- Email: [email protected]
Alzheimer's disease and other dementias: advances in 2013
2013 Round-up
Trial in Lobar Intracerebral Haemorrhage (STICH-II)12 showed that early surgical clot evacuation did not result in more favourable outcome or lower death rate at 6 months. Subanalysis from the trial, however, suggests that patients with poor prognosis (Glasgow coma scale 9–12) could benefit from early surgery, whereas those with good prognosis are better off with watchful waiting. Further evidence from two ongoing trials using minimally invasive procedures to reduce the haematoma (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage-III: CLEARIII and Minimally Invasive Surgery Plus rt-PA for ICH Evacuation-III: MISTIE-III) is eagerly awaited. Moving to secondary prevention, the specialty received controversial results from two large randomised controlled trials. Results of the Clopidogrel in HighRisk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE)13 trial showed superiority of the combination of clopidogrel and aspirin versus aspirin alone for reduction of the risk of recurrent stroke in the first 3 months after non-disabling stroke or transient ischaemic attack, without increasing haemorrhage risk. However, the Secondary Prevention of Small Subcortical Strokes (SPS3)14 trial provided contrasting results: the addition of clopidogrel to aspirin for a mean of 3·4 years resulted in more bleeding and death without reduction of stroke recurrence. Based on these results, there is no evidence to support aspirin plus clopidogrel for longterm stroke prevention; however, the CHANCE trial, and results of this combination given for several months in high-risk patients with symptomatic intracranial stenosis,15 suggest that ongoing studies of shortterm aspirin plus clopidogrel will establish efficacy of combination treatment after transient ischaemic attack, after minor stroke, and in other high-risk groups.
Amrou Sarraj, *James C Grotta Department of Neurology University of Texas-Houston, 6410 Fannin Street, Houston, TX, 77030, USA [email protected] We declare that we have no conflicts of interest. 1
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Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999; 282: 2003–11. Broderick JP, Palesch YY, Demchuk AM, et al, for the Interventional Management of Stroke (IMS) III Investigators. Endovascular therapy after intravenous t-PA vs t-PA alone for stroke. N Engl J Med 2013; 368: 893–903. Ciccone A, Valvassori L, Nichelatti M, et al, for the SYNTHESIS Expansion Investigators. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013; 368: 904–13. Kidwell CS, Jahan R, Gornbein J, et al, for the MR RESCUE Investigators. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013; 368: 914–23. Saver JL, Jahan R, Levy EI, et al, for the SWIFT Trialists. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet 2012; 380: 1241–49. Nogueira RG, Lutsep HL, Gupta R, et al, for the TREVO2 trialists. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. Lancet 2012; 380: 1231–40. Sarraj A, Albright K, Barreto AD, et al. Optimizing prediction scores for poor outcome after intra-arterial therapy in anterior circulation acute ischemic stroke. Stroke 2013; published online Aug 8. DOI:10.1161/ STROKEAHA.113.001050. Weber JE, Ebinger M, Rozanski M, et al. Prehospital thrombolysis in acute stroke: results of the PHANTOM-S pilot study. Neurology 2013; 80: 163–68. Walter S, Kostopoulos P, Haass A, et al. Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial. Lancet Neurol 2012; 11: 397–404. Pancioli AM, Adeoye O, Schmit PA, et al. The Combined Approach to Lysis Utilizing Eptifibatide and recombinant tissue plasminogen activator in Acute Ischemic Stroke-Enhanced Regimen Stroke Trial (CLEAR-ER). Stroke 2013; 44: 2381–87. Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013; 368: 2355–65. Mendelow AD, Gregson BA, Rowan EN, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet 2013; 382: 397–408. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013; 369: 11–19. SPS3 Investigators, Benavente OR, Hart RG. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med 2012; 367: 817–25. Chimowitz MI, Lynn MJ, Derdeyn CP, et al for the SAMPRISS investigators. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011; 365: 993–1003.
Alzheimer’s disease and other dementias: advances in 2013 2013 was marked by substantial progress and a simmering resolve to address dementia in a deliberate, collaborative, and effective way. Researchers continue to characterise biomarker trajectories in the preclinical, mild cognitive impairment, and dementia stages of Alzheimer’s disease. For example, studies suggest that fibrillar amyloid-β deposition begins more than two decades www.thelancet.com/neurology Vol 13 January 2014
before the onset of dementia.1–3 Results of MRI studies showed structural brain differences in infant ApoE e4 allele carriers and non-carriers, raising questions about the effect of neurodevelopmental factors on the subsequent pathogenesis of Alzheimer’s disease.4,5 A task force proposed criteria for the use of amyloid-β PET scans in clinical settings, seeking to limit use to situations most likely to have a clinically meaningful 3
Henny Allis/Science Photo Library
2013 Round-up
effect.6 The United States Centers for Medicare and Medicaid Services (CMS) reviewed these and other stakeholder recommendations and acknowledged the technology’s promise, but noted that empirical evidence is still needed to show the effect of amyloid-β PET on health outcomes. Reimbursement will be limited to scans acquired under the auspices of CMS-approved studies that assess the effect of the technology on health outcomes or differential diagnosis, or to enrich therapeutic trials in the clinical or preclinical stages of Alzheimer’s disease. Several PET ligands have shown promise in the assessment of tau pathology.7–10 Studies are needed to validate their affinity and specificity for tau aggregates in patients with Alzheimer’s disease, clarify their affinity for the slightly different tau aggregates in patients with other tauopathies, understand correlations between antemortem and post-mortem measurements, and use them in the detection and tracking of disease and the assessment of disease-modifying treatments. Studies continue to support the possibility that extracellular tau aggregates mediate the trans-neuronal propagation of tau pathology and provide a potentially accessible target for tau immunisation therapies, some of which are now in development for the treatment of Alzheimer’s disease and other tauopathies. In elegant experiments,11 anti-tau antibodies inhibited the cellular uptake and intracellular seeding of tau aggregates, and reduced phospho-tau burden and microgliosis in a mouse model of tau pathology. 4
Researchers have characterised about 20 Alzheimer’ssusceptibility genes,12 are poised to identify many more, and have begun to use this information to help clarify disease mechanisms and discover new treatment strategies. For example, rare variants of the TREM2 gene have been associated with risk of Alzheimer’s disease13,14 and other neurodegenerative diseases. The gene encodes a receptor protein that promotes phagocytosis and inhibits a cytokine-mediated inflammatory response; the protein is expressed in microglia and other immune cells, encouraging researchers to target relevant elements of the microglial-mediated inflammatory response in the discovery of new treatments for these diseases. Although clinical trials have had tribulations, they have also provided valuable pharmacodynamic, biomarker, and safety data, glimmers of hope, and lessons about the design of future trials. A view is emerging that some of the putative treatments now in development might need to be started in the preclinical stages to achieve a benefit. The US Food and Drug Administration has issued an encouraging draft guidance to industry on development of treatments for early Alzheimer’s disease and has been meeting with investigators to help advance the assessment of preclinical treatments in the most appropriate way.15 Researchers have begun to establish biomarker and cognitive endpoints to assess preclinical interventions. Representatives from academia and industry, regulatory and funding agencies, and advocacy organisations—such as those representing patients and families—have been meeting to navigate uncharted territory, vet a range of scientific, ethical, regulatory, and practical issues, and find new ways to work together in support of common goals. Registries are being developed to help accelerate enrolment in prevention trials. Efforts have been made to help to compare data and findings from different trials, and to secure agreements to make the data and biological samples available to the research community after the prevention trials are over. Several prevention trials are now underway and others are planned using biomarker, cognitive, or clinical endpoints, or a combination, in cognitively unimpaired individuals who, based on their genetic or biomarker features and age, are at increased risk for the clinical onset of Alzheimer’s disease. Some of the trials are supported by a combination of public and private resources, and others by industry alone. In addition to testing putative www.thelancet.com/neurology Vol 13 January 2014
2013 Round-up
disease-modifying treatments in preclinical Alzheimer’s disease, some of the trials have additional goals. Those that are assessing amyloid-modifying treatments promise to provide a better test of the amyloid hypothesis than do trials started in the clinical stages of the disease. Some of the trials aim to ascertain the extent to which biomarker effects are related to a clinical benefit, so that theragnostic endpoints might qualify for use in future licence-enabling trials. All of these trials will help in the effort to establish the scientific means and regulatory approval pathway needed to rapidly test the range of promising preclinical Alzheimer’s disease treatments. Several countries have called for national plans and major investments to address the burden of dementia, and have made considerable progress in development of those plans. The UK recently called for a coordinated global effort and hosted the first G8 Dementia Summit. We need a new standard of care for patients and family caregivers, more effective medications for patients in the clinical stages of Alzheimer’s disease, and established treatments to postpone, reduce the risk of, or completely prevent the clinical onset of Alzheimer’s disease as soon as possible.
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Eric M Reiman
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Banner Alzheimer’s Institute and Banner Research, University of Arizona College of Medicine, Translational Genomics Research Institute, and Arizona Alzheimer’s Consortium, Phoenix, AZ, USA [email protected]
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Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 2012; 367: 795–804. Fleisher AS, Chen K, Quiroz YT, et al. Florbetapir PET analysis of amyloid-β deposition in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross-sectional study. Lancet Neurol 2012; 11: 1057–65. Villemagne VL, Burnham S, Bourgeat P, et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol 2013; 12: 357–67. Knickmeyer RC, Wang J, Zhu H, et al. Common variants in psychiatric risk genes predict brain structure at birth. Cereb Cortex 2013; published online Jan 2. DOI:10.1093/cercor/bhs401. Dean CD III, Jerskey BA, Chen K, et al. Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study. JAMA Neurol 2013; published online Nov 25. DOI:10.1001/ jamaneurol.2013.4544. Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. Alzheimers Dement 2013; 9: e1–16. Chien DT, Bahri S, Szardenings AK, et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J Alzheimers Dis 2013; 34: 457–68. Okamura N, Furumoto S, Harada R, et al. Novel 18F-labeled arylquinoline derivatives for noninvasive imaging of tau pathology in Alzheimer disease. J Nucl Med 2013; 54: 1420–27. Maruyama M, Shimada H, Suhara T, et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 2013; 18: 1094–108. Chien DT, Szardenings AK, Bahri S, et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F18]-T808. J Alzheimers Dis 2014; 38: 171–84. Yanamandra K, Kfoury N, Jiang H, et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vitro. Neuron 2013; 80: 402–14. Lambert JC, Ibrahim-Verbaas CA, Harold D, et al. Meta-analysis of 74 046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 2013; published online Oct 27. DOI:10.1038/ng.2802. Jonsson T, Stefansson H, Steinberg S, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 2013; 368: 107–16. Guerreiro R, Wojtas A, Bras J, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med 2013; 368: 117–27. Kozauer N, Katz R. Regulatory innovation and drug development for early-stage Alzheimer’s disease. N Engl J Med 2013; 368: 1169–71.
My research studies are supported by the National Institute on Aging, Genentech, Avid Radiopharmaceuticals (a subsidiary of Eli Lilly), Colciencias, several philanthropic organisations, and the state of Arizona. I have served as a scientific adviser to AstraZeneca, Baxter, Bayer, Chiesi, Eisai, Elan, Novartis, Eli Lilly, GlaxoSmithKline, Novartis, Siemens, and Takeda.
Highlights in headache research in 2013 The headache specialty is huge in clinical practice but small in research. Academic groups dedicated to headache research are scarce, and funding is small relative to the huge effect of these disorders. Nonetheless, the subject has been characterised by progress on many fronts over the past few decades, and this trend continued in 2013. The most significant event was probably the publication of the third edition of the International Classification of Headache Disorders in a beta version (ICHD-3 beta).1 Since the publication of the first edition in 1988, headache has www.thelancet.com/neurology Vol 13 January 2014
been at the forefront of neurological disease classification. The new version is the result of more than 100 experts working for more than 3 years, and contains many improvements. New diagnostic criteria for migraine with aura and chronic migraine have been recognised within the main body of the classification. Many changes have been made to so-called other primary headaches, such as hypnic headache, cough-induced headache, and exercise-induced headache. The biggest change to the classification is in secondary headaches, which can now be diagnosed at the first patient encounter rather than only 5
Trial in Lobar Intracerebral Haemorrhage (STICH-II)12 showed that early surgical clot evacuation did not result in more favourable outcome or lower death rate at 6 months. Subanalysis from the trial, however, suggests that patients with poor prognosis (Glasgow coma scale 9–12) could benefit from early surgery, whereas those with good prognosis are better off with watchful waiting. Further evidence from two ongoing trials using minimally invasive procedures to reduce the haematoma (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage-III: CLEARIII and Minimally Invasive Surgery Plus rt-PA for ICH Evacuation-III: MISTIE-III) is eagerly awaited. Moving to secondary prevention, the specialty received controversial results from two large randomised controlled trials. Results of the Clopidogrel in HighRisk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE)13 trial showed superiority of the combination of clopidogrel and aspirin versus aspirin alone for reduction of the risk of recurrent stroke in the first 3 months after non-disabling stroke or transient ischaemic attack, without increasing haemorrhage risk. However, the Secondary Prevention of Small Subcortical Strokes (SPS3)14 trial provided contrasting results: the addition of clopidogrel to aspirin for a mean of 3·4 years resulted in more bleeding and death without reduction of stroke recurrence. Based on these results, there is no evidence to support aspirin plus clopidogrel for longterm stroke prevention; however, the CHANCE trial, and results of this combination given for several months in high-risk patients with symptomatic intracranial stenosis,15 suggest that ongoing studies of shortterm aspirin plus clopidogrel will establish efficacy of combination treatment after transient ischaemic attack, after minor stroke, and in other high-risk groups.
Amrou Sarraj, *James C Grotta Department of Neurology University of Texas-Houston, 6410 Fannin Street, Houston, TX, 77030, USA [email protected] We declare that we have no conflicts of interest. 1
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Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999; 282: 2003–11. Broderick JP, Palesch YY, Demchuk AM, et al, for the Interventional Management of Stroke (IMS) III Investigators. Endovascular therapy after intravenous t-PA vs t-PA alone for stroke. N Engl J Med 2013; 368: 893–903. Ciccone A, Valvassori L, Nichelatti M, et al, for the SYNTHESIS Expansion Investigators. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013; 368: 904–13. Kidwell CS, Jahan R, Gornbein J, et al, for the MR RESCUE Investigators. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013; 368: 914–23. Saver JL, Jahan R, Levy EI, et al, for the SWIFT Trialists. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet 2012; 380: 1241–49. Nogueira RG, Lutsep HL, Gupta R, et al, for the TREVO2 trialists. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. Lancet 2012; 380: 1231–40. Sarraj A, Albright K, Barreto AD, et al. Optimizing prediction scores for poor outcome after intra-arterial therapy in anterior circulation acute ischemic stroke. Stroke 2013; published online Aug 8. DOI:10.1161/ STROKEAHA.113.001050. Weber JE, Ebinger M, Rozanski M, et al. Prehospital thrombolysis in acute stroke: results of the PHANTOM-S pilot study. Neurology 2013; 80: 163–68. Walter S, Kostopoulos P, Haass A, et al. Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial. Lancet Neurol 2012; 11: 397–404. Pancioli AM, Adeoye O, Schmit PA, et al. The Combined Approach to Lysis Utilizing Eptifibatide and recombinant tissue plasminogen activator in Acute Ischemic Stroke-Enhanced Regimen Stroke Trial (CLEAR-ER). Stroke 2013; 44: 2381–87. Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013; 368: 2355–65. Mendelow AD, Gregson BA, Rowan EN, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet 2013; 382: 397–408. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013; 369: 11–19. SPS3 Investigators, Benavente OR, Hart RG. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med 2012; 367: 817–25. Chimowitz MI, Lynn MJ, Derdeyn CP, et al for the SAMPRISS investigators. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011; 365: 993–1003.
Alzheimer’s disease and other dementias: advances in 2013 2013 was marked by substantial progress and a simmering resolve to address dementia in a deliberate, collaborative, and effective way. Researchers continue to characterise biomarker trajectories in the preclinical, mild cognitive impairment, and dementia stages of Alzheimer’s disease. For example, studies suggest that fibrillar amyloid-β deposition begins more than two decades www.thelancet.com/neurology Vol 13 January 2014
before the onset of dementia.1–3 Results of MRI studies showed structural brain differences in infant ApoE e4 allele carriers and non-carriers, raising questions about the effect of neurodevelopmental factors on the subsequent pathogenesis of Alzheimer’s disease.4,5 A task force proposed criteria for the use of amyloid-β PET scans in clinical settings, seeking to limit use to situations most likely to have a clinically meaningful 3
Henny Allis/Science Photo Library
2013 Round-up
effect.6 The United States Centers for Medicare and Medicaid Services (CMS) reviewed these and other stakeholder recommendations and acknowledged the technology’s promise, but noted that empirical evidence is still needed to show the effect of amyloid-β PET on health outcomes. Reimbursement will be limited to scans acquired under the auspices of CMS-approved studies that assess the effect of the technology on health outcomes or differential diagnosis, or to enrich therapeutic trials in the clinical or preclinical stages of Alzheimer’s disease. Several PET ligands have shown promise in the assessment of tau pathology.7–10 Studies are needed to validate their affinity and specificity for tau aggregates in patients with Alzheimer’s disease, clarify their affinity for the slightly different tau aggregates in patients with other tauopathies, understand correlations between antemortem and post-mortem measurements, and use them in the detection and tracking of disease and the assessment of disease-modifying treatments. Studies continue to support the possibility that extracellular tau aggregates mediate the trans-neuronal propagation of tau pathology and provide a potentially accessible target for tau immunisation therapies, some of which are now in development for the treatment of Alzheimer’s disease and other tauopathies. In elegant experiments,11 anti-tau antibodies inhibited the cellular uptake and intracellular seeding of tau aggregates, and reduced phospho-tau burden and microgliosis in a mouse model of tau pathology. 4
Researchers have characterised about 20 Alzheimer’ssusceptibility genes,12 are poised to identify many more, and have begun to use this information to help clarify disease mechanisms and discover new treatment strategies. For example, rare variants of the TREM2 gene have been associated with risk of Alzheimer’s disease13,14 and other neurodegenerative diseases. The gene encodes a receptor protein that promotes phagocytosis and inhibits a cytokine-mediated inflammatory response; the protein is expressed in microglia and other immune cells, encouraging researchers to target relevant elements of the microglial-mediated inflammatory response in the discovery of new treatments for these diseases. Although clinical trials have had tribulations, they have also provided valuable pharmacodynamic, biomarker, and safety data, glimmers of hope, and lessons about the design of future trials. A view is emerging that some of the putative treatments now in development might need to be started in the preclinical stages to achieve a benefit. The US Food and Drug Administration has issued an encouraging draft guidance to industry on development of treatments for early Alzheimer’s disease and has been meeting with investigators to help advance the assessment of preclinical treatments in the most appropriate way.15 Researchers have begun to establish biomarker and cognitive endpoints to assess preclinical interventions. Representatives from academia and industry, regulatory and funding agencies, and advocacy organisations—such as those representing patients and families—have been meeting to navigate uncharted territory, vet a range of scientific, ethical, regulatory, and practical issues, and find new ways to work together in support of common goals. Registries are being developed to help accelerate enrolment in prevention trials. Efforts have been made to help to compare data and findings from different trials, and to secure agreements to make the data and biological samples available to the research community after the prevention trials are over. Several prevention trials are now underway and others are planned using biomarker, cognitive, or clinical endpoints, or a combination, in cognitively unimpaired individuals who, based on their genetic or biomarker features and age, are at increased risk for the clinical onset of Alzheimer’s disease. Some of the trials are supported by a combination of public and private resources, and others by industry alone. In addition to testing putative www.thelancet.com/neurology Vol 13 January 2014
2013 Round-up
disease-modifying treatments in preclinical Alzheimer’s disease, some of the trials have additional goals. Those that are assessing amyloid-modifying treatments promise to provide a better test of the amyloid hypothesis than do trials started in the clinical stages of the disease. Some of the trials aim to ascertain the extent to which biomarker effects are related to a clinical benefit, so that theragnostic endpoints might qualify for use in future licence-enabling trials. All of these trials will help in the effort to establish the scientific means and regulatory approval pathway needed to rapidly test the range of promising preclinical Alzheimer’s disease treatments. Several countries have called for national plans and major investments to address the burden of dementia, and have made considerable progress in development of those plans. The UK recently called for a coordinated global effort and hosted the first G8 Dementia Summit. We need a new standard of care for patients and family caregivers, more effective medications for patients in the clinical stages of Alzheimer’s disease, and established treatments to postpone, reduce the risk of, or completely prevent the clinical onset of Alzheimer’s disease as soon as possible.
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Eric M Reiman
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Banner Alzheimer’s Institute and Banner Research, University of Arizona College of Medicine, Translational Genomics Research Institute, and Arizona Alzheimer’s Consortium, Phoenix, AZ, USA [email protected]
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Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 2012; 367: 795–804. Fleisher AS, Chen K, Quiroz YT, et al. Florbetapir PET analysis of amyloid-β deposition in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross-sectional study. Lancet Neurol 2012; 11: 1057–65. Villemagne VL, Burnham S, Bourgeat P, et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol 2013; 12: 357–67. Knickmeyer RC, Wang J, Zhu H, et al. Common variants in psychiatric risk genes predict brain structure at birth. Cereb Cortex 2013; published online Jan 2. DOI:10.1093/cercor/bhs401. Dean CD III, Jerskey BA, Chen K, et al. Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study. JAMA Neurol 2013; published online Nov 25. DOI:10.1001/ jamaneurol.2013.4544. Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. Alzheimers Dement 2013; 9: e1–16. Chien DT, Bahri S, Szardenings AK, et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J Alzheimers Dis 2013; 34: 457–68. Okamura N, Furumoto S, Harada R, et al. Novel 18F-labeled arylquinoline derivatives for noninvasive imaging of tau pathology in Alzheimer disease. J Nucl Med 2013; 54: 1420–27. Maruyama M, Shimada H, Suhara T, et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 2013; 18: 1094–108. Chien DT, Szardenings AK, Bahri S, et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F18]-T808. J Alzheimers Dis 2014; 38: 171–84. Yanamandra K, Kfoury N, Jiang H, et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vitro. Neuron 2013; 80: 402–14. Lambert JC, Ibrahim-Verbaas CA, Harold D, et al. Meta-analysis of 74 046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 2013; published online Oct 27. DOI:10.1038/ng.2802. Jonsson T, Stefansson H, Steinberg S, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 2013; 368: 107–16. Guerreiro R, Wojtas A, Bras J, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med 2013; 368: 117–27. Kozauer N, Katz R. Regulatory innovation and drug development for early-stage Alzheimer’s disease. N Engl J Med 2013; 368: 1169–71.
My research studies are supported by the National Institute on Aging, Genentech, Avid Radiopharmaceuticals (a subsidiary of Eli Lilly), Colciencias, several philanthropic organisations, and the state of Arizona. I have served as a scientific adviser to AstraZeneca, Baxter, Bayer, Chiesi, Eisai, Elan, Novartis, Eli Lilly, GlaxoSmithKline, Novartis, Siemens, and Takeda.
Highlights in headache research in 2013 The headache specialty is huge in clinical practice but small in research. Academic groups dedicated to headache research are scarce, and funding is small relative to the huge effect of these disorders. Nonetheless, the subject has been characterised by progress on many fronts over the past few decades, and this trend continued in 2013. The most significant event was probably the publication of the third edition of the International Classification of Headache Disorders in a beta version (ICHD-3 beta).1 Since the publication of the first edition in 1988, headache has www.thelancet.com/neurology Vol 13 January 2014
been at the forefront of neurological disease classification. The new version is the result of more than 100 experts working for more than 3 years, and contains many improvements. New diagnostic criteria for migraine with aura and chronic migraine have been recognised within the main body of the classification. Many changes have been made to so-called other primary headaches, such as hypnic headache, cough-induced headache, and exercise-induced headache. The biggest change to the classification is in secondary headaches, which can now be diagnosed at the first patient encounter rather than only 5