Update Amyloid- und Tau-Bildgebung in der Diagnostik der Neurodegeneration

Zusammenfassung

Pathologische Aggregationen von bestimmten Proteinen und deren Ablagerung im Gehirn werden als eine mögliche Hauptursache vieler neurodegenerativer Erkrankungen diskutiert. Die bekanntesten Vertreter dieser Ablagerungen sind die extrazellulären Ablagerungen des ß-Amyloid-Peptids (sog. Amyloid-Plaques) und intraneuronalen Aggregationen des Tau-Proteins (sog. neurofibrilläre Tangles), welche als Kernmerkmale der Alzheimer-Erkrankung gelten.

Der histopathologische Nachweis dieser Veränderungen im Gehirngewebe post mortem stellte bislang den Goldstandard für die sichere Diagnose einer Alzheimer-Erkrankung dar. Neben der Bedeutung für die Diagnostik stehen die genannten Proteinablagerungen auch im Fokus neuer Therapieentwicklungen, da eine kausale Rolle bei der Entwicklung der Alzheimer-Demenz angenommen wird.

Neue Verfahren der molekularen Bildgebung eröffnen nun die Möglichkeit das Vorliegen dieser Neuropathologien in vivo auf nicht invasive Weise zu dokumentieren. Hinsichtlich der Amyloid-Bildgebung stehen bereits mehrere zugelassene PET-Tracer auch kommerziell zur Verfügung. Für die Amyloid-Bildgebung ist ein klinischer Nutzen in der Diagnosesicherung der Alzheimer-Demenz gerade bei atypischen und frühen Erscheinungsformen darstellbar. Zusätzlich kann die frühe Prognose im Stadium der leichten kognitiven Beschwerden optimiert werden. Bei unauffälligem Amyloid PET-Scan ist eine Alzheimer-Erkrankung als Ursache einer kognitiven Beeinträchtigung unwahrscheinlich. Hinsichtlich der Tau-Bildgebung sind bereits eine Reihe von Tracern in der Erprobung. Bisher besteht für diese Tracer noch keine Zulassung, die vorliegenden Daten sind jedoch als plausibel und vielversprechend zu bewerten. Zusammenfassend bietet die molekulare Bildgebung ein einzigartiges Potenzial für die klinische Diagnostik und Erforschung der Neurodegeneration.

Abstract

Pathological aggregations of specific proteins and their deposition in the brain is considered as a possible trigger of several neurodegenerative disorders. The best-known representatives are the extracellular depositions of the ß-amyloid peptide (amyloid-plaques) and the intraneuronal aggregations of the tau-protein (neurofibrillary tangles) both of which are hallmarks of Alzheimer’s disease.

The histopathological proof of these abnormalities in post mortem histopathological assessment of brain tissue represents the goldstandard for a definite diagnosis of Alzheimer’s disease. In addition to their importance for diagnosis, the mentionend protein aggregation pathologies are also in the focus of recent therapeutical approaches. Novel molecular imaging procedure opened the possibility to document the presence of these neuropathologies in vivo in a non-invasive fashion. With regard to imaging amyloid-plaques, several approved PET tracers are already commercially available. A clinical value of amyloid-imaging can be suggested for verification of the diagnosis “dementia due to Alzheimer’s disease”, particularly in clinically atypical or early onset cases. Furthermore, early prognosis can be optimized in stages with mild cognitive impairment. The exclusion of Alzheimer pathology as the probable reason of cognitive impairment by means of a normal amyloid-scan is of high clinical relevance.

A number of PET-tracers for tau-imaging is currently under investigation. These tracers are not yet approved or commercially available, however first results are very promising and plausible. In summary, molecular imaging offers unique potential for improved clinical diagnosis and exploration of neurodegenerative disorders.

Schlüsselwörter

Alzheimer-Demenz - Amyloid-Bildgebung - Tau-Bildgebung - PET - ß-Amyloid - Tau - Plaques - Tangles

Key words

Alzheimer‘s dementia - Amyloid imaging - Tau imaging - PET - Βeta-amyloid - Tau - Plaques - Tangles

• Literatur

• 1 Alafuzoff I. The pathology of dementias: an overview. Acta Neurol Scand Suppl 1992; 139: 8-15
• 2 Albert MS, DeKosky ST, Dickson D 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 2011; 7: 270-279
• 3 Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Vortrag in der Versammlung Südwestdeutscher Irrenärzte in Tübingen am 3. November 1906. Allgemeine Zeitschrift für Psychiatrie und psychisch-gerichtliche Medizin 1907; 64: 146-148
• 4 Bacskai BJ, Frosch MP, Freeman SH et al. Molecular imaging with Pittsburgh Compound B confirmed at autopsy: a case report. Arch Neurol 2007; 64: 431-434
• 5 Barthel H, Gertz HJ, Dresel S et al. Cerebral amyloid-beta PET with florbetaben (18F) in patients with Alzheimer’s disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol 2011; 10: 424-435
• 6 Barthel H, Meyer PT, Drzezga A et al. German Society of Nuclear Medicine procedure guideline on beta-amyloid brain PET imaging. Nuklearmedizin 2016; 55: 129-137
• 7 Bischof GN, Jessen F, Fliessbach K et al. Impact of Tau and Amyloid Burden on Glucose Metabolism in Alzheimer’s Disease. Ann Clin Transl Neurol 2016 [in press]
• 8 Bonner MF, Ash S, Grossman M. The new classification of primary progressive aphasia into semantic, logopenic, or nonfluent/agrammatic variants. Curr Neurol Neurosci Rep 2010; 10: 484-490
• 9 Braak E, Griffing K, Arai K et al. Neuropathology of Alzheimer’s disease: what is new since A. Alzheimer?. Eur Arch Psychiatry Clin Neurosci 1999; 249 (Suppl. 03) 14-22
• 10 Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 1997; 18: 351-357
• 11 Castello MA, Jeppson JD, Soriano S. Moving beyond anti-amyloid therapy for the prevention and treatment of Alzheimer’s disease. BMC Neurol 2014; 14: 169
• 12 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: 457-468
• 13 Clark CM, Schneider JA, Bedell BJ et al. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 2011; 305: 275-283
• 14 Crutch SJ, Lehmann M, Schott JM et al. Posterior cortical atrophy. Lancet Neurol 2012; 11: 170-178
• 15 Davies L, Wolska B, Hilbich C 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 1988; 38: 1688-1693
• 16 Davies RR, Hodges JR, Kril JJ et al. The pathological basis of semantic dementia. Brain 2005; 128: 1984-1995
• 17 de Souza LC, Corlier F, Habert MO et al. Similar amyloid-beta burden in posterior cortical atrophy and Alzheimer’s disease. Brain 2011; 134: 2036-2043
• 18 Deuschl G, Maier W et al. S3-Leitlinie Demenzen. 2016. In: Deutsche Gesellschaft für Neurologie. 2016; (Hrsg.). Leitlinien für Diagnostik und Therapie in der Neurologie
• 19 Diehl-Schmid J, Grimmer T, Drzezga A et al. Longitudinal changes of cerebral glucose metabolism in semantic dementia. Dement Geriatr Cogn Disord 2006; 22: 346-351
• 20 Drzezga A. Amyloid-plaque imaging in early and differential diagnosis of dementia. Ann Nucl Med 2010; 24: 55-66
• 21 Drzezga A, Becker JA, Van Dijk KR et al. Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden. Brain 2011; 134: 1635-1646
• 22 Drzezga A, Grimmer T, Henriksen G et al. Imaging of amyloid plaques and cerebral glucose metabolism in semantic dementia and Alzheimer’s disease. Neuroimage 2008; 39: 619-633
• 23 Dubois B, Feldman HH, Jacova C et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007; 6: 734-746
• 24 Edison P, Rowe CC, Rinne JO et al. Amyloid load in Parkinson’s disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography. J Neurol Neurosurg Psychiatry 2008; 79: 1331-1338
• 25 Engler H, Forsberg A, Almkvist O et al. Two-year follow-up of amyloid deposition in patients with Alzheimer’s disease. Brain 2006; 129: 2856-2866
• 26 Fleisher AS, Chen K, Liu X 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 2011; 68: 1404-1411
• 27 Formaglio M, Costes N, Seguin J et al. In vivo demonstration of amyloid burden in posterior cortical atrophy: a case series with PET and CSF findings. J Neurol 2011; 258: 1841-1851
• 28 Forsberg A, Engler H, Almkvist O et al. PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging 2008; 29: 1456-1465
• 29 Grimmer T, Tholen S, Yousefi BH et al. Progression of cerebral amyloid load is associated with the apolipoprotein E epsilon4 genotype in Alzheimer’s disease. Biol Psychiatry 2010; 68: 879-884
• 30 Grossman M. Primary progressive aphasia: clinicopathological correlations. Nat Rev Neurol 2010; 6: 88-97
• 31 Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 1992; 256: 184-185
• 32 Hebert LE, Weuve J, Scherr PA et al. Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology 2013; 80: 1778-1783
• 33 Hedden T, Van Dijk KR, Becker JA et al. Disruption of functional connectivity in clinically normal older adults harboring amyloid burden. J Neurosci 2009; 29: 12686-12694
• 34 Herrmann N, Chau SA, Kircanski I et al. Current and emerging drug treatment options for Alzheimer’s disease: a systematic review. Drugs 2011; 71: 2031-2065
• 35 Ikeda M, Ishikawa T, Tanabe H. Epidemiology of frontotemporal lobar degeneration. Dement Geriatr Cogn Disord 2004; 17: 265-268
• 36 Ikonomovic MD, Klunk WE, Abrahamson EE et al. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease. Brain 2008; 131: 1630-1645
• 37 Ishii K. Clinical application of positron emission tomography for diagnosis of dementia. Ann Nucl Med 2002; 16: 515-525
• 38 Jansen WJ, Ossenkoppele R, Knol DL et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 2015; 313: 1924-1938
• 39 Johnson JK, Diehl J, Mendez MF et al. Frontotemporal lobar degeneration: demographic characteristics of 353 patients. Arch Neurol 2005; 62: 925-930
• 40 Johnson JK, Head E, Kim R et al. Clinical and pathological evidence for a frontal variant of Alzheimer disease. Arch Neurol 1999; 56: 1233-1239
• 41 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. J Nucl Med 2013; 54: 476-490
• 42 Johnson KA, Schultz A, Betensky RA et al. Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol 2016; 79: 110-119
• 43 Kadir A, Marutle A, Gonzalez D et al. Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer’s disease. Brain 2011; 134: 301-317
• 44 Klunk WE, Engler H, Nordberg A et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 2004; 55: 306-319
• 45 Klunk WE, Koeppe RA, Price JC et al. The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET. Alzheimers Dement 2015; 11: 1-15 e11–e14
• 46 Koivunen J, Scheinin N, Virta JR et al. Amyloid PET imaging in patients with mild cognitive impairment: a 2-year follow-up study. Neurology 2011; 76: 1085-1090
• 47 Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci 2001; 24: 1121-1159
• 48 Leinonen V, Alafuzoff I, Aalto S et al. Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by positron emission tomography with carbon 11-labeled Pittsburgh Compound B. Arch Neurol 2008; 65: 1304-1309
• 49 McKeith IG, Dickson DW, Lowe J et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005; 65: 1863-1872
• 50 McKhann GM, Knopman DS, Chertkow H 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 2011; 7: 263-269
• 51 Mesulam M, Wieneke C, Rogalski E et al. Quantitative template for subtyping primary progressive aphasia. Arch Neurol 2009; 66: 1545-1551
• 52 Minoshima S, Drzezga AE, Barthel H et al. SNMMI Procedure Standard/EANM Practice Guideline for Amyloid PET Imaging of the Brain 1,0. J Nucl Med 2016; 57: 1316-1322
• 53 Mormino EC, Kluth JT, Madison CM et al. Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects. Brain 2009; 132: 1310-1323
• 54 Morris GP, Clark IA, Vissel B. Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease. Acta Neuropathol Commun 2014; 2: 135
• 55 Neary D, Snowden JS, Gustafson L et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51: 1546-1554
• 56 Neary D, Snowden JS, Mann DM. Classification and description of frontotemporal dementias. Ann N Y Acad Sci 2000; 920: 46-51
• 57 Nelson PT, Alafuzoff I, Bigio EH et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 2012; 71: 362-381
• 58 Nestor PJ, Caine D, Fryer TD et al. The topography of metabolic deficits in posterior cortical atrophy (the visual variant of Alzheimer’s disease) with FDG-PET. J Neurol Neurosurg Psychiatry 2003; 74: 1521-1529
• 59 Neumann M, Sampathu DM, Kwong LK et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006; 314: 130-133
• 60 Nordberg A, Carter SF, Rinne J et al. A European multicentre PET study of fibrillar amyloid in Alzheimer’s disease. Eur J Nucl Med Mol Imaging 2013; 40: 104-114
• 61 Okamura N, Furumoto S, Fodero-Tavoletti MT et al. Non-invasive assessment of Alzheimer’s disease neurofibrillary pathology using 18F-THK5105 PET. Brain 2014; 137: 1762-1771
• 62 Okello A, Koivunen J, Edison P et al. Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study. Neurology 2009; 73: 754-760
• 63 Ossenkoppele R, Jansen WJ, Rabinovici GD et al. Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA 2015; 313: 1939-1949
• 64 Ossenkoppele R, Pijnenburg YA, Perry DC et al. The behavioural/dysexecutive variant of Alzheimer’s disease: clinical, neuroimaging and pathological features. Brain 2015; 138: 2732-2749
• 65 Pike KE, Savage G, Villemagne VL et al. Beta-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer’s disease. Brain 2007; 130: 2837-2844
• 66 Plassman BL, Langa KM, Fisher GG et al. Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology 2007; 29: 125-132
• 67 Price JC, Klunk WE, Lopresti BJ et al. Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B. J Cereb Blood Flow Metab 2005; 25: 1528-1547
• 68 Rabinovici GD, Furst AJ, O’Neil JP et al. 11C-PIB PET imaging in Alzheimer disease and frontotemporal lobar degeneration. Neurology 2007; 68: 1205-1212
• 69 Rabinovici GD, Jagust WJ, Furst AJ et al. Abeta amyloid and glucose metabolism in three variants of primary progressive aphasia. Ann Neurol 2008; 64: 388-401
• 70 Ratner M. Biogen’s early Alzheimer’s data raise hopes, some eyebrows. Nat Biotechnol 2015; 33: 438
• 71 Rinne JO, Brooks DJ, Rossor MN et al. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol 2010; 9: 363-372
• 72 Rowe CC, Ellis KA, Rimajova M et al. Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol Aging 2010; 31: 1275-1283
• 73 Rowe CC, Ng S, Ackermann U et al. Imaging beta-amyloid burden in aging and dementia. Neurology 2007; 68: 1718-1725
• 74 Salloway S, Sperling R, Fox NC et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014; 370: 322-333
• 75 Schwarz AJ, Yu P, Miller BB et al. Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages. Brain 2016; 139: 1539-1550
• 76 Selkoe DJ. Folding proteins in fatal ways. Nature 2003; 426: 900-904
• 77 Shi J, Shaw CL, Du Plessis D et al. Histopathological changes underlying frontotemporal lobar degeneration with clinicopathological correlation. Acta Neuropathol 2005; 110: 501-512
• 78 Siemers ER, Sundell KL, Carlson C et al. Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer’s disease patients. Alzheimers Dement 2016; 12: 110-120
• 79 Snowden JS. Semantic dysfunction in frontotemporal lobar degeneration. Dement Geriatr Cogn Disord 1999; 10 (Suppl. 01) 33-36
• 80 Sojkova J, Driscoll I, Iacono D et al. In vivo fibrillar beta-amyloid detected using [11C]PiB positron emission tomography and neuropathologic assessment in older adults. Arch Neurol 2011; 68: 232-240
• 81 Sperling RA, Aisen PS, Beckett LA 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 2011; 7: 280-292
• 82 Sperling RA, Laviolette PS, O’Keefe K et al. Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron 2009; 63: 178-188
• 83 Sperling RA, Rentz DM, Johnson KA et al. The A4 study: stopping AD before symptoms begin?. Science translational medicine 2014; 6: 228fs213
• 84 Treusch S, Cyr DM, Lindquist S. Amyloid deposits: protection against toxic protein species?. Cell Cycle 2009; 8: 1668-1674
• 85 Vandenberghe R, Van Laere K, Ivanoiu A et al. 18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trial. Ann Neurol 2010; 68: 319-329
• 86 Villemagne VL, Klunk WE, Mathis CA et al. Abeta Imaging: feasible, pertinent, and vital to progress in Alzheimer’s disease. Eur J Nucl Med Mol Imaging 2012; 39: 209-219
• 87 Villemagne VL, McLean CA, Reardon K et al. 11C-PiB PET studies in typical sporadic Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 2009; 80: 998-1001
• 88 Villemagne VL, Okamura N. In vivo tau imaging: Obstacles and progress. Alzheimers Dement 2014; 10: S254-S264
• 89 Villemagne VL, Pike KE, Chetelat G et al. Longitudinal assessment of Abeta and cognition in aging and Alzheimer disease. Ann Neurol 2011; 69: 181-192
• 90 Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci 2016; 17: 22-35
• 91 Weisman D, Cho M, Taylor C et al. In dementia with Lewy bodies, Braak stage determines phenotype, not Lewy body distribution. Neurology 2007; 69: 356-359
• 92 Wischik CM, Staff RT, Wischik DJ et al. Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer’s disease. J Alzheimers Dis 2015; 44: 705-720
• 93 Wolk DA. Amyloid imaging in atypical presentations of Alzheimer’s disease. Curr Neurol Neurosci Rep 2013; 13: 412
• 94 Wolk DA, Grachev ID, Buckley C et al. Association between in vivo fluorine 18-labeled flutemetamol amyloid positron emission tomography imaging and in vivo cerebral cortical histopathology. Arch Neurol 2011; 68: 1398-1403
• 95 Zaccai J, McCracken C, Brayne C. A systematic review of prevalence and incidence studies of dementia with Lewy bodies. Age Ageing 2005; 34: 561-566
• 96 Zhang S, Han D, Tan X et al. Diagnostic accuracy of 18F-FDG and 11 C-PIB-PET for prediction of short-term conversion to Alzheimer’s disease in subjects with mild cognitive impairment. Int J Clin Pract 2012; 66: 185-198