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Clinical validity of CSF biomarkers for Alzheimer's disease: necessary indeed, but sufficient?
Comment
Clinical validity of CSF biomarkers for Alzheimer’s disease: necessary indeed, but sufficient? See Articles page 673
650
The availability of disease biomarkers to study Alzheimer’s disease has radically changed the understanding of disease pathophysiology and targets for drug development. Molecular biomarkers that reflect either the deposition of aggregated β-amyloid or hyperphosphorylated tau (the constituents of senile plaques and neurofibrillary tangles) can be detected in the CSF and visualised by PET imaging.1 Their use in large prospective and longitudinal studies, such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI)2 have shown that pathological changes associated with Alzheimer’s disease are present for at least a decade before overt cognitive symptoms develop. This finding opens a window in time for early diagnosis and treatment,3,4 and Alzheimer’s disease biomarkers can be used to identify people with yet no symptoms or only mild cognitive deficits that are at high risk of subsequently developing dementia due to Alzheimer’s disease. Such individuals have widespread, extensive, and irreversible neurodegeneration, and they are consequently more likely to respond to disease-modifying treatments directed against the underlying molecular pathological changes of Alzheimer’s disease. CSF and PET imaging biomarkers of β-amyloid and tau pathology are also used today in many clinical trials to study the effects of new drugs, in addition to measures of brain atrophy rate and cognitive decline. CSF biomarkers were among the first biomarkers to be used in clinical practice for the diagnosis of Alzheimer’s disease and an impressive amount of scientific literature has been produced in the past 20 years on this topic. Scandinavian countries have been forerunners in the research and clinical use of biomarkers for Alzheimer’s disease, and it is not by chance that the meta-analysis by Bob Olsson and colleagues5 published in The Lancet Neurology is co-authored by a largely Scandinavian group of experts. This analysis focused on 15 biomarkers, including the core Alzheimer’s disease biomarkers (ie, CSF Aβ42, CSF T-tau, and CSF P-tau), and thoroughly reviewed 231 articles with stringent meta-analytic techniques. The result of this impressive work, which included 15 699 patients with Alzheimer’s disease and 13 018 healthy controls, is that the core CSF Alzheimer’s disease biomarkers differentiated, with excellent performance, Alzheimer’s disease from controls, and
patients with stable from those with progressive mild cognitive impairment. Interestingly, newly emerging biomarkers such as neurofilament light protein in the CSF and tau in plasma had large effect sizes too, even though the diagnostic accuracy of tau in plasma needs to be determined in future larger studies. This work supports the many physicians who are currently using CSF markers to detect or rule out Alzheimer’s disease in patients with either mild cognitive impairment or dementia. The large effect size demonstrated in this meta-analysis (up to 2·5 fold change between Alzheimer’s disease patients and controls) supports the notion that a negative test in patients with suspected Alzheimer’s disease militates strongly against an Alzheimer’s disease diagnosis independent of the age of the patient, but a positive test supports an Alzheimer’s disease diagnosis, especially in individuals younger than about 70 years,6 in whom asymptomatic amyloidosis is not that common.7 Is this to mean that shortly patients with suspected Alzheimer’s disease will be routinely offered a lumbar tap, an earlier and better diagnosis, and that all this will be reimbursed by health-care payers? The road to the routine use of CSF biomarkers might not be that straightforward in many countries. Many health-care payers in Europe, such as those in Switzerland and Spain, are not reimbursing the full cost of CSF biomarkers analysis because of the perceived insufficient effect on patient management, even though the cost of analyses is relatively modest (eg, €35–150 for CSF Ab42).8 The reasoning is that biomarkers might have good analytical validity (the biomarker measures the biological phenomenon it is supposed to measure accurately and reliably), and might also be clinically valid (the biomarker readout is substantially different in patients with and without the disease), but if its clinical utility (improving pharmacological and non-pharmacological interventions, decreasing morbidity and mortality) and benefit on costs of health care cannot be demonstrated, why spend money on it? The answer is cogent for CSF Alzheimer’s disease biomarkers, but even more so for other fluid biomarkers that can be used in association with or as an alternative www.thelancet.com/neurology Vol 15 June 2016
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
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8 9 10
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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
Clinical validity of CSF biomarkers for Alzheimer’s disease: necessary indeed, but sufficient? See Articles page 673
650
The availability of disease biomarkers to study Alzheimer’s disease has radically changed the understanding of disease pathophysiology and targets for drug development. Molecular biomarkers that reflect either the deposition of aggregated β-amyloid or hyperphosphorylated tau (the constituents of senile plaques and neurofibrillary tangles) can be detected in the CSF and visualised by PET imaging.1 Their use in large prospective and longitudinal studies, such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI)2 have shown that pathological changes associated with Alzheimer’s disease are present for at least a decade before overt cognitive symptoms develop. This finding opens a window in time for early diagnosis and treatment,3,4 and Alzheimer’s disease biomarkers can be used to identify people with yet no symptoms or only mild cognitive deficits that are at high risk of subsequently developing dementia due to Alzheimer’s disease. Such individuals have widespread, extensive, and irreversible neurodegeneration, and they are consequently more likely to respond to disease-modifying treatments directed against the underlying molecular pathological changes of Alzheimer’s disease. CSF and PET imaging biomarkers of β-amyloid and tau pathology are also used today in many clinical trials to study the effects of new drugs, in addition to measures of brain atrophy rate and cognitive decline. CSF biomarkers were among the first biomarkers to be used in clinical practice for the diagnosis of Alzheimer’s disease and an impressive amount of scientific literature has been produced in the past 20 years on this topic. Scandinavian countries have been forerunners in the research and clinical use of biomarkers for Alzheimer’s disease, and it is not by chance that the meta-analysis by Bob Olsson and colleagues5 published in The Lancet Neurology is co-authored by a largely Scandinavian group of experts. This analysis focused on 15 biomarkers, including the core Alzheimer’s disease biomarkers (ie, CSF Aβ42, CSF T-tau, and CSF P-tau), and thoroughly reviewed 231 articles with stringent meta-analytic techniques. The result of this impressive work, which included 15 699 patients with Alzheimer’s disease and 13 018 healthy controls, is that the core CSF Alzheimer’s disease biomarkers differentiated, with excellent performance, Alzheimer’s disease from controls, and
patients with stable from those with progressive mild cognitive impairment. Interestingly, newly emerging biomarkers such as neurofilament light protein in the CSF and tau in plasma had large effect sizes too, even though the diagnostic accuracy of tau in plasma needs to be determined in future larger studies. This work supports the many physicians who are currently using CSF markers to detect or rule out Alzheimer’s disease in patients with either mild cognitive impairment or dementia. The large effect size demonstrated in this meta-analysis (up to 2·5 fold change between Alzheimer’s disease patients and controls) supports the notion that a negative test in patients with suspected Alzheimer’s disease militates strongly against an Alzheimer’s disease diagnosis independent of the age of the patient, but a positive test supports an Alzheimer’s disease diagnosis, especially in individuals younger than about 70 years,6 in whom asymptomatic amyloidosis is not that common.7 Is this to mean that shortly patients with suspected Alzheimer’s disease will be routinely offered a lumbar tap, an earlier and better diagnosis, and that all this will be reimbursed by health-care payers? The road to the routine use of CSF biomarkers might not be that straightforward in many countries. Many health-care payers in Europe, such as those in Switzerland and Spain, are not reimbursing the full cost of CSF biomarkers analysis because of the perceived insufficient effect on patient management, even though the cost of analyses is relatively modest (eg, €35–150 for CSF Ab42).8 The reasoning is that biomarkers might have good analytical validity (the biomarker measures the biological phenomenon it is supposed to measure accurately and reliably), and might also be clinically valid (the biomarker readout is substantially different in patients with and without the disease), but if its clinical utility (improving pharmacological and non-pharmacological interventions, decreasing morbidity and mortality) and benefit on costs of health care cannot be demonstrated, why spend money on it? The answer is cogent for CSF Alzheimer’s disease biomarkers, but even more so for other fluid biomarkers that can be used in association with or as an alternative www.thelancet.com/neurology Vol 15 June 2016
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