Functional neuroinflammatoryand serotonergic imaging in Alzheimer s disease: validation and preliminary clinical findings
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1 RIJKSUNIVERSITEIT GRONINGEN Functional neuroinflammatoryand serotonergic imaging in Alzheimer s disease: validation and preliminary clinical findings Jan Versijpt
2
3 Josef Sudek ( ) was a famous Czechoslovakian photographer known for his lyrical images that show a fine eye for life s intimate details. He once explained that everything around us, dead or alive, in the eyes of a crazy photographer mysteriously takes on many variations, so that a seemingly dead object comes to life through light or by its surroundings To capture some of this I suppose that s lyricism. The cover photograph shows the work Untitled (1940) where in the surrounding of this PhD thesis one can depict stoned plaques and tangles. The upper row represents the neuroinflammation part of this thesis where the first photograph shows an Alzheimer amyloid plaque (white) surrounded by reactive astrocytes (brown) and a cluster of microglial cells (black) sitting on top. Next to it, a three-dimensional model of the radioligand used in the present thesis PK11195 (either for PET or SPECT) is shown. The lower row represents the serotonergic part of this thesis where the first picture shows a three-dimensional structure of the 5-HT 2A receptor. Next to it, a model of the SPECT radioligand R91150 is shown. This work was financially supported by the Internationale stichting Alzheimer onderzoek. Aan Sabine
4
5 RIJKSUNIVERSITEIT GRONINGEN )XQFWLRQDOQHXURLQIODPPDWRU\ DQGVHURWRQHUJLFLPDJLQJ LQ$O]KHLPHU VGLVHDVH YDOLGDWLRQDQGSUHOLPLQDU\FOLQLFDOILQGLQJV PROEFSCHRIFT ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op woensdag 16 april 2003 om uur door Jan Jozef Albert Versijpt geboren op 10 november 1972 te Sint-Amandsberg
6 3 : PROF. DR. J. KORF PROF. DR. R.A. DIERCKX PROF. DR. G. SLEGERS % : PROF. DR. J. DE REUCK PROF. DR. W. VAALBURG PROF. DR. K. LEENDERS ISBN-nummer:
7 CONTENTS 1. Introduction and outline of the thesis 5 2. Introduction to neuroinflammation, Alzheimer s disease as an inflammatory 7 disease and neuroinflammatory imaging 2.1. Alzheimer s disease Scintigraphic visualisation of inflammation 17 in neurodegenerative disorders 3. Cobalt as an inflammatory tracer in Alzheimer s disease Co SPECT, 99m Tc-ECD SPECT, MRI, and neuropsychological testing in senile dementia of the Alzheimer type 4. Development and validation of radiolabelled PK11195 for 53 single photon emission computed tomography Biodistribution and dosimetry of [ 123 I]iodo-PK 11195: a potential agent for SPET imaging of the peripheral benzodiazepine receptor 5. Validation of radiolabelled PK11195 as an inflammatory tracer in Multiple Sclerosis Multiple Sclerosis PET visualisation of microglia in multiple sclerosis patients using [ 11 C]PK Imaging of microglial activation (PET) and atrophy (MRI) 103 in multiple sclerosis: interrelationship and clinical correlates 6. Radiolabelled PK11195 in Alzheimer s disease 117 Assessment of neuroinflammation and microglial activation in Alzheimer s disease with radiolabelled PK11195 and single photon emission computed tomography: a pilot study 7. Role and distribution of serotonin type 2A receptors in Alzheimer s disease Role of serotonin and serotonin type 2A receptors in Alzheimer s disease Imaging of the 5-HT 2A system: age-, gender-, and 141 Alzheimer s disease-related findings 8. Summary, discussion and perspectives Samenvatting, discussie en toekomstperspectieven Epilogue List of publications Resume 177
8 We must trust to nothing but facts. These are presented to us by Nature, and cannot deceive. We ought, in every instance, to submit our reasoning to the test of experiment, and never to search for truth but by the natural road of experiment and observation. Antoine Lavoisier ( )
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