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- Adams, David, et al.
(author)
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Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy : 12-month results of an open-label extension study
- 2021
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In: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 20:1, s. 49-59
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Journal article (peer-reviewed)abstract
- Background Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0.3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4.0, 95 % CI -7.7 to -0.3; phase 2 OLE patisiran -4.7, -11.9 to 2.4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1.4, 95% CI -6.2 to 3.5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran. Copyright (C) 2020 Elsevier Ltd. All rights reserved.
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2. |
- Akerlund, Cecilia A., I, et al.
(author)
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Clinical descriptors of disease trajectories in patients with traumatic brain injury in the intensive care unit (CENTER-TBI) : a multicentre observational cohort study
- 2024
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In: Lancet Neurology. - : Elsevier BV. - 1474-4422 .- 1474-4465. ; 23:1, s. 71-80
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Journal article (peer-reviewed)abstract
- Background Patients with traumatic brain injury are a heterogeneous population, and the most severely injured individuals are often treated in an intensive care unit (ICU). The primary injury at impact, and the harmful secondary events that can occur during the first week of the ICU stay, will affect outcome in this vulnerable group of patients. We aimed to identify clinical variables that might distinguish disease trajectories among patients with traumatic brain injury admitted to the ICU. Methods We used data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. We included patients aged 18 years or older with traumatic brain injury who were admitted to the ICU at one of the 65 CENTER-TBI participating centres, which range from large academic hospitals to small rural hospitals. For every patient, we obtained pre-injury data and injury features, clinical characteristics on admission, demographics, physiological parameters, laboratory features, brain biomarkers (ubiquitin carboxy-terminal hydrolase L1 [UCH-L1], S100 calcium-binding protein B [S100B], tau, neurofilament light [NFL], glial fibrillary acidic protein [GFAP], and neuron-specific enolase [NSE]), and information about intracranial pressure lowering treatments during the first 7 days of ICU stay. To identify clinical variables that might distinguish disease trajectories, we applied a novel clustering method to these data, which was based on a mixture of probabilistic graph models with a Markov chain extension. The relation of clusters to the extended Glasgow Outcome Scale (GOS-E) was investigated. Findings Between Dec 19, 2014, and Dec 17, 2017, 4509 patients with traumatic brain injury were recruited into the CENTER-TBI core dataset, of whom 1728 were eligible for this analysis. Glucose variation (defined as the difference between daily maximum and minimum glucose concentrations) and brain biomarkers (S100B, NSE, NFL, tau, UCH-L1, and GFAP) were consistently found to be the main clinical descriptors of disease trajectories (ie, the leading variables contributing to the distinguishing clusters) in patients with traumatic brain injury in the ICU. The disease trajectory cluster to which a patient was assigned in a model was analysed as a predictor together with variables from the IMPACT model, and prediction of both mortality and unfavourable outcome (dichotomised GOS-E <= 4) was improved. Interpretation First-day ICU admission data are not the only clinical descriptors of disease trajectories in patients with traumatic brain injury. By analysing temporal variables in our study, variation of glucose was identified as the most important clinical descriptor that might distinguish disease trajectories in the ICU, which should direct further research. Biomarkers of brain injury (S100B, NSE, NFL, tau, UCH-L1, and GFAP) were also top clinical descriptors over time, suggesting they might be important in future clinical practice.
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5. |
- Bazarian, Jeffrey J., et al.
(author)
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Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI) : a multicentre observational study
- 2018
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In: Lancet Neurology. - : Lancet Publishing Group. - 1474-4422 .- 1474-4465. ; 17:9, s. 782-789
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Journal article (peer-reviewed)abstract
- Background: More than 50 million people worldwide sustain a traumatic brain injury (TBI) annually. Detection of intracranial injuries relies on head CT, which is overused and resource intensive. Blood-based brain biomarkers hold the potential to predict absence of intracranial injury and thus reduce unnecessary head CT scanning. We sought to validate a test combining ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), at predetermined cutoff values, to predict traumatic intracranial injuries on head CT scan acutely after TBI.Methods: This prospective, multicentre observational trial included adults (≥18 years) presenting to participating emergency departments with suspected, non-penetrating TBI and a Glasgow Coma Scale score of 9-15. Patients were eligible if they had undergone head CT as part of standard emergency care and blood collection within 12 h of injury. UCH-L1 and GFAP were measured in serum and analysed using prespecified cutoff values of 327 pg/mL and 22 pg/mL, respectively. UCH-L1 and GFAP assay results were combined into a single test result that was compared with head CT results. The primary study outcomes were the sensitivity and the negative predictive value (NPV) of the test result for the detection of traumatic intracranial injury on head CT.Findings: Between Dec 6, 2012, and March 20, 2014, 1977 patients were recruited, of whom 1959 had analysable data. 125 (6%) patients had CT-detected intracranial injuries and eight (<1%) had neurosurgically manageable injuries. 1288 (66%) patients had a positive UCH-L1 and GFAP test result and 671 (34%) had a negative test result. For detection of intracranial injury, the test had a sensitivity of 0·976 (95% CI 0·931-0·995) and an NPV of 0·996 (0·987-0·999). In three (<1%) of 1959 patients, the CT scan was positive when the test was negative.Interpretation: These results show the high sensitivity and NPV of the UCH-L1 and GFAP test. This supports its potential clinical role for ruling out the need for a CT scan among patients with TBI presenting at emergency departments in whom a head CT is felt to be clinically indicated. Future studies to determine the value added by this biomarker test to head CT clinical decision rules could be warranted.Funding: Banyan Biomarkers and US Army Medical Research and Materiel Command.
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6. |
- Benatar, Michael, et al.
(author)
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Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01) : a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial
- 2024
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In: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 23:7, s. 687-699
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Journal article (peer-reviewed)abstract
- Background: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.Methods: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.Findings: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI –0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).Interpretation: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.Funding: Orphazyme.
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- Benkert, P., et al.
(author)
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Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study
- 2022
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In: The Lancet Neurology. - 1474-4422 .- 1474-4465. ; 21:3, s. 246-257
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Journal article (peer-reviewed)abstract
- Background: Serum neurofilament light chain (sNfL) is a biomarker of neuronal damage that is used not only to monitor disease activity and response to drugs and to prognosticate disease course in people with multiple sclerosis on the group level. The absence of representative reference values to correct for physiological age-dependent increases in sNfL has limited the diagnostic use of this biomarker at an individual level. We aimed to assess the applicability of sNfL for identification of people at risk for future disease activity by establishing a reference database to derive reference values corrected for age and body-mass index (BMI). Furthermore, we used the reference database to test the suitability of sNfL as an endpoint for group-level comparison of effectiveness across disease-modifying therapies. Methods: For derivation of a reference database of sNfL values, a control group was created, comprising participants with no evidence of CNS disease taking part in four cohort studies in Europe and North America. We modelled the distribution of sNfL concentrations in function of physiological age-related increase and BMI-dependent modulation, to derive percentile and Z score values from this reference database, via a generalised additive model for location, scale, and shape. We tested the reference database in participants with multiple sclerosis in the Swiss Multiple Sclerosis Cohort (SMSC). We compared the association of sNfL Z scores with clinical and MRI characteristics recorded longitudinally to ascertain their respective disease prognostic capacity. We validated these findings in an independent sample of individuals with multiple sclerosis who were followed up in the Swedish Multiple Sclerosis registry. Findings: We obtained 10 133 blood samples from 5390 people (median samples per patient 1 [IQR 1–2] in the control group). In the control group, sNfL concentrations rose exponentially with age and at a steeper increased rate after approximately 50 years of age. We obtained 7769 samples from 1313 people (median samples per person 6·0 [IQR 3·0–8·0]). In people with multiple sclerosis from the SMSC, sNfL percentiles and Z scores indicated a gradually increased risk for future acute (eg, relapse and lesion formation) and chronic (disability worsening) disease activity. A sNfL Z score above 1·5 was associated with an increased risk of future clinical or MRI disease activity in all people with multiple sclerosis (odds ratio 3·15, 95% CI 2·35–4·23; p<0·0001) and in people considered stable with no evidence of disease activity (2·66, 1·08–6·55; p=0·034). Increased Z scores outperformed absolute raw sNfL cutoff values for diagnostic accuracy. At the group level, the longitudinal course of sNfL Z score values in people with multiple sclerosis from the SMSC decreased to those seen in the control group with use of monoclonal antibodies (ie, alemtuzumab, natalizumab, ocrelizumab, and rituximab) and, to a lesser extent, oral therapies (ie, dimethyl fumarate, fingolimod, siponimod, and teriflunomide). However, longitudinal sNfL Z scores remained elevated with platform compounds (interferons and glatiramer acetate; p<0·0001 for the interaction term between treatment category and treatment duration). Results were fully supported in the validation cohort (n=4341) from the Swedish Multiple Sclerosis registry. Interpretation: The use of sNfL percentiles and Z scores allows for identification of individual people with multiple sclerosis at risk for a detrimental disease course and suboptimal therapy response beyond clinical and MRI measures, specifically in people with disease activity-free status. Additionally, sNfL might be used as an endpoint for comparing effectiveness across drug classes in pragmatic trials. Funding: Swiss National Science Foundation, Progressive Multiple Sclerosis Alliance, Biogen, Celgene, Novartis, Roche. © 2022 Elsevier Ltd
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8. |
- Berge, Eivind, et al.
(author)
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Effects of alteplase on survival after ischaemic stroke (IST-3) : 3 year follow-up of a randomised, controlled, open-label trial
- 2016
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In: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 15:10, s. 1028-34
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Journal article (peer-reviewed)abstract
- 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.
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10. |
- Chauhan, Ganesh, et al.
(author)
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Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies
- 2016
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In: The Lancet Neurology. - 1474-4465 .- 1474-4422. ; 15:7, s. 695-707
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Journal article (peer-reviewed)abstract
- Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10−6) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10−8), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05–1·12, p=1·48 × 10−8; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity—a marker of cerebral small vessel disease—in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2–32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b−/− cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. Funding NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq. © 2016 Elsevier Ltd
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11. |
- Chetelat, G., et al.
(author)
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Amyloid-PET and 18-F-FDG-PET in the diagnostic investigation of Alzheimer's disease and other dementias
- 2020
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In: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 19:11, s. 951-962
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Research review (peer-reviewed)abstract
- Various biomarkers are available to support the diagnosis of neurodegenerative diseases in clinical and research settings. Among the molecular imaging biomarkers, amyloid-PET, which assesses brain amyloid deposition, and F-18-fluorodeoxyglucose (F-18-FDG) PET, which assesses glucose metabolism, provide valuable and complementary information. However, uncertainty remains regarding the optimal timepoint, combination, and an order in which these PET biomarkers should be used in diagnostic evaluations because conclusive evidence is missing. Following an expert panel discussion, we reached an agreement on the specific use of the individual biomarkers, based on available evidence and clinical expertise. We propose a diagnostic algorithm with optimal timepoints for these PET biomarkers, also taking into account evidence from other biomarkers, for early and differential diagnosis of neurodegenerative diseases that can lead to dementia. We propose three main diagnostic pathways with distinct biomarker sequences, in which amyloid-PET and F-18-FDG-PET are placed at different positions in the order of diagnostic evaluations, depending on clinical presentation. We hope that this algorithm can support diagnostic decision making in specialist clinical settings with access to these biomarkers and might stimulate further research towards optimal diagnostic strategies.
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12. |
- Cudkowicz, Merit, et al.
(author)
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Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study) : a randomised, double-blind, placebo-controlled phase 3 trial
- 2021
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In: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 20:10, s. 821-831
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Journal article (peer-reviewed)abstract
- BACKGROUND: There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function.METHODS: The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60-90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178) has also been completed, but will be reported separately.FINDINGS: Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5-51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4-48·1) weeks. Change from baseline in supine SVC at 12 weeks was -6·73% with levosimendan and -6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI -2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI -15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis.INTERPRETATION: Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation.FUNDING: Orion Corporation.
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- Diener, Hans-Christoph, et al.
(author)
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Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack : a predefined subgroup analysis from AVERROES, a randomised trial
- 2012
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In: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 11:3, s. 225-231
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Journal article (peer-reviewed)abstract
- 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.
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14. |
- Diener, Hans Christoph, et al.
(author)
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Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke : a subgroup analysis of the RE-LY trial
- 2010
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In: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 9:12, s. 1157-1163
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Journal article (peer-reviewed)abstract
- 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.
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15. |
- Diener, Hans-Christoph, et al.
(author)
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Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial : a double-blind, active and placebo-controlled study.
- 2008
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In: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 7:10, s. 875-884
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Journal article (peer-reviewed)abstract
- BACKGROUND: The treatment of ischaemic stroke with neuroprotective drugs has been unsuccessful, and whether these compounds can be used to reduce disability after recurrent stroke is unknown. The putative neuroprotective effects of antiplatelet compounds and the angiotensin II receptor antagonist telmisartan were investigated in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial.METHODS: Patients who had had an ischaemic stroke were randomly assigned in a two by two factorial design to receive either 25 mg aspirin (ASA) and 200 mg extended-release dipyridamole (ER-DP) twice a day or 75 mg clopidogrel once a day, and either 80 mg telmisartan or placebo once per day. The predefined endpoints for this substudy were disability after a recurrent stroke, assessed with the modified Rankin scale (mRS) and Barthel index at 3 months, and cognitive function, assessed with the mini-mental state examination (MMSE) score at 4 weeks after randomisation and at the penultimate visit. Analysis was by intention to treat. The study was registered with ClinicalTrials.gov, number NCT00153062.FINDINGS: 20,332 patients (mean age 66 years) were randomised and followed-up for a median of 2.4 years. Recurrent strokes occurred in 916 (9%) patients randomly assigned to ASA with ER-DP and 898 (9%) patients randomly assigned to clopidogrel; 880 (9%) patients randomly assigned to telmisartan and 934 (9%) patients given placebo had recurrent strokes. mRS scores were not statistically different in patients with recurrent stroke who were treated with ASA and ER-DP versus clopidogrel (p=0.38), or with telmisartan versus placebo (p=0.61). There was no significant difference in the proportion of patients with recurrent stroke with a good outcome, as measured with the Barthel index, across all treatment groups. Additionally, there was no significant difference in the median MMSE scores, the percentage of patients with an MMSE score of 24 points or less, the percentage of patients with a drop in MMSE score of 3 points or more between 1 month and the penultimate visit, and the number of patients with dementia among the treatment groups. There were no significant differences in the proportion of patients with cognitive impairment or dementia among the treatment groups.INTERPRETATION: Disability due to recurrent stroke and cognitive decline in patients with ischaemic stroke were not different between the two antiplatelet regimens and were not affected by the preventive use of telmisartan.
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16. |
- Easton, J. Donald, et al.
(author)
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Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack : a subgroup analysis of the ARISTOTLE trial
- 2012
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In: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 11:6, s. 503-511
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Journal article (peer-reviewed)abstract
- BackgroundIn 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.MethodsBetween 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.FindingsOf 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.InterpretationThe 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.FundingBristol-Myers Squibb and Pfizer.
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17. |
- Edvardsson, David, et al.
(author)
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Person-centred care of people with severe Alzheimer's disease : current status and ways forward
- 2008
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In: Lancet Neurology. - New York : Elsevier. - 1474-4422 .- 1474-4465. ; 7:4, s. 362-367
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Journal article (peer-reviewed)abstract
- 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.
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18. |
- Ekman, Urban, et al.
(author)
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Functional brain activity and presynaptic dopamine uptake in patients with Parkinson's disease and mild cognitive impairment : a cross-sectional study
- 2012
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In: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 11:8, s. 679-687
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Journal article (peer-reviewed)abstract
- 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.
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19. |
- Engström, Mats, et al.
(author)
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Prednisolone and valaciclovir in Bell's palsy : a randomised, double-blind, placebo-controlled, multicentre trial
- 2008
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In: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 7:11, s. 993-1000
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Journal article (peer-reviewed)abstract
- 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.
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20. |
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21. |
- Feigin, Valery L., et al.
(author)
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Global, regional, and national burden of neurological disorders, 1990–2016 : a systematic analysis for the Global Burden of Disease Study 2016
- 2019
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In: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 18:5, s. 459-480
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Journal article (peer-reviewed)abstract
- 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.
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22. |
- Feigin, Valery L., et al.
(author)
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Global, regional, and national burden of stroke and its risk factors, 1990-2019 : a systematic analysis for the Global Burden of Disease Study 2019
- 2021
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In: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 20:10, s. 795-820
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Journal article (peer-reviewed)abstract
- Background Regularly updated data on stroke and its pathological types, including data on their incidence, prevalence, mortality, disability, risk factors, and epidemiological trends, are important for evidence-based stroke care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) aims to provide a standardised and comprehensive measurement of these metrics at global, regional, and national levels. Methods We applied GBD 2019 analytical tools to calculate stroke incidence, prevalence, mortality, disability-adjusted life-years (DALYs), and the population attributable fraction (PAF) of DALYs (with corresponding 95% uncertainty intervals [UIs]) associated with 19 risk factors, for 204 countries and territories from 1990 to 2019. These estimates were provided for ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and all strokes combined, and stratified by sex, age group, and World Bank country income level. Findings In 2019, there were 12.2 million (95% UI 11.0-13.6) incident cases of stroke, 101 million (93.2-111) prevalent cases of stroke, 143 million (133-153) DALYs due to stroke, and 6.55 million (6.00-7.02) deaths from stroke. Globally, stroke remained the second-leading cause of death (11.6% [10.8-12.2] of total deaths) and the third-leading cause of death and disability combined (5.7% [5.1-6.2] of total DALYs) in 2019. From 1990 to 2019, the absolute number of incident strokes increased by 70.0% (67.0-73.0), prevalent strokes increased by 85.0% (83.0-88.0), deaths from stroke increased by 43.0% (31.0-55.0), and DALYs due to stroke increased by 32.0% (22.0-42.0). During the same period, age-standardised rates of stroke incidence decreased by 17.0% (15.0-18.0), mortality decreased by 36.0% (31.0-42.0), prevalence decreased by 6.0% (5.0-7.0), and DALYs decreased by 36.0% (31.0-42.0). However, among people younger than 70 years, prevalence rates increased by 22.0% (21.0-24.0) and incidence rates increased by 15.0% (12.0-18.0). In 2019, the age-standardised stroke-related mortality rate was 3.6 (3.5-3.8) times higher in the World Bank low-income group than in the World Bank high-income group, and the age-standardised stroke-related DALY rate was 3.7 (3.5-3.9) times higher in the low-income group than the high-income group. Ischaemic stroke constituted 62.4% of all incident strokes in 2019 (7.63 million [6.57-8.96]), while intracerebral haemorrhage constituted 27.9% (3.41 million [2.97-3.91]) and subarachnoid haemorrhage constituted 9.7% (1.18 million [1.01-1.39]). In 2019, the five leading risk factors for stroke were high systolic blood pressure (contributing to 79.6 million [67.7-90.8] DALYs or 55.5% [48.2-62.0] of total stroke DALYs), high body-mass index (34.9 million [22.3-48.6] DALYs or 24.3% [15.7-33.2]), high fasting plasma glucose (28.9 million [19.8-41.5] DALYs or 20.2% [13.8-29.1]), ambient particulate matter pollution (28.7 million [23.4-33.4] DALYs or 20.1% [16.6-23.0]), and smoking (25.3 million [22.6-28.2] DALYs or 17.6% [16.4-19.0]). Interpretation The annual number of strokes and deaths due to stroke increased substantially from 1990 to 2019, despite substantial reductions in age-standardised rates, particularly among people older than 70 years. The highest age-standardised stroke-related mortality and DALY rates were in the World Bank low-income group. The fastest-growing risk factor for stroke between 1990 and 2019 was high body-mass index. Without urgent implementation of effective primary prevention strategies, the stroke burden will probably continue to grow across the world, particularly in low-income countries.
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23. |
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24. |
- Fratiglioni, Laura, et al.
(author)
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Ageing without dementia : can stimulating psychosocial and lifestyle experiences make a difference?
- 2020
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In: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 19:6, s. 533-543
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Research review (peer-reviewed)abstract
- In a world with an ageing population, dementia has become an urgent threat to global health and wellbeing. Psychosocial and lifestyle factors, such as higher socioeconomic positions, longer times spent in education, greater occupational complexity, reduced stress at work, and engagement in mental, physical, and social activities, have been hypothesised to supply resilience against dementia. Although questions remain surrounding the role of these factors in the development of dementia, scientific advancements have considerably expanded our understanding of modifiable psychosocial and lifestyle factors and their neuroprotective and compensatory influences over a life course. Evidence from observational studies is robust enough to suggest that stimulating psychosocial and lifestyle factors are protective against dementia. And, although the corresponding evidence from intervention studies is still scarce, public health campaigns promoting psychosocial and lifestyle factors might improve the health and wellbeing of people aged 60 years and older.
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25. |
- Fratiglioni, L, et al.
(author)
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An active and socially integrated lifestyle in late life might protect against dementia
- 2004
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In: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 3:6, s. 343-353
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Research review (peer-reviewed)abstract
- 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.
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26. |
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27. |
- Frisoni, Giovanni B., et al.
(author)
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European intersocietal recommendations for the biomarker-based diagnosis of neurocognitive disorders
- 2024
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In: The Lancet Neurology. - 1474-4422 .- 1474-4465. ; 23:3, s. 302-312
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Research review (peer-reviewed)abstract
- The recent commercialisation of the first disease-modifying drugs for Alzheimer's disease emphasises the need for consensus recommendations on the rational use of biomarkers to diagnose people with suspected neurocognitive disorders in memory clinics. Most available recommendations and guidelines are either disease-centred or biomarker-centred. A European multidisciplinary taskforce consisting of 22 experts from 11 European scientific societies set out to define the first patient-centred diagnostic workflow that aims to prioritise testing for available biomarkers in individuals attending memory clinics. After an extensive literature review, we used a Delphi consensus procedure to identify 11 clinical syndromes, based on clinical history and examination, neuropsychology, blood tests, structural imaging, and, in some cases, EEG. We recommend first-line and, if needed, second-line testing for biomarkers according to the patient's clinical profile and the results of previous biomarker findings. This diagnostic workflow will promote consistency in the diagnosis of neurocognitive disorders across European countries.
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28. |
- Frisoni, G. B., et al.
(author)
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Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers
- 2017
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In: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 16:8, s. 661-676
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Journal article (peer-reviewed)abstract
- The diagnosis of Alzheimer's disease can be improved by the use of biological measures. Biomarkers of functional impairment, neuronal loss, and protein deposition that can be assessed by neuroimaging (ie, MRI and PET) or CSF analysis are increasingly being used to diagnose Alzheimer's disease in research studies and specialist clinical settings. However, the validation of the clinical usefulness of these biomarkers is incomplete, and that is hampering reimbursement for these tests by health insurance providers, their widespread clinical implementation, and improvements in quality of health care. We have developed a strategic five-phase roadmap to foster the clinical validation of biomarkers in Alzheimer's disease, adapted from the approach for cancer biomarkers. Sufficient evidence of analytical validity (phase 1 of a structured framework adapted from oncology) is available for all biomarkers, but their clinical validity (phases 2 and 3) and clinical utility (phases 4 and 5) are incomplete. To complete these phases, research priorities include the standardisation of the readout of these assays and thresholds for normality, the evaluation of their performance in detecting early disease, the development of diagnostic algorithms comprising combinations of biomarkers, and the development of clinical guidelines for the use of biomarkers in qualified memory clinics.
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29. |
- Galimberti, Stefania, et al.
(author)
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Effect of frailty on 6-month outcome after traumatic brain injury : a multicentre cohort study with external validation
- 2022
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In: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 21:2, s. 153-162
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Journal article (peer-reviewed)abstract
- BACKGROUND: Frailty is known to be associated with poorer outcomes in individuals admitted to hospital for medical conditions requiring intensive care. However, little evidence is available for the effect of frailty on patients' outcomes after traumatic brain injury. Many frailty indices have been validated for clinical practice and show good performance to predict clinical outcomes. However, each is specific to a particular clinical context. We aimed to develop a frailty index to predict 6-month outcomes in patients after a traumatic brain injury.METHODS: A cumulative deficit approach was used to create a novel frailty index based on 30 items dealing with disease states, current medications, and laboratory values derived from data available from CENTER-TBI, a prospective, longitudinal observational study of patients with traumatic brain injury presenting within 24 h of injury and admitted to a ward or an intensive care unit at 65 centres in Europe between Dec 19, 2014, and Dec 17, 2017. From the individual cumulative CENTER-TBI frailty index (range 0-30), we obtained a standardised value (range 0-1), with high scores indicating higher levels of frailty. The effect of frailty on 6-month outcome evaluated with the extended Glasgow Outcome Scale (GOSE) was assessed through a proportional odds logistic model adjusted for known outcome predictors. An unfavourable outcome was defined as death or severe disability (GOSE score ≤4). External validation was performed on data from TRACK-TBI, a prospective observational study co-designed with CENTER-TBI, which enrolled patients with traumatic brain injury at 18 level I trauma centres in the USA from Feb 26, 2014, to July 27, 2018. CENTER-TBI is registered with ClinicalTrials.gov, NCT02210221; TRACK-TBI is registered at ClinicalTrials.gov, NCT02119182.FINDINGS: 2993 participants (median age was 51 years [IQR 30-67], 2058 [69%] were men) were included in this analysis. The overall median CENTER-TBI frailty index score was 0·07 (IQR 0·03-0·15), with a median score of 0·17 (0·08-0·27) in older adults (aged ≥65 years). The CENTER-TBI frailty index score was significantly associated with the probability of an increasingly unfavourable outcome (cumulative odds ratio [OR] 1·03, 95% CI 1·02-1·04; p<0·0001), and the association was stronger for participants admitted to hospital wards (1·04, 1·03-1·06, p<0·0001) compared with those admitted to the intensive care unit (1·02, 1·01-1·03 p<0·0001). External validation of the CENTER-TBI frailty index in data from the TRACK-TBI (n=1667) cohort supported the robustness and reliability of these findings. The overall median TRACK-TBI frailty index score was 0·03 (IQR 0-0·10), with the frailty index score significantly associated with the risk of an increasingly unfavourable outcome in patients admitted to hospital wards (cumulative OR 1·05, 95% CI 1·03-1·08; p<0·0001), but not in those admitted to the intensive care unit (1·01, 0·99-1·03; p=0·43).INTERPRETATION: We developed and externally validated a frailty index specific to traumatic brain injury. Risk of unfavourable outcome was significantly increased in participants with a higher CENTER-TBI frailty index score, regardless of age. Frailty identification could help to individualise rehabilitation approaches aimed at mitigating effects of frailty in patients with traumatic brain injury.FUNDING: European Union, Hannelore Kohl Stiftung, OneMind, Integra LifeSciences Corporation, NeuroTrauma Sciences, NIH-NINDS-TRACK-TBI, US Department of Defense.
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30. |
- GBD 2021 Nervous System Disorders Collaborators,, et al.
(author)
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Global, regional, and national burden of disorders affecting the nervous system, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021.
- 2024
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In: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 23:4, s. 344-381
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Journal article (peer-reviewed)abstract
- Disorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.We estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.Globally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378-521), affecting 3·40 billion (3·20-3·62) individuals (43·1%, 40·5-45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7-26·7) between 1990 and 2021. Age-standardised rates of deaths per 100000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6-38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5-32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7-2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.As the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed.Bill & Melinda Gates Foundation.
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- Gonzalez, Henrik, et al.
(author)
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Management of postpolio syndrome
- 2010
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In: Lancet Neurology. - : The Lancet Publishing Group. - 1474-4422 .- 1474-4465. ; 9:6, s. 634-642
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Journal article (peer-reviewed)abstract
- 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.
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33. |
- Hankey, Graeme, et al.
(author)
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Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY) : a randomised, double-blind, placebo-controlled trial.
- 2020
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In: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 19:8, s. 651-660
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Journal article (peer-reviewed)abstract
- BACKGROUND: Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population.METHODS: AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2-15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921.FINDINGS: Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76-1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months.INTERPRETATION: Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke.FUNDING: National Health and Medical Research Council of Australia.
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- Helmrich, Isabel R. A. Retel, et al.
(author)
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Incremental prognostic value of acute serum biomarkers for functional outcome after traumatic brain injury (CENTER-TBI) : an observational cohort study
- 2022
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In: Lancet Neurology. - : The Lancet Publishing Group. - 1474-4422 .- 1474-4465. ; 21:9, s. 792-802
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Journal article (peer-reviewed)abstract
- BACKGROUND: Several studies have reported an association between serum biomarker values and functional outcome following traumatic brain injury. We aimed to examine the incremental (added) prognostic value of serum biomarkers over demographic, clinical, and radiological characteristics and over established prognostic models, such as IMPACT and CRASH, for prediction of functional outcome.METHODS: We used data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core study. We included patients aged 14 years or older who had blood sampling within 24 h of injury, results from a CT scan, and outcome assessment according to the Glasgow Outcome Scale-Extended (GOSE) at 6 months. Amounts in serum of six biomarkers (S100 calcium-binding protein B, neuron-specific enolase, glial fibrillary acidic protein, ubiquitin C-terminal hydrolase L1 [UCH-L1], neurofilament protein-light, and total tau) were measured. The incremental prognostic value of these biomarkers was determined separately and in combination. The primary outcome was the GOSE 6 months after injury. Incremental prognostic value, using proportional odds and a dichotomised analysis, was assessed by delta C-statistic and delta R2 between models with and without serum biomarkers, corrected for optimism with a bootstrapping procedure.FINDINGS: Serum biomarker values and 6-month GOSE were available for 2283 of 4509 patients. Higher biomarker levels were associated with worse outcome. Adding biomarkers improved the C-statistic by 0·014 (95% CI 0·009-0·020) and R2 by 4·9% (3·6-6·5) for predicting GOSE compared with demographic, clinical, and radiological characteristics. UCH-L1 had the greatest incremental prognostic value. Adding biomarkers to established prognostic models resulted in a relative increase in R2 of 48-65% for IMPACT and 30-34% for CRASH prognostic models.INTERPRETATION: Serum biomarkers have incremental prognostic value for functional outcome after traumatic brain injury. Our findings support integration of biomarkers-particularly UCH-L1-in established prognostic models.
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- Karikari, Thomas, et al.
(author)
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Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts.
- 2020
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In: The Lancet. Neurology. - 1474-4465 .- 1474-4422. ; 19:5, s. 422-433
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Journal article (peer-reviewed)abstract
- CSF and PET biomarkers of amyloid β and tau accurately detect Alzheimer's disease pathology, but the invasiveness, high cost, and poor availability of these detection methods restrict their widespread use as clinical diagnostic tools. CSF tau phosphorylated at threonine 181 (p-tau181) is a highly specific biomarker for Alzheimer's disease pathology. We aimed to assess whether blood p-tau181 could be used as a biomarker for Alzheimer's disease and for prediction of cognitive decline and hippocampal atrophy.We developed and validated an ultrasensitive blood immunoassay for p-tau181. Assay performance was evaluated in four clinic-based prospective cohorts. The discovery cohort comprised patients with Alzheimer's disease and age-matched controls. Two validation cohorts (TRIAD and BioFINDER-2) included cognitively unimpaired older adults (mean age 63-69 years), participants with mild cognitive impairment (MCI), Alzheimer's disease, and frontotemporal dementia. In addition, TRIAD included healthy young adults (mean age 23 years) and BioFINDER-2 included patients with other neurodegenerative disorders. The primary care cohort, which recruited participants in Montreal, Canada, comprised control participants from the community without a diagnosis of a neurological condition and patients referred from primary care physicians of the Canadian National Health Service for specialist care. Concentrations of plasma p-tau181 were compared with established CSF and PET biomarkers and longitudinal measurements using Spearman correlation, area under the curve (AUC), and linear regression analyses.We studied 37 individuals in the discovery cohort, 226 in the first validation cohort (TRIAD), 763 in the second validation cohort (BioFINDER-2), and 105 in the primary care cohort (n=1131 individuals). In all cohorts, plasma p-tau181 showed gradual increases along the Alzheimer's disease continuum, from the lowest concentrations in amyloid β-negative young adults and cognitively unimpaired older adults, through higher concentrations in the amyloid β-positive cognitively unimpaired older adults and MCI groups, to the highest concentrations in the amyloid β-positive MCI and Alzheimer's disease groups (p<0·001, Alzheimer's disease vs all other groups). Plasma p-tau181 distinguished Alzheimer's disease dementia from amyloid β-negative young adults (AUC=99·40%) and cognitively unimpaired older adults (AUC=90·21-98·24% across cohorts), as well as other neurodegenerative disorders, including frontotemporal dementia (AUC=82·76-100% across cohorts), vascular dementia (AUC=92·13%), progressive supranuclear palsy or corticobasal syndrome (AUC=88·47%), and Parkinson's disease or multiple systems atrophy (AUC=81·90%). Plasma p-tau181 was associated with PET-measured cerebral tau (AUC=83·08-93·11% across cohorts) and amyloid β (AUC=76·14-88·09% across cohorts) pathologies, and 1-year cognitive decline (p=0·0015) and hippocampal atrophy (p=0·015). In the primary care cohort, plasma p-tau181 discriminated Alzheimer's disease from young adults (AUC=100%) and cognitively unimpaired older adults (AUC=84·44%), but not from MCI (AUC=55·00%).Blood p-tau181 can predict tau and amyloid β pathologies, differentiate Alzheimer's disease from other neurodegenerative disorders, and identify Alzheimer's disease across the clinical continuum. Blood p-tau181 could be used as a simple, accessible, and scalable test for screening and diagnosis of Alzheimer's disease.Alzheimer Drug Discovery Foundation, European Research Council, Swedish Research Council, Swedish Alzheimer Foundation, Swedish Dementia Foundation, Alzheimer Society Research Program.
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- Lannfelt, Lars, et al.
(author)
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Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial.
- 2008
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In: Lancet neurology. - 1474-4422 .- 1474-4465. ; 7:9, s. 779-86
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Journal article (peer-reviewed)abstract
- BACKGROUND: PBT2 is a metal-protein attenuating compound (MPAC) that affects the Cu2(+)-mediated and Zn2(+)-mediated toxic oligomerisation of Abeta 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 Abeta(42) concentration compared with those treated with placebo (difference in least squares mean change from baseline was -56.0 pg/mL, 95% CI -101.5 to -11.0; p=0.006). PBT2 had no effect on plasma biomarkers of AD or serum Zn(2+) and Cu(2+) 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 Abeta 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.
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40. |
- Lauwers, E., et al.
(author)
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Potential human transmission of amyloid beta pathology: surveillance and risks
- 2020
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In: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 19:10, s. 872-878
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Journal article (peer-reviewed)abstract
- Studies in experimental animals show transmissibility of amyloidogenic proteins associated with prion diseases, Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Although these data raise potential concerns for public health, convincing evidence for human iatrogenic transmission only exists for prions and amyloid beta after systemic injections of contaminated growth hormone extracts or dura mater grafts derived from cadavers. Even though these procedures are now obsolete, some reports raise the possibility of iatrogenic transmission of amyloid beta through putatively contaminated neurosurgical equipment. Iatrogenic transmission of amyloid beta might lead to amyloid deposition in the brain parenchyma and blood vessel walls, potentially resulting in cerebral amyloid angiopathy after several decades. Cerebral amyloid angiopathy can cause life-threatening brain haemorrhages; yet, there is no proof that the transmission of amyloid can also lead to Alzheimer's dementia. Large, long-term epidemiological studies and sensitive, cost-efficient tools to detect amyloid are needed to better understand any potential routes of amyloid beta transmission and to clarify whether other similar proteopathic seeds, such as tau or alpha-synuclein, can also be transferred iatrogenically.
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41. |
- Lundström, Erik, 1964-, et al.
(author)
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Safety and efficacy of fluoxetine on functional recovery after acute stroke (EFFECTS): a randomised, double-blind, placebo-controlled trial.
- 2020
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In: The Lancet. Neurology. - 1474-4465 .- 1474-4422. ; 19:8, s. 661-669
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Journal article (peer-reviewed)abstract
- Studies have suggested that fluoxetine could improve neurological recovery after stroke. The Efficacy oF Fluoxetine-a randomisEd Controlled Trial in Stroke (EFFECTS) trial aimed to assess whether administration of oral fluoxetine for 6 months after acute stroke improves functional outcome.EFFECTS was an investigator-led, multicentre, randomised, placebo-controlled, double-blind, parallel group trial that enrolled patients aged 18 years or older between 2 and 15 days after stroke onset in 35 stroke and rehabilitation centres in Sweden. Eligible patients had a clinical diagnosis of ischaemic or intracerebral haemorrhage, brain imaging that was consistent with intracerebral haemorrhage or ischaemic stroke, and had at least one persisting focal neurological deficit. A web-based randomisation system that incorporated a minimisation algorithm was used to randomly assign (1:1) participants to receive oral fluoxetine 20 mg once daily or matching placebo capsules for 6 months. Patients, care providers, investigators, and outcomes assessors were masked to the allocation. The primary outcome was functional status, measured with the modified Rankin Scale (mRS) at 6 months, analysed in all patients with available mRS data at the 6-month follow-up; we did an ordinal analysis adjusted for the minimisation variables used in the randomisation. This trial is registered with EudraCT, 2011-006130-16; ISRCTN, 13020412; and ClinicalTrials.gov, NCT02683213.Between Oct 20, 2014, and June 28, 2019, 1500 patients were enrolled, of whom 750 were randomly assigned to fluoxetine and 750 were randomly assigned to placebo. At 6 months, mRS data were available for 737 (98%) patients in the fluoxetine group and 742 (99%) patients in the placebo group. There was no effect of fluoxetine on the primary outcome-distribution across mRS score categories-compared with placebo (adjusted common odds ratio 0·94 [95% CI 0·78 to 1·13]; p=0·42). The proportion of patients with a new diagnosis of depression was lower with fluoxetine than with placebo (54 [7%] patients vs 81 [11%] patients; difference -3·60% [-6·49 to -0·71]; p=0·015), but fluoxetine was associated with more bone fractures (28 [4%] vs 11 [2%]; difference 2·27% [0·66 to 3·87]; p=0·0058) and hyponatraemia (11 [1%] vs one [<1%]; difference 1·33% [0·43 to 2·23]; p=0·0038) at 6 months.Functional outcome after acute stroke did not improve with oral fluoxetine 20 mg once daily for 6 months. Fluoxetine reduced the occurrence of depression but increased the risk of bone fractures and hyponatraemia. Our results do not support the use of fluoxetine after acute stroke.The Swedish Research Council, the Swedish Heart-Lung Foundation, the Swedish Brain Foundation, the Swedish Society of Medicine, King Gustav V and Queen Victoria's Foundation of Freemasons, and the Swedish Stroke Association (STROKE-Riksförbundet).
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- Maegele, Marc, et al.
(author)
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Coagulopathy and haemorrhagic progression in traumatic brain injury : advances in mechanisms, diagnosis, and management
- 2017
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In: The Lancet Neurology. - : Lancet Publishing Group. - 1474-4422 .- 1474-4465. ; 16:8, s. 630-647
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Research review (peer-reviewed)abstract
- Normal haemostasis depends on an intricate balance between mechanisms of bleeding and mechanisms of thrombosis, and this balance can be altered after traumatic brain injury (TBI). Impaired haemostasis could exacerbate the primary insult with risk of initiation or aggravation of bleeding; anticoagulant use at the time of injury can also contribute to bleeding risk after TBI. Many patients with TBI have abnormalities on conventional coagulation tests at admission to the emergency department, and the presence of coagulopathy is associated with increased morbidity and mortality. Further blood testing often reveals a range of changes affecting platelet numbers and function, procoagulant or anticoagulant factors, fibrinolysis, and interactions between the coagulation system and the vascular endothelium, brain tissue, inflammatory mechanisms, and blood flow dynamics. However, the degree to which these coagulation abnormalities affect TBI outcomes and whether they are modifiable risk factors are not known. Although the main challenge for management is to address the risk of hypocoagulopathy with prolonged bleeding and progression of haemorrhagic lesions, the risk of hypercoagulopathy with an increased prothrombotic tendency also warrants consideration.
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- Monbaliu, E., et al.
(author)
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Clinical presentation and management of dyskinetic cerebral palsy
- 2017
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In: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 16:9, s. 741-749
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Research review (peer-reviewed)abstract
- Cerebral palsy is the most frequent cause of severe physical disability in childhood. Dyskinetic cerebral palsy (DCP) is the second most common type of cerebral palsy after spastic forms. DCP is typically caused by non-progressive lesions to the basal ganglia or thalamus, or both, and is characterised by abnormal postures or movements associated with impaired tone regulation or movement coordination. In DCP, two major movement disorders, dystonia and choreoathetosis, are present together most of the time. Dystonia is often more pronounced and severe than choreoathetosis, with a major effect on daily activity, quality of life, and societal participation. The pathophysiology of both movement disorders is largely unknown. Some emerging hypotheses are an imbalance between indirect and direct basal ganglia pathways, disturbed sensory processing, and impaired plasticity in the basal ganglia. Rehabilitation strategies are typically multidisciplinary. Use of oral drugs to provide symptomatic relief of the movement disorders is limited by adverse effects and the scarcity of evidence that the drugs are effective. Neuromodulation interventions, such as intrathecal baclofen and deep brain stimulation, are promising options.
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48. |
- Ngugi, Anthony K., et al.
(author)
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Prevalence of active convulsive epilepsy in sub-Saharan Africa and associated risk factors : cross-sectional and case-control studies
- 2013
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In: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 12:3, s. 253-263
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Journal article (peer-reviewed)abstract
- 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.
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49. |
- Nichols, Emma, et al.
(author)
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Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2016 : a systematic analysis for the Global Burden of Disease Study 2016
- 2019
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In: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 18:1, s. 88-106
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Journal article (peer-reviewed)abstract
- 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.
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