and Abeta peptides.

  • 15.
    Freund-Levi, Yvonne
    et al.
    Division of Clinical Geriatrics, Department of Neurobiology, Caring Sciences and Society (NVS), Karolinska Institutet, Stockholm, Sweden; Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Jedenius, Erik
    Division of Clinical Geriatrics, Department of Neurobiology, Caring Sciences and Society (NVS), Karolinska Institutet, Stockholm, Sweden.
    Tysen-Bäckström, Ann Christine
    Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Lärksäter, Marie
    Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Wahlund, Lars-Olof
    Division of Clinical Geriatrics, Department of Neurobiology, Caring Sciences and Society (NVS), Karolinska Institutet, Stockholm, Sweden; Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Eriksdotter, Maria
    Division of Clinical Geriatrics, Department of Neurobiology, Caring Sciences and Society (NVS), Karolinska Institutet, Stockholm, Sweden; Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Galantamine versus risperidone treatment of neuropsychiatric symptoms in patients with probable dementia: an open randomized trial2014In: The American journal of geriatric psychiatry, ISSN 1064-7481, E-ISSN 1545-7214, Vol. 22, no 4, p. 341-248Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To examine the effects of galantamine and risperidone on neuropsychiatric symptoms in dementia (NPSD) and global function.

    METHODS: Using a randomized, controlled and open-blind, one-center trial at an in- and outpatient clinic at a university hospital, we studied 100 adults with probable dementia and NPSD. Participants received galantamine (N = 50, target dose 24 mg) or risperidone (N = 50, target dose 1.5 mg) for 12 weeks. The primary outcome was effects on NPSD assessed by the Neuropsychiatric Inventory (NPI). Secondary measures included the Mini-Mental State Examination (MMSE), Clinical Dementia Rating, Clinical Global Impression, and Simpson Angus scales. All tests were performed before and after treatment.

    RESULTS: Outcome measures were analyzed using analysis of covariance. Ninety-one patients (67% women, mean age 79 ± 7.5 years) with initial NPI score of 51.0 (± 25.8) and MMSE of 20.1 (± 4.6) completed the trial. Both galantamine and risperidone treatments resulted in improved NPSD symptoms and were equally effective in treating several NPI domains. However, risperidone showed a significant treatment advantage in the NPI domains irritation and agitation, F(1, 97) = 5.2, p = 0.02. Galantamine treatment also ameliorated cognitive functions where MMSE scores increased 2.8 points compared with baseline (95% confidence interval: 1.96-3.52). No treatment-related severe side effects occurred.

    CONCLUSIONS: These results support that galantamine, with its benign safety profile, can be used as first-line treatment of NPSD symptoms, unless symptoms of irritation and agitation are prominent, where risperidone is more efficient.

  • 16.
    Freund-Levi, Yvonne
    et al.
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Vedin, I
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Cederholm, T
    Department of Public Health and Caring Sciences, Uppsala University Hospital, Uppsala, Sweden; Division of Clinical Nutrition and Metabolism, Uppsala University Hospital, Uppsala, Sweden.
    Basun, H
    Department of Public Health and Caring Sciences, Uppsala University Hospital, Uppsala, Sweden; Geriatrics, Uppsala University Hospital, Uppsala, Sweden.
    Faxén Irving, G
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Eriksdotter, M
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Hjorth, E
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Schultzberg, M
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Vessby, B
    Department of Public Health and Caring Sciences, Uppsala University Hospital, Uppsala, Sweden; Geriatrics, Uppsala University Hospital, Uppsala, Sweden.
    Wahlund, L-O
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Salem, N
    National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville MD, United States.
    Palmblad, J
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Transfer of omega-3 fatty acids across the blood-brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with Alzheimer's disease: the OmegAD study2014In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 275, no 4, p. 428-436Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Little is known about the transfer of essential fatty acids (FAs) across the human blood-brain barrier (BBB) in adulthood. In this study, we investigated whether oral supplementation with omega-3 (n-3) FAs would change the FA profile of the cerebrospinal fluid (CSF).

    METHODS: A total of 33 patients (18 receiving the n-3 FA supplement and 15 receiving placebo) were included in the study. These patients were participants in the double-blind, placebo-controlled randomized OmegAD study in which 204 patients with mild Alzheimer's disease (AD) received 2.3 g n-3 FA [high in docosahexaenoic acid (DHA)] or placebo daily for 6 months. CSF FA levels were related to changes in plasma FA and to CSF biomarkers of AD and inflammation.

    RESULTS: At 6 months, the n-3 FA supplement group displayed significant increases in CSF (and plasma) eicosapentaenoic acid (EPA), DHA and total n-3 FA levels (P < 0.01), whereas no changes were observed in the placebo group. Changes in CSF and plasma levels of EPA and n-3 docosapentaenoic acid were strongly correlated, in contrast to those of DHA. Changes in DHA levels in CSF were inversely correlated with CSF levels of total and phosphorylated tau, and directly correlated with soluble interleukin-1 receptor type II. Thus, the more DHA increased in CSF, the greater the change in CSF AD/inflammatory biomarkers.

    CONCLUSIONS: Oral supplementation with n-3 FAs conferred changes in the n-3 FA profile in CSF, suggesting transfer of these FAs across the BBB in adults.

  • 17.
    Freund-Levi, Yvonne
    et al.
    Section of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Department of Geriatrics Karolinska University Hospital Stockholm, Sweden.
    Vedin, Inger
    Division of Haematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital at Huddinge, Stockholm, Sweden.
    Hjorth, Erik
    Division of Neurodegeneration, Department of Neurobiology, Care Sciences & Society, Karolinska Institutet, Stockholm, Sweden.
    Basun, Hans
    Division of Geriatrics, Uppsala University, Uppsala, Sweden; Chaire d'Excellence Program, Department of Biochemistry, Molecular Biology and Nutrition, Universite d'Auvergne, Clermont-Ferrand, France.
    Faxén Irving, Gerd
    Divisions of Clinical Nutrition, Karolinska Institutet, Karolinska University Hospital at Huddinge, Stockholm, Sweden.
    Schultzberg, Marianne
    Division of Neurodegeneration, Department of Neurobiology, Care Sciences & Society, Karolinska Institutet, Stockholm, Sweden.
    Eriksdotter, Maria
    Section of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Department of Geriatrics Karolinska University Hospital Stockholm, Sweden.
    Palmblad, Jan
    Division of Haematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital at Huddinge, Stockholm, Sweden.
    Vessby, Bengt
    Clinical Nutrition and Metabolism, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
    Wahlund, Lars-Olof
    Section of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Department of Geriatrics Karolinska University Hospital Stockholm, Sweden.
    Cederholm, Tommy
    Clinical Nutrition and Metabolism, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
    Basu, Samar
    Division of Oxidative Stress and Inflammation, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden; Chaire d'Excellence Program, Department of Biochemistry, Molecular Biology and Nutrition, Universite d'Auvergne, Clermont-Ferrand, France.
    Effects of supplementation with omega-3 fatty acids on oxidative stress and inflammation in patients with Alzheimer's disease: the OmegAD study2014In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 42, no 3, p. 823-831Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Oxidative stress and inflammation are two key mechanisms suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Omega-3 fatty acids (ω-3 FAs) found in fish and fish oil have several biological properties that may be beneficial in AD. However, they may also auto-oxidize and induce in vivo lipid peroxidation.

    OBJECTIVE: The objective of this study was to evaluate systemic oxidative stress and inflammatory biomarkers following oral supplementation of dietary ω-3 FA.

    METHODS: Forty patients with moderate AD were randomized to receive 1.7 g DHA (22:6) and 0.6 g EPA (20:5) or placebo for 6 months. Urinary samples were collected before and after supplementation. The levels of the major F2-isoprostane, 8-iso-PGF2α, a consistent in vivo biomarker of oxidative stress, and 15-keto-dihydro-PGF2α, a major metabolite of PGF2α and biomarker of inflammatory response, were measured.

    RESULTS: F2-isoprostane in urine increased in the placebo group after 6 months, but there was no clear difference in treatment effect between supplemented and non-supplemented patients on the urinary levels of F2-isoprostanes and 15-keto-dihydro-PGF2α. At baseline, the levels of 15-keto-dihydro-PGF2α showed negative correlative relationships to ω-3 FAs, and a positive correlation to linoleic acid. 8-iso-PGF2α correlated negatively to the ω-6 FA arachidonic acid.

    CONCLUSION: The findings indicate that supplementation of ω-3 FAs to patients with AD for 6 months does not have a clear effect on free radical-mediated formation of F2-isoprostane or cyclooxygenase-mediated formation of prostaglandin F2α. The correlative relationships to FAs indicate a potential role of FAs in immunoregulation.

  • 18.
    Hall, Anette
    et al.
    Institute of Clinical Medicine/Neurology, University of Eastern Finland, Kuopio, Finland.
    Mattila, Jussi
    VTT Technical Research Centre of Finland, Tampere, Finland.
    Koikkalainen, Juha
    VTT Technical Research Centre of Finland, Tampere, Finland.
    Lötjonen, Jyrki
    VTT Technical Research Centre of Finland, Tampere, Finland.
    Wolz, Robin
    Biomedical Image Analysis Group, Department of Computing, Imperial College London, London, United Kingdom.
    Scheltens, Philip
    Department of Neurology, Alzheimer Centre, VU University Medical Center, Amsterdam, Netherlands.
    Frisoni, Giovanni
    IRCCS San Giovanni, Laboratory of Epidemiology and Neuroimaging, Brescia, Italy.
    Tsolaki, Magdalini
    Aristotle University of Thessaloniki, Memory and Dementia Centre, 3rd Department of Neurology, "G Papanicolaou" General Hospital, Thessaloniki, Greece.
    Nobili, Flavio
    Clinical Neurology, Department of Neuroscience, Ophthalmology and Genetics, University of Genoa, Genoa, Italy.
    Freund-Levi, Yvonne
    Institution of NVS, Department of Geriatrics, Section of Clinical Geriatrics, Karolinska Institutet, Department of Geriatrics, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Minthon, Lennart
    Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden.
    Frölich, Lutz
    Department of Geriatric Psychiatry, Central Institute of Mental Health, Mannheim, University of Heidelberg, Mannheim, Germany.
    Hampel, Harald
    Sorbonne Universités, Université Pierre et Marie Curie, Institut de la Mémoire et de la Maladie d’Alzheimer & Institut du Cerveau et de la Moelle épinière (ICM), Département de Neurologie, Hôpital de la Pitié-Salpétrière, Paris, France.
    Visser, Pieter Jelle
    Department of Neurology, Alzheimer Centre, VU University Medical Center, Amsterdam, Netherlands; Department of Psychiatry and Neuropsychology, University of Maastricht, Maastricht, Netherlands.
    Soininen, Hilkka
    Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
    Predicting progression from cognitive impairment to Alzheimer's disease with the Disease State Index2015In: Current Alzheimer Research, ISSN 1567-2050, E-ISSN 1875-5828, Vol. 12, no 1, p. 69-79Article in journal (Refereed)
    Abstract [en]

    We evaluated the performance of the Disease State Index (DSI) method when predicting progression to Alzheimer's disease (AD) in patients with subjective cognitive impairment (SCI), amnestic or non-amnestic mild cognitive impairment (aMCI, naMCI). The DSI model measures patients' similarity to diagnosed cases based on available data, such as cognitive tests, the APOE genotype, CSF biomarkers and MRI. We applied the DSI model to data from the DESCRIPA cohort, where non-demented patients (N=775) with different subtypes of cognitive impairment were followed for 1 to 5 years. Classification accuracies for the subgroups were calculated with the DSI using leave-one-out crossvalidation. The DSI's classification accuracy in predicting progression to AD was 0.75 (AUC=0.83) in the total population, 0.70 (AUC=0.77) for aMCI and 0.71 (AUC=0.76) for naMCI. For a subset of approximately half of the patients with high or low DSI values, accuracy reached 0.86 (all), 0.78 (aMCI), and 0.85 (naMCI). For patients with MRI or CSF biomarker data available, theywere 0.78 (all), 0.76 (aMCI) and 0.76 (naMCI), while for clear cases the accuracies rose to 0.90 (all), 0.83 (aMCI) and 0.91 (naMCI). The results show that the DSI model can distinguish between clear and ambiguous cases, assess the severity of the disease and also provide information on the effectiveness of different biomarkers. While a specific test or biomarker may confound analysis for an individual patient, combining several different types of tests and biomarkers could be able to reveal the trajectory of the disease and improve the prediction of AD progression.

  • 19.
    Handels, Ron L. H.
    et al.
    Department of Psychiatry and Neuropsychology, Alzheimer Centre Limburg, School for Mental Health and Neurosciences, Maastricht University, Maastricht, The Netherlands.
    Vos, Stephanie J. B.
    Department of Psychiatry and Neuropsychology, Alzheimer Centre Limburg, School for Mental Health and Neurosciences, Maastricht University, Maastricht, The Netherlands.
    Kramberger, Milica G.
    Department of Neurology, Ljubljana University Medical Centre, Ljubljana, Slovenia.
    Jelic, Vesna
    Division of Clinical Geriatrics, Department of NVS, Karolinska Institutet, Center for Alzheimer Research, Division of Neurogeriatrics, Huddinge, Sweden.
    Blennow, Kaj
    Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.
    van Buchem, Mark
    Department of Radiology, Leiden University Medical Centre, Leiden, The Netherlands.
    van der Flier, Wiesje
    Alzheimer Centre and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands; Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
    Freund-Levi, Yvonne
    Division of Clinical Geriatrics, Department of NVS, Karolinska Institutet, Center for Alzheimer Research, Division of Neurogeriatrics, Huddinge, Sweden; Department of Psychiatry, Tiohundra AB Norrtälje Hospital, Stockholm Sweden.
    Hampel, Harald
    AXA Research Fund & UPMC Chair, Paris, France; Sorbonne Universités Pierre et Marie Curie (UPMC) Paris 06, Inserm, CNRS, Institut du cerveau et de la moelle (ICM), Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Hôpital Pitié-Salpêtrière, Paris, France.
    Olde Rikkert, Marcel
    Department of Geriatrics, Radboudumc Alzheimer Centre, Donders Institute for Brain Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands.
    Oleksik, Ania
    Department of Radiology, Leiden University Medical Centre, Leiden, The Netherlands.
    Pirtosek, Zvezdan
    Department of Neurology, Ljubljana University Medical Centre, Ljubljana, Slovenia.
    Scheltens, Philip
    Alzheimer Centre and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands.
    Soininen, Hilkka
    Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Neurocenter–Neurology, Kuopio University Hospital, Kuopio, Finland.
    Teunissen, Charlotte
    Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, VU University Medical Centre, Amsterdam, The Netherlands.
    Tsolaki, Magda
    Memory and Dementia Outpatient Clinic, 3rd Department of Neurology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
    Wallin, Asa K.
    Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Winblad, Bengt
    Division of Clinical Geriatrics, Department of NVS, Karolinska Institutet, Center for Alzheimer Research, Division of Neurogeriatrics, Huddinge, Sweden.
    Verhey, Frans R. J.
    Department of Psychiatry and Neuropsychology, Alzheimer Centre Limburg, School for Mental Health and Neurosciences, Maastricht University, Maastricht, The Netherlands.
    Visser, Pieter Jelle
    Department of Psychiatry and Neuropsychology, Alzheimer Centre Limburg, School for Mental Health and Neurosciences, Maastricht University, Maastricht, The Netherlands; Alzheimer Centre and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands.
    Predicting progression to dementia in persons with mild cognitive impairment using cerebrospinal fluid markers2017In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 13, no 8, p. 903-912Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: We aimed to determine the added value of cerebrospinal fluid (CSF) to clinical and imaging tests to predict progression from mild cognitive impairment (MCI) to any type of dementia.

    METHODS: The risk of progression to dementia was estimated using two logistic regression models based on 250 MCI participants: the first included standard clinical measures (demographic, clinical, and imaging test information) without CSF biomarkers, and the second included standard clinical measures with CSF biomarkers.

    RESULTS: Adding CSF improved predictive accuracy with 0.11 (scale from 0-1). Of all participants, 136 (54%) had a change in risk score of 0.10 or higher (which was considered clinically relevant), of whom in 101, it was in agreement with their dementia status at follow-up.

    DISCUSSION: An individual person's risk of progression from MCI to dementia can be improved by relying on CSF biomarkers in addition to recommended clinical and imaging tests for usual care.

  • 20.
    Hjorth, Erik
    et al.
    Department of Neurobiology, Care Sciences and Society, Division of Neurodegeneration, Karolinska Institutet, Stockholm, Sweden.
    Freund-Levi, Yvonne
    Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Immunomodulation of microglia by docosahexaenoic acid and eicosapentaenoic acid.2012In: Current opinion in clinical nutrition and metabolic care, ISSN 1363-1950, E-ISSN 1473-6519, Vol. 15, no 2, p. 134-143Article in journal (Refereed)
    Abstract [en]

    PURPOSE OF REVIEW: The omega-3 fatty acids (ω-3 FAs) docosahexaenoic acid and eicosapentaenoic acid are dietary components which have been ascribed many different health benefits. Inflammation is present in, and contributes to, pathological conditions in the central nervous system (CNS). Microglia are the primary cells with immune function in the CNS, and inflammation mediated by activated microglia is present in pathological conditions. In this review, we present and discuss findings on the modulation of microglial activities by ω-3 FAs in vivo as well as in vitro, and propose mechanisms for their effects.

    RECENT FINDINGS: The majority of studies show that ω-3 FAs have anti-inflammatory effects on microglia. However, phagocytosis is an activity associated with inflammation and is increased by ω-3 FAs. This can be understood in the light of recent research on the resolution of inflammation. Resolution is induced by proresolving factors, which are metabolites of ω-3 FAs. Proresolving factors are anti-inflammatory and have been shown to increase phagocytosis. Other mechanisms of the anti-inflammatory actions of ω-3 FAs involve the peroxisome proliferator-activated receptor-γ, ω-3 FA incorporation into the cell membrane, and inhibition of ion currents.

    SUMMARY: Immunomodulation by ω-3 FAs is mediated by several pathways that are interconnected and is a potential therapy for disorders in the CNS.

  • 21.
    Hjorth, Erik
    et al.
    Division of Neurodegeneration, Department of Neurobiology, Care Sciences & Society, Karolinska Institutet, Stockholm, Sweden.
    Zhu, Mingqin
    Division of Neurodegeneration, Department of Neurobiology, Care Sciences & Society, Karolinska Institutet, Stockholm, Sweden.
    Toro, Veronica Cortés
    Division of Neurodegeneration, Department of Neurobiology, Care Sciences & Society, Karolinska Institutet, Stockholm, Sweden.
    Vedin, Inger
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Palmblad, Jan
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Cederholm, Tommy
    Division of Clinical Nutrition and Metabolism, Department of Public Health & Caring Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Freund-Levi, Yvonne
    Clinical Geriatrics, Department of Neurobiology, Care Sciences & Society, Karolinska Institutet, Stockholm, Sweden.
    Faxen-Irving, Gerd
    Nutrition, Department of Neurobiology, Care Sciences & Society, Karolinska Institutet, Stockholm, Sweden.
    Wahlund, Lars-Olof
    Clinical Geriatrics, Department of Neurobiology, Care Sciences & Society, Karolinska Institutet, Stockholm, Sweden.
    Basun, Hans
    Division of Geriatrics, Department of Public Health & Caring Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Eriksdotter, Maria
    Clinical Geriatrics, Department of Neurobiology, Care Sciences & Society, Karolinska Institutet, Stockholm, Sweden.
    Schultzberg, Marianne
    Division of Neurodegeneration, Department of Neurobiology, Care Sciences & Society, Karolinska Institutet, Stockholm, Sweden.
    Omega-3 fatty acids enhance phagocytosis of Alzheimer's disease-related amyloid-β42 by human microglia and decrease inflammatory markers2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 35, no 4, p. 697-713Article in journal (Refereed)
    Abstract [en]

    The use of supplements with omega-3 (ω3) fatty acids (FAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is widespread due to proposed beneficial effects on the nervous and cardiovascular systems. Many effects of ω3 FAs are believed to be caused by down-regulation and resolution of inflammation. Alzheimer's disease (AD) is associated with inflammation mediated by microglia and astrocytes, and ω3 FAs have been proposed as potential treatments for AD. The focus of the present study is on the effects of DHA and EPA on microglial phagocytosis of the AD pathogen amyloid-β (Aβ), on secreted and cellular markers of immune activity, and on production of brain-derived neurotrophic factor (BDNF). Human CHME3 microglial cells were exposed to DHA or EPA, with or without the presence of Aβ42. Phagocytosis of Aβ42 was analyzed by flow cytometry in conjunction with immunocytochemistry using antibodies to cellular proteins. Secreted proteins were analyzed by ELISA. Both DHA and EPA were found to stimulate microglial phagocytosis of Aβ42. Phagocytosis of Aβ42 was performed by microglia with a predominance of M2 markers. EPA increased the levels of BDNF in the culture medium. The levels of TNF-α were decreased by DHA. Both DHA and EPA decreased the pro-inflammatory M1 markers CD40 and CD86, and DHA had a stimulatory effect on the anti-inflammatory M2 marker CD206. DHA and EPA can be beneficial in AD by enhancing removal of Aβ42, increasing neurotrophin production, decreasing pro-inflammatory cytokine production, and by inducing a shift in phenotype away from pro-inflammatory M1 activation.

  • 22.
    Holmgren, Simon
    et al.
    Department of Neurobiology, Care Sciences & Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.
    Hjorth, Erik
    Department of Neurobiology, Care Sciences & Society (NVS), Division of Neurodegeneration, Karolinska Institutet, Stockholm, Sweden.
    Schultzberg, Marianne
    Department of Neurobiology, Care Sciences & Society (NVS), Division of Neurodegeneration, Karolinska Institutet, Stockholm, Sweden.
    Lärksäter, Marie
    Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Frenkel, Dan
    Department of Neurobiology, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
    Tysen-Bäckström, Ann Christine
    Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Aarsland, Dag
    Department of Neurobiology, Care Sciences & Society (NVS), Division of Alzheimer’s Disease Research Centre, Karolinska Institutet, Stockholm, Sweden; Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
    Freund-Levi, Yvonne
    Department of Neurobiology, Care Sciences & Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden; Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Neuropsychiatric symptoms in dementia: a role for neuroinflammation?2014In: Brain Research Bulletin, ISSN 0361-9230, E-ISSN 1873-2747, Vol. 108, p. 88-93, article id S0361-9230(14)00136-1Article in journal (Refereed)
    Abstract [en]

    Dementia is characterized by a progressive cognitive decline and neuropsychiatric symptoms (NPSD) such as agitation, apathy and sleeping problems. There is some evidence of activation of inflammatory pathways in the brain in dementia, but little research has been performed regarding the role of neuroinflammation in NPSD, which might represent a potential novel target for treatment. The aim of this study was to examine the possible association between NPSD and cerebrospinal fluid (CSF) levels of the cytokines IL-6, TNF-α and IL-10, and the cytokine receptor sIL-1RII, in patients with dementia and NPSD. Ninety-four patients (mean age 79±8; 67% female) with a score on the neuropsychiatric inventory (NPI) ≥10 points, were included. Clinical assessment included administration of NPI, the mini-mental state examination (MMSE) and the Cohen-Mansfield agitation inventory (CMAI). The cytokine levels in CSF samples were analysed by enzyme-linked immunosorbent assay. Correlations were statistically examined using Spearman's rank correlation coefficient (r), and simple- and multiple-linear regression. The anti-inflammatory cytokine IL-10 showed reverse correlations with total NPI score (NPI-total=-0.001, t(90)= 8.50, p=0.004) and NPI sub-items agitation (agitation=-0.007, t(90)=7.02, p=0.009) and night-time behaviour (night time behaviour=-0.006, t(90)=6.34, p=0.01). There was a trend towards reverse correlation between IL-10 and depression (depression=-0.004, t(90)=2.96, p=0.09). Also, the soluble cytokine receptor sIL-1RII showed a trend towards correlation with apathy (apathy=0.82, t(82)=3.62, p=0.06). The levels of IL-6 showed no significant correlations with NPSD. Levels of TNF-α were non-detectable. In Alzheimer's disease (AD) subjects (n=33), IL-6 showed reverse correlation with anxiety (r=-0.35, p=0.049). In mixed AD subjects (n=26), IL-10 showed reverse correlations with the total NPI score (r=-0.46, p=0.02) and depression (r=-0.45, p=0.02). The findings indicate a relationship between neuroinflammation and neuropsychiatric symptoms in AD in which anti-inflammatory signalling by IL-10 is beneficial from a mental health perspective.

  • 23.
    Irving, Gerd Faxén
    et al.
    Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Freund-Levi, Yvonne
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Eriksdotter-Jönhagen, Maria
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Basun, Hans
    Divisions of Geriatrics, Uppsala University Hospital, Uppsala, Sweden.
    Brismar, Kerstin
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Hjorth, Erik
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Palmblad, Jan
    Department of Medicine, Karolinska University, Hospital, Huddinge, Stockholm, Sweden.
    Vessby, Bengt
    Department of Public Health and Caring Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Vedin, Inger
    Department of Medicine, Karolinska University, Hospital, Huddinge, Stockholm, Sweden.
    Wahlund, Lars-Olof
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Cederholm, Tommy
    Department of Medicine, Karolinska University, Hospital, Huddinge, Stockholm, Sweden.
    Omega-3 fatty acid supplementation effects on weight and appetite in patients with Alzheimer's disease: the omega-3 Alzheimer's disease study2009In: Journal of The American Geriatrics Society, ISSN 0002-8614, E-ISSN 1532-5415, Vol. 57, no 1, p. 11-17Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To study the effects of omega (Omega)-3 fatty acid (FA) supplements on weight and appetite in patients with mild to moderate Alzheimer's disease (AD) in relation to inflammatory biomarkers and apolipoprotein E epsilon4 (APOEepsilon4).

    DESIGN: Randomized, double-blind, placebo-controlled trial.

    SETTING: Specialist memory clinics in the Stockholm catchment area.

    PARTICIPANTS: Two hundred four patients (aged 73+/-9, 52% women) with mild to moderate AD.

    INTERVENTION: Patients with AD received 1.7 g of docosahexaenoic acid (DHA) and 0.6 g of eicosapentaenoic acid (EPA) (Omega-3/Omega-3 group; n=89, aged 73+/-9, 57% women) or placebo 0.6 g of linoleic acid per day (placebo/Omega-3 group; n=85, aged 73+/-9, 46% women) for 6 months. After 6 months, all patients received DHA and EPA for another 6 months.

    MEASUREMENTS: Anthropometry, biochemical nutritional and inflammatory markers, and appetite assessed by caregiver.

    RESULTS: Mean weight and body mass index (kg/m(2)) at baseline were 70.0+/-11.8 kg and 24.3+/-3.0 kg/m(2), respectively. At 6- and 12-month follow-up, weight had increased 0.7+/-2.5 kg (P=.02) and 1.4+/-2.9 kg (P<.001) in the Omega-3/Omega-3 group. In the placebo group, weight was unchanged at 6 months but had increased (P=.01) at 12 months follow-up after Omega-3 supplementation was initiated. Appetite improved in the Omega-3/Omega-3 group over the treatment period (P=.01). In logistic regression analyses, not carrying the APOEepsilon4 allele and high plasma DHA concentrations were independently related to weight gain in the combined group of patients at 6 months follow-up.

    CONCLUSION: A DHA-enriched Omega-3 FA supplement may positively affect weight and appetite in patients with mild to moderate AD. Not carrying the APOEepsilon4 allele and high DHA were independently associated with weight gain.

  • 24.
    Jernerén, Fredrik
    et al.
    Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
    Cederholm, Tommy
    Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden; Theme Ageing, Karolinska University Hospital, Stockholm, Sweden.
    Refsum, Helga
    Department of Nutrition, University of Oslo, Oslo, Norway; Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
    Smith, A. David
    Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
    Turner, Cheryl
    Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
    Palmblad, Jan
    Departments of Medicine and Hematology, Karolinska University Hospital Huddinge, and the Karolinska Institutet, Stockholm, Sweden.
    Eriksdotter, Maria
    Theme Ageing, Karolinska University Hospital, Stockholm, Sweden; Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Hjorth, Erik
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Faxen-Irving, Gerd
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Wahlund, Lars-Olof
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Schultzberg, Marianne
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Basun, Hans
    Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
    Freund-Levi, Yvonne
    Örebro University, School of Medical Sciences. Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden; Center for Alzheimer Research, Division of Clinical Geriatrics, Karolinska Institutet, Huddinge, Sweden; Department of Psychiatry in Region Örebro County and School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro; Department of Old Age Psychiatry, Psychology & Neuroscience, King’s College, London, UK.
    Homocysteine Status Modifies the Treatment Effect of Omega-3 Fatty Acids on Cognition in a Randomized Clinical Trial in Mild to Moderate Alzheimer's Disease: The OmegAD Study2019In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 69, no 1, p. 189-197Article in journal (Refereed)
    Abstract [en]

    Background: Trials of supplementation with omega-3 fatty acids (omega 3-FAs) in patients with mild cognitive impairment or Alzheimer's disease (AD) have produced inconsistent effects on cognitive decline. There is evidence of an interaction between B vitamin status and omega 3-FAs in relation to brain atrophy and cognitive decline.

    Objective: We investigated whether baseline levels of plasma total homocysteine (tHcy), a marker of B vitamin status, modify the effects of omega 3-FAs supplementation on cognitive performance in moderate AD.

    Methods: This post hoc analysis of the OmegAD trial included 171 community-based patients with AD (MMSE >= 15): 88 patients received daily doses of 1.7 g docosahexaenoic acid and 0.6 g eicosapentaenoic acid for 6 months. Treatment outcome on cognition was analyzed according to baseline levels of tHcy using a general linear model and ANCOVA.

    Results: We found significant interactions between omega 3-FA supplementation and tHcy on cognition and clinical stage assessed by MMSE (p = 0.040), global CDR (p = 0.059), and CDRsob (p = 0.023), but not on ADAS-cog (p = 0.649). In patients with tHcy levels <11.7 mu mol/L, omega 3-FA supplementation improved cognitive performance as measured by MMSE (+7.1%, 95% CI: 0.59 to 13.7%, p = 0.033) and clinical status as measured by CDRsob (-22.3%, 95% CI: -5.8 to -38.7%, p = 0.009) compared with placebo.

    Conclusion: The effect of omega 3-FA supplementation on MMSE and CDR appears to be influenced by baseline tHcy, suggesting that adequate B vitamin status is required to obtain beneficial effects of omega 3-FA on cognition.

  • 25.
    Karimi, Mohsen
    et al.
    Department of Medicine and Hematology (HERM), Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Vedin, Inger
    Department of Medicine and Hematology (HERM), Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Freund-Levi, Yvonne
    Department of Neurobiology, Care, Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Basun, Hans
    Department of Public Health and Caring Sciences, Division of Geriatrics, Uppsala University Hospital, Uppsala, Sweden.
    Faxén Irving, Gerd
    Department of Neurobiology, Care, Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Eriksdotter, Maria
    Department of Neurobiology, Care, Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Wahlund, Lars-Olof
    Department of Neurobiology, Care, Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Schultzberg, Marianne
    Department of Neurobiology, Care, Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Hjorth, Erik
    Department of Neurobiology, Care, Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Cederholm, Tommy
    Department of Clinical Nutrition and Metabolism, Uppsala University Hospital, Uppsala, Sweden.
    Palmblad, Jan
    Department of Medicine and Hematology (HERM), Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    DHA-rich n-3 fatty acid supplementation decreases DNA methylation in blood leukocytes: the OmegAD study2017In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 106, no 4, p. 1157-1165Article in journal (Refereed)
    Abstract [en]

    Background: Dietary fish oils, rich in long-chain n-3 (ω-3) fatty acids (FAs) [e.g., docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3)], modulate inflammatory reactions through various mechanisms, including gene expression, which is measured as messenger RNA concentration. However, the effects of long-term treatment of humans with DHA and EPA on various epigenetic factors-such as DNA methylation, which controls messenger RNA generation-are poorly described.

    Objective: We wanted to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global DNA methylation of peripheral blood leukocytes (PBLs) and the relation to plasma EPA and DHA concentrations in Alzheimer disease (AD) patients.

    Design: In the present study, DNA methylation in four 5'-cytosine-phosphate-guanine-3' (CpG) sites of long interspersed nuclear element-1 repetitive sequences was assessed in a group of 63 patients (30 given the n-3 FA preparation and 33 given placebo) as an estimation of the global DNA methylation in blood cells. Patients originated from the randomized, double-blind, placebo-controlled OmegAD study, in which 174 AD patients received either 1.7 g DHA and 0.6 g EPA (the n-3 FA group) or placebo daily for 6 mo.

    Results: At 6 mo, the n-3 FA group displayed marked increases in DHA and EPA plasma concentrations (2.6- and 3.5-fold), as well as decreased methylation in 2 out of 4 CpG sites (P < 0.05 for all), respectively. This hypomethylation in CpG2 and CpG4 sites showed a reverse correlation to changes in plasma EPA concentration (r = -0.25, P = 0.045; and r = -0.26, P = 0.041, respectively), but not to changes in plasma DHA concentration, and were not related to apolipoprotein E-4 allele frequency.

    Conclusion: Supplementation with n-3 FA for 6 mo was associated with global DNA hypomethylation in PBLs. Our data may be of importance in measuring various effects of marine oils, including gene expression, in patients with AD and in other patients taking n-3 FA supplements. This trial was registered at clinicaltrials.gov as NCT00211159.

  • 26.
    Mattsson, Niklas
    et al.
    Clinical Memory Research Unit, Clinical Sciences Malmö, Lund University, Lund, Sweden.
    Freund-Levi, Yvonne
    Department of Geriatrics, Karolinska University Hospital Huddinge, Section of Clinical Geriatrics, Institution of NVS, Karolinska Institutet, Stockholm, Sweden.
    Ossenkoppele, Rik
    Clinical Memory Research Unit, Clinical Sciences Malmö, Lund University, Lund, Sweden; Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands; Department of Radiology and Nuclear Medicine, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
    Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer's disease2018In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 14, no 7, p. 913-924Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology.

    METHODS: We included 3451 Aβ+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ε4 prevalence in relation to age, sex, education, and geographical location.

    RESULTS: The APOE ε4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aβ+ cognitively normal and Aβ+ mild cognitive impairment (P < .05) but not in Aβ+ AD dementia (P = .66). The prevalence was highest in Northern Europe but did not vary by sex or education.

    DISCUSSION: The APOE ε4 prevalence in AD was higher than that in previous studies, which did not require presence of Aβ pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.

  • 27.
    Nordberg, Agneta
    et al.
    Geriatriska kliniken, Karolinska universitetssjukhuset, Huddinge, Sweden.
    Eriksdotter-Jönhagen, Maria
    Geriatriska kliniken, Karolinska universitetssjukhuset, Huddinge, Sweden.
    Garlind, Anita
    Södra Stockholms geriatriska klinik, Dalens sjukhus, Stockholm, Sweden.
    Grut, Michaela
    Danderydsgeriatriken, Danderyds sjukhus, Stockholm, Sweden.
    Freund-Levi, Yvonne
    Geriatriska kliniken, Karolinska universitetssjukhuset, Huddinge, Sweden.
    Cornelius, Christel
    Geriatriska kliniken, Karolinska universitetssjukhuset, Huddinge, Sweden.
    Ekström, Anna
    Södersjukhuset, Stockholm, Sweden.
    Fastbom, Johan
    Aging Research Center, Äldrecentrum, Stockholm, Sweden.
    Sedvall, Marie
    Husläkarmottagningen Bennedich & Björk, Stockholm, Sweden.
    Viitanen, Matti
    Geriatriska kliniken, Karolinska universitetssjukhuset, Huddinge, Sweden.
    Värt ge symtomlindrande läkemedel vid Alzheimers sjukdom [Administration of symptom-relieving drugs in Alzheimer disease is beneficial]2006In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 103, no 6, p. 369-371Article in journal (Refereed)
  • 28.
    Nyberg, Svante
    et al.
    AstraZeneca R&D, Neuroscience Therapy Area, Södertälje, Sweden.
    Eriksdotter Jönhagen, Maria
    NVS Department, Karolinska Institute, Karolinska University Hospital Huddinge, Huddinge, Sweden.
    Cselényi, Zsolt
    AstraZeneca R&D, Neuroscience Therapy Area, Södertälje, Sweden.
    Halldin, Christer
    PET Centre, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Julin, Per
    AstraZeneca R&D, Neuroscience Therapy Area, Södertälje, Sweden.
    Olsson, Hans
    AstraZeneca R&D, Neuroscience Therapy Area, Södertälje, Sweden.
    Freund-Levi, Yvonne
    NVS Department, Karolinska Institute, Karolinska University Hospital Huddinge, Huddinge, Sweden.
    Andersson, Jan
    PET Centre, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Varnäs, Katarina
    PET Centre, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Svensson, Samuel
    AstraZeneca R&D, Neuroscience Therapy Area, Södertälje, Sweden.
    Farde, Lars
    AstraZeneca R&D, Neuroscience Therapy Area, Södertälje, Sweden; PET Centre, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Detection of amyloid in Alzheimer's disease with positron emission tomography using [11C]AZD21842009In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 36, no 11, p. 1859-1863Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Current positron emission tomography (PET) radioligands for detection of Aβ amyloid in Alzheimer's disease (AD) are not ideal for quantification. To improve the signal to noise ratio we have developed the radioligand [11C]AZD2184 and report here the first clinical evaluation.

    METHODS: Eight AD patients and four younger control subjects underwent 93-min PET measurements with [11C]AZD2184. A ratio approach using the cerebellum as reference region was applied to determine binding parameters.

    RESULTS: Brain uptake of [11C]AZD2184 peaked within 1 min at 3-4% of injected radioactivity. AD patients had high radioactivity in cortical regions while controls had uniformly low radioactivity uptake. Specific binding peaked within 30 min at which time standardized uptake value ratios (SUVR) ranged between 1.19 and 2.57.

    CONCLUSION: [11C]AZD2184 is a promising radioligand for detailed mapping of Aβ amyloid depositions in Alzheimer's disease, due to low non-specific binding, high signal to background ratio and reversible binding as evident from early peak equilibrium.

  • 29.
    Palmblad, Jan
    et al.
    Department of Medicine, Division of Hematology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Eriksdotter-Jönhagen, Maria
    Department of NVS, Section of Clinical Geriatrics, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Freund-Levi, Yvonne
    Department of NVS, Section of Clinical Geriatrics, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Cederholm, Tommy
    Clinical Nutrition Research, Department of Public Health and Caring Sciences, Uppsala University Hospital, Uppsala, Sweden.
    [Omega-3-fatty acids protect against dementia. Also early symptoms of mild Alzheimer disease seem to be inhibited]2007In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 104, no 44, p. 3268-3271Article in journal (Refereed)
  • 30.
    Shlisky, Julie
    et al.
    The Sackler Institute for Nutrition Science at the New York Academy of Sciences, New York, NY.
    Bloom, David E.
    Department of Global Health and Population, Harvard TH Chan School of Public Health, Boston, MA.
    Beaudreault, Amy R.
    World Food Center, University of California, Davis, Davis, CA.
    Tucker, Katherine L.
    Department of Clinical Laboratory and Nutritional Sciences, University of Massachusetts Lowell, Lowell, MA.
    Keller, Heather H.
    Schlegel-UW Research Institute for Aging, Applied Health Sciences, University of Waterloo, Ontario, Canada.
    Freund-Levi, Yvonne
    Department of Neurobiology, Care Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden; Department of Geriatrics, Karolinska University Hospital, Huddinge, Sweden; Department of Psychiatry, Tiohundra Hospital, Stockholm, Sweden.
    Fielding, Roger A.
    Nutrition, Exercise Physiology and Sarcopenia Laboratory and Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA.
    Cheng, Feon W.
    The Pennsylvania State University, University Park, PA, United States.
    Jensen, Gordon L.
    University of Vermont College of Medicine, Burlington, VT, United States.
    Wu, Dayong
    Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA.
    Meydani, Simin N.
    Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA.
    Nutritional Considerations for Healthy Aging and Reduction in Age-Related Chronic Disease2017In: Advances in Nutrition, ISSN 2161-8313, Vol. 8, no 1, p. 17-26Article in journal (Refereed)
    Abstract [en]

    A projected doubling in the global population of people aged ≥60 y by the year 2050 has major health and economic implications, especially in developing regions. Burdens of unhealthy aging associated with chronic noncommunicable and other age-related diseases may be largely preventable with lifestyle modification, including diet. However, as adults age they become at risk of "nutritional frailty," which can compromise their ability to meet nutritional requirements at a time when specific nutrient needs may be high. This review highlights the role of nutrition science in promoting healthy aging and in improving the prognosis in cases of age-related diseases. It serves to identify key knowledge gaps and implementation challenges to support adequate nutrition for healthy aging, including applicability of metrics used in body-composition and diet adequacy for older adults and mechanisms to reduce nutritional frailty and to promote diet resilience. This review also discusses management recommendations for several leading chronic conditions common in aging populations, including cognitive decline and dementia, sarcopenia, and compromised immunity to infectious disease. The role of health systems in incorporating nutrition care routinely for those aged ≥60 y and living independently and current actions to address nutritional status before hospitalization and the development of disease are discussed.

  • 31.
    van Maurik, Ingrid S.
    et al.
    Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands; Department of Epidemiology and Biostatistics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.
    Vos, Stephanie J.
    Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht, Netherlands.
    Bos, Isabelle
    Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands; Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht, Netherlands.
    Bouwman, Femke H.
    Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.
    Teunissen, Charlotte E.
    Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.
    Scheltens, Philip
    Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.
    Barkhof, Frederik
    Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam.
    Frolich, Lutz
    Department of Geriatric Psychiatry, Zentralinstitut für Seelische Gesundheit, Medical Faculty Mannheim University of Heidelberg, Germany.
    Kornhuber, Johannes
    Department of Psychiatry and Psychotherapy, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
    Wiltfang, Jens
    Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-University, Göttingen, Germany; German Center for Neurodegenerative Diseases, Göttingen, Germany; iBiMED, Medical Sciences Department, University of Aveiro, Aveiro, Portugal.
    Maier, Wolfgang
    Department of Neurodegenerative Diseases and Gerotopsychiatry, University of Bonn, German Center for Neurodegenerative Diseases, Bonn, Germany.
    Peters, Oliver
    Department of Psychiatry, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; German Center for Neurodegenerative Diseases, Berlin, Germany.
    Rüther, Eckart
    Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany.
    Nobili, Flavio
    Clinical Neurology, Department of Neurosciences, University of Genoa, Genoa, Italy; Neurology Department, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
    Frisoni, Giovanni B.
    Memory Clinic, University Hospital and University of Geneva, Geneva, Switzerland.
    Spiru, Luiza
    Geriatrics, Gerontology and Old Age Psychiatry Clinical Department, Carol Davila University of Medicine and Pharmacy-"Elias" Emergency Clinical Hospital, Bucharest, Romania; Memory Clinic and Longevity Medicine, Ana Aslan International Foundation, Romania.
    Freund-Levi, Yvonne
    Örebro University, School of Medical Sciences. Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Karolinska Institutet Center for Alzheimer Research, Stockholm, Sweden; Department of Old Age Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
    Wallin, Åsa K.
    Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.
    Hampel, Harald
    Alzheimer Precision Medicine, GRC 21, Sorbonne University, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; Eisai, Neurology Business Group, Woodcliff Lake, NJ, USA.
    Soininen, Hilkka
    Institute of Clinical Medicine, Neurology, University of Eastern Finland and Neurocenter, Neurology, Kuopio University Hospital, Kuopio, Finland.
    Tsolaki, Magda
    1st Department of Neurology, Aristotle University of Thessaloniki, Memory and Dementia Center, "AHEPA" General Hospital, Thessaloniki, Greece.
    Verhey, Frans
    Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht, Netherlands.
    Kłoszewska, Iwona
    Department of Geriatric Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland.
    Mecocci, Patrizia
    Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy.
    Vellas, Bruno
    UMR INSERM 1027, CHU Toulouse, Toulouse, France.
    Lovestone, Simon
    Department of Psychiatry, University of Oxford, Oxford, UK.
    Galluzzi, Samantha
    Lab Alzheimer's Neuroimaging and Epidemiology, IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
    Herukka, Sanna-Kaisa
    Institute of Clinical Medicine, Neurology, University of Eastern Finland and Neurocenter, Neurology, Kuopio University Hospital, Kuopio, Finland.
    Santana, Isabel
    Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
    Baldeiras, Ines
    Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
    de Mendonça, Alexandre
    Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
    Silva, Dina
    Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal; Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Centre for Biomedical Research, Universidade do Algarve, Faro, Portugal.
    Chetelat, Gael
    Université Normandie, Inserm, Université de Caen-Normandie, Inserm UMR-S U1237, GIP Cyceron, Caen, France.
    Egret, Stephanie
    Université Normandie, Inserm, Université de Caen-Normandie, Inserm UMR-S U1237, GIP Cyceron, Caen, France.
    Palmqvist, Sebastian
    Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden; Department of Neurology, Skåne University Hospital, Lund, Sweden.
    Hansson, Oskar
    Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden; Memory Clinic, Skåne University Hospital, Malmö, Sweden.
    Visser, Pieter Jelle
    Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands; Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht, Netherlands.
    Berkhof, Johannes
    Department of Epidemiology and Biostatistics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.
    van der Flier, Wiesje M.
    Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands; Department of Epidemiology and Biostatistics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.
    Biomarker-based prognosis for people with mild cognitive impairment (ABIDE): a modelling study2019In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Biomarker-based risk predictions of dementia in people with mild cognitive impairment are highly relevant for care planning and to select patients for treatment when disease-modifying drugs become available. We aimed to establish robust prediction models of disease progression in people at risk of dementia.

    METHODS: In this modelling study, we included people with mild cognitive impairment (MCI) from single-centre and multicentre cohorts in Europe and North America: the European Medical Information Framework for Alzheimer's Disease (EMIF-AD; n=883), Alzheimer's Disease Neuroimaging Initiative (ADNI; n=829), Amsterdam Dementia Cohort (ADC; n=666), and the Swedish BioFINDER study (n=233). Inclusion criteria were a baseline diagnosis of MCI, at least 6 months of follow-up, and availability of a baseline Mini-Mental State Examination (MMSE) and MRI or CSF biomarker assessment. The primary endpoint was clinical progression to any type of dementia. We evaluated performance of previously developed risk prediction models-a demographics model, a hippocampal volume model, and a CSF biomarkers model-by evaluating them across cohorts, incorporating different biomarker measurement methods, and determining prognostic performance with Harrell's C statistic. We then updated the models by re-estimating parameters with and without centre-specific effects and evaluated model calibration by comparing observed and expected survival. Finally, we constructed a model combining markers for amyloid deposition, tauopathy, and neurodegeneration (ATN), in accordance with the National Institute on Aging and Alzheimer's Association research framework.

    FINDINGS: We included all 2611 individuals with MCI in the four cohorts, 1007 (39%) of whom progressed to dementia. The validated demographics model (Harrell's C 0·62, 95% CI 0·59-0·65), validated hippocampal volume model (0·67, 0·62-0·72), and updated CSF biomarkers model (0·72, 0·68-0·74) had adequate prognostic performance across cohorts and were well calibrated. The newly constructed ATN model had the highest performance (0·74, 0·71-0·76).

    INTERPRETATION: We generated risk models that are robust across cohorts, which adds to their potential clinical applicability. The models could aid clinicians in the interpretation of CSF biomarker and hippocampal volume results in individuals with MCI, and help research and clinical settings to prepare for a future of precision medicine in Alzheimer's disease. Future research should focus on the clinical utility of the models, particularly if their use affects participants' understanding, emotional wellbeing, and behaviour.

    FUNDING: ZonMW-Memorabel.

  • 32.
    van Waalwijk van Doorn, Linda J. C.
    et al.
    Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Laboratory Medicine, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands .
    Freund-Levi, Yvonne
    Department of Neurobiology, Caring Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden; Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Verbeek, Marcel M.
    Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Laboratory Medicine, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands .
    Improved Cerebrospinal Fluid-Based Discrimination between Alzheimer's Disease Patients and Controls after Correction for Ventricular Volumes2017In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 56, no 2, p. 543-555Article in journal (Refereed)
    Abstract [en]

    Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer's disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., Aβ42, total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF Aβ42 levels inversely correlated to VV/TIV in the whole study population (Aβ42: r = -0.28; p < 0.0001). For CSF t-tau and p-tau, this association only reached statistical significance in the combined MCI and AD group (t-tau: r = -0.15; p-tau: r = -0.13; both p < 0.01). Correction for differences in VV/TIV improved the differentiation of AD versus controls based on CSF Aβ42 alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF Aβ42 levels.

  • 33.
    Vedin, Inger
    et al.
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Cederholm, Tommy
    Department of Public Health and Caring Sciences, Division of Clinical Nutrition and Metabolism Research, Uppsala University Hospital, Uppsala, Sweden.
    Freund-Levi, Yvonne
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Basun, Hans
    Department of Public Health and Caring Sciences, Division of Geriatrics, Uppsala University Hospital, Uppsala, Sweden.
    Garlind, Anita
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Faxén Irving, Gerd
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Jönhagen, Maria Eriksdotter
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Vessby, Bengt
    Department of Public Health and Caring Sciences, Division of Clinical Nutrition and Metabolism Research, Uppsala University Hospital, Uppsala, Sweden.
    Wahlund, Lars-Olof
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Palmblad, Jan
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Effects of docosahexaenoic acid-rich n-3 fatty acid supplementation on cytokine release from blood mononuclear leukocytes: the OmegAD study2008In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 87, no 6, p. 1616-1622Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Dietary fish or fish oil rich in n-3 fatty acids (n-3 FAs), eg, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), ameliorate inflammatory reactions by various mechanisms. Whereas most studies have explored the effects of predominantly EPA-based n-3 FAs preparations, few have addressed the effects of n-3 FAs preparations with DHA as the main FA.

    OBJECTIVE: The objective was to determine the effects of 6 mo of dietary supplementation with an n-3 FAs preparation rich in DHA on release of cytokines and growth factors from peripheral blood mononuclear cells (PBMCs).

    DESIGN: In a randomized, double-blind, placebo-controlled trial, 174 Alzheimer disease (AD) patients received daily either 1.7 g DHA and 0.6 g EPA (n-3 FAs group) or placebo for 6 mo. In the present study blood samples were obtained from the 23 first randomized patients, and PBMCs were isolated before and after 6 mo of treatment.

    RESULTS: Plasma concentrations of DHA and EPA were significantly increased at 6 mo in the n-3 FAs group. This group also showed significant decreases of interleukin (IL)-6, IL-1beta, and granulocyte colony-stimulating factor secretion after stimulation of PBMCs with lipopolysaccharide. Changes in the DHA and EPA concentrations were negatively associated with changes in IL-1beta and IL-6 release for all subjects. Reductions of IL-1beta and IL-6 were also significantly correlated with each other. In contrast, this n-3 FA treatment for 6 mo did not decrease tumor necrosis factor-alpha, IotaL-8, IL-10, and granulocyte-macrophage colony-stimulating factor secretion.

    CONCLUSION: AD patients treated with DHA-rich n-3 FAs supplementation increased their plasma concentrations of DHA (and EPA), which were associated with reduced release of IL-1beta, IL-6, and granulocyte colony-stimulating factor from PBMCs. This trial was registered at clinicaltrials.gov as NCT00211159.

  • 34.
    Vedin, Inger
    et al.
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden .
    Cederholm, Tommy
    Department of Public Health and Caring Sciences, Uppsala University Hospital, Uppsala, Sweden; Division of Clinical Nutrition and Metabolism, Uppsala University Hospital, Uppsala, Sweden .
    Freund-Levi, Yvonne
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden .
    Basun, Hans
    Department of Public Health and Caring Sciences, Uppsala University Hospital, Uppsala, Sweden; Division of Geriatrics, Uppsala University Hospital, Uppsala, Sweden .
    Garlind, Anita
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden .
    Irving, Gerd Faxén
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden .
    Eriksdotter-Jönhagen, Maria
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden .
    Wahlund, Lars-Olof
    Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden .
    Dahlman, Ingrid
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden .
    Palmblad, Jan
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden .
    Effects of DHA-rich n-3 fatty acid supplementation on gene expression in blood mononuclear leukocytes: the OmegAD study2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, article id e35425Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Dietary fish oil, rich in n-3 fatty acids (n-3 FAs), e.g. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), regulate inflammatory reactions by various mechanisms, e.g. gene activation. However, the effects of long-term treatment with DHA and EPA in humans, using genome wide techniques, are poorly described. Hence, our aim was to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global gene expression in peripheral blood mononuclear cells.

    METHODS AND FINDINGS: In the present study, blood samples were obtained from a subgroup of 16 patients originating from the randomized double-blind, placebo-controlled OmegAD study, where 174 Alzheimer disease (AD) patients received daily either 1.7 g of DHA and 0.6 g EPA or placebo for 6 months. In blood samples obtained from 11 patients receiving n-3 FA and five placebo, expressions of approximately 8000 genes were assessed by gene array. Significant changes were confirmed by real-time PCR. At 6 months, the n-3 FAs group displayed significant rises of DHA and EPA plasma concentrations, as well as up- and down-regulation of nine and ten genes, respectively, was noticed. Many of these genes are involved in inflammation regulation and neurodegeneration, e.g. CD63, MAN2A1, CASP4, LOC399491, NAIP, and SORL1 and in ubiqutination processes, e.g. ANAPC5 and UBE2V1. Down-regulations of ANAPC5 and RHOB correlated to increases of plasma DHA and EPA levels.

    CONCLUSIONS: We suggest that 6 months of dietary n-3 FA supplementation affected expression of genes that might influence inflammatory processes and could be of significance for AD.

    TRIAL REGISTRATION: ClinicalTrials.gov NCT00211159.

  • 35.
    Vermunt, Lisa
    et al.
    Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
    Sikkes, Sietske A. M.
    Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
    van den Hout, Ardo
    Department of Statistical Science, University College London, London, UK.
    Handels, Ron
    Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Alzheimer Centrum Limburg, Maastricht University, Maastricht, The Netherlands.
    Bos, Isabelle
    Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Alzheimer Centrum Limburg, Maastricht University, Maastricht, The Netherlands.
    van der Flier, Wiesje M.
    Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Department of Epidemiology and Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
    Kern, Silke
    Department of Psychiatry and Neurochemistry, Neuropsychiatric Epidemiology Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Ousset, Pierre-Jean
    CHU Toulouse, Gérontopôle and INSERM UMR 1027, Toulouse, France.
    Maruff, Paul
    Cogstate Ltd, Florey Institute, University of Melbourne, Melbourne, Australia.
    Skoog, Ingmar
    Department of Psychiatry and Neurochemistry, Neuropsychiatric Epidemiology Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Verhey, Frans R. J.
    Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Alzheimer Centrum Limburg, Maastricht University, Maastricht, The Netherlands.
    Freund-Levi, Yvonne
    Örebro University, School of Medical Sciences. Department of Neurobiology, Caring Sciences and Society (NVS), Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Old Age Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
    Tsolaki, Magda
    Wallin, Åsa K.
    3rd Department of Neurology, Aristotle University of Thessaloniki, Memory and Dementia Center, "G Papanicolau" General Hospital, Thessaloniki, Greece.
    Olde Rikkert, Marcel
    Department of Geriatric Medicine, Radboudumc Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands.
    Soininen, Hilkka
    Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland.
    Spiru, Luisa
    "Carol Davila" University of Medicine and Pharmacy, Geriatrics-Gerontology and Old Age Psychiatry Clinical Department -"Elias" University Clinical Hospital, Bucarest, Romenia; "Ana Aslan" International Academy of Aging - The Memory Clinic and Longevity Medicine, Bucarest, Romenia.
    Zetterberg, Henrik
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; UK Dementia Research Institute at UCL, London, UK.
    Blennow, Kaj
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Scheltens, Philip
    Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
    Muniz-Terrera, Graciela
    Centre for Dementia Prevention, University of Edinburgh, Edinburgh, UK.
    Visser, Pieter Jelle
    Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Alzheimer Centrum Limburg, Maastricht University, Maastricht, The Netherlands.
    Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype2019In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 15, no 7, p. 888-898Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: We estimated the age-specific duration of the preclinical, prodromal, and dementia stages of Alzheimer's disease (AD) and the influence of sex, setting, apolipoprotein E (APOE) genotype, and cerebrospinal fluid tau on disease duration.

    METHODS: We performed multistate modeling in a combined sample of 6 cohorts (n = 3268) with death as the end stage and estimated the preclinical, prodromal, and dementia stage duration.

    RESULTS: The overall AD duration varied between 24 years (age 60) and 15 years (age 80). For individuals presenting with preclinical AD, age 70, the estimated preclinical AD duration was 10 years, prodromal AD 4 years, and dementia 6 years. Male sex, clinical setting, APOE ε4 allele carriership, and abnormal cerebrospinal fluid tau were associated with a shorter duration, and these effects depended on disease stage.

    DISCUSSION: Estimates of AD disease duration become more accurate if age, sex, setting, APOE, and cerebrospinal fluid tau are taken into account. This will be relevant for clinical practice and trial design.

  • 36.
    Visser, Pieter Jelle
    et al.
    Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, University of Maastricht, Netherlands; Department of Neurology, Alzheimer Center, VU University Medical Center, Amsterdam, Netherlands.
    Verhey, Frans
    Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, University of Maastricht, Netherlands.
    Knol, Dirk L.
    Department of Clinical Epidemiology and Statistics, VU University Medical Center, Amsterdam, Netherlands.
    Scheltens, Philip
    Department of Neurology, Alzheimer Center, VU University Medical Center, Amsterdam, Netherlands.
    Wahlund, Lars-Olof
    Department of NVS, Section of Clinical Geriatrics, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
    Freund-Levi, Yvonne
    Department of NVS, Section of Clinical Geriatrics, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
    Tsolaki, Magda
    Aristotle University of Thessaloniki, Memory and Dementia Center, 3rd Department of Neurology, G Papanicolaou General Hospital, Thessaloniki, Greece.
    Minthon, Lennart
    Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
    Wallin, Åsa K.
    Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
    Hampel, Harald
    Alzheimer Memorial Center, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany; Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience (TCIN), Laboratory of Neuroimaging and Biomarker Research, Trinity College, University of Dublin, The Adelaide, Dublin, Ireland; Meath Hospital incorporating the National Children's Hospital (AMiNCH), Dublin, Ireland .
    Bürger, Katharina
    Alzheimer Memorial Center, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany.
    Pirttila, Tuula
    Department of Neurology, University and University Hospital of Kuopio, Kuopio, Finland.
    Soininen, Hilkka
    Department of Neurology, University and University Hospital of Kuopio, Kuopio, Finland.
    Rikkert, Marcel Olde
    Department of Geriatrics, Alzheimer Center, Nijmegen Centre for Evidence Based Practice, Radboud University Medical Center, Nijmegen, Netherlands.
    Verbeek, Marcel M.
    Department of Neurology, Donders Center for Brain, Cognition and Behaviour, Alzheimer Center, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands.
    Spiru, Luiza
    “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania.
    Blennow, Kaj
    Clinical Neurochemistry Laboratory, Göteborg University, Sahlgrenska University Hospital, Mölndal, Sweden.
    Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study2009In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 8, no 7, p. 619-627Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Alzheimer's disease (AD) pathology is common in patients with amnestic mild cognitive impairment (aMCI) without dementia, but the prevalence of AD pathology in patients with subjective cognitive impairment (SCI) and non-amnestic mild cognitive impairment (naMCI) is unknown. AD is characterised by decreased CSF concentrations of Abeta(42) and increased concentrations of tau. We investigated the prevalence of a CSF AD profile in patients with SCI, naMCI, or aMCI and the association of this profile with cognitive outcome in each group.

    METHODS: Patients with SCI, naMCI, aMCI, and neurologically healthy controls were recruited from 20 memory clinics across Europe, between January, 2003, and June, 2005, into this prospective cohort study. A CSF AD profile was defined as an abnormal ratio of Abeta(42):tau. Patients were assessed annually up to 3 years. Outcome measures were changes in memory, overall cognition, mini-mental state examination (MMSE) score, daily function, and progression to AD-type dementia.

    FINDINGS: The CSF AD profile was more common in patients with SCI (31 of 60 [52%]), naMCI (25 of 37 [68%]), and aMCI (56 of 71 [79%]) than in healthy controls (28 of 89 [31%]). The profile was associated with cognitive decline in patients with naMCI (memory, MMSE, and daily function) and in patients with aMCI (MMSE and daily function). In patients with aMCI, a CSF AD profile was predictive of AD-type dementia (OR 26.8, 95% CI 1.6-456.4).

    INTERPRETATION: AD is a common cause of SCI, naMCI, and aMCI and is associated with cognitive decline in patients with naMCI or aMCI. Patients with SCI might be in the early stages of AD, and cognitive decline might become apparent only after longer follow-up.

  • 37.
    Vos, Stephanie J. B.
    et al.
    Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht, The Netherlands.
    Verhey, Frans
    Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht, The Netherlands.
    Frölich, Lutz
    Department of Geriatric Psychiatry, Zentralinstitut für Seelische Gesundheit, University of Heidelberg, Mannheim, Germany.
    Kornhuber, Johannes
    Department of Psychiatry and Psychotherapy, Friedrich-Alexander University of Erlangen, Erlangen, Germany.
    Wiltfang, Jens
    Department of Psychiatry and Psychotherapy, University Medical Centre (UMG), Georg-August-University, Göttingen, Germany.
    Maier, Wolfgang
    Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany.
    Peters, Oliver
    Department of Psychiatry and Psychotherapy, Charité Berlin, Berlin, Germany.
    Rüther, Eckart
    Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany.
    Nobili, Flavio
    Clinical Neurophysiology Service, Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Genoa, Italy.
    Morbelli, Silvia
    Nuclear Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy.
    Frisoni, Giovanni B.
    IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy; University Hospitals and University of Geneva, Geneva, Switzerland.
    Drzezga, Alexander
    Department of Nuclear Medicine, University of Cologne, Cologne, Germany.
    Didic, Mira
    Service de Neurologie et Neuropsychologie, Pôle de neurosciences cliniques, AP-HM Timone, Aix Marseille Université, Marseille, France.
    van Berckel, Bart N. M.
    Department of Nuclear Medicine and PET Research, VU University Medical CentRE, Amsterdam, The Netherlands.
    Simmons, Andrew
    Department of Neuroimaging, Centre for Neuroimaging Science, King’s College London, Institute of Psychiatry, London, UK.
    Soininen, Hilkka
    Institute of Clinical Medicine, Neurology, University of Eastern Finland and Neurocenter, Neurology, Kuopio University Hospital, Kuopio, Finland.
    Kłoszewska, Iwona
    Medical University of Lodz, Lodz, Poland.
    Mecocci, Patrizia
    Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy.
    Tsolaki, Magda
    Aristotle University of Thessaloniki, Memory and Dementia Center, 3rd Department of Neurology, “G Papanicolaou” General Hospital, Thessaloniki, Greece.
    Vellas, Bruno
    UMR INSERM 1027, CHU Toulouse, Toulouse, France.
    Lovestone, Simon
    Department of Psychiatry, University of Oxford, Oxford, UK.
    Muscio, Cristina
    IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Fondazione Europea Ricerca Biomedica (FERB), Centro di Eccellenza Alzheimer, Ospedale Briolini, Gazzaniga, Bergamo, Italy; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
    Herukka, Sanna-Kaisa
    Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland; Neurocenter, Neurology, Kuopio University Hospital, Kuopio, Finland.
    Salmon, Eric
    Memory Clinic, Department of Neurology, CHU Liège, Belgium; Cyclotron Research Centre, University of Liège, Liège, Belgium.
    Bastin, Christine
    Cyclotron Research Centre, University of Liège, Liège, Belgium.
    Wallin, Anders
    Department of Psychiatry and Neurochemistry, Institute for Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Nordlund, Arto
    Department of Psychiatry and Neurochemistry, Institute for Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    de Mendonça, Alexandre
    Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Portugal.
    Silva, Dina
    Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Portugal.
    Santana, Isabel
    Department of Neurology, Coimbra University Hospital, Coimbra, Portugal.
    Lemos, Raquel
    Faculty of Psychology and Educational Sciences, University of Coimbra, Coimbra, Portugal.
    Engelborghs, Sebastiaan
    Reference Centre for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology and Memory Clinic, Hospital Network Antwerp, Middelheim and Hoge Beuken, Antwerp, Belgium.
    Van der Mussele, Stefan
    Reference Centre for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
    Freund-Levi, Yvonne
    Department of Neurobiology, Caring Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden; Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Wallin, Åsa K.
    Clinical Sciences Malmö, Clinical Memory Research Unit, Lund University, Lund, Sweden.
    Hampel, Harald
    Centre des Maladies Cognitives et Comportementales, Institut du Cerveau et de la Moelle épinière, Paris, France; Université Pierre et Marie Curie-Paris 6, AP-HP, Hôpital de la Salpêtrière, Paris, France.
    van der Flier, Wiesje
    Alzheimer Centre and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
    Scheltens, Philip
    Alzheimer Centre and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
    Visser, Pieter Jelle
    Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands; Alzheimer Centre Limburg, Maastricht, The Netherlands; Alzheimer Centre and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
    Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage2015In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 138, no 5, p. 1327-1338Article in journal (Refereed)
    Abstract [en]

    Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimer's disease at the mild cognitive impairment stage and progression to Alzheimer's disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimer's disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimer's disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimer's disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimer's disease likelihood group. The 3-year progression rate to Alzheimer's disease-type dementia was 59% in the high Alzheimer's disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimer's disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimer's disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimer's disease likelihood group or the International Working Group-2 prodromal Alzheimer's disease group could be considered.

  • 38.
    Wang, Xiuzhe
    et al.
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Stockholm, Sweden; Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
    Hjorth, Erik
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Stockholm, Sweden.
    Vedin, Inger
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Eriksdotter, Maria
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Stockholm, Sweden.
    Freund-Levi, Yvonne
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Stockholm, Sweden.
    Wahlund, Lars-Olof
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Stockholm, Sweden.
    Cederholm, Tommy
    Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
    Palmblad, Jan
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Schultzberg, Marianne
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Stockholm, Sweden.
    Effects of n-3 FA supplementation on the release of proresolving lipid mediators by blood mononuclear cells: the OmegAD study2015In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 56, no 3, p. 674-681Article in journal (Refereed)
    Abstract [en]

    Specialized proresolving mediators (SPMs) induce resolution of inflammation. SPMs are derivatives of n-3 and n-6 PUFAs and may mediate their beneficial effects. It is unknown whether supplementation with PUFAs influences the production of SPMs. Alzheimer's disease (AD) is associated with brain inflammation and reduced levels of SPMs. The OmegAD study is a randomized, double-blind, and placebo-controlled clinical trial on AD patients, in which placebo or a supplement of 1.7 g DHA and 0.6 g EPA was taken daily for 6 months. Plasma levels of arachidonic acid decreased, and DHA and EPA levels increased after 6 months of n-3 FA treatment. Peripheral blood mononuclear cells (PBMCs) were obtained before and after the trial. Analysis of the culture medium of PBMCs incubated with amyloid-β 1-40 showed unchanged levels of the SPMs lipoxin A4 and resolvin D1 in the group supplemented with n-3 FAs, whereas a decrease was seen in the placebo group. The changes in SPMs showed correspondence to cognitive changes. Changes in the levels of SPMs were positively correlated to changes in transthyretin. We conclude that supplementation with n-3 PUFAs for 6 months prevented a reduction in SPMs released from PBMCs of AD patients, which was associated with changes in cognitive function.

1 - 38 of 38
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