Molekulare Bildgebung in der Diagnostik von Demenzen

Zusammenfassung

Durch die Entwicklung molekularer Marker der zerebralen Amyloidablagerung in vivo hat die Positronenemissionstomografie (PET) eine zentrale Rolle für die Definition präklinischer und prädemenzieller Stadien der Alzheimer Krankheit erlangt. Darüber hinaus haben länger etablierte nuklearmedizinische Marker eine wichtige Funktion bei der Differenzial- und Frühdiagnose demenzieller Erkrankungen. Untersuchungen mit FDG-PET zeigen typische Muster eines kortikalen Hypo metabolismus, der die Ausprägung kognitiver Defizite in klinischen Verlauf prädiziert und eine hohe diagnostische Trennschärfe zwischen Frühstadien einer Alzheimer Krankheit und einer Erkrankung aus dem Formenkreis der frontotemporalen Lobärdegenerationen aufweist. Dopamin-PET, Dopamintransporter-SPECT und Dopaminrezeptor-Tracer für PET und SPET sind frühe Indikatoren einer extrapyramidalmotorischen Beteiligung beim Parkinson-Syndrom. Der Beitrag erläutert die technischen Grundlagen der Verfahren und wesentliche klinische Befunde sowie diagnostische Anwendungen aus monozentrischen und multizentrischen Studien für die Früh und Prädemenzdiagnostik. Besonderes Gewicht legen wir auf die klinische Frage, die ein molekularer Marker beantworten kann, und die methodischen und heuristischen Grenzen der Verfahren, die insbesondere gegen einen unkritischen Einsatz der demnächst klinisch verfügbaren Amyloid-PET-Tracer für das Screenen asymptomatischer Personen außerhalb klinischer Studien sprechen.

Summary

The development of novel amyloid PET tracers has fuelled the definition of preclincial and predementia stages of Alzheimer’s disease. In addition, more widely established radioligands play an important role in the early and differential diagnosis of dementia. FDG-PET allows discrimination between Alzheimer’s disease dementia and frontotemporal lobe degeneration in very early stages of disease, patterns of regional cerebral hypometabolism predict the decline of cognitive functions in clinical follow-up. Dopamine PET, dopamine transporter SPECT and PET and SPECT tracers of dopamine receptor binding allow the detection of the extrapyramidal component in very early stages of Parkinson’s syndrome. The following article describes key methodology of molecular imaging techniques, including amyloid PET, FGD-PET, and dopamine PET and SPECT. A special emphasize is laid on the clinical application of a marker and the findings from recent mono- and multicenter diagnostic trials. We also point out the limitations of a given methodology, arguing for a context specific use of novel and established molecular markers that would preclude the use of amyloid PET for screening of asymptomatic subjects outside of well-defined clinical trials.

Schlüsselwörter

Amyloid - kortikaler Stoffwechsel - dopaminerges System - Prädemenzdiagnose

Keywords

Amyloid - cerebral hypometabolism - dopamine system - diagnosis of predementia

• Literatur

• 1 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; 07: 270-279.
• 2 Alzheimer A. Über eigenartige Krankheitsfälle des späteren Alters. Zeitschrift für die gesamte Neurologie und Psychiatrie 1911; 04: 356-385.
• 3 Barthel H, Sabri O. Florbetaben to trace amyloidbeta in the Alzheimer brain by means of PET. J Alzheimers Dis 2011; 03: 117-121.
• 4 Bloudek LM, Spackman DE, Blankenburg M. et al. Review and meta-analysis of biomarkers and diagnostic imaging in Alzheimer’s disease. J Alzheimers Dis 2011; 26: 627-645.
• 5 Chetelat G, Villemagne VL, Pike KE. et al. Independent contribution of temporal beta-amyloid deposition to memory decline in the pre-dementia phase of Alzheimer’s disease. Brain 2011; 134: 798-807.
• 6 Doblhammer G, Ziegler U, Muth E. Trends und Muster in Lebenserwartung und Gesundheit und Prognose der Demenzerkrankungen in Deutschland bis 2050. In: Kumbier E TS, Herpertz SC. (Eds.) Ethik und Erinnerung. Zur Verantwortung der Psychiatrie in Vergangenheit und Gegenwart. Langerich: Pabst Science Publishers; 2009: 91-108.
• 7 Doraiswamy PM, Sperling RA, Coleman RE. et al. Amyloid-beta assessed by florbetapir F 18 PET and 18-month cognitive decline: a multicenter study. Neurology 2012; 79: 1636-1644.
• 8 Drzezga A, Lautenschlager N, Siebner H. et al. Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer’s disease: a PET follow-up study. Eur J Nucl Med Mol Imaging 2003; 30: 1104-1113.
• 9 Dukart J, Mueller K, Horstmann A. et al. Combined evaluation of FDG-PET and MRI improves detection and differentiation of dementia. PLoS One 2011; 06: e18111.
• 10 Forstl H, Burns A, Luthert P. et al. The Lewy-body variant of Alzheimer’s disease. Clinical and pathological findings. Br J Psychiatry 1993; 162: 385-392.
• 11 Gambhir SS, Czernin J, Schwimmer J. et al. A tabulated summary of the FDG PET literature. J Nucl Med 2001; 42: 1S-93S.
• 12 Gorno-Tempini ML, Hillis AE, Weintraub S. et al. Classification of primary progressive aphasia and its variants. Neurology 2011; 76: 1006-1014.
• 13 Hampel H, Frank R, Broich K. et al. Biomarkers for Alzheimer’s disease: academic, industry and regulatory perspectives. Nat Rev Drug Discov 2010; 09: 560-574.
• 14 Iqbal K, Liu F, Gong CX. et al. Tau in Alzheimer disease and related tauopathies. Curr Alzheimer Res 2010; 07: 656-664.
• 15 Jack Jr CR. Alzheimer disease: new concepts on its neurobiology and the clinical role imaging will play. Radiology 2012; 263: 344-361.
• 16 Jack CR, Albert MS, Knopman DS. et al. Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 07: 257-262.
• 17 Jack CR, Knopman DS, Jagust WJ. et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 2010; 09: 119-128.
• 18 Kawachi T, Ishii K, Sakamoto S. et al. Comparison of the diagnostic performance of FDG-PET and VBM-MRI in very mild Alzheimer’s disease. Eur J Nucl Med Mol Imaging 2006; 33: 801-809.
• 19 Kovacs GG, Gelpi E. Clinical neuropathology practice news 3-2012: the “ABC” in AD-revised and updated guideline for the neuropathologic assessment of Alzheimer’s disease. Clin Neuropathol 2012; 31: 116-118.
• 20 Kuhl DE. Imaging local brain function with emission computed tomography. Radiology 1984; 150: 625-631.
• 21 Lim SM, Katsifis A, Villemagne VL. et al. The 18F-FDG PET cingulate island sign and comparison to 123I-beta-CIT SPECT for diagnosis of dementia with Lewy bodies. J Nucl Med 2009; 50: 1638-1645.
• 22 Lomen-Hoerth C. Clinical phenomenology and neuroimaging correlates in ALS-FTD. J Mol Neurosci 2011; 45: 656-662.
• 23 Magistretti PJ, Pellerin L, Rothman DL. et al. Energy on demand. Science 1999; 283: 496-497.
• 24 Maier W, Jessen F, Schneider F. et al. Diagnoseund Behandlungsleitlinie Demenz. Berlin: Springer; 2010
• 25 Mathis CA, Mason NS, Lopresti BJ. et al. Development of positron emission tomography beta-amyloid plaque imaging agents. Semin Nucl Med 2012; 42: 423-432.
• 26 Mckeith I, O’brien J, Walker Z. et al. Sensitivity and specificity of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia with Lewy bodies: a phase III, multicentre study. Lancet Neurol 2007; 06: 305-313.
• 27 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.
• 28 Minoshima S, Frey KA, Koeppe RA. et al. A diagnostic approach in Alzheimer’s disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET. J Nucl Med 1995; 36: 1238-1248.
• 29 Mosconi L, Tsui WH, Herholz K. et al. Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer’s disease, and other dementias. J Nucl Med 2008; 49: 390-398.
• 30 Neary D, Snowden JS, Gustafson L. et al. Fronto-temporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51: 1546-1554.
• 31 Perneczky R, Mosch D, Neumann M. et al. The Alzheimer variant of lewy body disease: a pathologically confirmed case-control study. Dement Geriatr Cogn Disord 2005; 20: 89-94.
• 32 Ransmayr G, Katzenschlager R, Dal-Bianco P. et al. Lewy-Körper-Demenz und ihre differentialdagnostische Abgrenzung von Alzheimer’scher Erkrankung. Neuropsychiatr 2007; 21: 63-74.
• 33 Rascovsky K, Hodges JR, Knopman D. et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011; 134: 2456-2477.
• 34 Reiman EM, Caselli RJ, Yun LS. et al. Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med 1996; 334: 752-758.
• 35 Reivich M, Kuhl D, Wolf A. et al. Measurement of local cerebral glucose metabolism in man with 18F-2-fluoro-2-deoxy-d-glucose. Acta Neurol Scand Suppl 1977; 64: 190-191.
• 36 Shaffer JL, Petrella JR, Sheldon FC. et al. Predicting cognitive decline in subjects at risk for Alzheimer disease by using combined cerebrospinal fluid, MR imaging, and PET biomarkers. Radiology 2013; 266: 583-591.
• 37 Signorini M, Paulesu E, Friston K. et al. Rapid assessment of regional cerebral metabolic abnormalities in single subjects with quantitative and nonquantitative (18F)FDG PET: A clinical validation of statistical parametric mapping. Neuroimage 1999; 09: 63-80.
• 38 Silverman DH, Alavi A. PET imaging in the assessment of normal and impaired cognitive function. Radiol Clin North Am 2005; 43: 67-77. x.
• 39 Sokoloff L. Quantitative measurements of cerebral blood flow in man. Methods Med Res 1960; 08: 253-261.
• 40 Sokoloff L. Relation between physiological function and energy metabolism in the central nervous system. J Neurochem 1977; 29: 13-26.
• 41 Teune LK, Bartels AL, De Jong BM. et al. Typical cerebral metabolic patterns in neurodegenerative brain diseases. Mov Disord 2010; 25: 2395-2404.
• 42 Villemagne VL, Ong K, Mulligan RS. et al. Amyloid imaging with (18)F-florbetaben in Alzheimer disease and other dementias. J Nucl Med 2011; 52: 1210-1217.
• 43 Zakzanis KK, Graham SJ, Campbell Z. A metaanalysis of structural and functional brain imaging in dementia of the Alzheimer’s type: a neuroimaging profile. Neuropsychol Rev 2003; 13: 1-18.
• 44 Zhang S, Han D, Tan X. et al. Diagnostic accuracy of 18 F-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.
• 45 Ziegler U, Doblhammer G. Prävalenz und Inzidenz von Demenz in Deutschland. Eine Studie auf Basis von Daten der gesetzlichen Krankenversicherungen von 2002. Gesundheitswesen 2009; 71: 281-290.