Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Imaging tau and amyloid-β proteinopathies in Alzheimer disease and other conditions

An Author Correction to this article was published on 07 June 2018

This article has been updated

Key Points

  • The clinical phenotypes of patients with proteinopathies do not always enable identification of the underlying cause of the disorder, especially in early disease

  • By contrast, biochemical and imaging biomarkers can identify, even at presymptomatic stages, the underlying proteinopathy likely to cause the disease

  • Imaging biomarkers of pathology and neuronal injury can also help to stage these diseases

  • Amyloid-β and tau imaging studies can aid in patient selection, assess target engagement and monitor intervention efficacy in disease-specific treatment trials

  • Incorporation of biochemical and imaging biomarkers into new diagnostic criteria for Alzheimer disease offers a rational and flexible diagnostic approach that does not require the presence of dementia

  • Integration of biochemical and imaging biomarker findings with cognitive assessment is also expected to improve the predictive paradigm for Alzheimer disease

Abstract

Most neurodegenerative disorders are associated with aggregated protein deposits. In the case of Alzheimer disease (AD), extracellular amyloid-β (Aβ) aggregates and intracellular tau neurofibrillary tangles are the two neuropathological hallmarks of the disease. Aβ-PET imaging has already been approved for clinical use and is being used in clinical trials of anti-Aβ therapies both for patient recruitment and as an outcome measure. These studies have shown that Aβ accumulation is a protracted process that can extend for more than 2 decades before the onset of clinical AD. This Review describes how in vivo brain imaging of Aβ pathology has revolutionized the evaluation of patients with clinical AD by providing robust and reproducible statements of global or regional brain Aβ burden and enabling the monitoring of disease progression. The role of selective tau imaging is discussed, focusing on how longitudinal tau and Aβ imaging studies might reveal the various effects (sequential and/or parallel, independent and/or synergistic) of these proteins on progression, cognition and other disease-specific biomarkers of neurodegeneration. Finally, imaging studies are discussed in the context of elucidating the respective roles of Aβ and tau in AD and in advancing our understanding of the relationship and/or interplay between these two proteinopathies.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Chemical structures of the most widely used Aβ tracers and tau tracers.
Figure 2: Aβ-PET scans obtained using different tracers.
Figure 3: Tau imaging.

Similar content being viewed by others

Change history

  • 07 June 2018

    In Figure 1 of this article as originally published, the chemical structure at bottom right was incorrectly labelled 18F-PM-PBB3. The text label has been corrected to 18F-PBB3 in the PDF and HTML versions of the article. As of this date, the structure of PM-PBB3 (also known as APN-1607) has not yet been published.

References

  1. O'Brien, J., Ames, D. & Burns, A. Dementia 2nd edn (Arnold, 2000).

    Google Scholar 

  2. Sperling, R. A. et al. The A4 study: stopping AD before symptoms begin? Sci. Transl Med. 6, 228fs13 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Sperling, R. A., Jack, C. R. Jr & Aisen, P. S. Testing the right target and right drug at the right stage. Sci. Transl Med. 3, 111cm33 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Jellinger, K. in Alzheimer Disease: Epidemiology, Neuropathology, Neurochemistry, and Clinics. (eds Maurer, K. et al.) 61–77 (Springer, 1990).

    Book  Google Scholar 

  5. Masters, C. L. in Dementia 3rd edn (eds Burns, A. et al.) 393–407 (Hodder Arnold, 2005).

    Google Scholar 

  6. Eberling, J. L., Dave, K. D. & Frasier, M. A. α-Synuclein imaging: a critical need for Parkinson's disease research. J. Parkinson' Dis. 3, 565–567 (2013).

    CAS  Google Scholar 

  7. Honer, M. et al. in Human Amyloid Imaging Handbook 48. Presented at 7th Human Amyloid Imaging conference (Miami, USA, 2013).

    Google Scholar 

  8. Khachaturian, Z. S. Diagnosis of Alzheimer's disease. Arch. Neurol. 42, 1097–1105 (1985).

    Article  CAS  PubMed  Google Scholar 

  9. Masters, C. L., Cappai, R., Barnham, K. J. & Villemagne, V. L. Molecular mechanisms for Alzheimer's disease: implications for neuroimaging and therapeutics. J. Neurochem. 97, 1700–1725 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Isacson, O., Seo, H., Lin, L., Albeck, D. & Granholm, A. C. Alzheimer's disease and Down's syndrome: roles of APP, trophic factors and ACh. Trends Neurosci. 25, 79–84 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Petersen, R. C. Mild cognitive impairment: transition between aging and Alzheimer's disease. Neurologia 15, 93–101 (2000).

    CAS  PubMed  Google Scholar 

  12. Petersen, R. C. et al. Mild cognitive impairment: clinical characterization and outcome. Arch. Neurol. 56, 303–308 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Winblad, B. et al. Mild cognitive impairment — beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J. Intern. Med. 256, 240–246 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Farrer, L. A. et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278, 1349–1356 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Morris, J. C. et al. APOE predicts amyloid-β but not tau Alzheimer pathology in cognitively normal aging. Ann. Neurol. 67, 122–131 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Reiman, E. M. et al. Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proc. Natl Acad. Sci. USA 106, 6820–6825 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rowe, C. C. et al. Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol. Aging 31, 1275–1283 (2010).

    Article  PubMed  Google Scholar 

  18. Ossenkoppele, R. et al. Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA 313, 1939–1949 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Villemagne, V. L. et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol. 12, 357–367 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. McKhann, G. M. et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 263–269 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Dubois, B. et al. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol. 9, 1118–1127 (2010).

    Article  PubMed  Google Scholar 

  22. Villemagne, V. L. et al. in Aβ Peptide and Alzheimer's Disease (eds Barrow, C. J. & Small, B. J.) 5–32 (Springer, 2006).

    Google Scholar 

  23. Hardy, J. Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci. 20, 154–159 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Johnson, K. A. 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. 9, E1–E16 (2013).

    Article  Google Scholar 

  25. Apostolova, L. G. et al. Critical review of the Appropriate Use Criteria for amyloid imaging: effect on diagnosis and patient care. Alzheimers Dement. 5, 15–22 (2016).

    Google Scholar 

  26. Villemagne, V. L. & Rowe, C. C. Amyloid PET ligands for dementia. PET Clin. 5, 33–53 (2010).

    Article  PubMed  Google Scholar 

  27. Lister-James, J. et al. Florbetapir F-18: a histopathologically validated β-amyloid positron emission tomography imaging agent. Semin. Nucl. Med. 41, 300–304 (2011).

    Article  PubMed  Google Scholar 

  28. Sperling, R. A. et al. Amyloid deposition detected with florbetapir F 18 (18F-AV-45) is related to lower episodic memory performance in clinically normal older individuals. Neurobiol. Aging 34, 822–831 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Fleisher, A. S. et al. Using positron emission tomography and florbetapir F18 to image cortical amyloid in patients with mild cognitive impairment or dementia due to Alzheimer disease. Arch. Neurol. 68, 1404–1411 (2011).

    Article  PubMed  Google Scholar 

  30. Doraiswamy, P. M. et al. Amyloid-β assessed by florbetapir F 18 PET and 18-month cognitive decline: a multicenter study. Neurology 79, 1636–1644 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Doraiswamy, P. M. et al. Florbetapir F 18 amyloid PET and 36-month cognitive decline:a prospective multicenter study. Mol. Psychiatry 19, 1044–1051 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Clark, C. M. et al. Use of florbetapir-PET for imaging β-amyloid pathology. JAMA 305, 275–283 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Clark, C. M. et al. Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-β plaques: a prospective cohort study. Lancet Neurol. 11, 669–678 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Camus, V. et al. Using PET with 18F-AV-45 (florbetapir) to quantify brain amyloid load in a clinical environment. Eur. J. Nucl. Med. Mol. Imag. 39, 621–631 (2012).

    Article  CAS  Google Scholar 

  35. Zhang, W. et al. F-18 stilbenes as PET imaging agents for detecting β-amyloid plaques in the brain. J. Med. Chem. 48, 5980–5988 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fodero-Tavoletti, M. T. et al. In vitro characterisation of 18F-florbetaben, an Aβ imaging radiotracer. Nucl. Med. Biol. 39, 1042–1048 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Villemagne, V. L. et al. Amyloid imaging with 18F-florbetaben in Alzheimer disease and other dementias. J. Nucl. Med. 52, 1210–1217 (2011).

    Article  PubMed  Google Scholar 

  38. Rowe, C. C. et al. Imaging of amyloid β in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism. Lancet Neurol. 7, 129–135 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Barthel, H. et al. Cerebral amyloid-β PET with florbetaben (18F) in patients with Alzheimer's disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol. 10, 424–435 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Sabri, O. et al. Florbetaben PET imaging to detect amyloid β plaques in Alzheimer's disease: phase 3 study. Alzheimers Dement. 11, 964–974 (2015).

    Article  PubMed  Google Scholar 

  41. Ong, K. et al. 18F-florbetaben Aβ imaging in mild cognitive impairment. Alzheimers Res. Ther. 5, 4 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ong, K. T. et al. Aβ imaging with 18F-florbetaben in prodromal Alzheimer's disease: a prospective outcome study. J. Neurol. Neurosurg. Psychiatry 86, 431–436 (2015).

    Article  PubMed  Google Scholar 

  43. Serdons, K. et al. Synthesis of 18F-labelled 2-(4′-fluorophenyl)-1,3-benzothiazole and evaluation as amyloid imaging agent in comparison with [11C]PIB. Bioorg. Med. Chem. Lett. 19, 602–605 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Vandenberghe, R. et al. 18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trial. Ann. Neurol. 68, 319–329 (2010).

    Article  PubMed  Google Scholar 

  45. Nelissen, N. et al. Phase 1 study of the Pittsburgh compound B derivative 18F-flutemetamol in healthy volunteers and patients with probable Alzheimer disease. J. Nucl. Med. 50, 1251–1259 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Thurfjell, L. et al. Combination of biomarkers: PET [18F]flutemetamol imaging and structural MRI in dementia and mild cognitive impairment. Neurodegener. Dis. 10, 246–249 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. Wolk, D. A. et al. Association between in vivo fluorine 18-labeled flutemetamol amyloid positron emission tomography imaging and in vivo cerebral cortical histopathology. Arch. Neurol 68, 1398–1403 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Curtis, C. et al. Phase 3 trial of flutemetamol labeled with radioactive fluorine 18 imaging and neuritic plaque density. JAMA Neurol. 72, 287–294 (2015).

    Article  PubMed  Google Scholar 

  49. Ye, L. et al. Delineation of positron emission tomography imaging agent binding sites on β-amyloid peptide fibrils. J. Biol. Chem. 280, 23599–23604 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Cohen, A. D. et al. Using Pittsburgh compound B for in vivo PET imaging of fibrillar amyloid-β. Adv. Pharmacol 64, 27–81 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Braak, H. & Braak, E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18, 351–357 (1997).

    Article  CAS  PubMed  Google Scholar 

  52. Ikonomovic, M. D. et al. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease. Brain 131, 1630–1645 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Villemagne, V. L. et al. 11C-PiB PET studies in typical sporadic Creutzfeldt–Jakob disease. J. Neurol. Neurosurg. Psychiatry 80, 998–1001 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Sojkova, J. et al. In vivo fibrillar β-amyloid detected using [11C]PiB positron emission tomography and neuropathologic assessment in older adults. Arch. Neurol. 68, 232–240 (2011).

    PubMed  PubMed Central  Google Scholar 

  55. Sabbagh, M. N. et al. Positron emission tomography and neuropathologic estimates of fibrillar amyloid-β in a patient with Down syndrome and Alzheimer disease. Arch. Neurol. 68, 1461–1466 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Wong, D. F. et al. An in vivo evaluation of cerebral cortical amyloid with [18F]flutemetamol using positron emission tomography compared with parietal biopsy samples in living normal pressure hydrocephalus patients. Mol. Imag. Biol. 15, 230–237 (2012).

    Article  Google Scholar 

  57. Arnold, S. E., Han, L. Y., Clark, C. M., Grossman, M. & Trojanowski, J. Q. Quantitative neurohistological features of frontotemporal degeneration. Neurobiol. Aging 21, 913–919 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Naslund, J. et al. Correlation between elevated levels of amyloid β-peptide in the brain and cognitive decline. JAMA 283, 1571–1577 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Ni, R., Gillberg, P. G., Bergfors, A., Marutle, A. & Nordberg, A. Amyloid tracers detect multiple binding sites in Alzheimer's disease brain tissue. Brain 136, 2217–2227 (2013).

    Article  PubMed  Google Scholar 

  60. Klunk, W. E. et al. Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J. Neurosci. 27, 6174–6184 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Villemagne, V. L. et al. High striatal amyloid β-peptide deposition across different autosomal Alzheimer disease mutation types. Arch. Neurol. 66, 1537–1544 (2009).

    Article  PubMed  Google Scholar 

  62. Koivunen, J. et al. PET amyloid ligand [11C]PIB uptake shows predominantly striatal increase in variant Alzheimer's disease. Brain 131, 1845–1853 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Ng, S. Y., Villemagne, V. L., Masters, C. L. & Rowe, C. C. Evaluating atypical dementia syndromes using positron emission tomography with carbon 11 labeled Pittsburgh compound B. Arch. Neurol. 64, 1140–1144 (2007).

    Article  PubMed  Google Scholar 

  64. Formaglio, M. et al. In vivo demonstration of amyloid burden in posterior cortical atrophy: a case series with PET and CSF findings. J. Neurol. 258, 1841–1851 (2011).

    Article  PubMed  Google Scholar 

  65. Dierksen, G. A. et al. Spatial relation between microbleeds and amyloid deposits in amyloid angiopathy. Ann. Neurol. 68, 545–548 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Johnson, K. A. et al. Imaging of amyloid burden and distribution in cerebral amyloid angiopathy. Ann. Neurol. 62, 229–234 (2007).

    Article  PubMed  Google Scholar 

  67. Klunk, W. E. et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh compound-B. Ann. Neurol. 55, 306–319 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Rowe, C. C. et al. Imaging β-amyloid burden in aging and dementia. Neurology 68, 1718–1725 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Villain, N. et al. Regional dynamics of amyloid-β deposition in healthy elderly, mild cognitive impairment and Alzheimer's disease: a voxelwise PiB-PET longitudinal study. Brain 135, 2126–2139 (2012).

    Article  PubMed  Google Scholar 

  70. Villemagne, V. L. et al. Longitudinal assessment of Aβ and cognition in aging and Alzheimer disease. Ann. Neurol. 69, 181–192 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sojkova, J. et al. Longitudinal patterns of β-amyloid deposition in nondemented older adults. Arch. Neurol. 68, 644–649 (2011).

    PubMed  PubMed Central  Google Scholar 

  72. Resnick, S. M. et al. Longitudinal cognitive decline is associated with fibrillar amyloid-β measured by [11C]PiB. Neurology 74, 807–815 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Jack, C. R. Jr. et al. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease. Brain 132, 1355–1365 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Okello, A. et al. Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study. Neurology 73, 754–760 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Rinne, J. O. et al. 11C-PiB PET assessment of change in fibrillar amyloid-β load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 9, 363–372 (2010).

    Article  CAS  PubMed  Google Scholar 

  76. Landau, S. M. et al. Measurement of longitudinal β-amyloid change with 18F-florbetapir PET and standardized uptake value ratios. J. Nucl. Med. 56, 567–574 (2015).

    Article  CAS  PubMed  Google Scholar 

  77. Jack, C. R. Jr. et al. Brain β-amyloid load approaches a plateau. Neurology 80, 890–896 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Vlassenko, A. G. et al. Amyloid-β plaque growth in cognitively normal adults: longitudinal [11C]Pittsburgh compound B data. Ann. Neurol. 70, 857–861 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02420756 (2017).

  80. Klunk, W. E. et al. The Centiloid project: standardizing quantitative amyloid plaque estimation by PET. Alzheimers Dement. 11, 1–15.e4 (2015).

    Article  PubMed  Google Scholar 

  81. Rowe, C. C. et al. Standardized expression of 18F-NAV4694 and 11C-PiB β-amyloid PET results with the Centiloid scale. J. Nucl. Med. 57, 1233–1237 (2016).

    Article  CAS  PubMed  Google Scholar 

  82. Rowe, C. C. et al. 18F-Florbetaben PET β-amyloid binding expressed in Centiloids. Eur. J. Nucl. Med. Mol. Imag. 44, 2053–2059 (2017).

    Article  CAS  Google Scholar 

  83. Wolk, D. A. et al. Amyloid imaging in dementias with atypical presentation. Alzheimers Dement. 8, 389–398 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Gomperts, S. N. et al. Imaging amyloid deposition in Lewy body diseases. Neurology 71, 903–910 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Johansson, A. et al. [11C]-PIB imaging in patients with Parkinson's disease: preliminary results. Parkinsonism Relat. Disord. 14, 345–347 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Edison, P. et al. Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography. J. Neurol. Neurosurg. Psychiatry 79, 1331–1338 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Kalaitzakis, M. E., Walls, A. J., Pearce, R. K. & Gentleman, S. M. Striatal Aβ peptide deposition mirrors dementia and differentiates DLB and PDD from other parkinsonian syndromes. Neurobiol. Dis. 41, 377–384 (2011).

    Article  CAS  PubMed  Google Scholar 

  88. Rabinovici, G. D. & Miller, B. L. Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management. CNS Drugs 24, 375–398 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Rabinovici, G. D. et al. 11C-PIB PET imaging in Alzheimer disease and frontotemporal lobar degeneration. Neurology 68, 1205–1212 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Drzezga, A. et al. Imaging of amyloid plaques and cerebral glucose metabolism in semantic dementia and Alzheimer's disease. Neuroimage 39, 619–633 (2008).

    Article  PubMed  Google Scholar 

  91. Engler, H. et al. In vivo amyloid imaging with PET in frontotemporal dementia. Eur. J. Nucl. Med. Mol. Imag. 35, 100–106 (2008).

    Article  Google Scholar 

  92. Rabinovici, G. D. et al. Amyloid versus FDG-PET in the differential diagnosis of AD and FTLD. Neurology 77, 2034–2042 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Rabinovici, G. D. et al. Aβ amyloid and glucose metabolism in three variants of primary progressive aphasia. Ann. Neurol. 64, 388–401 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Leyton, C. E. et al. Subtypes of progressive aphasia: application of the international consensus criteria and validation using β-amyloid imaging. Brain 134, 3030–3043 (2011).

    Article  PubMed  Google Scholar 

  95. Mackenzie, I. R., Foti, D., Woulfe, J. & Hurwitz, T. A. Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions. Brain 131, 1282–1293 (2008).

    Article  PubMed  Google Scholar 

  96. Josephs, K. A. et al. Frontotemporal lobar degeneration and ubiquitin immunohistochemistry. Neuropathol. Appl. Neurobiol. 30, 369–373 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Mintun, M. A. et al. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 67, 446–452 (2006).

    Article  CAS  PubMed  Google Scholar 

  98. Villemagne, V. L. et al. Aβ deposits in older non-demented individuals with cognitive decline are indicative of preclinical Alzheimer's disease. Neuropsychologia 46, 1688–1697 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Mormino, E. C. et al. Episodic memory loss is related to hippocampal-mediated β-amyloid deposition in elderly subjects. Brain 132, 1310–1323 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Davies, L. et al. A4 amyloid protein deposition and the diagnosis of Alzheimer's disease: prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques. Neurology 38, 1688–1693 (1988).

    Article  CAS  PubMed  Google Scholar 

  101. Forman, M. S. et al. Cortical biochemistry in MCI and Alzheimer disease: lack of correlation with clinical diagnosis. Neurology 68, 757–763 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Morris, J. C. & Price, A. L. Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer's disease. J. Mol. Neurosci. 17, 101–118 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Price, J. L. & Morris, J. C. Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease. Ann. Neurol. 45, 358–368 (1999).

    Article  CAS  PubMed  Google Scholar 

  104. Pike, K. E. et al. β-Amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer's disease. Brain 130, 2837–2844 (2007).

    Article  PubMed  Google Scholar 

  105. Lowe, V. J. et al. Comparison of 18F-FDG and PiB PET in cognitive impairment. J. Nucl. Med. 50, 878–886 (2009).

    Article  PubMed  Google Scholar 

  106. Albert, M. S. et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging — Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 270–279 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Dubois, B. et al. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 13, 614–629 (2014).

    Article  PubMed  Google Scholar 

  108. Sojkova, J. & Resnick, S. M. In vivo human amyloid imaging. Curr. Alzheimer Res. 8, 366–372 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Rabinovici, G. D. et al. Increased metabolic vulnerability in early-onset Alzheimer's disease is not related to amyloid burden. Brain 133, 512–528 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  110. de Leon, M. J. et al. Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment. Neurobiol. Aging 27, 394–401 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Blennow, K. et al. Longitudinal stability of CSF biomarkers in Alzheimer's disease. Neurosci. Lett. 419, 18–22 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Storandt, M., Head, D., Fagan, A. M., Holtzman, D. M. & Morris, J. C. Toward a multifactorial model of Alzheimer disease. Neurobiol. Aging 33, 2262–2271 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Jack, C. R. Jr. et al. 11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment. Brain 131, 665–680 (2008).

    Article  PubMed  Google Scholar 

  114. Archer, H. A. et al. Amyloid load and cerebral atrophy in Alzheimer's disease: an 11C-PIB positron emission tomography study. Ann. Neurol. 60, 145–147 (2006).

    Article  PubMed  Google Scholar 

  115. Chetelat, G. et al. Relationship between atrophy and β-amyloid deposition in Alzheimer disease. Ann. Neurol. 67, 317–324 (2010).

    CAS  PubMed  Google Scholar 

  116. Becker, J. A. et al. Amyloid-β associated cortical thinning in clinically normal elderly. Ann. Neurol. 69, 1032–1042 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Bourgeat, P. et al. β-Amyloid burden in the temporal neocortex is related to hippocampal atrophy in elderly subjects without dementia. Neurology 74, 121–127 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Tosun, D., Schuff, N., Mathis, C. A., Jagust, W. & Weiner, M. W. Spatial patterns of brain amyloid-β burden and atrophy rate associations in mild cognitive impairment. Brain 134, 1077–1088 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Drzezga, A. et al. Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden. Brain 134, 1635–1646 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Forster, S. et al. Regional expansion of hypometabolism in Alzheimer's disease follows amyloid deposition with temporal delay. Biol. Psychiatry 71, 792–797 (2011).

    Article  PubMed  CAS  Google Scholar 

  121. Chetelat, G. et al. Accelerated cortical atrophy in cognitively normal elderly with high β-amyloid deposition. Neurology 78, 477–484 (2012).

    Article  CAS  PubMed  Google Scholar 

  122. Dore, V. et al. Cross-sectional and longitudinal analysis of the relationship between Aβ deposition, cortical thickness, and memory in cognitively unimpaired individuals and in Alzheimer disease. JAMA Neurol. 70, 903–911 (2013).

    Article  PubMed  Google Scholar 

  123. Andrews, K. A. et al. Atrophy rates in asymptomatic amyloidosis: implications for Alzheimer prevention trials. PLoS ONE 8, e58816 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Andrews, K. A. et al. Acceleration of hippocampal atrophy rates in asymptomatic amyloidosis. Neurobiol. Aging 39, 99–107 (2016).

    Article  CAS  PubMed  Google Scholar 

  125. Fagan, A. M. et al. Cerebrospinal fluid tau/β-amyloid42 ratio as a prediction of cognitive decline in nondemented older adults. Arch. Neurol. 64, 343–349 (2007).

    Article  PubMed  Google Scholar 

  126. Fagan, A. M. et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans. Ann. Neurol 59, 512–519 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Fagan, A. M. et al. Cerebrospinal fluid tau and ptau181 increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer's disease. EMBO Mol. Med. 1, 371–380 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Koivunen, J. et al. PET amyloid ligand [11C]PiB uptake and cerebrospinal fluid β-amyloid in mild cognitive impairment. Dement. Geriatr. Cogn. Disord. 26, 378–383 (2008).

    Article  CAS  PubMed  Google Scholar 

  129. Forsberg, A. et al. PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol. Aging 29, 1456–1465 (2008).

    Article  CAS  PubMed  Google Scholar 

  130. Toledo, J. B., Xie, S. X., Trojanowski, J. Q. & Shaw, L. M. Longitudinal change in CSF tau and Aβ biomarkers for up to 48 months in ADNI. Acta Neuropathol. 126, 659–670 (2013).

    Article  CAS  PubMed  Google Scholar 

  131. Li, Q. X. et al. Alzheimer's disease normative cerebrospinal fluid biomarkers validated in PET amyloid-β characterized subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. J. Alzheimers Dis. 48, 175–187 (2015).

    Article  CAS  PubMed  Google Scholar 

  132. Toledo, J. B. et al. Nonlinear association between cerebrospinal fluid and florbetapir F-18 β-amyloid measures across the spectrum of Alzheimer disease. JAMA Neurol. 72, 571–581 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Landau, S. M. et al. Comparing positron emission tomography imaging and cerebrospinal fluid measurements of β-amyloid. Ann. Neurol. 74, 826–836 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Forsberg, A. et al. High PiB retention in Alzheimer's disease is an early event with complex relationship with CSF biomarkers and functional parameters. Curr. Alzheimer Res. 7, 56–66 (2010).

    Article  CAS  PubMed  Google Scholar 

  135. Tolboom, N. et al. Relationship of cerebrospinal fluid markers to 11C-PiB and 18F-FDDNP binding. J. Nucl. Med. 50, 1464–1470 (2009).

    Article  CAS  PubMed  Google Scholar 

  136. Aizenstein, H. J. et al. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch. Neurol. 65, 1509–1517 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Furst, A. J. et al. Cognition, glucose metabolism and amyloid burden in Alzheimer's disease. Neurobiol. Aging 33, 215–225 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Cohen, A. D. et al. Basal cerebral metabolism may modulate the cognitive effects of Aβ in mild cognitive impairment: an example of brain reserve. J. Neurosci. 29, 14770–14778 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Edison, P. et al. Amyloid, hypometabolism, and cognition in Alzheimer disease: an [11C]PiB and [F]FDG PET study. Neurology 68, 501–508 (2007).

    Article  CAS  PubMed  Google Scholar 

  140. Sperling, R. & Johnson, K. Pro: can biomarkers be gold standards in Alzheimer's disease? Alzheimers Res. Ther. 2, 17 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Sperling, R. A. et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging — Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 280–292 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Jack, C. R. Jr. et al. An operational approach to National Institute on Aging — Alzheimer's Association criteria for preclinical Alzheimer disease. Ann. Neurol. 71, 765–775 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Mormino, E. C. et al. Synergistic effect of β-amyloid and neurodegeneration on cognitive decline in clinically normal individuals. JAMA Neurol. 71, 1379–1385 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Vos, S. J. et al. Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study. Lancet Neurol. 12, 957–965 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  145. van Harten, A. C. et al. Preclinical AD predicts decline in memory and executive functions in subjective complaints. Neurology 81, 1409–1416 (2013).

    Article  CAS  PubMed  Google Scholar 

  146. Burnham, S. C. et al. Clinical and cognitive trajectories in cognitively healthy elderly individuals with suspected non-Alzheimer's disease pathophysiology (SNAP) or Alzheimer's disease pathology: a longitudinal study. Lancet Neurol. 15, 1044–1053 (2016).

    Article  PubMed  Google Scholar 

  147. Johnson, K. A. et al. Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann. Neurol. 79, 110–119 (2016).

    Article  PubMed  Google Scholar 

  148. Ossenkoppele, R. et al. The behavioural/dysexecutive variant of Alzheimer's disease: clinical, neuroimaging and pathological features. Brain 138, 2732–2749 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Scholl, M. et al. PET Imaging of tau deposition in the aging human brain. Neuron 89, 971–982 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Villemagne, V. L., Fodero-Tavoletti, M. T., Masters, C. L. & Rowe, C. C. Tau imaging: early progress and future directions. Lancet Neurol. 14, 114–124 (2015).

    Article  PubMed  Google Scholar 

  151. Chien, D. T. et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J. Alzheimers Dis. 34, 457–468 (2013).

    Article  CAS  PubMed  Google Scholar 

  152. Maruyama, M. et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 79, 1094–1108 (2013).

    Article  CAS  PubMed  Google Scholar 

  153. Walji, A. M. et al. Discovery of 6-(Fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([18F]-MK-6240): a positron emission tomography (PET) imaging agent for quantification of neurofibrillary tangles (NFTs). J. Med. Chem. 59, 4778–4789 (2016).

    Article  CAS  PubMed  Google Scholar 

  154. Okamura, N. et al. Characterization of [18F]THK-5351, a novel PET tracer for imaging tau pathology in Alzheimer's disease. Eur. J. Nucl. Med. Mol. Imag. 41, S260 (2014).

    Article  Google Scholar 

  155. Gobbi, L. C. et al. Identification of three novel radiotracers for imaging aggregated tau in Alzheimer's disease with positron emission tomography. J. Med. Chem. 60, 7350–7370 (2017).

    Article  CAS  PubMed  Google Scholar 

  156. Declercq, L. et al. Preclinical evaluation of 18F-JNJ64349311, a novel PET tracer for tau imaging. J. Nucl. Med. 58, 975–981 (2017).

    Article  CAS  PubMed  Google Scholar 

  157. Fawaz, M. V. et al. High affinity radiopharmaceuticals based upon lansoprazole for PET imaging of aggregated tau in Alzheimer's disease and progressive supranuclear palsy: synthesis, preclinical evaluation, and lead selection. ACS Chem. Neurosci. 5, 718–730 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Stephens, A. et al. Characterization of novel PET tracers for the assessment of tau pathology In Alzheimer's disease and other tauopathies. Neurodegener. Dis. 17 (Suppl. 1), ADPD7-0858 8-590, (2017).

    Google Scholar 

  159. Delacourte, A. et al. Tau aggregation in the hippocampal formation: an ageing or a pathological process? Exp. Gerontol. 37, 1291–1296 (2002).

    Article  CAS  PubMed  Google Scholar 

  160. Xia, C. et al. Association of in vivo [18F]AV-1451 tau PET imaging results with cortical atrophy and symptoms in typical and atypical Alzheimer disease. JAMA Neurol. 74, 427–436 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  161. van Eimeren, T., Bischof, G. N. & Drzezga, A. E. Is tau imaging more than just “upside-down” 18F-FDG imaging? J. Nucl. Med. 58, 1357–1359 (2017).

    Article  CAS  PubMed  Google Scholar 

  162. Chiotis, K. et al. Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer's disease dementia. Mol. Psychiatry https://doi.org/10.1038/mp.2017.108 (2017).

    Article  PubMed  CAS  Google Scholar 

  163. Royall, D. R. Location, location, location! Neurobiol. Aging 28, 1481–1482 (2007).

    Article  PubMed  Google Scholar 

  164. Delacourte, A. et al. The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease. Neurology 52, 1158–1165 (1999).

    Article  CAS  PubMed  Google Scholar 

  165. Pontecorvo, M. J. et al. Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition. Brain 140, 748–763 (2017).

    PubMed  PubMed Central  Google Scholar 

  166. Brier, M. R. et al. Tau and Aβ imaging, CSF measures, and cognition in Alzheimer's disease. Sci. Transl Med. 8, 338ra66 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Lockhart, S. N. et al. Dynamic PET measures of tau accumulation in cognitively normal older adults and Alzheimer's disease patients measured using [18F] THK-5351. PLoS ONE 11, e0158460 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Sarazin, M., Lagarde, J. & Bottlaender, M. Distinct tau PET imaging patterns in typical and atypical Alzheimer's disease. Brain 139, 1321–1324 (2016).

    Article  PubMed  Google Scholar 

  169. Wang, L. et al. Evaluation of tau imaging in staging Alzheimer disease and revealing interactions between β-amyloid and tauopathy. JAMA Neurol. 73, 1070–1077 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Cho, H. et al. Tau PET in Alzheimer disease and mild cognitive impairment. Neurology 87, 375–383 (2016).

    Article  CAS  PubMed  Google Scholar 

  171. Ossenkoppele, R. et al. Atrophy patterns in early clinical stages across distinct phenotypes of Alzheimer's disease. Hum. Brain Mapp. 36, 4421–4437 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Ossenkoppele, R. et al. Tau, amyloid, and hypometabolism in a patient with posterior cortical atrophy. Ann. Neurol. 77, 338–342 (2015).

    Article  CAS  PubMed  Google Scholar 

  173. Gordon, B. A. et al. The relationship between cerebrospinal fluid markers of Alzheimer pathology and positron emission tomography tau imaging. Brain 139, 2249–2260 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Tomlinson, B. E., Blessed, G. & Roth, M. Observations on the brains of demented old people. J. Neurol. Sci. 11, 205–242 (1970).

    Article  CAS  PubMed  Google Scholar 

  175. Crary, J. F. et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 128, 755–766 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Jellinger, K. A. et al. PART, a distinct tauopathy, different from classical sporadic Alzheimer disease. Acta Neuropathol. 129, 757–762 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Duyckaerts, C. et al. PART is part of Alzheimer disease. Acta Neuropathol. 129, 749–756 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Jack, C. R. Jr. PART and SNAP. Acta Neuropathol. 128, 773–776 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Josephs, K. A. et al. Tau aggregation influences cognition and hippocampal atrophy in the absence of β-amyloid: a clinico-imaging-pathological study of primary age-related tauopathy (PART). Acta Neuropathol. 133, 705–715 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Jack, C. R. Jr & Holtzman, D. M. Biomarker modeling of Alzheimer's disease. Neuron 80, 1347–1358 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Villemagne, V. L. et al. In vivo evaluation of a novel tau imaging tracer for Alzheimer's disease. Eur. J. Nucl. Med. Mol. Imag. 41, 816–826 (2014).

    Article  CAS  Google Scholar 

  182. Kantarci, K. et al. AV-1451 tau and β-amyloid positron emission tomography imaging in dementia with Lewy bodies. Ann. Neurol. 81, 58–67 (2017).

    Article  CAS  PubMed  Google Scholar 

  183. Ishiki, A. et al. Tau imaging with [18F]THK-5351 in progressive supranuclear palsy. Eur. J. Neurol. 24, 130–136 (2017).

    Article  CAS  PubMed  Google Scholar 

  184. Perez-Soriano, A. & Stoessl, A. J. Tau imaging in progressive supranuclear palsy. Mov. Disord. 32, 91–93 (2017).

    Article  PubMed  Google Scholar 

  185. Taniguchi, S. et al. The neuropathology of frontotemporal lobar degeneration with respect to the cytological and biochemical characteristics of tau protein. Neuropathol. Appl. Neurobiol. 30, 1–18 (2004).

    Article  CAS  PubMed  Google Scholar 

  186. Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).

    Article  CAS  PubMed  Google Scholar 

  187. Neumann, M. et al. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132, 2922–2931 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Mott, R. T. et al. Neuropathologic, biochemical, and molecular characterization of the frontotemporal dementias. J. Neuropathol. Exp. Neurol. 64, 420–428 (2005).

    Article  CAS  PubMed  Google Scholar 

  189. Ikonomovic, M. D., Abrahamson, E. E., Price, J. C., Mathis, C. A. & Klunk, W. E. [F-18]AV-1451 positron emission tomography retention in choroid plexus: more than “off-target” binding. Ann. Neurol. 80, 307–308 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Marquie, M. et al. Pathological correlations of [F-18]-AV-1451 imaging in non-Alzheimer tauopathies. Ann. Neurol. 81, 117–128 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Marquie, M. et al. Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann. Neurol. 78, 787–800 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Chen, R., Chen, C. P. & Preston, J. E. Effects of transthyretin on thyroxine and β-amyloid removal from cerebrospinal fluid in mice. Clin. Exp. Pharmacol. Physiol. 43, 844–850 (2016).

    Article  CAS  PubMed  Google Scholar 

  193. Wen, G. Y., Wisniewski, H. M. & Kascsak, R. J. Biondi ring tangles in the choroid plexus of Alzheimer's disease and normal aging brains: a quantitative study. Brain Res. 832, 40–46 (1999).

    Article  CAS  PubMed  Google Scholar 

  194. Lowe, V. J. et al. An autoradiographic evaluation of AV-1451 tau PET in dementia. Acta Neuropathol. Commun. 4, 58 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Mukaetova-Ladinska, E. B., Harrington, C. R., Roth, M. & Wischik, C. M. Biochemical and anatomical redistribution of tau protein in Alzheimer's disease. Am. J. Pathol. 143, 565–578 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Beach, T. G., Monsell, S. E., Phillips, L. E. & Kukull, W. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010. J. Neuropathol. Exp. Neurol. 71, 266–273 (2012).

    Article  PubMed  Google Scholar 

  197. Marquie, M. et al. [F-18]-AV-1451 binding correlates with postmortem neurofibrillary tangle Braak staging. Acta Neuropathol. 134, 619–628 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Schonhaut, D. R. et al. 18F-flortaucipir tau positron emission tomography distinguishes established progressive supranuclear palsy from controls and Parkinson disease: A multicenter study. Ann. Neurol. 82, 622–634 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Ng, K. P. et al. Monoamine oxidase B inhibitor, selegiline, reduces 18F-THK5351 uptake in the human brain. Alzheimers Res. Ther. 9, 25 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  200. Villemagne, V. L. et al. The ART of loss: Aβ imaging in the evaluation of Alzheimer's disease and other dementias. Mol. Neurobiol. 38, 1–15 (2008).

    Article  CAS  PubMed  Google Scholar 

  201. Clark, C. M. et al. Biomarkers for early detection of Alzheimer pathology. Neurosignals 16, 11–18 (2008).

    Article  CAS  PubMed  Google Scholar 

  202. Sperling, R. & Johnson, K. Biomarkers of Alzheimer disease: current and future applications to diagnostic criteria. Continuum 19, 325–338 (2013).

    PubMed  Google Scholar 

  203. Prestia, A. et al. Prediction of dementia in MCI patients based on core diagnostic markers for Alzheimer disease. Neurology 80, 1048–1056 (2013).

    Article  CAS  PubMed  Google Scholar 

  204. Jack, C. R. Jr. et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 9, 119–128 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Ossenkoppele, R., van Berckel, B. N. & Prins, N. D. Amyloid imaging in prodromal Alzheimer's disease. Alzheimers Res. Ther. 3, 26 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Hyman, B. T. Amyloid-dependent and amyloid-independent stages of Alzheimer disease. Arch. Neurol. 68, 1062–1064 (2011).

    Article  PubMed  Google Scholar 

  207. Karran, E., Mercken, M. & De Strooper, B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discov. 10, 698–712 (2011).

    Article  CAS  PubMed  Google Scholar 

  208. Roe, C. M. et al. Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later. Neurology 80, 1784–1791 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Smith, E. E. et al. Magnetic resonance imaging white matter hyperintensities and brain volume in the prediction of mild cognitive impairment and dementia. Arch. Neurol. 65, 94–100 (2008).

    PubMed  Google Scholar 

  210. Chang, C. Y. & Silverman, D. H. Accuracy of early diagnosis and its impact on the management and course of Alzheimer's disease. Expert Rev. Mol. Diagn. 4, 63–69 (2004).

    Article  PubMed  Google Scholar 

  211. Rowe, C. C. et al. Predicting Alzheimer disease with β-amyloid imaging: results from the Australian Imaging, Biomarkers, and Lifestyle study of ageing. Ann. Neurol. 74, 905–913 (2013).

    Article  CAS  PubMed  Google Scholar 

  212. Shaw, L. M., Korecka, M., Clark, C. M., Lee, V. M. & Trojanowski, J. Q. Biomarkers of neurodegeneration for diagnosis and monitoring therapeutics. Nat. Rev. Drug Discov. 6, 295–303 (2007).

    Article  CAS  PubMed  Google Scholar 

  213. Dubois, B. et al. Preclinical Alzheimer's disease: definition, natural history, and diagnostic criteria. Alzheimers Dement. 12, 292–323 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  214. Jack, C. R. Jr. et al. A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology 87, 539–547 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Wischik, C. & Staff, R. Challenges in the conduct of disease-modifying trials in AD: practical experience from a phase 2 trial of tau-aggregation inhibitor therapy. J. Nutr. Health Aging 13, 367–369 (2009).

    Article  CAS  PubMed  Google Scholar 

  216. Ostrowitzki, S. et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch. Neurol. 69, 198–207 (2011).

    Article  PubMed  Google Scholar 

  217. Sperling, R. et al. Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 11, 241–249 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Morris, J. C. & Selkoe, D. J. Recommendations for the incorporation of biomarkers into Alzheimer clinical trials: an overview. Neurobiol. Aging 32 (Suppl. 1), S1–S3 (2011).

    Article  PubMed  Google Scholar 

  219. Scheltens, P. & Rockwood, K. How golden is the gold standard of neuropathology in dementia? Alzheimers Dement. 7, 486–489 (2011).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank S. Laws, G. R. Mulligan, G. Savage, J. Robertson, S. Bozinovski, D. El-Sheikh and the Brain Research Institute for their assistance with the preparation of this Review. The authors' research work is supported in part by project grants 1044361, 1011689 and 1071430 from the National Health and Medical Research Council of Australia to C.C.R. and V.L.V.

Author information

Authors and Affiliations

Authors

Contributions

V.L.V. wrote the manuscript. V.L.V., V.D., S.C.B. and C.C.R. researched data for the article, and V.D., S.C.B., C.L.M. and C.C.R. contributed substantially to discussions of its content. All authors undertook review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Victor L. Villemagne.

Ethics declarations

Competing interests

V.L.V. declares that he has received consultancy fees from AbbVie, Hoffmann-La Roche, Lundbeck, Novartis and Shanghai Green Valley Pharmaceutical as well as honoraria for speaking from AbbVie, AstraZeneca, Avid Radiopharmaceuticals, GE Healthcare, Hoffmann-La Roche and Piramal Imaging. C.L.M. declares that he owns stock in or is a company director of Prana Biotechnology. C.C.R. declares that he has received consultancy fees from AstraZeneca, Avid Radiopharmaceuticals, Biogen, GE Healthcare and Piramal Imaging as well as honoraria for speaking from AbbVie, AstraZeneca, Avid Radiopharmaceuticals, GE Healthcare, Hoffmann-La Roche and Piramal Imaging and grants or research support from AstraZeneca, Avid Radiopharmaceuticals, Biogen, GE Healthcare and Piramal Imaging. V.D. and S.C.B. declare no competing interests.

Related links

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Villemagne, V., Doré, V., Burnham, S. et al. Imaging tau and amyloid-β proteinopathies in Alzheimer disease and other conditions. Nat Rev Neurol 14, 225–236 (2018). https://doi.org/10.1038/nrneurol.2018.9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2018.9

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research