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Der Nuklearmediziner 2016; 39(04): 309-315
DOI: 10.1055/s-0042-113849
Neurobildgebung
© Georg Thieme Verlag KG Stuttgart · New York

In-vivo-Bildgebung „neuroinflammatorischer Veränderungen“ mit PET; Grundlagen und Anwendung bei Parkinson-Syndromen

In vivo Imaging of “Neuroinflammatory Changes” with PET; Background and Applications in Parkinsonian disorders
A. Gerhard
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Publication History

Publication Date:
14 December 2016 (online)

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Zusammenfassung

Mikroglia sind residente immunkompetente Zellen des Gehirns, die durch unspezifische Schädigung aktiviert werden. Im aktivierten Zustand exprimieren sie das „translocator protein 18 kD“ (TSPO) – früher peripherer Benzodiazepinrezeptor genannt, an welches hochspezifisch das Isoquinolin PK11195 bindet. Radioaktiv markiert kann das R-Enantiomer [11C] PK11195 als Ligand in der Positronenemissionstomografie (PET) genutzt werden und ermöglicht so die in-vivo-Darstellung „aktiver“ neuroinflammatorischer Veränderungen.

Mit der [11C](R) PK11195 PET konnte bisher in-vivo-Mikroglia-Aktivierung bei ischämischen (Schlaganfall), entzündlichen (Multiple Sklerose) und degenerativen (Morbus Alzheimer und Parkinson) Erkrankungen demonstriert werden. In der vorliegenden Kurzübersicht werden die Ergebnisse bei idiopathischen und atypischen Parkinson-Syndromen vorgestellt.

Zusätzlich wurden in den letzten Jahren neue, teilweise 18F-markierte PET-Liganden mit unterschiedlichen Bindungseigenschaften entwickelt, die z. T. in klinischen Studien evaluiert wurden.

Longitudinale Studien, kombiniert mit therapeutischer Intervention und neuropathologischer Evaluierung, werden helfen, die Beziehung von Lokalisation und Ausmaß der Mikroglia-Aktivierung zur klinischen Krankheitsausprägung zu explorieren.

Abstract

Microglia are the brain’s resident, immunocompetent cells that can be activated by unspecific (damaging) stimuli. In their activated state they express „translocator protein 18 kD“ (TSPO) – previously called the peripheral benzodiazepine binding site – which binds the isoquinolin PK11195 in a highly specific manner. When radioactively labelled the R-enantiomer [11C] PK11195 can be used with Positron Emission Tomography (PET) to demonstrate neuroinflammatory changes in vivo.

So far [11C](R) PK11195 PET has been successfully used to show in vivo microglial activation in ischemic (stroke), inflammatory (multiple sclerosis) and degenerative (Alzheimer’s and Parkinson’s disease) conditions.

This short review summarises the findings in idiopathic and atypical Parkinsonian syndromes.

Currently longitudinal studies are in progress to help clarifying the relationship between localisation and extent of microglial activation and the clinical findings in these disorders. This will assist to determine the role of [11C](R) PK11195 PET as a diagnostic tool and a surrogate marker of “neuroinflammation” in therapeutic trials.

Schlüsselwörter

Parkinson-Syndrome - Mikroglia - Neuroinflammation - PET

Key words

Parkinson‘s Disease - microglia - neuroinflammation - PET
 

  • Literatur

  • 1 Ahmad R, Postnov A, Bormans G et al. Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer’s disease. Eur J Nucl Med Mol Imaging 2016; 43: 2219-2227
    CrossrefPubMedGoogle Scholar
  • 2 Banati RB, Myers R, Kreutzberg GW. PK (‘peripheral benzodiazepine’) – binding sites in the CNS indicate early and discrete brain lesions: microautoradiographic detection of [3H]PK11195 binding to activated microglia. J Neurocytol 1997; 26: 77-82
    CrossrefPubMedGoogle Scholar
  • 3 Benavides J, Quarteronet D, Imbault F et al. Labelling of “peripheral-type” benzodiazepine binding sites in the rat brain by using [3H]PK 11195, an isoquinoline carboxamide derivative: kinetic studies and autoradiographic localization. J Neurochem 1983; 41: 1744-1750
    CrossrefPubMedGoogle Scholar
  • 4 Braak H, Del Tredici K, Rub U et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24: 197-211
    CrossrefPubMedGoogle Scholar
  • 5 Cabral GA, Raborn ES, Griffin L et al. CB2 receptors in the brain: role in central immune function. Br J Pharmacol 2008; 153: 240-251
    CrossrefPubMedGoogle Scholar
  • 6 Calne DB, Mizuno Y. The neuromythology of Parkinson’s Disease. Parkinsonism Relat Disord 2004; 10: 319-322
    CrossrefPubMedGoogle Scholar
  • 7 Carter SF, Scholl M, Almkvist O et al. Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med 2012; 53: 37-46
    CrossrefPubMedGoogle Scholar
  • 8 Chauveau F, Boutin H, Van Camp N et al. Nuclear imaging of neuroinflammation: a comprehensive review of [(11)C]PK11195 challengers. Eur J Nucl Med Mol Imaging 2008; 1: 1
    PubMedGoogle Scholar
  • 9 del Rio-Hortega P In: Penfield W. editor. Cytology and cellular pathology of the nervous system. New York: Hafner; 1932: 482-584
  • 10 Dickson DW, Bergeron C, Chin SS et al. Office of Rare Diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol 2002; 61: 935-946
    CrossrefPubMedGoogle Scholar
  • 11 Dodel R, Spottke A, Gerhard A et al. Minocycline 1-year therapy in multiple-system-atrophy: Effect on clinical symptoms and [(11)C] (R)-PK11195 PET (MEMSA-trial). Mov Disord 2010; 25: 11
    PubMedGoogle Scholar
  • 12 Edison P, Ahmed I, Fan Z et al. Microglia, amyloid, and glucose metabolism in Parkinson’s disease with and without dementia. Neuropsychopharmacology 2013; 38: 938-949
    CrossrefPubMedGoogle Scholar
  • 13 Evens N, Vandeputte C, Coolen C et al. Preclinical evaluation of [11C]NE40, a type 2 cannabinoid receptor PET tracer. Nucl Med Biol 2012; 39: 389-399
    CrossrefPubMedGoogle Scholar
  • 14 Fowler JS, Wang GJ, Logan J et al. Selective reduction of radiotracer trapping by deuterium substitution: comparison of carbon-11-L-deprenyl and carbon-11- deprenyl-D2 for MAO B mapping. Journal of Nuclear Medicine 1995; 36: 1255
    PubMedGoogle Scholar
  • 15 Gehrmann J, Matsumoto Y, Kreutzberg GW. Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 1995; 20: 269-287
    CrossrefPubMedGoogle Scholar
  • 16 Gerhard A, Banati RB, Goerres GB et al. [11C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy. Neurology 2003; 61: 686-689
    CrossrefPubMedGoogle Scholar
  • 17 Gerhard A, Pavese N, Hotton G et al. In vivo imaging of microglial activation with [(11)C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis 2006; 21: 404-412 Epub 2005 Sep 21
    CrossrefPubMedGoogle Scholar
  • 18 Gerhard A, Trender-Gerhard I, Turkheimer F et al. In vivo imaging of microglial activation with [(11)C](R)-PK11195 PET in progressive supranuclear palsy. Mov Disord 2006; 21: 89-93
    CrossrefPubMedGoogle Scholar
  • 19 Gerhard A, Watts J, Trender-Gerhard I et al. In vivo imaging of microglial activation with [(11)C](R)-PK11195 PET in corticobasal degeneration. Mov Disord 2004; 19: 1221-1226
    CrossrefPubMedGoogle Scholar
  • 20 Ginhoux F, Greter M, Leboeuf M et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010; 330: 841-845
    CrossrefPubMedGoogle Scholar
  • 21 Goedert M. NEURODEGENERATION. Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Abeta, tau, and alpha-synuclein. Science 2015; 349: 1255555
    CrossrefPubMedGoogle Scholar
  • 22 Gulyas B, Pavlova E, Kasa P et al. Activated MAO-B in the brain of Alzheimer patients, demonstrated by [11C]-L-deprenyl using whole hemisphere autoradiography. Neurochem Int 2011; 58: 60-68
    CrossrefPubMedGoogle Scholar
  • 23 Hauw JJ, Daniel SE, Dickson D et al. Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology 1994; 44: 2015-2019
    CrossrefPubMedGoogle Scholar
  • 24 Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nature reviews Immunology 2014; 14: 463-477
    CrossrefPubMedGoogle Scholar
  • 25 Hertz L. Binding characteristics of the receptor and coupling to transport proteins. In: Giessen-Crouse E. editor. Peripheral Benzodiazeoine Receptors. London: Academic Press; 1993: 27-51
    Google Scholar
  • 26 Iannaccone S, Cerami C, Alessio M et al. In vivo microglia activation in very early dementia with Lewy bodies, comparison with Parkinson’s disease. Parkinsonism Relat Disord 2013; 19: 47-52
    CrossrefPubMedGoogle Scholar
  • 27 Imamura K, Hishikawa N, Ono K et al. Cytokine production of activated microglia and decrease in neurotrophic factors of neurons in the hippocampus of Lewy body disease brains. Acta Neuropathol 2005; 109: 141-150 Epub 2004 Dec 24
    CrossrefPubMedGoogle Scholar
  • 28 Ishizawa K, Dickson DW. Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration. J Neuropathol Exp Neurol 2001; 60: 647-657
    CrossrefPubMedGoogle Scholar
  • 29 Ishizawa K, Komori T, Sasaki S et al. Microglial activation parallels system degeneration in multiple system atrophy. J Neuropathol Exp Neurol 2004; 63: 43-52
    CrossrefPubMedGoogle Scholar
  • 30 Jaremko L, Jaremko M, Giller K et al. Structure of the mitochondrial translocator protein in complex with a diagnostic ligand. Science 2014; 343: 1363-1366
    CrossrefPubMedGoogle Scholar
  • 31 Jiang T, Hoekstra J, Heng X et al. P2X7 receptor is critical in alpha-synuclein–mediated microglial NADPH oxidase activation. Neurobiol Aging 2015; 36: 2304-2318
    CrossrefPubMedGoogle Scholar
  • 32 Jucaite A, Svenningsson P, Rinne JO et al. Effect of the myeloperoxidase inhibitor AZD3241 on microglia: a PET study in Parkinson’s disease. Brain 2015; 138: 2687-2700
    CrossrefPubMedGoogle Scholar
  • 33 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
    CrossrefPubMedGoogle Scholar
  • 34 Kettenmann H, Hanisch UK, Noda M et al. Physiology of microglia. Physiological reviews 2011; 91: 461-553
    CrossrefPubMedGoogle Scholar
  • 35 Kobylecki C, Counsell SJ, Cabanel N et al. Diffusion-weighted imaging and its relationship to microglial activation in parkinsonian syndromes. Parkinsonism Relat Disord 2013; 19: 527-532
    CrossrefPubMedGoogle Scholar
  • 36 Koshimori Y, Ko JH, Mizrahi R et al. Imaging Striatal Microglial Activation in Patients with Parkinson’s Disease. PloS one 2015; 10: e0138721
    CrossrefPubMedGoogle Scholar
  • 37 Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996; 19: 312-318
    CrossrefPubMedGoogle Scholar
  • 38 Langston JW, Forno LS, Tetrud J et al. Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure [see comments]. Ann Neurol 1999; 46: 598-605
    CrossrefPubMedGoogle Scholar
  • 39 McGeer PL, Itagaki S, Boyes BE et al. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 1988; 38: 1285-1291
    CrossrefPubMedGoogle Scholar
  • 40 McGeer PL, Schwab C, Parent A et al. Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Ann Neurol 2003; 54: 599-604
    CrossrefPubMedGoogle Scholar
  • 41 Nakamura S, Kawamata T, Akiguchi I et al. Expression of monoamine oxidase B activity in astrocytes of senile plaques. Acta Neuropathol 1990; 80: 419-425
    CrossrefPubMedGoogle Scholar
  • 42 Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005; 308: 1314-1318 Epub 2005 Apr 14
    CrossrefPubMedGoogle Scholar
  • 43 Ouchi Y, Yoshikawa E, Sekine Y et al. Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann Neurol 2005; 57: 168-175
    CrossrefPubMedGoogle Scholar
  • 44 Owen DR, Yeo AJ, Gunn RN et al. An 18-kDa Translocator Protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab 2012; 32: 1-5
    CrossrefPubMedGoogle Scholar
  • 45 Palazuelos J, Aguado T, Pazos MR et al. Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity. Brain 2009; 132: 3152-3164
    CrossrefPubMedGoogle Scholar
  • 46 Perry VH. Innate inflammation in Parkinson’s disease. Cold Spring Harbor perspectives in medicine 2012; 2: a009373
    PubMedGoogle Scholar
  • 47 Perry VH, Nicoll JA, Holmes C. Microglia in neurodegenerative disease. Nat 2010; 6: 193-201 Epub 2010 Mar 16
    PubMedGoogle Scholar
  • 48 Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 2014; 15: 300-312
    CrossrefPubMedGoogle Scholar
  • 49 Probst Cousin S, Rickert CH, Schmid KW et al. Cell death mechanisms in multiple system atrophy. J Neuropathol Exp Neurol 1998; 57: 814-821
    CrossrefPubMedGoogle Scholar
  • 50 Ramirez BG, Blazquez C, Gomez del Pulgar T et al. Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci 2005; 25: 1904-1913
    CrossrefPubMedGoogle Scholar
  • 51 Rezaie P, Male D. Mesoglia & microglia – a historical review of the concept of mononuclear phagocytes within the central nervous system. J Hist Neurosci 2002; 11: 325-374
    CrossrefPubMedGoogle Scholar
  • 52 Rodriguez-Vieitez E, Saint-Aubert L, Carter SF et al. Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer’s disease. Brain 2016; 139: 922-936
    CrossrefPubMedGoogle Scholar
  • 53 Rupprecht R, Papadopoulos V, Rammes G et al. Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat 2010; 9: 971-988
    PubMedGoogle Scholar
  • 54 Schwarz SC, Seufferlein T, Liptay S et al. Microglial activation in multiple system atrophy: a potential role for NF-kappaB/rel proteins. Neuroreport 1998; 9: 3029-3032
    CrossrefPubMedGoogle Scholar
  • 55 Turkheimer FE, Edison P, Pavese N et al. Reference and Target Region Modeling of [11C]-(R)-PK11195 Brain Studies. J Nucl Med 2007; 48: 158-167
    PubMedGoogle Scholar
  • 56 Turkheimer FE, Rizzo G, Bloomfield Peter S et al. The methodology of TSPO imaging with positron emission tomography. Biochemical Society transactions 2015; 43: 586-592
    CrossrefPubMedGoogle Scholar
  • 57 Venneti S, Lopresti BJ, Wiley CA. The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging. Prog Neurobiol 2006; 80: 308-322 Epub 2006 Dec 6
    CrossrefPubMedGoogle Scholar