Parkinson's Disease Portman, Axel Tiddo

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1 Parkinson's Disease Portman, Axel Tiddo IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2005 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Portman, A. T. (2005). Parkinson's Disease: deep brain stimulation and FDOPA-PET Groningen: s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Samenvatting en conclusies 97

3 Samenvatting De ziekte van Parkinson (ZvP) is één van de meest vóórkomende hersenziekten. Het wordt gekenmerkt door progressieve celdood van verschillende populaties zenuwcellen, waaronder dopamineproducerende neuronen in de middenhersenen. De typische motorische manifestaties van de ZvP (langzaamheid in intiatie en uitvoering van bewegingen, spierstijfheid, trillen van ledematen en eventueel balansstoornissen), worden vaak vergezeld door mentale ziekteverschijnselen. De oorzaak van de ZvP is vooralsnog onbekend, maar is zeer waarschijnlijk het gevolg van complexe interacties tussen omgevings- en genetische factoren. De huidige (mediamenteuze en chirurgische) behandelingen van de ZvP zijn symptomatisch en met name gericht op vermindering van de motorische klachten. Gezien het feit dat deze behandelingen géén invloed uitoefenen op de onderliggende ziekteprogressie, is men op zoek naar een therapie die deze ziekteprogressie verlangzaamt of zelfs stopt. Chronische dubbelzijdige Deep Brain Stimulation (DBS) van de subthalamische kern (STN) is een relatief nieuwe, stereotactisch uitgevoerde hersenoperatie die bij de ZvP kan worden toegepast. STN-DBS werkt waarschijnlijk via remming van de overactiviteit van de STN bij de ZvP en leidt tot een sterke verbetering van motorische klachten. Echter, deze overactiviteit van de STN (via glutamaat-gemedieerde excitotoxiciteit ) zou mogelijk óók kunnen bijdragen aan de versnelde celdood van dopaminecellen bij de ZvP. Toepassing van STN-DBS zou dan, naast het verlichten van ziektesymptomen, ook ziekteprogressie kunnen vertragen. Positron Emmissie Tomografie (PET) is een nucleair geneeskundige onderzoekstechniek, waarbij m.b.v. de tracer FDOPA een betrouwbare maat kan worden verkregen van het nigrostriatale dopaminerge systeem. FDOPA-PET onderzoek is tevens in staat om ziekteprogressie bij de ZvP te objectiveren en te kwantificeren. Het doel van de studies in dit proefschrift was allereerst, om, via herhaald FDOPA- PET onderzoek, na te gaan of de ziekteprogressie van de ZvP door STN-DBS wordt beïnvloedt. Tevens werd de klinische effectiviteit van STN-DBS op motorische symptomen van de ZvP onderzocht, en werd de relatie tussen mentale ziektesymptomen en striataal dopaminegebrek bij de ZvP nader geëvalueerd. Tenslotte onderzochten we of de presynaptische nigrostriatale dopaminestatus een voorspellende waarde bezet ten aanzien van de klinische effectiviteit van STN-DBS bij de ZvP. In Hoofdstuk 1 beschreven we de motorische en niet-motorische kenmerken van de ZvP, alsmede de diffentiaaldiagnose van parkinsonisme. De huidige kennis omtrent etiologie en pathofysiologie bij de ZvP werd besproken, en huidige therapeutische opties, en dan met name STN-DBS, werden geëvalueerd. Aansluitend werd de mogelijke relatie tussen STN-overactiviteit en ziekteprogressie bij de ZvP bediscussieerd, en de glutamaat-gemedieerde excitotoxische hypothese geïntroduceerd. We concludeerden dat de klinische toepassing van STN-DBS bij de ZvP tevens de 98

4 Samenvatting en conclusies mogelijkheid biedt tot onderzoek naar de potentiële neuroprotectieve eigenschappen van deze chirurgische ingreep. In Hoofdstuk 2 werden de gehanteerde inclusiecriteria en onderzoeksprotocollen van alle beschreven studies in het UMCG beschreven. In Hoofdstuk 3 onderzochten we het effect van STN-DBS op motorische symptomen van de ZvP via klinische onderzoeken en patiëntendagboeken. We toonden aan dat STN- DBS deze symptomen fors verbeterde: dit resulteerde dan ook in een sterke toename van het aantal uren over de dag waarin de patiënten met goede beweeglijkheid maar zònder overbeweeglijkheid functioneerden. Deze data bevestigden de effectiviteit van STN-DBS bij de ZvP, en in aanvulling op de klinische onderzoeken raadden we het gebruik van patiëntendagboeken in de evaluatie van het operatie-effect ten zeerste aan. Hoofdstuk 4 beschreef de relatie tussen striataal dopaminedeficiëntie en mentale functies in een populatie parkinsonpatiënten, welke om klinische redenen reeds was geselecteerd voor een stereotactische hersenoperatie. Uit neuropsychologische onderzoeken en FDOPA-PET data bleek, dat zowel putamen als caudatus FDOPA-uptake was gerelateerd aan cognitieve maten. Waar de putamen FDOPA-opname met name was gerelateerd aan executieve functies, d.w.z. cognitieve flexibiliteit in de vorm van cognitief switchen en responsinhibitie, bleek de caudatus FDOPA-opname samen te hangen met de organisatorische aspecten van executive functies (verbale geheugen en fluency ). We concludeerden, dat het putamen (dat deel uitmaakt van de motor loop in de basale ganglia) mogelijk betrokken is bij motorische acties na een cognitieve switch. Aansluitend testten we in Hoofdstuk 5 de glutamaat-gemedieerde excitotoxische hypothese, door overactiviteit van de STN, bij de ZvP. In een prospectieve two center-studie bepaalden we, met behulp van repetitief FDOPA-PET onderzoek, de dopaminerge ziekteprogressie na succesvolle STN-DBS bij 30 Parkinsonpatiënten. Op basis van de resultaten concludeerden we dat hun ziekteprogressie niet verschilt van die van niet-geopereerde patiënten, en een neuroprotectief effect van STN-DBS op de dopaminerge celpopulatie kon dan ook niet worden bevestigd. Tenslotte, in Hoofstuk 6 bepaalden we of de integriteit van het presynaptische nigrostriatale systeem het operatieresultaat van STN-DBS bij de ZvP kon voorspellen. Door middel van preoperatief FDOPA-PET onderzoek toonden we aan dat het operatieeffect bij patiënten met de ZvP negatief was gecorreleerd aan hun preoperatieve dopaminerge status. We concludeerden echter dat de preoperatieve nigrostriatale dopaminerge status geen betrouwbare voorspellende waarde bezit voor het operatieresultaat van STN-DBS bij de ZvP. 99

5 Conclusies van het proefschrift STN-DBS verbetert de motorische verschijnselen van de ZvP in een geselecteerde patiëntenpopulatie aanzienlijk Het cognitieve (dys) functioneren van Parkinsonpatiënten is afhankelijk van de dopaminerge integriteit van zowel de caudatus als het putamen STN-DBS geeft géén protectie van het nigrostriatale dopaminerge systeem De nigrostriatale dopaminerge status bezit geen betrouwbare voorspellende waarde voor het operatie-effect van STN-DBS bij de ZvP 100

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