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  • 1.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    ALS and FTD: two sides of the same coin?2013In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 12, no 10, p. 937-938Article in journal (Other academic)
  • 2.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Mutation in C9orf72 changes the boundaries of ALS and FTD2012In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 11, no 3, p. 205-207Article in journal (Refereed)
  • 3. Berge, Eivind
    et al.
    Cohen, Geoffrey
    Roaldsen, Melinda B
    Lundström, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Isaksson, Eva
    Rudberg, Ann-Sofie
    Slot, Karsten Bruins
    Forbes, John
    Smith, Joel
    Drever, Jonathan
    Wardlaw, Joanna M
    Lindley, Richard I
    Sandercock, Peter A G
    Whiteley, William N
    Effects of alteplase on survival after ischaemic stroke (IST-3): 3 year follow-up of a randomised, controlled, open-label trial2016In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 15, no 10, p. 1028-34, article id S1474-4422(16)30139-9Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The effect of alteplase on patient survival after ischaemic stroke is the subject of debate. We report the effect of intravenous alteplase on long-term survival after ischaemic stroke of participants in the Third International Stroke Trial (IST-3).

    METHODS: In IST-3, done at 156 hospitals in 12 countries (Australia, Europe, and the UK), participants (aged >18 years) were randomly assigned with a telephone voice-activated or web-based system in a 1:1 ratio to treatment with intravenous 0·9 mg/kg alteplase plus standard care or standard care alone within 6 h of ischaemic stroke. We followed up participants in the UK and Scandinavia (Sweden and Norway) for survival up to 3 years after randomisation using data from national registries and compared survival in the two groups with proportional hazards survival analysis, adjusting for key prognostic variables. IST-3 is registered with the ISRCTN registry, number ISRCTN25765518.

    FINDINGS: Between May 5, 2000, and July 27, 2011, 3035 participants were enrolled in IST-3. Of these, 1948 (64%) of 3035 participants were scheduled for analysis of 3 year survival, and 1946 (>99%) of these were included in the analysis (967 [50%] in the alteplase plus standard care group and 979 [50%] in the standard care alone group). By 3 years after randomisation, 453 (47%) of 967 participants in the alteplase plus standard care group and 494 (50%) of 979 in the standard care alone group had died (risk difference 3·6% [95% CI -0·8 to 8·1]). Participants allocated to alteplase had a significantly higher hazard of death during the first 7 days (99 [10%] of 967 died in the alteplase plus standard care group vs 65 [7%] of 979 in the standard care alone group; hazard ratio 1·52 [95% CI 1·11-2·08]; p=0·004) and a significantly lower hazard of death between 8 days and 3 years (354 [41%] of 868 vs 429 [47%] of 914; 0·78 [0·68-0·90]; p=0·007).

    INTERPRETATION: Alteplase treatment within 6 h after ischaemic stroke was associated with a small, non-significant reduction in risk of death at 3 years, but among individuals who survived the acute phase, treatment was associated with a significant increase in long-term survival. These results are reassuring for clinicians who have expressed concerns about the effect of alteplase on survival.

    FUNDING: Heart and Stroke Scotland, UK Medical Research Council, Health Foundation UK, Stroke Association UK, Research Council of Norway, AFA Insurance, Swedish Heart Lung Fund, Foundation of Marianne and Marcus Wallenberg, Polish Ministry of Science and Education, Australian Heart Foundation, Australian National Health and Medical Research Council, Swiss National Research Foundation, Swiss Heart Foundation, Assessorato alla Sanita (Regione dell'Umbria), and Danube University.

  • 4. Diener, Hans Christoph
    et al.
    Connolly, Stuart J.
    Ezekowitz, Michael D.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Reilly, Paul A.
    Yang, Sean
    Xavier, Denis
    Di Pasquale, Giuseppe
    Yusuf, Salim
    Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial2010In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 9, no 12, p. 1157-1163Article in journal (Refereed)
    Abstract [en]

    Background In the Randomised Evaluation of Long Term Anticoagulation Therapy (RE LY) trial dabigatran reduced occurrence of both stroke and haemorrhage compared with warfarin in patients who had atrial fibrillation and were at increased risk of stroke We aimed to assess the effects of dabigatran compared with warfarin in the subgroup of patients with previous stroke or transient ischaemic attack

    Methods In the RE LY trial 18113 patients from 967 centres in 44 countries were randomly assigned to 110 mg or 150 mg dabigatran twice daily or to warfarin dose adjusted to international normalised ratio 2 0 to 3 0 Median follow up was 2 0 years (IQR 1 14-2 86) and the primary outcome was stroke or systemic embolism The primary safety outcome was major haemorrhage Patients and investigators were aware of whether patients received warfarin or dabigatran but not of dabigatran dose and event adjudicators were masked to treatment In a predefined analysis we investigated the outcomes of the RE LY trial in subgroups of patients with or without previous stroke or transient ischaemic attack RE LY is registered with ClimcalTriaLs gov NCT00262600

    Findings Within the subgroup of patients with previous stroke or transient ischaemic attack, 1195 patients were from the 110 mg dabigatran group 1233 from the 150 mg dabigatran group and 1195 from the warfarin group Stroke or systemic embolism occurred m 65 patients (2 78% per year) on warfarin compared with 55 (2 32% per year) on 110 mg dabigatran (relative risk 0 84, 95% CI 0 58-1 20) and 51 (2 07% per year) on 150 mg dabigatran (0 75 0 52-1 08) The rate of major bleeding was significantly lower in patients on 110 mg dabigatran (RR 0 66 95% CI 0 48-0 90) and similar in those on 150 mg dabigatran (RR 1 01 95% CI 0 77-1 34) compared with those on warfarin The effects of both doses of dabigatran compared with warfarin were not significantly different between patients with previous stroke or transient ischaemic attack and those without for any of the outcomes from RE LY apart from vascular death (110 mg group compared with warfaric group mteraction p=0 038)

    Interpretation In patients with previous stroke or transient ischaemic attack, the effects of 110 mg dabigatran and 150 mg dabigatran on stroke or systemic embolism were similar to those of warfarin Most effects of both dabigatran doses were consistent in patients with versus those without previous stroke or transient ischaemic attack.

  • 5. Diener, Hans-Christoph
    et al.
    Eikelboom, John
    Connolly, Stuart J
    Joyner, Campbell D
    Hart, Robert G
    Lip, Gregory Y H
    O'Donnell, Martin
    Hohnloser, Stefan H
    Hankey, Graeme J
    Shestakovska, Olga
    Yusuf, Salim
    Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial2012In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 11, no 3, p. 225-231Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    In the AVERROES study, apixaban, a novel factor Xa inhibitor, reduced the risk of stroke or systemic embolism in patients with atrial fibrillation who were at high risk of stroke but unsuitable for vitamin K antagonist therapy. We aimed to investigate whether the subgroup of patients with previous stroke or transient ischaemic attack (TIA) would show a greater benefit from apixaban compared with aspirin than would patients without previous cerebrovascular events.

    METHODS:

    In AVERROES, 5599 patients (mean age 70 years) with atrial fibrillation who were at increased risk of stroke and unsuitable for vitamin K antagonist therapy were randomly assigned to receive apixaban (5 mg twice daily) or aspirin (81-324 mg per day). The mean follow-up was 1·1 years. The primary efficacy outcome was stroke or systemic embolism; the primary safety outcome was major bleeding. Patients and investigators were masked to study treatment. In this prespecified subgroup analysis, we used Kaplan-Meier estimates of 1-year event risk and Cox proportional hazards regression models to compare the effects of apixaban in patients with and without previous stroke or TIA. AVERROES is registered at ClinicalTrials.gov, number NCT00496769.

    FINDINGS:

    In patients with previous stroke or TIA, ten events of stroke or systemic embolism occurred in the apixaban group (n=390, cumulative hazard 2·39% per year) compared with 33 in the aspirin group (n=374, 9·16% per year; hazard ratio [HR] 0·29, 95% CI 0·15-0·60). In those without previous stroke or TIA, 41 events occurred in the apixaban group (n=2417, 1·68% per year) compared with 80 in the aspirin group (n=2415, 3·06% per year; HR 0·51, 95% CI 0·35-0·74). The p value for interaction of the effects of aspirin and apixaban with previous cerebrovascular events was 0·17. Major bleeding was more frequent in patients with history of stroke or TIA than in patients without (HR 2·88, 95% CI 1·77-4·55) but risk of this event did not differ between treatment groups.

    INTERPRETATION:

    In patients with atrial fibrillation, apixaban is similarly effective whether or not patients have had a previous stroke or TIA. Given that those with previous stroke or TIA have a higher risk of stroke, the absolute benefits might be greater in these patients.

    FUNDING:

    Bristol-Myers Squibb and Pfizer.

  • 6. Easton, J. Donald
    et al.
    Lopes, Renato D.
    Bahit, M. Cecilia
    Wojdyla, Daniel M.
    Granger, Christopher B.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Alings, Marco
    Goto, Shinya
    Lewis, Basil S.
    Rosenqvist, Marten
    Hanna, Michael
    Mohan, Puneet
    Alexander, John H.
    Diener, Hans-Christoph
    Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial2012In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 11, no 6, p. 503-511Article in journal (Refereed)
    Abstract [en]

    Background

    In the ARISTOTLE trial, the rate of stroke or systemic embolism was reduced by apixaban compared with warfarin in patients with atrial fibrillation (AF). Patients with AF and previous stroke or transient ischaemic attack (TIA) have a high risk of stroke. We therefore aimed to assess the efficacy and safety of apixaban compared with warfarin in prespecified subgroups of patients with and without previous stroke or TIA.

    Methods

    Between Dec 19,2006, and April 2,2010, patients were enrolled in the ARISTOTLE trial at 1034 clinical sites in 39 countries. 18 201 patients with AF or atrial flutter were randomly assigned to receive apixaban 5 mg twice daily or warfarin (target international normalised ratio 2.0-3.0). The median duration of follow-up was 1.8 years (IQR 1.4-2.3). The primary efficacy outcome was stroke or systemic embolism, analysed by intention to treat. The primary safety outcome was major bleeding in the on-treatment population. All participants, investigators, and sponsors were masked to treatment assignments. In this subgroup analysis, we estimated event rates and used Cox models to compare outcomes in patients with and without previous stroke or TIA. The ARISTOTLE trial is registered with ClinicalTrials.gov, number NTC00412984.

    Findings

    Of the trial population, 3436 (19%) had a previous stroke or TIA. In the subgroup of patients with previous stroke or TIA, the rate of stroke or systemic embolism was 2.46 per 100 patient-years of follow-up in the apixaban group and 3.24 in the warfarin group (hazard ratio [HR] 0.76, 95% CI 0.56 to 1.03); in the subgroup of patients without previous stroke or TLA, the rate of stroke or systemic embolism was 1.01 per 100 patient-years of follow-up with apixaban and 1.23 with warfarin (HR 0.82, 95% CI 0.65 to 1.03; p for interaction=0.71). The absolute reduction in the rate of stroke and systemic embolism with apixaban versus warfarin was 0.77 per 100 patient-years of follow-up (95% CI -0.08 to 1.63) in patients with and 0.22 (-0.03 to 0.47) in those without previous stroke or TIA. The difference in major bleeding with apixaban compared with warfarin was 1.07 per 100 patient-years (95% CI 0.09-2.04) in patients with and 0.93 (0.54-1.32) in those without previous stroke or TIA.

    Interpretation

    The effects of apixaban versus warfarin were consistent in patients with AF with and without previous stroke or TIA. Owing to the higher risk of these outcomes in patients with previous stroke or TIA, the absolute benefits of apixaban might be greater in this population.

    Funding

    Bristol-Myers Squibb and Pfizer.

  • 7.
    Edvardsson, David
    et al.
    Umeå University, Faculty of Medicine, Department of Nursing. Australian Centre for Evidence-Based Aged Care (ACEBAC), La Trobe University, Australia.
    Winblad, Bengt
    Sandman, Per-Olof
    Umeå University, Faculty of Medicine, Department of Nursing.
    Person-centred care of people with severe Alzheimer's disease: current status and ways forward2008In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 7, no 4, p. 362-367Article in journal (Refereed)
    Abstract [en]

    When caring for people with severe Alzheimer's disease (AD), the concept of the person being central is increasingly advocated in clinical practice and academia as an approach to deliver high-quality care. The aim of person-centred care, which emanates from phenomological perspectives on AD, is to acknowledge the personhood of people with AD in all aspects of their care. It generally includes the recognition that the personality of the person with AD is increasingly concealed rather than lost; personalisation of the person's care and their environment; offering shared decision-making; interpretation of behaviour from the viewpoint of the person; and prioritising the relationship as much as the care tasks. However, questions remain about how to provide, measure, and explore clinical outcomes of person-centred care. In this Review, we summarise the current knowledge about person-centred care for people with severe AD and highlight the areas in need of further research.

  • 8.
    Ekman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Jakobson Mo, Susanna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Functional brain activity and presynaptic dopamine uptake in patients with Parkinson's disease and mild cognitive impairment: a cross-sectional study2012In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 11, no 8, p. 679-687Article in journal (Refereed)
    Abstract [en]

    Background: Many patients with Parkinson's disease have mild cognitive impairment (MCI). Deficits in executive functions and working memory suggest dysfunctional frontostriatal brain circuitry. We aimed to assess brain responses during a working memory task in a cohort of newly diagnosed drug-naive patients with Parkinson's disease with and without MCI.

    Methods: Participants were recruited within a prospective cohort study of incident patients with idiopathic parkinsonism, including Parkinson's disease. Between Jan 1, 2004, and April 30, 2009, all physicians in the Umea catchment area were requested to refer all individuals with suspected parkinsonism to the Department of Neurology at lima University. Included patients fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria for Parkinson's disease. Control individuals were matched on the basis of age and sex with the first 50 patients included in the study. Participants who scored 1.5 SDs or more below the population mean on at least two cognitive measures were diagnosed with MCI. The primary outcome measures were functional MRI blood-oxygen-level-dependent signal and SPECT presynaptic uptake. Functional MRI was done during a verbal two-back working memory task. Presynaptic dopamine SPECT was done to assess presynaptic striatal dopaminergic system integrity. Event-related transient analyses of functional MRI data were done for the whole brain and for frontostriatal regions of interest, and semi-quantitative SPECT analyses were done for striatal regions of interest.

    Findings: Compared with controls (n=24), patients with Parkinson's disease (n=77) had under-recruitment in an extensive brain network including bilateral striatal and frontal regions (p<0.001). Within the Parkinson's disease group, patients with Parkinson's disease and MCI (n=30) had additional under-recruitment in the right dorsal caudate nucleus (p=0.005) and the bilateral anterior cingulate cortex (p<0.001) compared with patients with Parkinson's disease without MCI (n=26). In patients with Parkinson's disease and MCI, SPECT uptake in the right caudate was lower than in patients with Parkinson's disease without MCI (p=0.008) and correlated with striatal functional MRI blood-oxygen-level-dependent signal (r=0.32, p=0.031).

    Interpretation: These altered brain responses in patients with Parkinson's disease and MCI suggest that cognitive impairment is linked to frontostriatal dysfunction.

  • 9.
    Engström, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Berg, Thomas
    Stjernquist-Desatnik, Anna
    Axelsson, Sara
    Pitkaranta, Anne
    Hultcrantz, Malou
    Kanerva, Mervi
    Hanner, Per
    Jonsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Prednisolone and valaciclovir in Bell's palsy: a randomised, double-blind, placebo-controlled, multicentre trial2008In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 7, no 11, p. 993-1000Article in journal (Refereed)
    Abstract [en]

    Background Previous trials of corticosteroid or antiviral treatments for Bell's palsy have been underpowered or have had insufficient follow-up. The aim of this study was to compare the short-term and long-term effects of prednisolone and valaciclovir in the recovery of the affected facial nerve in a large number of patients. Methods In this randomised, double-blind, placebo-controlled, multicentre trial, patients aged 18 to 75 years who sought care directly or were referred from emergency departments or general practitioners within 72 h of onset of acute, unilateral, peripheral facial palsy, between May, 2001, and September, 2006, were assessed. Patients were randomly assigned in permuted blocks of eight to receive placebo plus placebo; 60 mg prednisolone per day for 5 days then reduced by 10 mg per day (for a total treatment time of 10 days) plus placebo; 1000 mg valaciclovir three times per day for 7 days plus placebo; or prednisolone (10 days) plus valaciclovir (7 days). Follow-up was for 12 months. The primary outcome event was time to complete recovery of facial function, as assessed with a regional Sunnybrook scale score of 100 points. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT00510263. Findings Of 839 patients who were randomly assigned, 829 were included in the modified intention-to-treat analysis: 206 received placebo plus placebo, 210 prednisolone plus placebo, 207 valaciclovir plus placebo, and 206 prednisolone plus valaciclovir. Time to recovery was significantly shorter in the 416 patients who received prednisolone compared with the 413 patients who did not (hazard ratio 1.40, 95% CI 1.18 to 1.64; p<0.0001). There was no difference in time to recovery between the 413 patients treated with valaciclovir and the 416 patients who did not receive valaciclovir (1.01, 0.85 to 1.19; p=0.90). The number of patients with adverse events was similar in all treatment arms. Interpretation Prednisolone shortened the time to complete recovery in patients with Bell's palsy, whereas valaciclovir did not affect facial recovery.

  • 10. Feigin, Valery L
    et al.
    Abajobir, Amanuel
    Abate, Kalkidan
    Abd-Allah, Foad
    Abdulle, Abdishakur
    Abera, Semaw
    Abyu, Gebre
    Ahmed, Muktar
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Karolinska institutet.
    Vos, Theo
    Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 20152017In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 16, no 11, p. 877-897Article in journal (Refereed)
    Abstract [en]

    Background

    Comparable data on the global and country-specific burden of neurological disorders and their trends are crucial for health-care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions. In this systematic analysis, we quantified the global disease burden due to neurological disorders in 2015 and its relationship with country development level.

    Methods

    We estimated global and country-specific prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) for various neurological disorders that in the GBD classification have been previously spread across multiple disease groupings. The more inclusive grouping of neurological disorders included stroke, meningitis, encephalitis, tetanus, Alzheimer's disease and other dementias, Parkinson's disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, medication overuse headache, brain and nervous system cancers, and a residual category of other neurological disorders. We also analysed results based on the Socio-demographic Index (SDI), a compound measure of income per capita, education, and fertility, to identify patterns associated with development and how countries fare against expected outcomes relative to their level of development.

    Findings

    Neurological disorders ranked as the leading cause group of DALYs in 2015 (250·7 [95% uncertainty interval (UI) 229·1 to 274·7] million, comprising 10·2% of global DALYs) and the second-leading cause group of deaths (9·4 [9·1 to 9·7] million], comprising 16·8% of global deaths). The most prevalent neurological disorders were tension-type headache (1505·9 [UI 1337·3 to 1681·6 million cases]), migraine (958·8 [872·1 to 1055·6] million), medication overuse headache (58·5 [50·8 to 67·4 million]), and Alzheimer's disease and other dementias (46·0 [40·2 to 52·7 million]). Between 1990 and 2015, the number of deaths from neurological disorders increased by 36·7%, and the number of DALYs by 7·4%. These increases occurred despite decreases in age-standardised rates of death and DALYs of 26·1% and 29·7%, respectively; stroke and communicable neurological disorders were responsible for most of these decreases. Communicable neurological disorders were the largest cause of DALYs in countries with low SDI. Stroke rates were highest at middle levels of SDI and lowest at the highest SDI. Most of the changes in DALY rates of neurological disorders with development were driven by changes in YLLs.

    Interpretation

    Neurological disorders are an important cause of disability and death worldwide. Globally, the burden of neurological disorders has increased substantially over the past 25 years because of expanding population numbers and ageing, despite substantial decreases in mortality rates from stroke and communicable neurological disorders. The number of patients who will need care by clinicians with expertise in neurological conditions will continue to grow in coming decades. Policy makers and health-care providers should be aware of these trends to provide adequate services.

    Funding

    Bill & Melinda Gates Foundation.

  • 11. Feigin, Valery L.
    et al.
    Nichols, Emma
    Alam, Tahiya
    Bannick, Marlena S.
    Beghi, Ettore
    Blake, Natacha
    Culpepper, William J.
    Dorsey, E. Ray
    Elbaz, Alexis
    Ellenbogen, Richard G.
    Fisher, James L.
    Fitzmaurice, Christina
    Giussani, Giorgia
    Glennie, Linda
    James, Spencer L.
    Johnson, Catherine Owens
    Kassebaum, Nicholas J.
    Logroscino, Giancarlo
    Marin, Benoit
    Mountjoy-Venning, W. Cliff
    Nguyen, Minh
    Ofori-Asenso, Richard
    Patel, Anoop P.
    Piccininni, Marco
    Roth, Gregory A.
    Steiner, Timothy J.
    Stovner, Lars Jacob
    Szoeke, Cassandra E. I.
    Theadom, Alice
    Vollset, Stein Emil
    Wallin, Mitchell Taylor
    Wright, Claire
    Zunt, Joseph Raymond
    Abbasi, Nooshin
    Abd-Allah, Foad
    Abdelalim, Ahmed
    Abdollahpour, Ibrahim
    Aboyans, Victor
    Abraha, Haftom Niguse
    Acharya, Dilaram
    Adamu, Abdu A.
    Adebayo, Oladimeji M.
    Adeoye, Abiodun Moshood
    Adsuar, Jose C.
    Afarideh, Mohsen
    Agrawal, Sutapa
    Ahmadi, Alireza
    Ahmed, Muktar Beshir
    Aichour, Amani Nidhal
    Aichour, Ibtihel
    Aichour, Miloud Taki Eddine
    Akinyemi, Rufus Olusola
    Akseer, Nadia
    Al-Eyadhy, Ayman
    Salman, Rustam Al-Shahi
    Alahdab, Fares
    Alene, Kefyalew Addis
    Aljunid, Syed Mohamed
    Altirkawi, Khalid
    Alvis-Guzman, Nelson
    Anber, Nahla Hamed
    Antonio, Carl Abelardo T.
    Arabloo, Jalal
    Aremu, Olatunde
    Arnlov, Johan
    Asayesh, Hamid
    Asghar, Rana Jawad
    Atalay, Hagos Tasew
    Awasthi, Ashish
    Ayala Quintanilla, Beatriz Paulina
    Ayuk, Tambe B.
    Badawi, Alaa
    Banach, Maciej
    Banoub, Joseph Adel Mattar
    Barboza, Miguel A.
    Barker-Collo, Suzanne Lyn
    Barnighausen, Till Winfried
    Baune, Bernhard T.
    Bedi, Neeraj
    Behzadifar, Masoud
    Behzadifar, Meysam
    Bejot, Yannick
    Bekele, Bayu Begashaw
    Belachew, Abate Bekele
    Bennett, Derrick A.
    Bensenor, Isabela M.
    Berhane, Adugnaw
    Beuran, Mircea
    Bhattacharyya, Krittika
    Bhutta, Zulfiqar A.
    Biadgo, Belete
    Bijani, Ali
    Bililign, Nigus
    Bin Sayeed, Muhammad Shahdaat
    Blazes, Christopher Kynrint
    Brayne, Carol
    Butt, Zahid A.
    Campos-Nonato, Ismael R.
    Cantu-Brito, Carlos
    Car, Mate
    Cardenas, Rosario
    Carrero, Juan J.
    Carvalho, Felix
    Castaneda-Orjuela, Carlos A.
    Castro, Franz
    Catala-Lopez, Ferran
    Cerin, Ester
    Chaiah, Yazan
    Chang, Jung-Chen
    Chatziralli, Irini
    Chiang, Peggy Pei-Chia
    Christensen, Hanne
    Christopher, Devasahayam J.
    Cooper, Cyrus
    Cortesi, Paolo Angelo
    Costa, Vera M.
    Criqui, Michael H.
    Crowe, Christopher Stephen
    Damasceno, Albertino Antonio Moura
    Daryani, Ahmad
    De la Cruz-Gongora, Vanessa
    Pio De la Hoz, Fernando
    De Leo, Diego
    Degefa, Meaza Girma
    Demoz, Gebre Teklemariam
    Deribe, Kebede
    Dharmaratne, Samath Dhamminda
    Diaz, Daniel
    Dinberu, Mesfin Tadese
    Djalalinia, Shirin
    Doku, David Teye
    Dubey, Manisha
    Dubljanin, Eleonora
    Duken, Eyasu Ejeta
    Edvardsson, David
    Umeå University, Faculty of Medicine, Department of Nursing.
    El-Khatib, Ziad
    Endres, Matthias
    Endries, Aman Yesuf
    Eskandarieh, Sharareh
    Esteghamati, Alireza
    Esteghamati, Sadaf
    Farhadi, Farzaneh
    Faro, Andre
    Farzadfar, Farshad
    Farzaei, Mohammad Hosein
    Fatima, Batool
    Fereshtehnejad, Seyed-Mohammad
    Fernandes, Eduarda
    Feyissa, Garumma Tolu
    Filip, Irina
    Fischer, Florian
    Fukumoto, Takeshi
    Ganji, Morsaleh
    Gankpe, Fortune Gbetoho
    Garcia-Gordillo, Miguel A.
    Gebre, Abadi Kahsu
    Gebremichael, Teklu Gebrehiwo
    Gelaw, Belayneh K.
    Geleijnse, Johanna M.
    Geremew, Demeke
    Gezae, Kebede Embaye
    Ghasemi-Kasman, Maryam
    Gidey, Mahari Y.
    Gill, Paramjit Singh
    Gill, Tiffany K.
    Gnedovskaya, Elena V.
    Goulart, Alessandra C.
    Grada, Ayman
    Grosso, Giuseppe
    Guo, Yuming
    Gupta, Rahul
    Gupta, Rajeev
    Haagsma, Juanita A.
    Hagos, Tekleberhan B.
    Haj-Mirzaian, Arvin
    Haj-Mirzaian, Arya
    Hamadeh, Randah R.
    Hamidi, Samer
    Hankey, Graeme J.
    Hao, Yuantao
    Haro, Josep Maria
    Hassankhani, Hadi
    Hassen, Hamid Yimam
    Havmoeller, Rasmus
    Hay, Simon I.
    Hegazy, Mohamed I.
    Heidari, Behnam
    Henok, Andualem
    Heydarpour, Fatemeh
    Hoang, Chi Linh
    Hole, Michael K.
    Rad, Enayatollah Homaie
    Hosseini, Seyed Mostafa
    Hu, Guoqing
    Igumbor, Ehimario U.
    Ilesanmi, Olayinka Stephen
    Irvani, Seyed Sina Naghibi
    Islam, Sheikh Mohammed Shariful
    Jakovljevic, Mihajlo
    Javanbakht, Mehdi
    Jha, Ravi Prakash
    Jobanputra, Yash B.
    Jonas, Jost B.
    Jozwiak, Jacek Jerzy
    Jurisson, Mikk
    Kahsay, Amaha
    Kalani, Rizwan
    Kalkonde, Yogeshwar
    Kamil, Teshome Abegaz
    Kanchan, Tanuj
    Karami, Manoochehr
    Karch, Andre
    Karimi, Narges
    Kasaeian, Amir
    Kassa, Tesfaye Dessale
    Kassa, Zemenu Yohannes
    Kaul, Anil
    Kefale, Adane Teshome
    Keiyoro, Peter Njenga
    Khader, Yousef Saleh
    Khafaie, Morteza Abdullatif
    Khalil, Ibrahim A.
    Khan, Ejaz Ahmad
    Khang, Young-Ho
    Khazaie, Habibolah
    Kiadaliri, Aliasghar A.
    Kiirithio, Daniel N.
    Kim, Anthony S.
    Kim, Daniel
    Kim, Young-Eun
    Kim, Yun Jin
    Kisa, Adnan
    Kokubo, Yoshihiro
    Koyanagi, Ai
    Krishnamurthi, Rita V.
    Defo, Barthelemy Kuate
    Bicer, Burcu Kucuk
    Kumar, Manasi
    Lacey, Ben
    Lafranconi, Alessandra
    Lansingh, Van C.
    Latifi, Arman
    Leshargie, Cheru Tesema
    Li, Shanshan
    Liao, Yu
    Linn, Shai
    Lo, Warren David
    Lopez, Jaifred Christian F.
    Lorkowski, Stefan
    Lotufo, Paulo A.
    Lucas, Robyn M.
    Lunevicius, Raimundas
    Mackay, Mark T.
    Mahotra, Narayan Bahadur
    Majdan, Marek
    Majdzadeh, Reza
    Majeed, Azeem
    Malekzadeh, Reza
    Malta, Deborah Carvalho
    Manafi, Navid
    Mansournia, Mohammad Ali
    Mantovani, Lorenzo Giovanni
    Marz, Winfried
    Mashamba-Thompson, Tivani Phosa
    Massenburg, Benjamin Ballard
    Mate, Kedar K. V.
    McAlinden, Colm
    McGrath, John J.
    Mehta, Varshil
    Meier, Toni
    Meles, Hagazi Gebre
    Melese, Addisu
    Memiah, Peter T. N.
    Memish, Ziad A.
    Mendoza, Walter
    Mengistu, Desalegn Tadese
    Mengistu, Getnet
    Meretoja, Atte
    Meretoja, Tuomo J.
    Mestrovic, Tomislav
    Miazgowski, Bartosz
    Miazgowski, Tomasz
    Miller, Ted R.
    Mini, G. K.
    Mirrakhimov, Erkin M.
    Moazen, Babak
    Mohajer, Bahram
    Mezerji, Naser Mohammad Gholi
    Mohammadi, Moslem
    Mohammadi-Khanaposhtani, Maryam
    Mohammadibakhsh, Roghayeh
    Mohammadnia-Afrouzi, Mousa
    Mohammed, Shafiu
    Mohebi, Farnam
    Mokdad, Ali H.
    Monasta, Lorenzo
    Mondello, Stefania
    Moodley, Yoshan
    Moosazadeh, Mahmood
    Moradi, Ghobad
    Moradi-Lakeh, Maziar
    Moradinazar, Mehdi
    Moraga, Paula
    Velasquez, Ilais Moreno
    Morrison, Shane Douglas
    Mousavi, Seyyed Meysam
    Muhammed, Oumer Sada
    Muruet, Walter
    Musa, Kamarul Imran
    Mustafa, Ghulam
    Naderi, Mehdi
    Nagel, Gabriele
    Naheed, Aliya
    Naik, Gurudatta
    Najafi, Farid
    Nangia, Vinay
    Negoi, Ionut
    Negoi, Ruxandra Irina
    Newton, Charles Richard James
    Ngunjiri, Josephine W.
    Nguyen, Cuong Tat
    Nguyen, Long Hoang
    Ningrum, Dina Nur Anggraini
    Nirayo, Yirga Legesse
    Nixon, Molly R.
    Norrving, Bo
    Noubiap, Jean Jacques
    Shiadeh, Malihe Nourollahpour
    Nyasulu, Peter S.
    Ogbo, Felix Akpojene
    Oh, In-Hwan
    Olagunju, Andrew T.
    Olagunju, Tinuke O.
    Olivares, Pedro R.
    Onwujekwe, Obinna E.
    Oren, Eyal
    Owolabi, Mayowa Ojo
    Mahesh, P. A.
    Pakpour, Amir H.
    Pan, Wen-Harn
    Panda-Jonas, Songhomitra
    Pandian, Jeyaraj Durai
    Patel, Sangram Kishor
    Pereira, David M.
    Petzold, Max
    Pillay, Julian David
    Piradov, Michael A.
    Polanczyk, Guilherme V.
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    Postma, Maarten J.
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    Radfar, Amir
    Rafay, Anwar
    Rafiei, Alireza
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    Rahman, Mahfuzar
    Rahman, Mohammad Hifz Ur
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    Sharif, Mehdi
    Sharif-Alhoseini, Mahdi
    She, Jun
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    Shiri, Rahman
    Shirkoohi, Reza
    Shiue, Ivy
    Siabani, Soraya
    Siddiqi, Tariq J.
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    Sigurvinsdottir, Rannveig
    Silberberg, Donald H.
    Silva, Joao Pedro
    Silveira, Dayane Gabriele Alves
    Singh, Jasvinder A.
    Sinha, Dhirendra Narain
    Skiadaresi, Eirini
    Smith, Mari
    Sobaih, Badr Hasan
    Sobhani, Soheila
    Soofi, Moslem
    Soyiri, Ireneous N.
    Sposato, Luciano A.
    Stein, Dan J.
    Stein, Murray B.
    Stokes, Mark A.
    Sufiyan, Mu'awiyyah Babale
    Sykes, Bryan L.
    Sylaja, Pn
    Tabares-Seisdedos, Rafael
    Ao, Braden James Te
    Tehrani-Banihashemi, Arash
    Temsah, Mohamad-Hani
    Temsah, Omar
    Thakur, Jarnail Singh
    Thrift, Amanda G.
    Topor-Madry, Roman
    Tortajada-Girbes, Miguel
    Tovani-Palone, Marcos Roberto
    Tran, Bach Xuan
    Tran, Khanh Bao
    Truelsen, Thomas Clement
    Tsadik, Afewerki Gebremeskel
    Car, Lorainne Tudor
    Ukwaja, Kingsley Nnanna
    Ullah, Irfan
    Usman, Muhammad Shariq
    Uthman, Olalekan A.
    Valdez, Pascual R.
    Vasankari, Tommi Juhani
    Vasanthan, Rajagopalan
    Veisani, Yousef
    Venketasubramanian, Narayanaswamy
    Violante, Francesco S.
    Vlassov, Vasily
    Vosoughi, Kia
    Vu, Giang Thu
    Vujcic, Isidora S.
    Wagnew, Fasil Shiferaw
    Waheed, Yasir
    Wang, Yuan-Pang
    Weiderpass, Elisabete
    Weiss, Jordan
    Whiteford, Harvey A.
    Wijeratne, Tissa
    Winkler, Andrea Sylvia
    Wiysonge, Charles Shey
    Wolfe, Charles D. A.
    Xu, Gelin
    Yadollahpour, Ali
    Yamada, Tomohide
    Yano, Yuichiro
    Yaseri, Mehdi
    Yatsuya, Hiroshi
    Yimer, Ebrahim M.
    Yip, Paul
    Yisma, Engida
    Yonemoto, Naohiro
    Yousefifard, Mahmoud
    Yu, Chuanhua
    Zaidi, Zoubida
    Bin Zaman, Sojib
    Zamani, Mohammad
    Zandian, Hamed
    Zare, Zohreh
    Zhang, Yunquan
    Zodpey, Sanjay
    Naghavi, Mohsen
    Murray, Christopher J. L.
    Vos, Theo
    Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 20162019In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 18, no 5, p. 459-480Article in journal (Refereed)
    Abstract [en]

    Background: Neurological disorders are increasingly recognised as major causes of death and disability worldwide. The aim of this analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 is to provide the most comprehensive and up-to-date estimates of the global, regional, and national burden from neurological disorders.

    Methods: We estimated prevalence, incidence, deaths, and disability-adjusted life-years (DALYs; the sum of years of life lost [YLLs] and years lived with disability [YLDs]) by age and sex for 15 neurological disorder categories (tetanus, meningitis, encephalitis, stroke, brain and other CNS cancers, traumatic brain injury, spinal cord injury, Alzheimer's disease and other dementias, Parkinson's disease, multiple sclerosis, motor neuron diseases, idiopathic epilepsy, migraine, tension-type headache, and a residual category for other less common neurological disorders) in 195 countries from 1990 to 2016. DisMod-MR 2.1, a Bayesian meta-regression tool, was the main method of estimation of prevalence and incidence, and the Cause of Death Ensemble model (CODEm) was used for mortality estimation. We quantified the contribution of 84 risks and combinations of risk to the disease estimates for the 15 neurological disorder categories using the GBD comparative risk assessment approach.

    Findings: Globally, in 2016, neurological disorders were the leading cause of DALYs (276 million [95% UI 247–308]) and second leading cause of deaths (9·0 million [8·8–9·4]). The absolute number of deaths and DALYs from all neurological disorders combined increased (deaths by 39% [34–44] and DALYs by 15% [9–21]) whereas their age-standardised rates decreased (deaths by 28% [26–30] and DALYs by 27% [24–31]) between 1990 and 2016. The only neurological disorders that had a decrease in rates and absolute numbers of deaths and DALYs were tetanus, meningitis, and encephalitis. The four largest contributors of neurological DALYs were stroke (42·2% [38·6–46·1]), migraine (16·3% [11·7–20·8]), Alzheimer's and other dementias (10·4% [9·0–12·1]), and meningitis (7·9% [6·6–10·4]). For the combined neurological disorders, age-standardised DALY rates were significantly higher in males than in females (male-to-female ratio 1·12 [1·05–1·20]), but migraine, multiple sclerosis, and tension-type headache were more common and caused more burden in females, with male-to-female ratios of less than 0·7. The 84 risks quantified in GBD explain less than 10% of neurological disorder DALY burdens, except stroke, for which 88·8% (86·5–90·9) of DALYs are attributable to risk factors, and to a lesser extent Alzheimer's disease and other dementias (22·3% [11·8–35·1] of DALYs are risk attributable) and idiopathic epilepsy (14·1% [10·8–17·5] of DALYs are risk attributable).

    Interpretation: Globally, the burden of neurological disorders, as measured by the absolute number of DALYs, continues to increase. As populations are growing and ageing, and the prevalence of major disabling neurological disorders steeply increases with age, governments will face increasing demand for treatment, rehabilitation, and support services for neurological disorders. The scarcity of established modifiable risks for most of the neurological burden demonstrates that new knowledge is required to develop effective prevention and treatment strategies.

    Funding: Bill & Melinda Gates Foundation.

  • 12. Feigin, VL
    et al.
    Abate, KH
    Abd-Allah, F
    Abdulle, AM
    Abera, SF
    Abyu, GY
    Ahmed, MB
    Aichour, AN
    Aichour, I
    Aichour, MTE
    Akinyemi, RO
    Alabed, S
    Al-Raddadi, R
    Alvis-Guzman, N
    Amare, AT
    Ärnlöv, Johan
    Karolinska institute; Dalarna university.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Yimam, HH, ,
    Yonemoto, N,
    Yu, C,
    Zaidi, Z
    El Sayed Zaki, M
    Zunt, JR
    Murray, CJL
    Vos, T
    Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.2017In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 16, no 11, p. 877-897Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Comparable data on the global and country-specific burden of neurological disorders and their trends are crucial for health-care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions. In this systematic analysis, we quantified the global disease burden due to neurological disorders in 2015 and its relationship with country development level.

    METHODS: We estimated global and country-specific prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) for various neurological disorders that in the GBD classification have been previously spread across multiple disease groupings. The more inclusive grouping of neurological disorders included stroke, meningitis, encephalitis, tetanus, Alzheimer's disease and other dementias, Parkinson's disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, medication overuse headache, brain and nervous system cancers, and a residual category of other neurological disorders. We also analysed results based on the Socio-demographic Index (SDI), a compound measure of income per capita, education, and fertility, to identify patterns associated with development and how countries fare against expected outcomes relative to their level of development.

    FINDINGS: Neurological disorders ranked as the leading cause group of DALYs in 2015 (250·7 [95% uncertainty interval (UI) 229·1 to 274·7] million, comprising 10·2% of global DALYs) and the second-leading cause group of deaths (9·4 [9·1 to 9·7] million], comprising 16·8% of global deaths). The most prevalent neurological disorders were tension-type headache (1505·9 [UI 1337·3 to 1681·6 million cases]), migraine (958·8 [872·1 to 1055·6] million), medication overuse headache (58·5 [50·8 to 67·4 million]), and Alzheimer's disease and other dementias (46·0 [40·2 to 52·7 million]). Between 1990 and 2015, the number of deaths from neurological disorders increased by 36·7%, and the number of DALYs by 7·4%. These increases occurred despite decreases in age-standardised rates of death and DALYs of 26·1% and 29·7%, respectively; stroke and communicable neurological disorders were responsible for most of these decreases. Communicable neurological disorders were the largest cause of DALYs in countries with low SDI. Stroke rates were highest at middle levels of SDI and lowest at the highest SDI. Most of the changes in DALY rates of neurological disorders with development were driven by changes in YLLs.

    INTERPRETATION: Neurological disorders are an important cause of disability and death worldwide. Globally, the burden of neurological disorders has increased substantially over the past 25 years because of expanding population numbers and ageing, despite substantial decreases in mortality rates from stroke and communicable neurological disorders. The number of patients who will need care by clinicians with expertise in neurological conditions will continue to grow in coming decades. Policy makers and health-care providers should be aware of these trends to provide adequate services.

    FUNDING: Bill & Melinda Gates Foundation.

  • 13. Feigin, VL
    et al.
    Nichols, E
    Alam, T
    Bannick, MS
    Beghi, E
    Blake, N
    Culpepper, WJ
    Dorsey, ER
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Karolinska institutet.
    Vos, T
    Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 20162019In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 18, no 5, p. 459-480Article in journal (Refereed)
  • 14.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Estimations of the prevalence of epilepsy in sub-Saharan Africa.2008In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 7, no 1, p. 21-2Article in journal (Refereed)
  • 15.
    Fratiglioni, L
    et al.
    The Aging Research Center, Division of Geriatric Epidemiology and Medicine, Neurotec Department, Karolinska Institute and Stockholm Gerontology Research Center, Stockholm.
    Paillard-Borg, Stéphanie
    The Aging Research Center, Division of Geriatric Epidemiology and Medicine, Neurotec Department, Karolinska Institute and Stockholm Gerontology Research Center, Stockholm.
    Winblad, B
    The Aging Research Center, Division of Geriatric Epidemiology and Medicine, Neurotec Department, Karolinska Institute and Stockholm Gerontology Research Center, Stockholm.
    An active and socially integrated lifestyle in late life might protect against dementia2004In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, ISSN 1474-4422, Vol. 3, no 6, p. 343-353Article, review/survey (Refereed)
    Abstract [en]

    The recent availability of longitudinal data on the possible association of different lifestyles with dementia and Alzheimer's disease (AD) allow some preliminary conclusions on this topic. This review systematically analyses the published longitudinal studies exploring the effect of social network, physical leisure, and non-physical activity on cognition and dementia and then summarises the current evidence taking into account the limitations of the studies and the biological plausibility. For all three lifestyle components (social, mental, and physical), a beneficial effect on cognition and a protective effect against dementia are suggested. The three components seem to have common pathways, rather than specific mechanisms, which might converge within three major aetiological hypotheses for dementia and AD: the cognitive reserve hypothesis, the vascular hypothesis, and the stress hypothesis. Taking into account the accumulated evidence and the biological plausibility of these hypotheses, we conclude that an active and socially integrated lifestyle in late life protects against dementia and AD. Further research is necessary to better define the mechanisms of these associations and better delineate preventive and therapeutic strategies.

  • 16.
    Fratiglioni, Laura
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Qiu, Chengxuan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Prevention of cognitive decline in ageing: dementia as the target, delayed onset as the goal2011In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 10, no 9, p. 778-779Article in journal (Refereed)
  • 17. Giaccone, Giorgio
    et al.
    Arzberger, Thomas
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Al-Sarraj, Safa
    Budka, Herbert
    Duyckaerts, Charles
    Falkai, Peter
    Ferrer, Isidro
    Ironside, James W.
    Kovacs, Gabor G.
    Meyronet, David
    Parchi, Piero
    Patsouris, Efstratios
    Revesz, Tomas
    Riederer, Peter
    Rozemuller, Annemieke
    Schmitt, Andrea
    Winblad, Bengt
    Kretzschmar, Hans
    New lexicon and criteria for the diagnosis of Alzheimer's disease2011In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 10, no 4, p. 298-299Article in journal (Refereed)
  • 18. Gonzalez, Henrik
    et al.
    Olsson, Tomas
    Borg, Kristian
    Management of postpolio syndrome2010In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 9, no 6, p. 634-642Article in journal (Refereed)
    Abstract [en]

    Postpolio syndrome is characterised by the exacerbation of existing or new health problems, most often muscle weakness and fatigability, general fatigue, and pain, after a period of stability subsequent to acute polio infection. Diagnosis is based on the presence of a lower motor neuron disorder that is supported by neurophysiological findings, with exclusion of other disorders as causes of the new symptoms. The muscle-related effects of postpolio syndrome are possibly associated with an ongoing process of denervation and reinnervation, reaching a point at which denervation is no longer compensated for by reinnervation. The cause of this denervation is unknown, but an inflammatory process is possible. Rehabilitation in patients with postpolio syndrome should take a multiprofessional and multidisciplinary approach, with an emphasis on physiotherapy, including enhanced or individually modified physical activity, and muscle training. Patients with postpolio syndrome should be advised to avoid both inactivity and overuse of weak muscles. Evaluation of the need for orthoses and assistive devices is often required.

  • 19.
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Unit of Functional Neurosurgery, UCL Institute of Neurology, London, UK.
    Early surgery for Parkinson's disease?: Maybe, but not just yet2013In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 12, no 10, p. 938-939Article in journal (Other academic)
  • 20. Johnson, CO
    et al.
    Nguyen, M
    Roth, GA
    Nichols, E
    Alam, T
    Abate, D
    Abd-Allah, F
    Abdelalim, A
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Karolinska institutet.
    Murray, CJL
    Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 20162019In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 18, no 5, p. 439-458Article in journal (Refereed)
  • 21.
    Lannfelt, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Blennow, Kaj
    Zetterberg, Henrik
    Batsman, Stellan
    Ames, David
    Hrrison, John
    Masters, Colin L.
    Targum, Steve
    Bush, Ashley I.
    Murdoch, Ross
    Wilson, Janet
    Ritchie, Craig W.
    Safety, efficacy, and biomarker findings of PBT2 in targeting A beta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial2008In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 7, no 9, p. 779-786Article in journal (Refereed)
    Abstract [en]

    Background PBT2 is a metal-protein attenuating compound (MPAC) that affects the Cu2+-mediated and Zn2+-mediated toxic oligomerisation of A beta seen in Alzheimer's disease (AD). Strong preclinical efficacy data and the completion of early, clinical safety studies have preceded this phase IIa study, the aim of which was to assess the effects of PBT2 on safety, efficacy, and biomarkers of AD. Methods Between December 6, 2006, and September 21, 2007, community-dwelling patients over age 55 years were recruited to this 12-week, double-blind, randomised trial of PBT2. Patients were randomly allocated to receive 50 mg PBT2, 250 mg PBT2, or placebo. Inclusion criteria were early AD (mini-mental state examination [MMSE] score between 20 and 26 points or Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) score between 10 and 25 points), taking a stable dose of acetylcholinesterase inhibitor (donepezil, galantamine, or rivastigmine) for at least 4 months, a modified Hachinski score of 4 points or less, and CT or MRI results that were consistent with AD. The principal outcomes were safety and tolerability. Secondary outcomes were plasma and CSF biomarkers and cognition. Analysis was intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00471211. Findings 78 patients were randomly assigned (29 to placebo, 20 to PBT2 50 mg, and 29 to PBT2 250 mg) and 74 (95%) completed the study. 42 (54%) patients had at least one treatment emergent adverse event (10 [50%] on PBT2 50 mg, 18 [62%] on PBT2 250 mg, and 14 [48%] on placebo). No serious adverse events were reported by patients on PBT2. Patients treated with PBT2 250 mg had a dose-dependent (p=0.023) and significant reduction in CSF A beta(42) concentration compared with those treated with placebo (difference in least squares mean change from baseline was -56.0 pg/mL, 95% Cl -101.5 to -11.0; p=0.006). PBT2 had no effect on plasma biomarkers of AD or serum Zn2+ and Cu2+ concentrations. Cognition testing included ADAS-cog, MMSE, and a neuropsychological test battery (NTB). Of these tests, two executive function component tests of the NTB showed significant improvement over placebo in the PBT2 250 mg group: category fluency test (2.8 words, 0.1 to 5.4; p=0.041) and trail making part B (-48.0 s, -83.0 to -13.0; p=0.009). Interpretation The safety profile is favourable for the ongoing development of PBT2. The effect on putative biomarkers for AD in CSF but not in plasma is suggestive of a central effect of the drug on A beta metabolism. Cognitive efficacy was restricted to two measures of executive function. Future trials that are larger and longer will establish if the effects of PBT2 on biomarkers and cognition that are reported here translate into clinical effectiveness.

  • 22. Maas, Andrew I. R.
    et al.
    Menon, David K.
    Adelson, P. David
    Andelic, Nada
    Bell, Michael J.
    Belli, Antonio
    Bragge, Peter
    Brazinova, Alexandra
    Büki, András
    Chesnut, Randall M.
    Citerio, Giuseppe
    Coburn, Mark
    Cooper, D. Jamie
    Crowder, A. Tamara
    Czeiter, Endre
    Czosnyka, Marek
    Diaz-Arrastia, Ramon
    Dreier, Jens P.
    Duhaime, Ann-Christine
    Ercole, Ari
    van Essen, Thomas A.
    Feigin, Valery L.
    Gao, Guoyi
    Giacino, Joseph
    Gonzalez-Lara, Laura E.
    Gruen, Russell L.
    Gupta, Deepak
    Hartings, Jed A.
    Hill, Sean
    Jiang, Ji-Yao
    Ketharanathan, Naomi
    Kompanje, Erwin J. O.
    Lanyon, Linda
    Laureys, Steven
    Lecky, Fiona
    Levin, Harvey
    Lingsma, Hester F.
    Maegele, Marc
    Majdan, Marek
    Manley, Geoffrey
    Marsteller, Jill
    Mascia, Luciana
    McFadyen, Charles
    Mondello, Stefania
    Newcombe, Virginia
    Palotie, Aarno
    Parizel, Paul M.
    Peul, Wilco
    Piercy, James
    Polinder, Suzanne
    Puybasset, Louis
    Rasmussen, Todd E.
    Rossaint, Rolf
    Smielewski, Peter
    Söderberg, Jeannette
    Stanworth, Simon J.
    Stein, Murray B.
    von Steinbüchel, Nicole
    Stewart, William
    Steyerberg, Ewout W.
    Stocchetti, Nino
    Synnot, Anneliese
    Te Ao, Braden
    Tenovuo, Olli
    Theadom, Alice
    Tibboel, Dick
    Videtta, Walter
    Wang, Kevin K. W.
    Williams, W. Huw
    Wilson, Lindsay
    Yaffe, Kristine
    Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research2017In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 16, no 12, p. 987-1048Article in journal (Refereed)
  • 23.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Improving research and care for patients with idiopathic NPH2015In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 14, no 6, p. 561-563Article in journal (Other academic)
  • 24. Ngugi, Anthony K.
    et al.
    Bottomley, Christian
    Kleinschmidt, Immo
    Wagner, Ryan G.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Kakooza-Mwesige, Angelina
    Ae-Ngibise, Kenneth
    Owusu-Agyei, Seth
    Masanja, Honorati
    Kamuyu, Gathoni
    Odhiambo, Rachael
    Chengo, Eddie
    Sander, Josemir W.
    Newton, Charles R.
    Prevalence of active convulsive epilepsy in sub-Saharan Africa and associated risk factors: cross-sectional and case-control studies2013In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 12, no 3, p. 253-263Article in journal (Refereed)
    Abstract [en]

    Background The prevalence of epilepsy in sub-Saharan Africa seems to be higher than in other parts of the world, but estimates vary substantially for unknown reasons. We assessed the prevalence and risk factors of active convulsive epilepsy across five centres in this region. Methods We did large population-based cross-sectional and case-control studies in five Health and Demographic Surveillance System centres: Kilifi, Kenya (Dec 3, 2007-July 31, 2008); Agincourt, South Africa (Aug 4, 2008-Feb 27, 2009); Iganga-Mayuge, Uganda (Feb 2, 2009-Oct 30, 2009); Ifakara, Tanzania (May 4, 2009-Dec 31, 2009); and Kintampo, Ghana (Aug 2, 2010-April 29, 2011). We used a three-stage screening process to identify people with active convulsive epilepsy. Prevalence was estimated as the ratio of confirmed cases to the population screened and was adjusted for sensitivity and attrition between stages. For each case, an age-matched control individual was randomly selected from the relevant centre's census database. Fieldworkers masked to the status of the person they were interviewing administered questionnaires to individuals with active convulsive epilepsy and control individuals to assess sociodemographic variables and historical risk factors (perinatal events, head injuries, and diet). Blood samples were taken from a randomly selected subgroup of 300 participants with epilepsy and 300 control individuals from each centre and were screened for antibodies to Toxocara canis, Toxoplasma gondii, Onchocerca volvulus, Plasmodium falciparum, Taenia solium, and HIV. We estimated odds ratios (ORs) with logistic regression, adjusted for age, sex, education, employment, and marital status. Results 586 607 residents in the study areas were screened in stage one, of whom 1711 were diagnosed as having active convulsive epilepsy. Prevalence adjusted for attrition and sensitivity varied between sites: 7.8 per 1000 people (95% CI 7.5-8.2) in Kilifi, 7.0 (6.2-7.4) in Agincourt, 10.3 (9.5-11.1) in Iganga-Mayuge, 14.8 (13.8-15.4) in Ifakara, and 10.1 (9.5-10.7) in Kintampo. The 1711 individuals with the disorder and 2032 control individuals were given questionnaires. In children (aged <18 years), the greatest relative increases in prevalence were associated with difficulties feeding, crying, or breathing after birth (OR 10.23, 95% CI 5 85-1788; p<0.0001); abnormal antenatal periods (2.15, 1.53-3.02; p<0.0001); and head injury (1.97, 1.28-3.03; p=0.002). In adults (aged >= 18 years), the disorder was significantly associated with admission to hospital with malaria or fever (2.28, 1.06-4.92; p=0.036), exposure to T canis (1.74, 1.27-2.40; p=0.0006), exposure to T gondii (1.39, 1.05-1.84; p=0.021), and exposure to 0 volvulus (2.23, 1.56-3.19; p<0.0001). Hypertension (2.13, 1.08-4.20; p=0.029) and exposure to T solium (7.03, 2.06-24.00; p=0.002) were risk factors for adult-onset disease. Interpretation The prevalence of active convulsive epilepsy varies in sub-Saharan Africa and that the variation is probably a result of differences in risk factors. Programmes to control parasitic diseases and interventions to improve antenatal and perinatal care could substantially reduce the prevalence of epilepsy in this region.

  • 25. Nichols, Emma
    et al.
    Szoeke, Cassandra E. I.
    Vollset, Stein Emil
    Abbasi, Nooshin
    Abd-Allah, Foad
    Abdela, Jemal
    Aichour, Miloud Taki Eddine
    Akinyemi, Rufus O.
    Alahdab, Fares
    Asgedom, Solomon W.
    Awasthi, Ashish
    Barker-Collo, Suzanne L.
    Baune, Bernhard T.
    Bejot, Yannick
    Belachew, Abate B.
    Bennett, Derrick A.
    Bijani, Belete Biadgo Ali
    Bin Sayeed, Muhammad Shahdaat
    Brayne, Carol
    Carpenter, David O.
    Carvalho, Felix
    Catala-Lopez, Ferran
    Cerin, Ester
    Choi, Jee-Young J.
    Dang, Ahn K.
    Degefa, Meaza G.
    Djalalinia, Shirin
    Dubey, Manisha
    Duken, Eyasu Ejeta
    Edvardsson, David
    Umeå University, Faculty of Medicine, Department of Nursing. School of Nursing and Midwifery, La Trobe University, Melbourne, VIC, Australia.
    Endres, Matthias
    Eskandarieh, Sharareh
    Faro, Andre
    Farzadfar, Farshad
    Fereshtehnejad, Seyed-Mohammad
    Fernandes, Eduarda
    Filip, Irina
    Fischer, Florian
    Gebre, Abadi K.
    Geremew, Demeke
    Ghasemi-Kasman, Maryam
    Gnedovskaya, Elena V.
    Gupta, Rajeev
    Hachinski, Vladimir
    Hagos, Tekleberhan B.
    Hamidi, Samer
    Hankey, Graeme J.
    Haro, Josep M.
    Hay, Simon I.
    Irvani, Seyed Sina N.
    Jha, Ravi P.
    Jonas, Jost B.
    Kalani, Rizwan
    Karch, Andre
    Kasaeian, Amir
    Khader, Yousef Saleh
    Khalil, Ibrahim A.
    Khan, Ejaz Ahmad
    Khanna, Tripti
    Khoja, Tawfik A. M.
    Khubchandani, Jagdish
    Kisa, Adnan
    Kissimova-Skarbek, Katarzyna
    Kivimaki, Mika
    Koyanagi, Ai
    Krohn, Kristopher J.
    Logroscino, Giancarlo
    Lorkowski, Stefan
    Majdan, Marek
    Malekzadeh, Reza
    Marz, Winfried
    Massano, Joao
    Mengistu, Getnet
    Meretoja, Atte
    Mohammadi, Moslem
    Mohammadi-Khanaposhtani, Maryam
    Mokdad, Ali H.
    Mondello, Stefania
    Moradi, Ghobad
    Nagel, Gabriele
    Naghavi, Mohsen
    Naik, Gurudatta
    Nguyen, Long H.
    Nguyen, Trang H.
    Nirayo, Yirga L.
    Nixon, Molly R.
    Ofori-Asenso, Richard
    Ogbo, Felix A.
    Olagunju, Andrew T.
    Owolabi, Mayowa O.
    Panda-Jonas, Songhomitra
    Passos, Valeria M. de Azeredo
    Pereira, David M.
    Pinilla-Monsalve, Gabriel D.
    Piradov, Michael A.
    Pond, Constance D.
    Poustchi, Hossein
    Qorbani, Mostafa
    Radfar, Amir
    Reiner, Robert C.
    Robinson, Stephen R.
    Roshandel, Gholamreza
    Rostami, Ali
    Russ, Tom C.
    Sachdev, Perminder S.
    Safari, Hosein
    Safiri, Saeid
    Sahathevan, Ramesh
    Salimi, Yahya
    Satpathy, Maheswar
    Sawhney, Monika
    Saylan, Mete
    Sepanlou, Sadaf G.
    Shafieesabet, Azadeh
    Shaikh, Masood A.
    Sahraian, Mohammad A.
    Shigematsu, Mika
    Shiri, Rahman
    Shiue, Ivy
    Silva, Joao P.
    Smith, Mari
    Sobhani, Soheila
    Stein, Dan J.
    Tabares-Seisdedos, Rafael
    Tovani-Palone, Marcos R.
    Tran, Bach X.
    Tran, Tung T.
    Tsegay, Amanuel T.
    Ullah, Irfan
    Venketasubramanian, Narayanaswamy
    Vlassov, Vasily
    Wang, Yuan-Pang
    Weiss, Jordan
    Westerman, Ronny
    Wijeratne, Tissa
    Wyper, Grant M. A.
    Yano, Yuichiro
    Yimer, Ebrahim M.
    Yonemoto, Naohiro
    Yousefifard, Mahmoud
    Zaidi, Zoubida
    Zare, Zohreh
    Feigin, Valery L.
    Vos, Theo
    Murray, Christopher J. L.
    Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 20162019In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 18, no 1, p. 88-106Article in journal (Refereed)
    Abstract [en]

    Background: The number of individuals living with dementia is increasing, negatively affecting families, communities, and health-care systems around the world. A successful response to these challenges requires an accurate understanding of the dementia disease burden. We aimed to present the first detailed analysis of the global prevalence, mortality, and overall burden of dementia as captured by the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016, and highlight the most important messages for clinicians and neurologists.

    Methods: GBD 2016 obtained data on dementia from vital registration systems, published scientific literature and surveys, and data from health-service encounters on deaths, excess mortality, prevalence, and incidence from 195 countries and territories from 1990 to 2016, through systematic review and additional data-seeking efforts. To correct for differences in cause of death coding across time and locations, we modelled mortality due to dementia using prevalence data and estimates of excess mortality derived from countries that were most likely to code deaths to dementia relative to prevalence. Data were analysed by standardised methods to estimate deaths, prevalence, years of life lost (YLLs), years of life lived with disability (YLDs), and disability-adjusted life-years (DALYs; computed as the sum of YLLs and YLDs), and the fractions of these metrics that were attributable to four risk factors that met GBD criteria for assessment (high body-mass index [BMI], high fasting plasma glucose, smoking, and a diet high in sugarsweetened beverages).

    Findings: In 2016, the global number of individuals who lived with dementia was 43.8 million (95% uncertainty interval [UI] 3 7. 8-51.0), increased from 20.2 million (17. 4-23 5) in 1990. This increase of 117% (95% UI 114-121) contrasted with a minor increase in age-standardised prevalence of 1.7% (1.0-2.4), from 701 cases (95% UI 602-815) per 100 000 population in 1990 to 712 cases (614-828) per 100 000 population in 2016. More women than men had dementia in 2016 (27.0 million, 95% UI 23 .3-31. 4, vs 16.8 million, 14.4-19.6), and dementia was the fifth leading cause of death globally, accounting for 2.4 million (95% UI 2.1-2.8) deaths. Overall, 28.8 million (95% UI 24. 5-34. 0) DALYs were attributed to dementia; 6.4 million (95% UI 3 .4-10. 5) of these could be attributed to the modifiable GBD risk factors of high BMI, high fasting plasma glucose, smoking, and a high intake of sugar-sweetened beverages.

    Interpretation: The global number of people living with dementia more than doubled from 1990 to 2016, mainly due to increases in population ageing and growth. Although differences in coding for causes of death and the heterogeneity in case-ascertainment methods constitute major challenges to the estimation of the burden of dementia, future analyses should improve on the methods for the correction of these biases. Until breakthroughs are made in prevention or curative treatment, dementia will constitute an increasing challenge to health-care systems worldwide.

  • 26. Pressler, Ronit M.
    et al.
    Boylan, Geraldine B.
    Marlow, Neil
    Blennow, Mats
    Chiron, Catherine
    Cross, J. Helen
    de Vries, Linda S.
    Hallberg, Boubou
    Hellström-Westas, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Jullien, Vincent
    Livingstone, Vicki
    Mangum, Barry
    Murphy, Brendan
    Murray, Deirdre
    Pons, Gerard
    Rennie, Janet
    Swarte, Renate
    Toet, Mona C.
    Vanhatalo, Sampsa
    Zohar, Sarah
    Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial2015In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 14, no 5, p. 469-477Article in journal (Refereed)
    Abstract [en]

    Background Predinical data suggest that the loop-diuretic bumetanide might be an effective treatment for neonatal seizures. We aimed to assess dose and feasibility of intravenous bumetanide as an add-on to phenobarbital for treatment of neonatal seizures. Methods In this open-label, dose finding, and feasibility phase 1/2 trial, we recruited full-term infants younger than 48 h who had hypoxic ischaemic encephalopathy and electrographic seizures not responding to a loading-dose of phenobarbital from eight neonatal intensive care units across Europe. Newborn babies were allocated to receive an additional dose of phenobarbital and one of four bumetanide dose levels by use of a bivariate Bayesian sequential dose-escalation design to assess safety and efficacy. We assessed adverse events, pharmacokinetics, and seizure burden during 48 h continuous electroencephalogram (EEG) monitoring. The primary efficacy endpoint was a reduction in electrographic seizure burden of more than 80% without the need for rescue antiepileptic drugs in more than 50% of infants. The trial is registered with ClinicalTrials.gov, number NCT01434225. Findings Between Sept 1, 2011, and Sept 28, 2013, we screened 30 infants who had electrographic seizures due to hypoxic ischaemic encephalopathy. 14 of these infants (10 boys) were included in the study (dose allocation: 0.05 mg/kg, n=4; 0.1 mg/kg, n=3; 0. 2 mg/kg, n=6; 0.3 mg/kg, n=1). All babies received at least one dose of bumetanide with the second dose of phenobarbital; three were withdrawn for reasons unrelated to bumetanide, and one because of dehydration. All but one infant also received aminoglycosides. Five infants met EEG criteria for seizure reduction (one on 0.05 mg/kg, one on 0.1 mg/kg and three on 0.2 mg/kg), and only two did not need rescue antiepileptic drugs (ie, met rescue criteria; one on 0.05 mg/kg and one on 0.3 mg/kg). We recorded no short-term dose-limiting toxic effects, but three of 11 surviving infants had hearing impairment confirmed on auditory testing between 17 and 108 days of age. The most common non-serious adverse reactions were moderate dehydration in one, mild hypotension in seven, and mild to moderate electrolyte disturbances in 12 infants. The trial was stopped early because of serious adverse reactions and limited evidence for seizure reduction. Interpretation Our findings suggest that bumetanide as an add-on to phenobarbital does not improve seizure control in newborn infants who have hypoxic ischaemic encephalopathy and might increase the risk of hearing loss, highlighting the risks associated with the off-label use of drugs in newborn infants before safety assessment in controlled trials.

  • 27. Ryvlin, Philippe
    et al.
    Nashef, Lina
    Lhatoo, Samden D.
    Bateman, Lisa M.
    Bird, Jonathan
    Bleasel, Andrew
    Boon, Paul
    Crespel, Arielle
    Dworetzky, Barbara A.
    Hogenhaven, Hans
    Lerche, Holger
    Maillard, Louis
    Molter, Michael P.
    Marchal, Cecile
    Murthy, Jagarlapudi M. K.
    Nitsche, Michael
    Pataraia, Ekaterina
    Rabben, Tede
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Rheims, Sylvain
    Sadzot, Bernard
    Schulze-Bonhage, Andreas
    Seyal, Masud
    So, Elson L.
    Spitz, Mark
    Szucs, Anna
    Tan, Meng
    Tao, James X.
    Tomson, Torbjorn
    Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study2013In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 12, no 10, p. 966-977Article in journal (Refereed)
    Abstract [en]

    Background Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in people with chronic refractory epilepsy. Very rarely, SUDEP occurs in epilepsy monitoring units, providing highly informative data for its still elusive pathophysiology. The MORTEMUS study expanded these data through comprehensive evaluation of cardiorespiratory arrests encountered in epilepsy monitoring units worldwide. Methods Between Jan 1,2008, and Dec 29,2009, we did a systematic retrospective survey of epilepsy monitoring units located in Europe, Israel, Australia, and New Zealand, to retrieve data for all cardiorespiratory arrests recorded in these units and estimate their incidence. Epilepsy monitoring units from other regions were invited to report similar cases to further explore the mechanisms. An expert panel reviewed data, including video electroencephalogram (VEEG) and electrocardiogram material at the time of cardiorespiratory arrests whenever available. Findings 147 (92%) of 160 units responded to the survey. 29 cardiorespiratory arrests, including 16 SUDEP (14 at night), nine near SUDEP, and four deaths from other causes, were reported. Cardiorespiratory data, available for ten cases of SUDEP, showed a consistent and previously unrecognised pattern whereby rapid breathing (18-50 breaths per min) developed after secondary generalised tonic-clonic seizure, followed within 3 min by transient or terminal cardiorespiratory dysfunction. Where transient, this dysfunction later recurred with terminal apnoea occurring within 11 min of the end of the seizure, followed by cardiac arrest. SUDEP incidence in adult epilepsy monitoring units was 5.1 (95% CI 2.6-9.2) per 1000 patient-years, with a risk of 1.2 (0.6-2.1) per 10 000 VEEG monitorings, probably aggravated by suboptimum supervision and possibly by antiepileptic drug withdrawal. Interpretation SUDEP in epilepsy monitoring units primarily follows an early postictal, centrally mediated, severe alteration of respiratory and cardiac function induced by generalised tonic-clonic seizure, leading to immediate death or a short period of partly restored cardiorespiratory function followed by terminal apnoea then cardiac arrest. Improved supervision is warranted in epilepsy monitoring units, in particular during night time.

  • 28. Shatunov, Aleksey
    et al.
    Mok, Kin
    Newhouse, Stephen
    Weale, Michael E
    Smith, Bradley
    Vance, Caroline
    Johnson, Lauren
    Veldink, Jan H
    van Es, Michael A
    van den Berg, Leonard H
    Robberecht, Wim
    Van Damme, Philip
    Hardiman, Orla
    Farmer, Anne E
    Lewis, Cathryn M
    Butler, Amy W
    Abel, Olubunmi
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Fogh, Isabella
    Silani, Vincenzo
    Chiò, Adriano
    Traynor, Bryan J
    Melki, Judith
    Meininger, Vincent
    Landers, John E
    McGuffin, Peter
    Glass, Jonathan D
    Pall, Hardev
    Leigh, P Nigel
    Hardy, John
    Brown, Robert H
    Powell, John F
    Orrell, Richard W
    Morrison, Karen E
    Shaw, Pamela J
    Shaw, Christopher E
    Al-Chalabi, Ammar
    Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study2010In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 9, no 10, p. 986-994Article in journal (Refereed)
    Abstract [en]

    We have found strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent GWAS of ALS and linkage studies of ALS-frontotemporal dementia. Our findings together with these earlier findings suggest that genetic variation at this locus on chromosome 9 causes sporadic ALS and familial ALS-frontotemporal dementia. Resequencing studies and then functional analysis should be done to identify the defective gene.

  • 29. Smith, A. David
    et al.
    Mangialasche, Francesca
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Kivipelto, Miia
    Dementia research priorities-22017In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 16, no 3, p. 181-182Article in journal (Refereed)
  • 30. Sorensen, Per Soelberg
    et al.
    Mellgren, Svein Ivar
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Elovaara, Irina
    Frederiksen, Jette Lautrup
    Beiske, Antonie Giaever
    Myhr, Kjell-Morten
    Søgaard, Lise Vejby
    Olsen, Inge Christoffer
    Sandberg-Wollheim, Magnhild
    NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis (NORMIMS study): a randomised, placebo-controlled trial2009In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 8, no 6, p. 519-529Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Treatment of relapsing-remitting multiple sclerosis with interferon beta is only partly effective, and new more effective and safe strategies are needed. Our aim was to assess the efficacy of oral methylprednisolone as an add-on therapy to subcutaneous interferon beta-1a to reduce the yearly relapse rate in patients with relapsing-remitting multiple sclerosis. METHODS: NORMIMS (NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis) was a randomised, placebo-controlled trial done in 29 neurology departments in Denmark, Norway, Sweden, and Finland. We enrolled outpatients with relapsing-remitting multiple sclerosis who had had at least one relapse within the previous 12 months despite subcutaneous interferon beta-1a treatment (44 microg three times per week). We randomly allocated patients by computer to add-on therapy of either 200 mg methylprednisolone or matching placebo, both given orally on 5 consecutive days every 4 weeks for at least 96 weeks. The primary outcome measure was mean yearly relapse rate. Primary analyses were by intention to treat. This trial is registered, number ISRCTN16202527. FINDINGS: 66 patients were assigned to interferon beta and oral methylprednisolone and 64 were assigned to interferon beta and placebo. A high proportion of patients withdrew from the study before week 96 (26% [17 of 66] on methylprednisolone vs 17% [11 of 64] on placebo). The mean yearly relapse rate was 0.22 for methylprednisolone compared with 0.59 for placebo (62% reduction, 95% CI 39-77%; p<0.0001). Sleep disturbance and neurological and psychiatric symptoms were the most frequent adverse events recorded in the methylprednisolone group. Bone mineral density had not changed after 96 weeks. INTERPRETATION: Oral methylprednisolone given in pulses every 4 weeks as an add-on therapy to subcutaneous interferon beta-1a in patients with relapsing-remitting multiple sclerosis leads to a significant reduction in relapse rate. However, because of the small number of patients and the high dropout rate, these findings need to be corroborated in larger cohorts.

  • 31. Steyerberg., Ewout W
    et al.
    Wiegers, Eveline
    Sewalt, Charlie
    Buki, Andras
    Citerio, Giuseppe
    De Keyser, Véronique
    Ercole, Ari
    Kunzmann, Kevin
    Lanyon, Linda
    Lecky, Fiona
    Lingsma, Hester
    Manley, Geoffrey
    Nelson, David
    Peul, Wilco
    Stocchetti, Nino
    von Steinbüchel, Nicole
    Vande Vyvere, Thijs
    Verheyden, Jan
    Wilson, Lindsay
    Maas, Andrew I. R.
    Menon, David K.
    Case-mix, care pathways, and outcomes in patients with traumatic brain injury in CENTER-TBI: a European prospective, multicentre, longitudinal, cohort study2019In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 18, no 10, p. 923-934Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The burden of traumatic brain injury (TBI) poses a large public health and societal problem, but the characteristics of patients and their care pathways in Europe are poorly understood. We aimed to characterise patient case-mix, care pathways, and outcomes of TBI.

    METHODS: CENTER-TBI is a Europe-based, observational cohort study, consisting of a core study and a registry. Inclusion criteria for the core study were a clinical diagnosis of TBI, presentation fewer than 24 h after injury, and an indication for CT. Patients were differentiated by care pathway and assigned to the emergency room (ER) stratum (patients who were discharged from an emergency room), admission stratum (patients who were admitted to a hospital ward), or intensive care unit (ICU) stratum (patients who were admitted to the ICU). Neuroimages and biospecimens were stored in repositories and outcome was assessed at 6 months after injury. We used the IMPACT core model for estimating the expected mortality and proportion with unfavourable Glasgow Outcome Scale Extended (GOSE) outcomes in patients with moderate or severe TBI (Glasgow Coma Scale [GCS] score ≤12). The core study was registered with ClinicalTrials.gov, number NCT02210221, and with Resource Identification Portal (RRID: SCR_015582).

    FINDINGS: Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study and from 22 782 patients in the registry. In the core study, 848 (19%) patients were in the ER stratum, 1523 (34%) in the admission stratum, and 2138 (47%) in the ICU stratum. In the ICU stratum, 720 (36%) patients had mild TBI (GCS score 13-15). Compared with the core cohort, the registry had a higher proportion of patients in the ER (9839 [43%]) and admission (8571 [38%]) strata, with more than 95% of patients classified as having mild TBI. Patients in the core study were older than those in previous studies (median age 50 years [IQR 30-66], 1254 [28%] aged >65 years), 462 (11%) had serious comorbidities, 772 (18%) were taking anticoagulant or antiplatelet medication, and alcohol was contributory in 1054 (25%) TBIs. MRI and blood biomarker measurement enhanced characterisation of injury severity and type. Substantial inter-country differences existed in care pathways and practice. Incomplete recovery at 6 months (GOSE <8) was found in 207 (30%) patients in the ER stratum, 665 (53%) in the admission stratum, and 1547 (84%) in the ICU stratum. Among patients with moderate-to-severe TBI in the ICU stratum, 623 (55%) patients had unfavourable outcome at 6 months (GOSE <5), similar to the proportion predicted by the IMPACT prognostic model (observed to expected ratio 1·06 [95% CI 0·97-1·14]), but mortality was lower than expected (0·70 [0·62-0·76]).

    INTERPRETATION: Patients with TBI who presented to European centres in the core study were older than were those in previous observational studies and often had comorbidities. Overall, most patients presented with mild TBI. The incomplete recovery of many patients should motivate precision medicine research and the identification of best practices to improve these outcomes.

    FUNDING: European Union 7th Framework Programme, the Hannelore Kohl Stiftung, OneMind, and Integra LifeSciences Corporation.

  • 32.
    Steyerberg, Ewout W.
    et al.
    Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands.
    Wiegers, Eveline
    Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.
    Sewalt, Charlie
    Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.
    Buki, Andras
    Department of Neurosurgery, Medical School, University of Pécs, Pécs, Hungary; Neurotrauma Research Group, János Szentágothai Research Centre, University of Pécs, Pécs, Hungary.
    Citerio, Giuseppe
    NeuroIntensive Care, ASST di Monza, Monza, Italy; School of Medicine and Surgery, Università Milano Bicocca, Milan, Italy.
    De Keyser, Véronique
    Department of Neurosurgery, Antwerp University Hospital, Edegem, Belgium.
    Ercole, Ari
    Division of Anaesthesia, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Kunzmann, Kevin
    MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
    Lanyon, Linda
    International Neuroinformatics Coordinating Facility, Karolinska Institute, Stockholm, Sweden.
    Lecky, Fiona
    Centre for Urgent and Emergency Care Research, Health Services Research Section, School of Health and Related Research, University of Sheffield, Sheffield, UK.
    Lingsma, Hester
    Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.
    Manley, Geoffrey
    Department of Neurological Surgery, University of California, San Francisco, CA, USA.
    Nelson, David
    Department of Physiology and Pharmacology, Section of Perioperative Medicine and Intensive Care, Karolinska Institute, Stockholm, Sweden.
    Peul, Wilco
    Leiden University Medical Centre and Haaglanden Medical Centre, University Neurosurgical Centre Holland, The Hague and Leiden, Netherlands.
    Stocchetti, Nino
    Department of Pathophysiology and Transplantation, Milan University, Milan, Italy; Neuroscience Intensive Care Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
    von Steinbüchel, Nicole
    Institute of Medical Psychology and Medical Sociology, Universitätsmedizin Göttingen, Göttingen, Germany.
    Vande Vyvere, Thijs
    Department of Radiology, Antwerp University Hospital, Edegem, Belgium; Division of Psychology, University of Stirling, Stirling, UK.
    Verheyden, Jan
    Icometrix, Leuven, Belgium.
    Wilson, Lindsay
    Division of Psychology, University of Stirling, Stirling, UK.
    Maas, Andrew I. R.
    Department of Neurosurgery, Antwerp University Hospital, Edegem, Belgium; University of Antwerp, Edegem, Belgium.
    Menon, David K
    CENTER-TBI, Participants and Investigators
    Case-mix, care pathways, and outcomes in patients with traumatic brain injury in CENTER-TBI: a European prospective, multicentre, longitudinal, cohort study2019In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 18, no 10, p. 923-934Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The burden of traumatic brain injury (TBI) poses a large public health and societal problem, but the characteristics of patients and their care pathways in Europe are poorly understood. We aimed to characterise patient case-mix, care pathways, and outcomes of TBI.

    METHODS: CENTER-TBI is a Europe-based, observational cohort study, consisting of a core study and a registry. Inclusion criteria for the core study were a clinical diagnosis of TBI, presentation fewer than 24 h after injury, and an indication for CT. Patients were differentiated by care pathway and assigned to the emergency room (ER) stratum (patients who were discharged from an emergency room), admission stratum (patients who were admitted to a hospital ward), or intensive care unit (ICU) stratum (patients who were admitted to the ICU). Neuroimages and biospecimens were stored in repositories and outcome was assessed at 6 months after injury. We used the IMPACT core model for estimating the expected mortality and proportion with unfavourable Glasgow Outcome Scale Extended (GOSE) outcomes in patients with moderate or severe TBI (Glasgow Coma Scale [GCS] score ≤12). The core study was registered with ClinicalTrials.gov, number NCT02210221, and with Resource Identification Portal (RRID: SCR_015582).

    FINDINGS: Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study and from 22 782 patients in the registry. In the core study, 848 (19%) patients were in the ER stratum, 1523 (34%) in the admission stratum, and 2138 (47%) in the ICU stratum. In the ICU stratum, 720 (36%) patients had mild TBI (GCS score 13-15). Compared with the core cohort, the registry had a higher proportion of patients in the ER (9839 [43%]) and admission (8571 [38%]) strata, with more than 95% of patients classified as having mild TBI. Patients in the core study were older than those in previous studies (median age 50 years [IQR 30-66], 1254 [28%] aged >65 years), 462 (11%) had serious comorbidities, 772 (18%) were taking anticoagulant or antiplatelet medication, and alcohol was contributory in 1054 (25%) TBIs. MRI and blood biomarker measurement enhanced characterisation of injury severity and type. Substantial inter-country differences existed in care pathways and practice. Incomplete recovery at 6 months (GOSE <8) was found in 207 (30%) patients in the ER stratum, 665 (53%) in the admission stratum, and 1547 (84%) in the ICU stratum. Among patients with moderate-to-severe TBI in the ICU stratum, 623 (55%) patients had unfavourable outcome at 6 months (GOSE <5), similar to the proportion predicted by the IMPACT prognostic model (observed to expected ratio 1·06 [95% CI 0·97-1·14]), but mortality was lower than expected (0·70 [0·62-0·76]).

    INTERPRETATION: Patients with TBI who presented to European centres in the core study were older than were those in previous observational studies and often had comorbidities. Overall, most patients presented with mild TBI. The incomplete recovery of many patients should motivate precision medicine research and the identification of best practices to improve these outcomes.

    FUNDING: European Union 7th Framework Programme, the Hannelore Kohl Stiftung, OneMind, and Integra LifeSciences Corporation.

  • 33.
    Tomson, Torbjorn
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neurol, SE-17176 Stockholm, Sweden..
    Battino, Dina
    Carlo Besta Fdn, IRCCS Neurol Inst, Dept Neurophysiol & Expt Epileptol, Epilepsy Ctr, Milan, Italy..
    Bonizzoni, Erminio
    Univ Milan, Dept Clin Sci & Community, Sect Med Stat Biometry & Epidemiol, Fac Med & Surg, Milan, Italy..
    Craig, John
    Belfast Hlth & Social Care Trust, Dept Neurosci Acute & Unscheduled Care, Belfast, Antrim, North Ireland..
    Lindhout, Dick
    Univ Med Ctr Utrecht, Dept Genet, Utrecht, Netherlands.;SEIN, Heemstede, Netherlands..
    Perucca, Emilio
    Univ Pavia, Dept Internal Med & Therapeut, Pavia, Italy.;IRCCS Mondino Fdn, Clin Trial Ctr, Pavia, Italy..
    Sabers, Anne
    Univ State Hosp, Epilepsy Clin, Dept Neurol, Rigshosp Blegdamsvej, Copenhagen, Denmark..
    Thomas, Sanjeev V.
    Sree ChitraTirunal Inst Med Sci & Technol, Dept Neurol, Trivandrum, Kerala, India..
    Vajda, Frank
    Univ Melbourne, Royal Melbourne Hosp, Dept Med, Melbourne, Vic, Australia.;Univ Melbourne, Royal Melbourne Hosp, Dept Neurol, Melbourne, Vic, Australia..
    Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry2018In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 17, no 6, p. 530-538Article in journal (Refereed)
    Abstract [en]

    Background Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. Methods We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. Findings Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10.3%) of 1381 pregnancies for valproate, 19 (6.5%) of 294 for phenobarbital, eight (6.4%) of 125 for phenytoin, 107 (5 .5%) of 1957 for carbamazepine, six (3.9%) of 152 for topiramate, ten (3.0%) of 333 for oxcarbazepine, 74 (2.9%) of 2514 for lamotrigine, and 17 (2.8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0.0140), lamotrigine (p=0.0145), phenobarbital (13=0.0390), and valproate (p<0.0001). After adjustment, multivariable analysis showed that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate as well as for phenobarbital at doses of more than 80 mg/day than for lamotrigine at doses of 325 mg/day or less. Valproate at doses of 650 mg/day or less was also associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (odds ratio [OR] 2.43, 95% CI 1.30-4.55; p=0.0069). Carbamazepine at doses of more than 700 mg/day was associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (OR 2.41, 95% CI 1.33-4.38; p=0.0055) and oxcarbazepine at doses of 75-4500 mg/day (2.37, 1.17-4.80; 13=0.0169). Interpretation Different antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study. Copyright (C) 2018 Elsevier Ltd. All rights reserved.

  • 34. van Es, Michael A
    et al.
    Van Vught, Paul W
    Blauw, Hylke M
    Franke, Lude
    Saris, Christiaan G
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Van Den Bosch, Ludo
    de Jong, Sonja W
    van 't Slot, Ruben
    Birve, Anna
    Lemmens, Robin
    de Jong, Vianney
    Baas, Frank
    Schelhaas, Helenius J
    Sleegers, Kristel
    Van Broeckhoven, Christine
    Wokke, John H J
    Wijmenga, Cisca
    Robberecht, Wim
    Veldink, Jan H
    Ophoff, Roel A
    van den Berg, Leonard H
    ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study.2007In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 6, no 10, p. 869-77Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease characterised by progressive degeneration of motor neurons in the brain and spinal cord. ALS is thought to be multifactorial, with both environmental and genetic causes. Our aim was to identify genetic variants that predispose for sporadic ALS. METHODS: We did a three-stage genome-wide association study in 461 patients with ALS and 450 controls from The Netherlands, using Illumina 300K single-nucleotide polymorphism (SNP) chips. The SNPs that were most strongly associated with ALS were analysed in a further 876 patients and 906 controls in independent sample series from The Netherlands, Belgium, and Sweden. We also investigated the possible pathological functions of associated genes using expression data from whole blood of patients with sporadic ALS and of control individuals who were included in the genome-wide association study. FINDINGS: A genetic variant in the inositol 1,4,5-triphosphate receptor 2 gene (ITPR2) was associated with ALS (p=0.012 after Bonferroni correction). Combined analysis of all samples (1337 patients and 1356 controls) confirmed this association (p=3.28x10(-6), odds ratio 1.58, 95% CI 1.30-1.91). ITPR2 expression was greater in the peripheral blood of 126 ALS patients than in that of 126 healthy controls (p=0.00016). INTERPRETATION: Genetic variation in ITPR2 is a susceptibility factor for ALS. ITPR2 is a strong candidate susceptibility gene for ALS because it is involved in glutamate-mediated neurotransmission, is one of the main regulators of intracellular calcium concentrations, and has an important role in apoptosis.

  • 35.
    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 1474-4465, Vol. 18, no 11, p. 1034-1044Article 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.

  • 36. Vellas, Bruno
    et al.
    Andrieu, Sandrine
    Sampaio, Cristina
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Wilcock, Gordon
    Disease-modifying trials in Alzheimer's disease: a European task force consensus.2007In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 6, no 1, p. 56-62Article, review/survey (Refereed)
    Abstract [en]

    After symptomatic treatments, the new target for therapeutic approaches in Alzheimer's disease is the development of disease-modifying drugs. The concept of disease modification in Alzheimer's disease is controversial and the design of these trials raises many questions. Which populations should be studied? For how long? With which principal and secondary endpoints? Are surrogate markers available? Here, we present a European consensus on disease-modifying trials in Alzheimer's disease, agreed under the auspices of the European Alzheimer's Disease Consortium and based on the European perspective of the concept of disease modification, study designs, the role for biomarkers, risk benefit, and pharmacoeconomic issues.

  • 37. Vellas, Bruno
    et al.
    Andrieu, Sandrine
    Sampaio, Cristina
    Coley, Nicola
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Wilcock, Gordon
    Endpoints for trials in Alzheimer's disease: a European task force consensus.2008In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 7, no 5, p. 436-450Article, review/survey (Refereed)
    Abstract [en]

    Harmful consequences in health status caused by disease are referred to as outcomes, and in clinical studies the measures of these outcomes are called endpoints. A major challenge when deciding on endpoints is to represent the outcomes of interest accurately, and the accuracy of such representation is assessed through validation. Complex diseases like Alzheimer's disease have many different and interdependent outcomes. We present a consensus for endpoints to be used in clinical trials in Alzheimer's disease, agreed by a European task force under the auspices of the European Alzheimer Disease Consortium. We suggest suitable endpoints for primary and secondary prevention trials, for symptomatic and disease-modifying trials in very early, mild, and moderate Alzheimer's disease, and for trials in severe Alzheimer's disease. A clear and consensual definition of endpoints is crucial for the success of further clinical trials in the field and will allow comparison of data across studies.

  • 38.
    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.

  • 39. Winblad, Bengt
    et al.
    Amouyel, Philippe
    Andrieu, Sandrine
    Ballard, Clive
    Brayne, Carol
    Brodaty, Henry
    Cedazo-Minguez, Angel
    Dubois, Bruno
    Edvardsson, David
    Feldman, Howard
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Frisoni, Giovanni B.
    Gauthier, Serge
    Georges, Jean
    Graff, Caroline
    Iqbal, Khalid
    Jessen, Frank
    Johansson, Gunilla
    Jonsson, Linus
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Karolinska University Hospital, Sweden.
    Knapp, Martin
    Mangialasche, Francesca
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Melis, Rene
    Nordberg, Agneta
    Rikkert, Marcel Olde
    Qiu, Chengxuan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Sakmar, Thomas P.
    Scheltens, Philip
    Schneider, Lon S.
    Sperling, Reisa
    Tjernberg, Lars O.
    Waldemar, Gunhild
    Wimo, Anders
    Zetterberg, Henrik
    Defeating Alzheimer's disease and other dementias: a priority for European science and society2016In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 15, no 5, p. 455-532Article in journal (Refereed)
  • 40. Winblad, Bengt
    et al.
    Amouyel, Philippe
    Andrieu, Sandrine
    Ballard, Clive
    Brayne, Carol
    Brodaty, Henry
    Cedazo-Minguez, Angel
    Dubois, Bruno
    Edvardsson, David
    Umeå University, Faculty of Medicine, Department of Nursing. School of Nursing and Midwifery, La Trobe University, Melbourne, VIC, Australia.
    Feldman, Howard
    Fratiglioni, Laura
    Frisoni, Giovanni B.
    Gauthier, Serge
    Georges, Jean
    Graff, Caroline
    Iqbal, Khalid
    Jessen, Frank
    Johansson, Gunilla
    Jonsson, Linus
    Kivipelto, Miia
    Knapp, Martin
    Mangialasche, Francesca
    Melis, Rene
    Nordberg, Agneta
    Rikkert, Marcel Olde
    Qiu, Chengxuan
    Sakmar, Thomas P.
    Scheltens, Philip
    Schneider, Lon S.
    Sperling, Reisa
    Tjernberg, Lars O.
    Waldemar, Gunhild
    Wimo, Anders
    Zetterberg, Henrik
    Defeating Alzheimer's disease and other dementias: a priority for European science and society2016In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 15, no 5, p. 455-532Article in journal (Refereed)
  • 41. Wu, Yu-Tzu
    et al.
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Matthews, Fiona E.
    Lobo, Antonio
    Breteler, Monique M. B.
    Skoog, Ingmar
    Brayne, Carol
    Dementia in western Europe: epidemiological evidence and implications for policy making2016In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 15, no 1, p. 116-124Article in journal (Refereed)
    Abstract [en]

    Dementia is receiving increasing attention from governments and politicians. Epidemiological research based on western European populations done 20 years ago provided key initial evidence for dementia policy making, but these estimates are now out of date because of changes in life expectancy, living conditions, and health profiles. To assess whether dementia occurrence has changed during the past 20-30 years, investigators of five different studies done in western Europe (Sweden [Stockholm and Gothenburg], the Netherlands [Rotterdam], the UK [England], and Spain [Zaragoza]) have compared dementia occurrence using consistent research methods between two timepoints in well-defined geographical areas. Findings from four of the five studies showed non-significant changes in overall dementia occurrence. The only significant reduction in overall prevalence was found in the study done in the UK, powered and designed explicitly from its outset to detect change across generations (decrease in prevalence of 22%; p=0.003). Findings from the study done in Zaragoza (Spain) showed a significant reduction in dementia prevalence in men (43%; p=0.0002). The studies estimating incidence done in Stockholm and Rotterdam reported non-significant reductions. Such reductions could be the outcomes from earlier population-level investments such as improved education and living conditions, and better prevention and treatment of vascular and chronic conditions. This evidence suggests that attention to optimum health early in life might benefit cognitive health late in life. Policy planning and future research should be balanced across primary (policies reducing risk and increasing cognitive reserve), secondary (early detection and screening), and tertiary (once dementia is present) prevention. Each has their place, but upstream primary prevention has the largest effect on reduction of later dementia occurrence and disability.

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