- Email: [email protected]
Early CT Score to establish stroke treatment
Comment
to those in the CSF. With the aim of facilitating the uptake of Alzheimer’s disease biomarker analysis in routine clinical practice, an international task force of experts on biomarkers, representatives of scientific societies, patient advocates, and regulators has estimated the degree of validity of Alzheimer’s disease biomarkers on the basis of available evidence.9 They found that although CSF biomarkers are those with the largest amount of evidence, substantial gaps in knowledge must be filled before health-care payers worldwide will be persuaded to reimburse the cost of these analyses in full.10 For example, it is the experience of many physicians that a more accurate diagnostic work-up of neurocognitive disorders is meaningful for many patients and their relatives. Further, it is also very likely that accurate diagnosis improves treatment and care (eg, when the test has ruled out Alzheimer’s disease, an alternative and maybe curable disorder might be diagnosed). However, these benefits are yet to be firmly proven in prospective studies. A small but interesting piece of information that might allow CSF biomarkers to advance on the pathway towards large-scale fully reimbursed use comes from the recent development of an assay11 that might substantially reduce current unacceptably high inter-assay and interlaboratory variability. The argument from health-care payers makes sense, but the neurological community should never forget that our ultimate aim is to give the patient the best care possible. Patients surely want a cure, but they also rate certainty and hope as very important, especially when a cure is not available.12 Balancing budget limitations with patient wishes is certainly not an easy exercise. However, the art and science of medicine has never been easy—but this is probably part of its beauty and charm.
*Giovanni B Frisoni, Oskar Hansson University Hospitals and University of Geneva, Geneva, Switzerland (GBF); and Skåne University Hospital and Lund University, Lund, Sweden (OH) [email protected] GBF reports grants, personal fees, and non-financial support from Lilly, Piramal, and GE; personal fees from BMS, Bayer, Lundbeck, Elan, Astra Zeneca, Pfizer, Baxter, and from Taurx; grants and personal fees from Wyeth; grants from Lundbeck Italia, Roche, and Alzheimer’s Association; and grants and nonfinancial support from Avid/Lilly. OH reports consultant related activities from GE Healthcare and Hoffmann La-Roche. 1
2 3
4
5
6
7
8 9 10
11
12
Scheltens P, Blennow K, Breteler MBB, et al. Alzheimer’s Disease. Lancet Neurol 2016; published online Feb 23. http://dx.doi.org/10.1016/ S0140-6736(15)01124-1 Carrillo MC, Bain LJ, Frisoni GB, Weiner MW. Worldwide Alzheimer’s Disease Neuroimaging Initiative. Alzheimers Dement 2012; 8: 337–42. Bateman RJ, Xiong C, Benzinger TL, et al. Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 2012; 367: 795–804. Buchhave P, Minthon L, Zetterberg H, Wallin AK, Blennow K, Hansson O. Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry 2012; 69: 98–106. Olsson B, Lautner R, Andreasson U, et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol 2016; 15: 673–84. Schmand B, Eikelenboom P, van Gool WA; Alzheimer’s Disease Neuroimaging Initiative. Value of diagnostic tests to predict conversion to Alzheimer’s disease in young and old patients with amnestic mild cognitive impairment. J Alzheimers Dis 2012; 29: 641–48. Jansen WJ, Ossenkoppele R, Knol DL, et al. Prevalence of cerebral amyloid pathology in persons without dementia. A meta-analysis. JAMA 2015; 313: 1924–38. Blennow K, Mattsson N, Schöll M, Hansson O, Zetterberg H. Amyloid biomarkers in Alzheimer’s disease. Trends Pharmacol Sci 2015; 36: 297–309. Frisoni GB, Jack CR, Winblad B. Alzheimer’s disease biomarker development: a call to funding bodies. Neurobiol Aging 2016, in press. Mattson N, Lönneborg A, Boccardi M, Blennow K, Hansson O, and the Geneva Task Force for the Roadmap of Alzheimer’s Biomarkers. Clinical validity of Aβ42, tau, and phospho-tau in the cerebrospinal fluid as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework. Neurobiol Aging 2016, in press. Bittner T, Zetterberg H, Teunissen CE, et al. Technical performance of a novel, fully automated electrochemiluminescence immunoassay for the quantitation of β-amyloid (1-42) in human cerebrospinal fluid. Alzheimers Dement 2015; published online Nov 10. DOI:10.1016/j. jalz.2015.09.009. Detsky AS. What patients really want from health care. JAMA 2011; 306: 2500–01.
Early CT Score to establish stroke treatment In The Lancet Neurology, Albert Yoo and colleagues1 report their findings from a subgroup analysis of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN).2 They provide results from the first prespecified analysis of the therapeutic efficacy of early CT for patients who have had an ischaemic stroke. Yoo and colleagues categorised patients into three groups using the modified Alberta Stroke Program Early CT Score (ASPECTS): 0–4 (large www.thelancet.com/neurology Vol 15 June 2016
volumes of hypoattenuating brain tissue; n=30), 5–7 (large volumes; n=93), and 8–10 (small or no volumes; n=373). Their results suggest that use of trichotomised ASPECTS does not modify intra-arterial treatment effects, although no significant benefit was observed in the two small groups with ASPECTS of less than 8 by contrast with the group with ASPECTS of more than 7. Moreover, an association between low ASPECTS and poor clinical outcome was evident. The crucial question is do
See Articles page 685
651
Comment
these results justify intra-arterial treatment in patients with proximal middle cerebral artery occlusion and hypoattenuation of the total or subtotal middle cerebral artery territory (ASPECTS 0–4)? To answer this question, we would need to know what type of stroke pathology ASPECTS is scoring, take into account similar former studies, and assess the safety of intra-arterial treatment in patients with large or very large hypoattenuating tissue volumes. Different terms are used to refer to non-contrast CT hypoattenuation of grey matter in the brain within the first few hours of stroke onset (eg, early ischaemic changes, early infarct signs, insular ribbon sign, and obscuration of the lentiform nucleus), reflecting the uncertainty about what kind of ischaemic stroke decreases grey matter x-ray attenuation. According to histological studies, ASPECTS is unlikely to be useful for the quantification of infarctions as presumed by the MR CLEAN investigators. Within 6 h of middle cerebral artery occlusion in a rat animal model, less than 20% of neurons showed subtle changes in staining that were barely detectable with the microscope.3 X-ray attenuation decreases with increases in water content of the tissue. In severe ischaemia, tissue takes up water from capillaries with residual blood flow. This type of ischaemic oedema, known as ionic oedema,4 can be assessed with CT because x-ray attenuation is indirectly associated with tissue water content.5,6 Ionic oedema is triggered by a blood flow of less than 10 mL/100 g per min; this threshold indicates injury that is not reversible by reperfusion after at least 1 h of ischaemia.6,7 Accordingly, findings from a largescale prospective study8 lent support to hypoattenuation on early CT as being highly predictive for established infarctions in 213 (95%) of 224 patients given placebo and 220 (98%) of 225 patients given alteplase. Modified ASPECTS thus quantifies the extent of ionic oedema in brain tissue that cannot recover with reperfusion. ECASS 1–3 were the first studies9–11 in which x-ray hypoattenuation of brain tissue was regarded as an irreversible injury and patients with hypodensity on non-contrast CT exceeding a third of the middle cerebral artery territory were excluded from the target patient population. A post-hoc analysis12 of the placebo-controlled effect of intravenous alteplase on the proportion of patients without disability at 3 months (modified Rankin score of 0–2) showed a non-significant increase from 70 (41%) of 169 to 79 (47%) of 167 in patients without 652
hypoattenuation on baseline CT (p=0·278), a significant increase from 11 (10%) of 110 to 29 (28%) of 105 (p=0·0014) in patients with hypoattenuation in less than or equal to a third of the middle cerebral artery territory, and a non-significant decrease from three (14%) of 21 to two (6%) of 31 patients with extended hypodensity (p=0·383). A similar effect of early CT findings on treatment outcome was seen in the PROACT II with use of ASPECTS.13 On the basis of the uncertainty of the effect of stroke pathology and clinical experience, many investigators became reluctant to include patients with an ASPECTS of less than 8 in clinical trials. However, even in patients with low ASPECTS, tissue at risk might recover with reperfusion. A distal occlusion of the internal carotid artery might cause irreversible injury of the total middle cerebral artery territory (ASPECTS of 0) and less severe, but symptomatic, ischaemia in the territory of the anterior cerebral artery that might recover with arterial recanalisation. Conversely, an ASPECTS of 9 might indicate total and irreversible injury of a small middle cerebral artery branch’s territory. So, the arterial occlusion site should always be considered when discussing the consequences of baseline ASPECTS. As in the ECASS, the small number of patients with ASPECTS 0–4 (n=30) in MR CLEAN does not allow firm conclusions to be drawn. Based on the MR CLEAN data, intra-arterial treatment (thrombectomy combined with intravenous alteplase in most cases) might have a small benefit, no benefit, or might harm the patient. Fortunately, the MR CLEAN investigators did not find significant differences in their safety outcomes between both treatment groups for any of the ASPECTS subgroups. The risk of harming a patient with low ASPECTS seems to be low. This finding, in my view, is the best argument to not exclude patients from intra-arterial treatment on the basis of baseline ASPECTS and to prospectively study the treatment effects in patients with ASPECT 0–4 under controlled conditions. Rüdiger von Kummer Institute of Diagnostic and Interventional Neuroradiology, University Hospital Carl Gustav Carus, 01307 Dresden, Germany [email protected] I report personal fees from Lundbeck, Boehringer Ingelheim, Covidien, Brainsgate, and Penumbra outside the submitted work.
www.thelancet.com/neurology Vol 15 June 2016
Comment
1
2
3
4
5
6
Yoo AJ, Berkhemer OA, Fransen PS, et al, for the MR CLEAN Investigators. Effect of baseline Alberta Stroke Program Early CT Score on safety and efficacy of intra-arterial treatment: a subgroup analysis of a randomised phase 3 trial (MR CLEAN). Lancet Neurol 2016; 15: 685–94. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015; 372: 11–20. Garcia J, Liu KF, Ho KL. Neuronal necrosis after middle cerebral artery occlusion in Wistar rats progresses at different time intervals in the caudoputamen and the cortex. Stroke 1995; 26: 636–43. Simard J, Kent T, Chen, Tarasov K, Gerzanich V. Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol 2007; 6: 258–68. Dzialowski I, Weber J, Doerfler A, Forsting M, von Kummer R. Brain tissue water uptake after middle cerebral artery occlusion assessed with CT. J Neuroimaging 2004; 14: 42–48. Dzialowski I, Weber J, Klotz E, et al. CT monitoring of ischemic brain tissue water content during middle cerebral artery occlusion and reperfusion. Radiology 2007; 243: 720–26.
7 8
9
10
11 12 13
Heiss W, Rosner G. Fuctional recovery of cortical neurons as related to degree and duration of ischemia. Ann Neurol 1983; 14: 294–301. von Kummer R, Bourquain H, Bastianello S, et al. Early prediction of irreversible brain damage after ischemic stroke by computed tomography. Radiology 2001; 219: 95–100. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995; 274: 1017–25. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998; 352: 1245–51. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4·5 hours after acute ischemic stroke. N Engl J Med 2008; 359: 1317–29. von Kummer R, Allen K, Holle R, et al. Acute stroke: usefulness of early CT findings before thrombolytic therapy. Radiology 1997; 205: 327–33. Hill M, Rowley H, Adler F, et al. Selection of acute ischemic stroke patients for intra-arterial thrombolysis with pro-urokinase by using ASPECTS. Stroke 2003; 34: 1925–31.
A stroke of insight from genetics Risk factors for common diseases, including neurological disorders such as stroke and dementia, are multifactorial and include both genetic and environmental effects. The discovery and identification of individual genetic variants that contribute to risk might lead to a better understanding of biological mechanisms and new drug targets. However, apart from the discovery of rare, fully penetrant Mendelian mutations that cause early-onset disease, efforts to find new genetic loci have been frustratingly difficult. All of that changed when the experimental design of the genome-wide association study (GWAS) came on the scene less than 10 years ago.1 GWAS correlates the trait of interest with common DNA variation in the genome and can discover robust single nucleotide polymorphismdisease associations. GWAS has led to the discovery of tens-to-hundreds of associations for a wide range of diseases and quantitative traits.2 The effect on risk of each individual variant is typically very small (eg, odds ratio of 1·1 per allele), so large sample sizes are needed to find additional loci with sufficient statistical support. For a disorder such as schizophrenia, a sample size of about 3000 people led to the discovery of a single locus in 2009,3 but only 5 years later, a huge international collaborative effort combined data for 35 000 people and identified 108 loci.4 Therefore, in human genetics studies on complex traits, researchers aim to obtain ever growing sample sizes that allow genetic evidence to grow as well. To achieve this goal, large-scale and international collaborations are needed in which www.thelancet.com/neurology Vol 15 June 2016
preferably all data for an individual genotype level can be analysed to maximise statistical power. Stéphanie Debette and colleagues5 report on a novel risk locus for stroke and small artery disease. The strategy used by the investigators was original in the sense that the initial discovery cohort was drawn from a large prospective cohort study in which more than 4000 participants developed incident stroke. The advantage of such a design is to avoid the potential problem of frailty bias in casecontrol studies: patients with more severe disease who die before study entry (which might be related to specific genetic variants). The disadvantage is the relatively small sample size, especially within the context of complex traits and expected effect sizes of risk loci. Association results of 177 variants that met predefined statistical criteria were followed up using data from four independent, previously published cross-sectional studies on stroke in more than 19 000 cases.6,7,8,9,10 Two variants were found to be statistically replicating, one of which was in a novel locus near the FOXF2 gene. This finding brings the number of loci associated with stroke discovered by GWAS to about eight (depending on stroke subtype). Unlike many other reports of loci identified from GWAS, Debette and colleagues followed up the FOXF2 gene with a range of functional studies in mice and zebrafish and also explored the association between the gene and brain imaging in healthy human beings. Deletion of the Foxf2 gene in mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The zebrafish equivalents of FOXF2 were expressed in brain pericytes, and cerebral
Published Online April 7, 2016 http://dx.doi.org/10.1016/ S1474-4422(16)30028-X See Articles page 695
653
to those in the CSF. With the aim of facilitating the uptake of Alzheimer’s disease biomarker analysis in routine clinical practice, an international task force of experts on biomarkers, representatives of scientific societies, patient advocates, and regulators has estimated the degree of validity of Alzheimer’s disease biomarkers on the basis of available evidence.9 They found that although CSF biomarkers are those with the largest amount of evidence, substantial gaps in knowledge must be filled before health-care payers worldwide will be persuaded to reimburse the cost of these analyses in full.10 For example, it is the experience of many physicians that a more accurate diagnostic work-up of neurocognitive disorders is meaningful for many patients and their relatives. Further, it is also very likely that accurate diagnosis improves treatment and care (eg, when the test has ruled out Alzheimer’s disease, an alternative and maybe curable disorder might be diagnosed). However, these benefits are yet to be firmly proven in prospective studies. A small but interesting piece of information that might allow CSF biomarkers to advance on the pathway towards large-scale fully reimbursed use comes from the recent development of an assay11 that might substantially reduce current unacceptably high inter-assay and interlaboratory variability. The argument from health-care payers makes sense, but the neurological community should never forget that our ultimate aim is to give the patient the best care possible. Patients surely want a cure, but they also rate certainty and hope as very important, especially when a cure is not available.12 Balancing budget limitations with patient wishes is certainly not an easy exercise. However, the art and science of medicine has never been easy—but this is probably part of its beauty and charm.
*Giovanni B Frisoni, Oskar Hansson University Hospitals and University of Geneva, Geneva, Switzerland (GBF); and Skåne University Hospital and Lund University, Lund, Sweden (OH) [email protected] GBF reports grants, personal fees, and non-financial support from Lilly, Piramal, and GE; personal fees from BMS, Bayer, Lundbeck, Elan, Astra Zeneca, Pfizer, Baxter, and from Taurx; grants and personal fees from Wyeth; grants from Lundbeck Italia, Roche, and Alzheimer’s Association; and grants and nonfinancial support from Avid/Lilly. OH reports consultant related activities from GE Healthcare and Hoffmann La-Roche. 1
2 3
4
5
6
7
8 9 10
11
12
Scheltens P, Blennow K, Breteler MBB, et al. Alzheimer’s Disease. Lancet Neurol 2016; published online Feb 23. http://dx.doi.org/10.1016/ S0140-6736(15)01124-1 Carrillo MC, Bain LJ, Frisoni GB, Weiner MW. Worldwide Alzheimer’s Disease Neuroimaging Initiative. Alzheimers Dement 2012; 8: 337–42. Bateman RJ, Xiong C, Benzinger TL, et al. Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 2012; 367: 795–804. Buchhave P, Minthon L, Zetterberg H, Wallin AK, Blennow K, Hansson O. Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry 2012; 69: 98–106. Olsson B, Lautner R, Andreasson U, et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol 2016; 15: 673–84. Schmand B, Eikelenboom P, van Gool WA; Alzheimer’s Disease Neuroimaging Initiative. Value of diagnostic tests to predict conversion to Alzheimer’s disease in young and old patients with amnestic mild cognitive impairment. J Alzheimers Dis 2012; 29: 641–48. Jansen WJ, Ossenkoppele R, Knol DL, et al. Prevalence of cerebral amyloid pathology in persons without dementia. A meta-analysis. JAMA 2015; 313: 1924–38. Blennow K, Mattsson N, Schöll M, Hansson O, Zetterberg H. Amyloid biomarkers in Alzheimer’s disease. Trends Pharmacol Sci 2015; 36: 297–309. Frisoni GB, Jack CR, Winblad B. Alzheimer’s disease biomarker development: a call to funding bodies. Neurobiol Aging 2016, in press. Mattson N, Lönneborg A, Boccardi M, Blennow K, Hansson O, and the Geneva Task Force for the Roadmap of Alzheimer’s Biomarkers. Clinical validity of Aβ42, tau, and phospho-tau in the cerebrospinal fluid as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework. Neurobiol Aging 2016, in press. Bittner T, Zetterberg H, Teunissen CE, et al. Technical performance of a novel, fully automated electrochemiluminescence immunoassay for the quantitation of β-amyloid (1-42) in human cerebrospinal fluid. Alzheimers Dement 2015; published online Nov 10. DOI:10.1016/j. jalz.2015.09.009. Detsky AS. What patients really want from health care. JAMA 2011; 306: 2500–01.
Early CT Score to establish stroke treatment In The Lancet Neurology, Albert Yoo and colleagues1 report their findings from a subgroup analysis of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN).2 They provide results from the first prespecified analysis of the therapeutic efficacy of early CT for patients who have had an ischaemic stroke. Yoo and colleagues categorised patients into three groups using the modified Alberta Stroke Program Early CT Score (ASPECTS): 0–4 (large www.thelancet.com/neurology Vol 15 June 2016
volumes of hypoattenuating brain tissue; n=30), 5–7 (large volumes; n=93), and 8–10 (small or no volumes; n=373). Their results suggest that use of trichotomised ASPECTS does not modify intra-arterial treatment effects, although no significant benefit was observed in the two small groups with ASPECTS of less than 8 by contrast with the group with ASPECTS of more than 7. Moreover, an association between low ASPECTS and poor clinical outcome was evident. The crucial question is do
See Articles page 685
651
Comment
these results justify intra-arterial treatment in patients with proximal middle cerebral artery occlusion and hypoattenuation of the total or subtotal middle cerebral artery territory (ASPECTS 0–4)? To answer this question, we would need to know what type of stroke pathology ASPECTS is scoring, take into account similar former studies, and assess the safety of intra-arterial treatment in patients with large or very large hypoattenuating tissue volumes. Different terms are used to refer to non-contrast CT hypoattenuation of grey matter in the brain within the first few hours of stroke onset (eg, early ischaemic changes, early infarct signs, insular ribbon sign, and obscuration of the lentiform nucleus), reflecting the uncertainty about what kind of ischaemic stroke decreases grey matter x-ray attenuation. According to histological studies, ASPECTS is unlikely to be useful for the quantification of infarctions as presumed by the MR CLEAN investigators. Within 6 h of middle cerebral artery occlusion in a rat animal model, less than 20% of neurons showed subtle changes in staining that were barely detectable with the microscope.3 X-ray attenuation decreases with increases in water content of the tissue. In severe ischaemia, tissue takes up water from capillaries with residual blood flow. This type of ischaemic oedema, known as ionic oedema,4 can be assessed with CT because x-ray attenuation is indirectly associated with tissue water content.5,6 Ionic oedema is triggered by a blood flow of less than 10 mL/100 g per min; this threshold indicates injury that is not reversible by reperfusion after at least 1 h of ischaemia.6,7 Accordingly, findings from a largescale prospective study8 lent support to hypoattenuation on early CT as being highly predictive for established infarctions in 213 (95%) of 224 patients given placebo and 220 (98%) of 225 patients given alteplase. Modified ASPECTS thus quantifies the extent of ionic oedema in brain tissue that cannot recover with reperfusion. ECASS 1–3 were the first studies9–11 in which x-ray hypoattenuation of brain tissue was regarded as an irreversible injury and patients with hypodensity on non-contrast CT exceeding a third of the middle cerebral artery territory were excluded from the target patient population. A post-hoc analysis12 of the placebo-controlled effect of intravenous alteplase on the proportion of patients without disability at 3 months (modified Rankin score of 0–2) showed a non-significant increase from 70 (41%) of 169 to 79 (47%) of 167 in patients without 652
hypoattenuation on baseline CT (p=0·278), a significant increase from 11 (10%) of 110 to 29 (28%) of 105 (p=0·0014) in patients with hypoattenuation in less than or equal to a third of the middle cerebral artery territory, and a non-significant decrease from three (14%) of 21 to two (6%) of 31 patients with extended hypodensity (p=0·383). A similar effect of early CT findings on treatment outcome was seen in the PROACT II with use of ASPECTS.13 On the basis of the uncertainty of the effect of stroke pathology and clinical experience, many investigators became reluctant to include patients with an ASPECTS of less than 8 in clinical trials. However, even in patients with low ASPECTS, tissue at risk might recover with reperfusion. A distal occlusion of the internal carotid artery might cause irreversible injury of the total middle cerebral artery territory (ASPECTS of 0) and less severe, but symptomatic, ischaemia in the territory of the anterior cerebral artery that might recover with arterial recanalisation. Conversely, an ASPECTS of 9 might indicate total and irreversible injury of a small middle cerebral artery branch’s territory. So, the arterial occlusion site should always be considered when discussing the consequences of baseline ASPECTS. As in the ECASS, the small number of patients with ASPECTS 0–4 (n=30) in MR CLEAN does not allow firm conclusions to be drawn. Based on the MR CLEAN data, intra-arterial treatment (thrombectomy combined with intravenous alteplase in most cases) might have a small benefit, no benefit, or might harm the patient. Fortunately, the MR CLEAN investigators did not find significant differences in their safety outcomes between both treatment groups for any of the ASPECTS subgroups. The risk of harming a patient with low ASPECTS seems to be low. This finding, in my view, is the best argument to not exclude patients from intra-arterial treatment on the basis of baseline ASPECTS and to prospectively study the treatment effects in patients with ASPECT 0–4 under controlled conditions. Rüdiger von Kummer Institute of Diagnostic and Interventional Neuroradiology, University Hospital Carl Gustav Carus, 01307 Dresden, Germany [email protected] I report personal fees from Lundbeck, Boehringer Ingelheim, Covidien, Brainsgate, and Penumbra outside the submitted work.
www.thelancet.com/neurology Vol 15 June 2016
Comment
1
2
3
4
5
6
Yoo AJ, Berkhemer OA, Fransen PS, et al, for the MR CLEAN Investigators. Effect of baseline Alberta Stroke Program Early CT Score on safety and efficacy of intra-arterial treatment: a subgroup analysis of a randomised phase 3 trial (MR CLEAN). Lancet Neurol 2016; 15: 685–94. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015; 372: 11–20. Garcia J, Liu KF, Ho KL. Neuronal necrosis after middle cerebral artery occlusion in Wistar rats progresses at different time intervals in the caudoputamen and the cortex. Stroke 1995; 26: 636–43. Simard J, Kent T, Chen, Tarasov K, Gerzanich V. Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol 2007; 6: 258–68. Dzialowski I, Weber J, Doerfler A, Forsting M, von Kummer R. Brain tissue water uptake after middle cerebral artery occlusion assessed with CT. J Neuroimaging 2004; 14: 42–48. Dzialowski I, Weber J, Klotz E, et al. CT monitoring of ischemic brain tissue water content during middle cerebral artery occlusion and reperfusion. Radiology 2007; 243: 720–26.
7 8
9
10
11 12 13
Heiss W, Rosner G. Fuctional recovery of cortical neurons as related to degree and duration of ischemia. Ann Neurol 1983; 14: 294–301. von Kummer R, Bourquain H, Bastianello S, et al. Early prediction of irreversible brain damage after ischemic stroke by computed tomography. Radiology 2001; 219: 95–100. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995; 274: 1017–25. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998; 352: 1245–51. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4·5 hours after acute ischemic stroke. N Engl J Med 2008; 359: 1317–29. von Kummer R, Allen K, Holle R, et al. Acute stroke: usefulness of early CT findings before thrombolytic therapy. Radiology 1997; 205: 327–33. Hill M, Rowley H, Adler F, et al. Selection of acute ischemic stroke patients for intra-arterial thrombolysis with pro-urokinase by using ASPECTS. Stroke 2003; 34: 1925–31.
A stroke of insight from genetics Risk factors for common diseases, including neurological disorders such as stroke and dementia, are multifactorial and include both genetic and environmental effects. The discovery and identification of individual genetic variants that contribute to risk might lead to a better understanding of biological mechanisms and new drug targets. However, apart from the discovery of rare, fully penetrant Mendelian mutations that cause early-onset disease, efforts to find new genetic loci have been frustratingly difficult. All of that changed when the experimental design of the genome-wide association study (GWAS) came on the scene less than 10 years ago.1 GWAS correlates the trait of interest with common DNA variation in the genome and can discover robust single nucleotide polymorphismdisease associations. GWAS has led to the discovery of tens-to-hundreds of associations for a wide range of diseases and quantitative traits.2 The effect on risk of each individual variant is typically very small (eg, odds ratio of 1·1 per allele), so large sample sizes are needed to find additional loci with sufficient statistical support. For a disorder such as schizophrenia, a sample size of about 3000 people led to the discovery of a single locus in 2009,3 but only 5 years later, a huge international collaborative effort combined data for 35 000 people and identified 108 loci.4 Therefore, in human genetics studies on complex traits, researchers aim to obtain ever growing sample sizes that allow genetic evidence to grow as well. To achieve this goal, large-scale and international collaborations are needed in which www.thelancet.com/neurology Vol 15 June 2016
preferably all data for an individual genotype level can be analysed to maximise statistical power. Stéphanie Debette and colleagues5 report on a novel risk locus for stroke and small artery disease. The strategy used by the investigators was original in the sense that the initial discovery cohort was drawn from a large prospective cohort study in which more than 4000 participants developed incident stroke. The advantage of such a design is to avoid the potential problem of frailty bias in casecontrol studies: patients with more severe disease who die before study entry (which might be related to specific genetic variants). The disadvantage is the relatively small sample size, especially within the context of complex traits and expected effect sizes of risk loci. Association results of 177 variants that met predefined statistical criteria were followed up using data from four independent, previously published cross-sectional studies on stroke in more than 19 000 cases.6,7,8,9,10 Two variants were found to be statistically replicating, one of which was in a novel locus near the FOXF2 gene. This finding brings the number of loci associated with stroke discovered by GWAS to about eight (depending on stroke subtype). Unlike many other reports of loci identified from GWAS, Debette and colleagues followed up the FOXF2 gene with a range of functional studies in mice and zebrafish and also explored the association between the gene and brain imaging in healthy human beings. Deletion of the Foxf2 gene in mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The zebrafish equivalents of FOXF2 were expressed in brain pericytes, and cerebral
Published Online April 7, 2016 http://dx.doi.org/10.1016/ S1474-4422(16)30028-X See Articles page 695
653