Correspondence
*Olivier Naggara, Tim Darsaut, Denis Trystram, Lambros Tselikas, Jean Raymond [email protected] Department of Neuroradiology, Paris-Descartes University, Centre Hospitalier Sainte-Anne, INSERM UMR894, 75014 Paris, France (ON, DT, LT); Division of Neurosurgery, Department of Surgery, University of Alberta Hospital, Mackenzie Health Sciences Centre, Edmonton, Alberta, Canada (TD); and International Consortium of Neuroendovascular Centres, Interventional Neuroradiology Research Unit, Department of Radiology, University of Montreal, CHUM Notre-Dame Hospital, Montreal, QC, Canada (JR) 1
2
3
4
5
6
7
8
Greving JP, Wermer MJ, Brown RD Jr, et al. Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol 2014; 13: 59–66. Raymond J, Darsaut TE, Molyneux AJ. A trial on unruptured intracranial aneurysms (the TEAM trial): results, lessons from a failure and the necessity for clinical care trials. Trials 2011; 12: 64. Brinjikji W, Rabinstein AA, Nasr DM, Lanzino G, Kallmes DF, Cloft HJ. Better outcomes with treatment by coiling relative to clipping of unruptured intracranial aneurysms in the United States, 2001-2008. AJNR Am J Neuroradiol 2011; 32: 1071–75. International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms—risk of rupture and risks of surgical intervention. N Eng J Med 1998; 339: 1725–33. Morita A, Kirino T, Hashi K, et al. The natural course of unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med 2012; 366: 2474–82. Kotowski M, Naggara O, Darsaut TE, et al. Safety and occlusion rates of surgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis of the literature from 1990 to 2011. J Neurol Neurosurg Psychiatry 2013; 84: 42–48. Naggara ON, Lecler A, Oppenheim C, Meder JF, Raymond J. Endovascular treatment of intracranial unruptured aneurysms: a systematic review of the literature on safety with emphasis on subgroup analyses. Radiology 2012; 263: 828–35. Naggara ON, White PM, Guilbert F, Roy D, Weill A, Raymond J. Endovascular treatment of intracranial unruptured aneurysms: systematic review and meta-analysis of the literature on safety and efficacy. Radiology 2010; 256: 887–97.
Authors’ reply We thank Olivier Nagarra and colleagues for their interest in our pooled analysis of individual patient data on risk of rupture.1 Their comments focus on insufficient evidence from randomised clinical trials for prophylactic vascular interventions of unruptured 538
intracranial aneurysms. The Trial on Endovascular Aneurysm Management (TEAM) was such an enterprise that failed because of poor recruitment.2 We agree that treatment recommendations ideally should be assessed in properly designed randomised clinical trials. However, whether such a trial could be accomplished for unruptured intracranial aneurysms is unclear. Our study showed that in populations from North America and European countries other than Finland, most aneurysms have a very small (3% risk in 5 years), a trial of endovascular or surgical intervention would also be challenging because of the concern about risk of rupture, and many patients and providers would not agree to randomisation. Some have also argued that the intervention techniques used during a trial could already have become outdated by the trial’s conclusion, which precludes the results from being generalisable to future practice. How should we proceed in the assessment of the effectiveness of endovascular and surgical interventions for aneurysms with a high risk of rupture? First, we should have better risk predictions for complications of interventions. These predictions lag far behind the risk predictions of rupture. Second, once valid contemporary aneurysm site-specific and size-specific interventional treatment outcome data are available, we propose to use decision analytical techniques to determine which patients with unruptured intracranial aneurysms
would benefit from an endovascular or surgical intervention.3 The PHASES score can then be used to quantify risks of rupture for these decision models. For now, although there are some limitations, the PHASES score can be used to better define the risk of rupture and to weigh these risks against the undetermined risks and effectiveness of endovascular or surgical interventions in terms of the prevention of future rupture. We declare that we have no competing interests.
*Jacoba P Greving, Marieke J H Wermer, Gabriël J E Rinkel, Ale Algra [email protected] Julius Center for Health Sciences and Primary Care (JPG, AA), Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus (AA, GJER), University Medical Center Utrecht, Utrecht, Netherlands; and Department of Neurology, Leiden University Medical Center, Leiden, Netherlands (MJHW) 1
2
3
Greving JP, Wermer MJ, Brown RD Jr, et al. Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol 2014; 13: 59–66. Raymond J, Darsaut TE, Molyneux AJ. A trial on unruptured intracranial aneurysms (the TEAM trial): results, lessons from a failure and the necessity for clinical care trials. Trials 2011; 12: 64. Greving JP, Rinkel GJ, Buskens E, Algra A. Cost-effectiveness of preventive treatment of intracranial aneurysms: new data and uncertainties. Neurology 2009; 73: 258–65.
Developing biomarkers for cerebral amyloid angiopathy trials: do potential disease phenotypes hold promise? We read with great interest the Review by Steve Greenberg and colleagues1 about possible outcome markers in disease-modifying trials of cerebral amyloid angiopathy. Sporadic cerebral amyloid angiopathy is generally identified in elderly people and is characterised by the accumulation of amyloid β in cortical www.thelancet.com/neurology Vol 13 June 2014
Correspondence
and leptomeningeal vessels,2,3 but the disease is usually mild and clinically silent. Only a fraction of patients with cerebral amyloid angiopathy will go on to develop symptomatic intracerebral haemorrhage, despite the fact that many more might have evidence of haemorrhagic manifestations on neuroimaging, such as multiple lobar cerebral microbleeds or cortical superficial siderosis. 2,3 In other patients, the disease might cause white matter hyperintensities and cognitive impairment (chronic or subacute). Cerebral amyloid angiopathy is also often present in cases of Alzheimer’s disease. From these and other observations, a picture arises in which cerebral amyloid angiopathy might have a spectrum of distinct phenotypes of neuropathology and neuroimaging manifestations, comorbidities, and ultimately clinical expression.4 At present, at least two pathological subtypes of cerebral amyloid angiopathy have been identified: cerebral amyloid angiopathytype 1, characterised by amyloid in cortical capillaries (with or without involvement of other vessels), and cerebral amyloid angiopathy-type 2, in which amyloid deposits are restricted to leptomeningeal and cortical arteries, but not capillaries. The APOE ε4 allele is strongly associated with type 1 disease, whereas APOE ε2 is associated with type 2. Additionally, it is generally accepted that APOE ε4 promotes vascular amyloid deposition, whereas APOE ε2 promotes structural vasculopathic changes in amyloid-laden vessels, making them prone to rupture and intracerebral bleeding. Cerebral amyloid angiopathy type 1 (especially capillary, more than arteriolar) seems to be associated with parenchymal amyloid deposition in Alzheimer’s disease, and might cause luminal obstruction in the most severe stages, potentially explaining the www.thelancet.com/neurology Vol 13 June 2014
low incidence of microbleeds and intracerebral haemorrhage in patients with Alzheimer’s disease, and the association between microinfarcts and cognitive impairment in cerebral amyloid angiopathy. Thus, APOE genotype probably affects the phenotype of cerebral amyloid angiopathy, but it is likely that this is not the whole story. Although multiple lobar microbleeds are a marker of increased risk of intracerebral haemorrhage, an interesting study suggests that microbleeds arising from cerebral amyloid angiopathy-related pathology might in some respects differ from macrobleeds.5 In patients who underwent autopsy, those with high microbleeds counts (microbleeders) had increased wall thickness of amyloid-positive vessels compared with those with fairly low microbleeds counts (macrobleeders).5 Surprisingly, cortical superficial siderosis, another marker of cerebral amyloid angiopathy associated with high risk of haemorrhage, is not associated with lobar microbleeds.6 A possible explanation is that siderosis is predominantly due to severe leptomeningeal rather than deeper cortical cerebral amyloid angiopathy that manifests itself increasingly by microbleeds. It is tempting to speculate that several different endophenotypes of cerebral amyloid angiopathy exist. This assumption touches onto the very basic question of what pathophysiological mechanisms determine whether cerebral amyloid angiopathy causes intracerebral haemorrhage or other haemorrhagic manifestations versus nonhaemorrhagic manifestations, or cognitive decline. Although literature to support firm conclusions is not yet available, we suggest that a so-called phenotype approach for cerebral amyloid angiopathy provides a conceptual model, which might allow greater reliance on the clusters of the different surrogate
A T2*-weighted MRI in a 69-year-old man with probable cerebral amyloid angiopathy
biomarkers in future trials.1 Cerebral amyloid angiopathy is a chronically progressive disease, and future longitudinal studies should assess whether the described phenotypes of cerebral amyloid angiopathy are really distinct entities adhering to their characteristic imaging feature with time. Another key requirement is the identification of the exact role of cerebral amyloid angiopathy in the context of Alzheimer’s disease: what are the differences and similarities with sporadic cerebral amyloid angiopathy, and what lessons can we learn from immunotherapeutic trials of Alzheimer’s disease that can be applied to the design of trials for cerebral amyloid angiopathy? AC receives research support from the Greek State Scholarship Foundation, the Stroke Association, and the British Heart Foundation. RJJ has received research support from the Samantha Dickson Brain Tumour Trust and the Brain Research Trust. We declare that we have no competing interests.
*Andreas Charidimou, Hans Rolf J Jäger [email protected] Stroke Research Group, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, WC1N 3BG, UK (AC); Lysholm Department of Neuroradiology, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK (HRJ); and Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, UK (HRJ) 1
Greenberg SM, Salman RA, Biessels GJ, et al. Outcome markers for clinical trials in cerebral amyloid angiopathy. Lancet Neurol 2014; 13: 419–28.
539
Correspondence
2
3 4
5
6
Charidimou A, Gang Q, Werring DJ. Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum. J Neurol Neurosurg Psychiatry 2012; 83: 124–37. Vinters HV. Cerebral amyloid angiopathy. A critical review. Stroke 1987; 18: 311–24. Greenberg SM, Vonsattel JP, Stakes JW, Gruber M, Finklestein SP. The clinical spectrum of cerebral amyloid angiopathy: presentations without lobar hemorrhage. Neurology 1993; 43: 2073–79. Greenberg SM, Nandigam RN, Delgado P, et al. Microbleeds versus macrobleeds: evidence for distinct entities. Stroke 2009; 40: 2382–86. Charidimou A, Jäger RH, Fox Z, et al. Prevalence and mechanisms of cortical superficial siderosis in cerebral amyloid angiopathy. Neurology 2013; 81: 626–32.
Authors’ reply We appreciate the insightful comments from Andreas Charidimou and Hans Rolf Jäger regarding the distinct phenotypes associated with cerebral amyloid angiopathy and their effect on selection of outcome markers for clinical trials.1 As the authors correctly note, cerebral amyloid angiopathy is a complex entity that can follow several different pathways, each associated with its own cluster of biomarkers. It
540
follows that a key factor in selection of outcome markers for a trial of cerebral amyloid angiopathy is the pathophysiological target of the particular treatment under investigation. Although studies of phenotypes of cerebral amyloid angiopathy often focus on the extreme forms (such as microbleeders and macrobleeders), most patients probably fall into a mixed category in which various cerebral amyloid angiopathy-related vascular processes coexist. We therefore encourage investigators of cerebral amyloid angiopathy to collect and analyse a full range of measures of focal injury and overall brain structure and function. We declare that we have no competing interests.
*Steven M Greenberg, Rustam Al-Shahi Salman, Geert Jan Biessels, Mark van Buchem, Charlotte Cordonnier, Jin-Moo Lee, Joan Montaner, Julie A Schneider,
MGH Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA (SMG); Division of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK (RAS); Brain Centre Rudolf Magnus, University Medical Center of Utrecht, Utrecht, Netherlands (GJB); Department of Radiology, Leiden University Medical Center, Leiden, Netherlands (MvB); Department of Neurology, Universite Lille Nord de France, Lille University Hospital, Lille, France (CC); Department of Neurology,Department of Radiology, and Department of Biomedical Engineering, Washington University School of Medicine, St Louis, MO, USA (J-ML); Department of Neurology, Vall d’Hebron University Hospital and Research Institute, Autonomus University of Barcelona, Barcelona, Spain (JM); Department of Pathology and Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA (JAS); Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada (EES); Department of Radiology and Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands (MV); and UCL Institute of Neurology, London, UK (DJW) 1
Greenberg SM, Salman RA, Biessels GJ, et al. Outcome markers for clinical trials in cerebral amyloid angiopathy. Lancet Neurol 2014; 13: 419–28.
Eric E Smith, Meike Vernooij, David J Werring [email protected]
www.thelancet.com/neurology Vol 13 June 2014
*Olivier Naggara, Tim Darsaut, Denis Trystram, Lambros Tselikas, Jean Raymond [email protected] Department of Neuroradiology, Paris-Descartes University, Centre Hospitalier Sainte-Anne, INSERM UMR894, 75014 Paris, France (ON, DT, LT); Division of Neurosurgery, Department of Surgery, University of Alberta Hospital, Mackenzie Health Sciences Centre, Edmonton, Alberta, Canada (TD); and International Consortium of Neuroendovascular Centres, Interventional Neuroradiology Research Unit, Department of Radiology, University of Montreal, CHUM Notre-Dame Hospital, Montreal, QC, Canada (JR) 1
2
3
4
5
6
7
8
Greving JP, Wermer MJ, Brown RD Jr, et al. Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol 2014; 13: 59–66. Raymond J, Darsaut TE, Molyneux AJ. A trial on unruptured intracranial aneurysms (the TEAM trial): results, lessons from a failure and the necessity for clinical care trials. Trials 2011; 12: 64. Brinjikji W, Rabinstein AA, Nasr DM, Lanzino G, Kallmes DF, Cloft HJ. Better outcomes with treatment by coiling relative to clipping of unruptured intracranial aneurysms in the United States, 2001-2008. AJNR Am J Neuroradiol 2011; 32: 1071–75. International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms—risk of rupture and risks of surgical intervention. N Eng J Med 1998; 339: 1725–33. Morita A, Kirino T, Hashi K, et al. The natural course of unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med 2012; 366: 2474–82. Kotowski M, Naggara O, Darsaut TE, et al. Safety and occlusion rates of surgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis of the literature from 1990 to 2011. J Neurol Neurosurg Psychiatry 2013; 84: 42–48. Naggara ON, Lecler A, Oppenheim C, Meder JF, Raymond J. Endovascular treatment of intracranial unruptured aneurysms: a systematic review of the literature on safety with emphasis on subgroup analyses. Radiology 2012; 263: 828–35. Naggara ON, White PM, Guilbert F, Roy D, Weill A, Raymond J. Endovascular treatment of intracranial unruptured aneurysms: systematic review and meta-analysis of the literature on safety and efficacy. Radiology 2010; 256: 887–97.
Authors’ reply We thank Olivier Nagarra and colleagues for their interest in our pooled analysis of individual patient data on risk of rupture.1 Their comments focus on insufficient evidence from randomised clinical trials for prophylactic vascular interventions of unruptured 538
intracranial aneurysms. The Trial on Endovascular Aneurysm Management (TEAM) was such an enterprise that failed because of poor recruitment.2 We agree that treatment recommendations ideally should be assessed in properly designed randomised clinical trials. However, whether such a trial could be accomplished for unruptured intracranial aneurysms is unclear. Our study showed that in populations from North America and European countries other than Finland, most aneurysms have a very small (3% risk in 5 years), a trial of endovascular or surgical intervention would also be challenging because of the concern about risk of rupture, and many patients and providers would not agree to randomisation. Some have also argued that the intervention techniques used during a trial could already have become outdated by the trial’s conclusion, which precludes the results from being generalisable to future practice. How should we proceed in the assessment of the effectiveness of endovascular and surgical interventions for aneurysms with a high risk of rupture? First, we should have better risk predictions for complications of interventions. These predictions lag far behind the risk predictions of rupture. Second, once valid contemporary aneurysm site-specific and size-specific interventional treatment outcome data are available, we propose to use decision analytical techniques to determine which patients with unruptured intracranial aneurysms
would benefit from an endovascular or surgical intervention.3 The PHASES score can then be used to quantify risks of rupture for these decision models. For now, although there are some limitations, the PHASES score can be used to better define the risk of rupture and to weigh these risks against the undetermined risks and effectiveness of endovascular or surgical interventions in terms of the prevention of future rupture. We declare that we have no competing interests.
*Jacoba P Greving, Marieke J H Wermer, Gabriël J E Rinkel, Ale Algra [email protected] Julius Center for Health Sciences and Primary Care (JPG, AA), Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus (AA, GJER), University Medical Center Utrecht, Utrecht, Netherlands; and Department of Neurology, Leiden University Medical Center, Leiden, Netherlands (MJHW) 1
2
3
Greving JP, Wermer MJ, Brown RD Jr, et al. Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol 2014; 13: 59–66. Raymond J, Darsaut TE, Molyneux AJ. A trial on unruptured intracranial aneurysms (the TEAM trial): results, lessons from a failure and the necessity for clinical care trials. Trials 2011; 12: 64. Greving JP, Rinkel GJ, Buskens E, Algra A. Cost-effectiveness of preventive treatment of intracranial aneurysms: new data and uncertainties. Neurology 2009; 73: 258–65.
Developing biomarkers for cerebral amyloid angiopathy trials: do potential disease phenotypes hold promise? We read with great interest the Review by Steve Greenberg and colleagues1 about possible outcome markers in disease-modifying trials of cerebral amyloid angiopathy. Sporadic cerebral amyloid angiopathy is generally identified in elderly people and is characterised by the accumulation of amyloid β in cortical www.thelancet.com/neurology Vol 13 June 2014
Correspondence
and leptomeningeal vessels,2,3 but the disease is usually mild and clinically silent. Only a fraction of patients with cerebral amyloid angiopathy will go on to develop symptomatic intracerebral haemorrhage, despite the fact that many more might have evidence of haemorrhagic manifestations on neuroimaging, such as multiple lobar cerebral microbleeds or cortical superficial siderosis. 2,3 In other patients, the disease might cause white matter hyperintensities and cognitive impairment (chronic or subacute). Cerebral amyloid angiopathy is also often present in cases of Alzheimer’s disease. From these and other observations, a picture arises in which cerebral amyloid angiopathy might have a spectrum of distinct phenotypes of neuropathology and neuroimaging manifestations, comorbidities, and ultimately clinical expression.4 At present, at least two pathological subtypes of cerebral amyloid angiopathy have been identified: cerebral amyloid angiopathytype 1, characterised by amyloid in cortical capillaries (with or without involvement of other vessels), and cerebral amyloid angiopathy-type 2, in which amyloid deposits are restricted to leptomeningeal and cortical arteries, but not capillaries. The APOE ε4 allele is strongly associated with type 1 disease, whereas APOE ε2 is associated with type 2. Additionally, it is generally accepted that APOE ε4 promotes vascular amyloid deposition, whereas APOE ε2 promotes structural vasculopathic changes in amyloid-laden vessels, making them prone to rupture and intracerebral bleeding. Cerebral amyloid angiopathy type 1 (especially capillary, more than arteriolar) seems to be associated with parenchymal amyloid deposition in Alzheimer’s disease, and might cause luminal obstruction in the most severe stages, potentially explaining the www.thelancet.com/neurology Vol 13 June 2014
low incidence of microbleeds and intracerebral haemorrhage in patients with Alzheimer’s disease, and the association between microinfarcts and cognitive impairment in cerebral amyloid angiopathy. Thus, APOE genotype probably affects the phenotype of cerebral amyloid angiopathy, but it is likely that this is not the whole story. Although multiple lobar microbleeds are a marker of increased risk of intracerebral haemorrhage, an interesting study suggests that microbleeds arising from cerebral amyloid angiopathy-related pathology might in some respects differ from macrobleeds.5 In patients who underwent autopsy, those with high microbleeds counts (microbleeders) had increased wall thickness of amyloid-positive vessels compared with those with fairly low microbleeds counts (macrobleeders).5 Surprisingly, cortical superficial siderosis, another marker of cerebral amyloid angiopathy associated with high risk of haemorrhage, is not associated with lobar microbleeds.6 A possible explanation is that siderosis is predominantly due to severe leptomeningeal rather than deeper cortical cerebral amyloid angiopathy that manifests itself increasingly by microbleeds. It is tempting to speculate that several different endophenotypes of cerebral amyloid angiopathy exist. This assumption touches onto the very basic question of what pathophysiological mechanisms determine whether cerebral amyloid angiopathy causes intracerebral haemorrhage or other haemorrhagic manifestations versus nonhaemorrhagic manifestations, or cognitive decline. Although literature to support firm conclusions is not yet available, we suggest that a so-called phenotype approach for cerebral amyloid angiopathy provides a conceptual model, which might allow greater reliance on the clusters of the different surrogate
A T2*-weighted MRI in a 69-year-old man with probable cerebral amyloid angiopathy
biomarkers in future trials.1 Cerebral amyloid angiopathy is a chronically progressive disease, and future longitudinal studies should assess whether the described phenotypes of cerebral amyloid angiopathy are really distinct entities adhering to their characteristic imaging feature with time. Another key requirement is the identification of the exact role of cerebral amyloid angiopathy in the context of Alzheimer’s disease: what are the differences and similarities with sporadic cerebral amyloid angiopathy, and what lessons can we learn from immunotherapeutic trials of Alzheimer’s disease that can be applied to the design of trials for cerebral amyloid angiopathy? AC receives research support from the Greek State Scholarship Foundation, the Stroke Association, and the British Heart Foundation. RJJ has received research support from the Samantha Dickson Brain Tumour Trust and the Brain Research Trust. We declare that we have no competing interests.
*Andreas Charidimou, Hans Rolf J Jäger [email protected] Stroke Research Group, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, WC1N 3BG, UK (AC); Lysholm Department of Neuroradiology, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK (HRJ); and Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, UK (HRJ) 1
Greenberg SM, Salman RA, Biessels GJ, et al. Outcome markers for clinical trials in cerebral amyloid angiopathy. Lancet Neurol 2014; 13: 419–28.
539
Correspondence
2
3 4
5
6
Charidimou A, Gang Q, Werring DJ. Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum. J Neurol Neurosurg Psychiatry 2012; 83: 124–37. Vinters HV. Cerebral amyloid angiopathy. A critical review. Stroke 1987; 18: 311–24. Greenberg SM, Vonsattel JP, Stakes JW, Gruber M, Finklestein SP. The clinical spectrum of cerebral amyloid angiopathy: presentations without lobar hemorrhage. Neurology 1993; 43: 2073–79. Greenberg SM, Nandigam RN, Delgado P, et al. Microbleeds versus macrobleeds: evidence for distinct entities. Stroke 2009; 40: 2382–86. Charidimou A, Jäger RH, Fox Z, et al. Prevalence and mechanisms of cortical superficial siderosis in cerebral amyloid angiopathy. Neurology 2013; 81: 626–32.
Authors’ reply We appreciate the insightful comments from Andreas Charidimou and Hans Rolf Jäger regarding the distinct phenotypes associated with cerebral amyloid angiopathy and their effect on selection of outcome markers for clinical trials.1 As the authors correctly note, cerebral amyloid angiopathy is a complex entity that can follow several different pathways, each associated with its own cluster of biomarkers. It
540
follows that a key factor in selection of outcome markers for a trial of cerebral amyloid angiopathy is the pathophysiological target of the particular treatment under investigation. Although studies of phenotypes of cerebral amyloid angiopathy often focus on the extreme forms (such as microbleeders and macrobleeders), most patients probably fall into a mixed category in which various cerebral amyloid angiopathy-related vascular processes coexist. We therefore encourage investigators of cerebral amyloid angiopathy to collect and analyse a full range of measures of focal injury and overall brain structure and function. We declare that we have no competing interests.
*Steven M Greenberg, Rustam Al-Shahi Salman, Geert Jan Biessels, Mark van Buchem, Charlotte Cordonnier, Jin-Moo Lee, Joan Montaner, Julie A Schneider,
MGH Stroke Research Center, Massachusetts General Hospital, Boston, MA 02114, USA (SMG); Division of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK (RAS); Brain Centre Rudolf Magnus, University Medical Center of Utrecht, Utrecht, Netherlands (GJB); Department of Radiology, Leiden University Medical Center, Leiden, Netherlands (MvB); Department of Neurology, Universite Lille Nord de France, Lille University Hospital, Lille, France (CC); Department of Neurology,Department of Radiology, and Department of Biomedical Engineering, Washington University School of Medicine, St Louis, MO, USA (J-ML); Department of Neurology, Vall d’Hebron University Hospital and Research Institute, Autonomus University of Barcelona, Barcelona, Spain (JM); Department of Pathology and Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA (JAS); Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada (EES); Department of Radiology and Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands (MV); and UCL Institute of Neurology, London, UK (DJW) 1
Greenberg SM, Salman RA, Biessels GJ, et al. Outcome markers for clinical trials in cerebral amyloid angiopathy. Lancet Neurol 2014; 13: 419–28.
Eric E Smith, Meike Vernooij, David J Werring [email protected]
www.thelancet.com/neurology Vol 13 June 2014
