University of Groningen Characterizing postoperative ... · PDF fileAncelin, M.L., de Roquefeuil, G., Ledesert, B ... Baddely, A., Eysenk, M.W ... Harvey, P.D., 2006. Administration

University of Groningen

Characterizing postoperative cognitive dysfunction in the elderlyHovens, Iris Bertha

DOI:10.1152/ajpregu.00002.2015

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SUMMARY

232

Postoperative cognitive dysfunction

In the Netherlands more than 400.000 persons over 60 years old undergo surgery

every year. Although these surgeries are aimed at improving health and well-being, it is

estimated that ten percent of the older surgery patients will experience a long-lasting

postoperative impairment of cognitive functions, such as memory, concentration,

planning, and information processing. This postoperative cognitive dysfunction

(POCD) seriously affects the life of patients and their near friends and relatives, as it

is associated with a reduced quality of life, increased dependency on social care, and

an increased risk of lasting mental and functional disability .

Initially, research focused on anesthesia as the culprit behind POCD. Intuitively,

it seems logical that substances that clearly affect the brain could also have a long-

lasting negative effect on brain function. However, the majority of studies found no

relation or only a modest association between anesthesia and POCD, indicating that

other mechanisms are more important.

The inflammation-hypothesis of POCD

Surgery, inevitably, is associated with tissue damage. The response of the body to this

tissue damage is an inflammatory response. Cells of the immune system, the body’s

defense against damage and disease, are attracted to the damaged tissue. These

cells initiate processes involved in repair and recovery, including adjusting the blood

flow to the tissue, repairing or removing damaged cells, and killing germs. The immune

cells produce inflammatory factors that serve as signals in the regulation of the above

mentioned processes. The inflammatory factors are also released in the blood and

spread through the body, which is known as the systemic inflammatory response. Via

the blood, the inflammatory factors reach the brain, where they activate the primary

immune cells of the brain, the microglia. Normally, microglia have a small cell body

and many thin processes that constantly scan the environment. When microglia are

activated, their processes retract, their cell body enlarges, and they start producing

inflammatory factors of their own. This inflammatory response in the brain is called

233

SUMMARY

Figure 1: The inflammation-hypothesis of POCD. Surgery-induced tissue damage (1) attracts immune cells

(2) that produce inflammatory factors (3). The inflammatory factors are dispersed through the body via the

blood (4), which is the systemic inflammatory response. The inflammatory factors reach the brain (5) and

encounter microglial cells (6) which become activated and produce more inflammatory factors (7). This

is the neuroinflammatory response. An excessive neuroinflammatory response can have a detrimental

effect on the neuronal processes (8) involved in cognition and behavior. Aging has been associated with

an increased (neuro)inflammatory response, which could explain the increased risk of POCD in the elderly.

neuroinflammation. Neuroinflammation fulfills an important role by influencing behavior

in such a way that the body can cope best with the inflicted damage. Examples are:

staying in bed, sleeping longer, a preference for easily digestible food, and minimizing

the use of the injured body part. Thus, all aspects of inflammation, from the local

inflammatory response to neuroinflammation, are important for recovery from surgery.

234

However, excessive and prolonged neuroinflammation can have a detrimental effect

on processes in neurons, including those involved in cognitive functioning. Therefore,

the inflammation-hypothesis of POCD states that an excessive (neuro)inflammatory

response to surgery may be involved in the development of POCD (Figure 1). Since

aging is associated with increased neuroinflammation following infection or injury, the

inflammation-hypothesis may also explain why older persons are specifically at risk

for POCD.

Aim of this thesis

Research of the last decades has provided convincing evidence supporting the

inflammation- hypothesis, but it remains unclear why some older surgical patients

develop POCD, whereas others do not. Moreover, it has proven difficult to translate

outcomes of animal studies to clinical practice, which impedes the development of

adequate therapies.

Based on a literature review, presented in Chapter 2, we concluded that a wide

range of cognitive functions may be affected by surgery and that the experienced

cognitive problems vary greatly between patients. This led to the hypothesis that a

combination of risk-factors and intrinsic properties of distinct brain areas determines

the vulnerability of these brain areas to surgery and thereby causes the variety in

extent and type of cognitive problems patients experience.

Interestingly, animal studies so far mainly focused on the effects of surgery on

one specific brain region, the hippocampus, and the cognitive function related to

this region, spatial learning. Meanwhile, clinical research mainly investigated POCD

in general, without specifying which cognitive functions were impaired. To test

our hypothesis, we had to take a different approach and examine the influence of

surgery on several cognitive functions and brain regions. This thesis describes a

series of animal- experiments and a patient study that were aimed at investigating the

involvement of inflammatory processes and other risk-factors in the development of

235

SUMMARY

distinct cognitive impairments following surgery.

Postoperative cognitive performance and neuroinflammation in a

rat-model for POCD

The experiments in Chapter 3 to 6 of this thesis were performed in a rat-model for

POCD (Figure 2). Rats were subjected to a standardized abdominal surgery protocol

in which the blood flow to the upper part of the intestines was temporarily reduced,

mimicking effects of major abdominal surgery in humans. After a recovery period,

distinct aspects of behavior and cognitive performance were examined: Exploratory

and anxiety-related behavior reflecting mood; spatial learning and memory;

object memory; and cognitive flexibility, the ability to adapt behavior to a changed

situation. Additionally, markers for the systemic inflammatory response and for

neuroinflammation and neuronal functioning were analyzed in specific brain areas:

The hippocampus for spatial learning and memory, the prefrontal cortex for object

recognition; and the striatum for cognitive flexibility.

Figure 2: A rat-model to investigate the involvement of inflammatory processes in POCD development.

Rats receive abdominal surgery and, after a recovery period, undergo tests to measure distinct aspects

of behavior and cognitive performance. During the postoperative period markers for the systemic

inflammatory response are measured. After the test protocol brains are collected and analyzed for

markers for neuroinflammation and neuronal function in brain regions critically associated with cognitive

performance: 1) Prefrontal cortex associated with object memory; 2) striatum associated with cognitive

flexibility: 3) hippocampus associated with spatial learning and memory.

236

In Chapter 3 the development of postoperative cognitive impairment under

conditions associated with a low risk of POCD were investigated by an experiment

in healthy young rats. Under these conditions surgery only impaired spatial memory,

in the first two postoperative weeks, but not thereafter. This finding indicates that

spatial memory, which is associated with hippocampal function, may be particularly

vulnerable to the effects of surgery. Although in the hippocampus and prefrontal

cortex signs of neuroinflammation were observed, only in the hippocampus markers

for neuronal function were decreased. Hence, it seems that neuroinflammation alone

may not be sufficient to cause cognitive impairment, but that subsequent neuronal

dysfunction must be induced for cognitive impairment to occur. These findings are

supported by similar results in healthy middle-aged rats described in Chapter 6.

The influence of increased age on cognition and behavior was examined two

weeks (Chapter 4) and six weeks (Chapter 5) following surgery. As is the case in

humans, in rats increased aged was associated with impairment of learning, memory,

and behavior. In the early postoperative period, old rats showed a more generalized

postoperative cognitive and behavioral dysfunction compared to young rats, including

spatial memory, object recognition and exploratory behavior. In contrast to the isolated

spatial memory dysfunction of young rats, the postoperative cognitive impairment

of aged rats is more in line with POCD in humans. We did not find any long-lasting

effects of surgery on cognitive performance. However, aged rats displayed decreased

exploratory behavior for at least six weeks after surgery, whereas this decrease was

not observed in young rats. The cognitive and behavioral outcomes were correlated

to microglial activation in related brain areas. Together, these outcomes suggest

that neuroinflammatory signaling may indeed be involved in POCD and that an

exacerbated neuroinflammatory response to surgery may contribute to the increased

risk of POCD in aged patients.

The outcomes described above do not explain why only some older individuals

develop POCD, whereas others do not. In Chapter 6 we propose that inflammatory

events, such as surgery, infection, or chronic inflammatory disease, may contribute to

237

SUMMARY

the exacerbated neuroinflammatory response in aged persons. As a first step to test

this, we investigated the effects of a lung infection in the period preceding surgery

on the development of postoperative cognitive impairment and neuroinflammation in

middle-aged rats. The outcomes of this experiment suggest that in middle-aged rats,

an infection is associated with long-lasting (neuro)inflammation which predisposes

these rats to more severe and more generalized postoperative cognitive and

behavioral impairment. This supports the hypothesis that exposure to inflammatory

events prior to surgery could increase the risk for POCD.

Microglia are considered to play a pivotal role in POCD development. To facilitate

the analysis of microglial activity in brain sections a novel image analysis method

was developed, which is described in Chapter 7. The method provides a sensitive

marker for microglial activation in the rat brain, which is quick and easy to perform

and provides additional information about the size of the microglial cell body and

processes.

Postoperative cognitive performance and inflammation in surgery

patients

In Chapter 8 an analysis was performed on data from the ‘PICNIC – postoperative

cognitive dysfunction in elderly cancer patients’ study, that included patients

undergoing surgery for removal of a tumor. We investigated the influence of changes

in blood-concentrations of inflammatory factors and the risk-factors age, surgery

duration, education level, and preoperative memory, planning, and information

processing. The postoperative performance in all cognitive domains was strongly

influenced by age, preoperative cognitive performance, and education level, but not

by anesthesia duration. An increase in the inflammatory marker C-reactive protein

was related to a reduced postoperative information processing, but only in patients

with a good preoperative cognitive performance. These outcomes suggest that the

sensitivity to the surgery-induced inflammatory response differs between cognitive

domains and between individuals.

238

Concluding remarks

In previous research little attention has been given to the cognitive domains and

brain regions involved in POCD. The outcomes of this thesis indicate that distinct

brain areas and related cognitive functions respond differently to the effects of

surgery, and that this may depend on risk factors such as age, preoperative infection,

and preoperative cognitive performance. Additonally, we found that inflammatory

processes may be involved in the development of and vulnerability to postoperative

cognitive impairment. Future research will be aimed at the modulation of these

inflammatory processes as a potential therapy for POCD.

SAMENVATTING

242

Postoperatieve cognitieve disfunctie

In Nederland worden elk jaar meer dan 400.000 ouderen boven de 60 jaar

geopereerd. Hoewel deze operaties worden uitgevoerd met het doel om de

gezondheid en het welzijn te verbeteren, zal naar schatting tien procent van de

oudere operatiepatiënten langdurige cognitieve klachten ontwikkelen, zoals

geheugenproblemen, concentratieproblemen en een verminderd vermogen om

te plannen of informatie te verwerken. Deze postoperatieve cognitieve disfunctie

(POCD) heeft een grote invloed op het leven van patiënten en hun naasten: het leidt

tot een verminderde kwaliteit van leven, een grotere afhankelijkheid van sociale

steun en voorzieningen en een groter risico op blijvende invaliditeit.

Het onderzoek naar POCD heeft zich in eerste instantie vooral gericht op

anesthesie als mogelijke oorzaak. Intuïtief lijkt het logisch dat middelen die de

hersenen beïnvloeden, ook een negatief effect op de hersenen zouden kunnen

hebben. Echter uit de vele studies naar de invloed van anesthesie op POCD blijkt dat

het type anesthesie geen of slechts een kleine invloed heeft op het risico om POCD

te ontwikkelen. Waarschijnlijk spelen andere mechanismen dus een belangrijkere rol

in de ontwikkeling van POCD.

De ontstekingshypothese

Weefselschade is een onvermijdelijke bijkomstigheid van operaties. De respons

van het lichaam op weefselschade is een ontstekingsreactie. De meest bekende

effecten hiervan zijn roodheid, zwelling, warmte en pijn. Deze ontstekingsreactie

ontstaat lokaal doordat cellen van het immuunsysteem aangetrokken worden naar

het beschadigde weefsel en hier processen in gang zetten die van belang zijn

voor weefselherstel. Zo wordt de bloedtoevoer naar het weefsel aangepast, wordt

beschadigd weefsel te verwijderd of hersteld en worden ziekteverwekkers gedood.

Hierbij produceren immuuncellen ontstekingsfactoren die dienen als signaalstoffen

ter regulatie van deze processen. De ontstekingsfactoren komen in het bloed

terecht en worden door het hele lichaam verspreid, de zogeheten systemische

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SAMENVATTING

Figuur 1: De ontstekingshypothese van POCD. Weefselschade ten gevolge van de operatie (1) trekt

immuuncellen aan (2) welke inflammatoire factoren produceren (3). De inflammatoire factoren komen

in het bloed terecht en verspreiden door het hele lichaam (4), de systemische ontstekingsreactie. De

ontstekingsfactoren bereiken de hersenen (5) waar ze immuuncellen van de hersenen, de microglia

(6), activeren. Deze ondergaan vormveranderingen en produceren inflammatoire factoren (7), ook wel

neuroinflammatie genoemd. Hevige en langdurige neuroinflammatie kan een nadelige invloed hebben op

zenuwfuncties (8) die betrokken zijn bij cognitie en gedrag. Veroudering is geassocieerd met een toename

van systemische inflammatie en neuroinflammatie na letsel of infectie en zou daardoor kunnen zorgen

voor een verhoogd risico op POCD.

ontstekingsrespons. Via het bloed bereiken de ontstekingsfactoren de hersenen,

waar ze immuuncellen van de hersenen, de microglia, activeren. Normaliter

hebben microglia een klein cellichaam en veel lange, dunne uitlopers waarmee ze

244

constant hun omgeving scannen. Wanneer de microglia door ontstekingssignalen

geactiveerd worden, trekken hun uitlopers in, worden hun cellichamen groter en

gaan ze ontstekingsfactoren produceren. Deze ontstekingsrespons in de hersenen

wordt neuroinflammatie genoemd. Neuroinflammatie speelt een belangrijke rol

in het lichamelijk herstel omdat het gedragingen stimuleert die ervoor zorgen dat

het lichaam goed kan herstellen. Voorbeelden zijn: in bed blijven, veel slapen, een

voorkeur voor gemakkelijk verteerbaar voedsel en het weinig belasten van het

beschadigde lichaamsdeel.

Al de bovengenoemde ontstekingsprocessen, van lokale ontsteking tot

neuroinflammatie, spelen een belangrijke rol bij het herstel na een operatie.

Echter, hevige en langdurige neuroinflammatie kan een nadelige invloed hebben

op de zenuwfuncties die verantwoordelijk zijn voor het cognitief functioneren. De

ontstekingshypothese voor POCD stelt daarom dat een excessieve ontstekingsrespons

ten gevolge van een operatie een rol speelt in de ontwikkeling van POCD (Figuur

1). De ontstekingshypothese kan ook verklaren waarom vooral ouderen POCD

krijgen, namelijk omdat veroudering geassocieerd is met toename van systemische

inflammatie en neuroinflammatie bij infecties en lichamelijk letsel.

Doel van dit proefschrift

Onderzoek van de laatste decennia levert bewijs ter ondersteuning van de

ontstekingshypothese. Echter, tot op heden is het onduidelijk waarom sommige

ouderen POCD krijgen en anderen niet. Daarnaast laten resultaten van dierstudies

zich lastig vertalen naar de kliniek, wat de ontwikkeling van een geschikte behandeling

belemmert.

Op basis van een systematisch literatuuronderzoek naar POCD, beschreven in

Hoofdstuk 2, concludeerden wij dat verschillende cognitieve functies aangedaan

kunnen zijn na een operatie en dat cognitieve problemen sterk verschillen per

patiënt. Deze conclusie leidde tot de hypothese dat een combinatie van risicofactoren

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SAMENVATTING

en eigenschappen van specifieke hersengebieden de gevoeligheid van deze

hersengebieden voor een operatie bepaalt en daarmee welke postoperatieve

cognitieve problemen de patiënt ervaart.

Dierstudies hebben zich vooral gericht op de invloed van een operatie op één

specifiek hersengebied, de hippocampus, en de cognitieve functie die de hippocampus

medieert in knaagdieren, het ruimtelijk leren en geheugen. Patiëntstudies richtten

zich daarentegen vooral op POCD in het algemeen, zonder onderscheid te maken

tussen verschillende cognitieve functies. Om onze hypothese te testen moesten

wij een andere aanpak gebruiken en de invloed van een operatie op verschillende

cognitieve functies en hersengebieden onderzoeken. In dit proefschrift worden

dierstudies en een patiëntstudie beschreven die tot doel hadden de betrokkenheid

te onderzoeken van de ontstekingsrespons en andere risicofactoren voor POCD bij

het ontstaan van postoperatieve cognitieve problemen in specifieke gebieden.

Postoperatieve cognitieve problemen en neuroinflammatie in een

rat-model voor POCD

Voor de experimenten in Hoofdstuk 3 tot 6 hebben we gebruik gemaakt van een model

voor POCD in ratten (Figuur 2). Ratten kregen een gestandaardiseerde buikoperatie

waarbij tijdelijk de bloedtoevoer naar het bovenste deel van het darmstelsel werd

verminderd, om de effecten van een grote buikoperatie bij mensen te simuleren. Na

een herstelperiode werden specifieke aspecten van gedrag en cognitief functioneren

onderzocht: exploratie- en angstgedrag als uiting van de gemoedstoestand; ruimtelijk

leren en geheugen; het geheugen voor objecten; en cognitieve flexibiliteit, het

vermogen om gedrag aan te passen aan een veranderde situatie. Daarnaast werden

markers geanalyseerd voor de systemische ontstekingsrespons, neuroinflammatie

en functioneren van zenuwcellen in hersengebieden: de hippocampus voor ruimtelijk

leren en geheugen, de prefrontale cortex voor objectherkenning en het striatum voor

cognitieve flexibiliteit.

246

Figuur 2: Een rat-model om de betrokkenheid van de ontstekingsrespons in POCD te onderzoeken.

Ratten ondergaan een buikoperatie. Na een herstelperiode worden testen afgenomen die specifieke

aspecten van gedrag en cognitief functioneren meten. Gedurende de postoperatieve periode worden

markers voor de systemische ontstekingsrespons geanalyseerd. Na afloop van de cognitieve testen

worden de hersenen verzameld en markers voor neuroinflammatie en het functioneren van zenuwcellen

geanalyseerd in 1) de prefrontale cortex voor object herkenning, 2) het striatum voor cognitieve flexibiliteit

en 3) de hippocampus voor ruimtelijk leren en geheugen.

Allereerst onderzochten wij in Hoofdstuk 3 hoe postoperatieve cognitieve

problemen zich ontwikkelen in de eerste weken na een operatie onder

omstandigheden die geassocieerd zijn met een laag risico op POCD, door middel van

een experiment in jonge gezonde ratten. Wij vonden dat een operatie in deze ratten

alleen invloed had op het ruimtelijk geheugen, en dit enkel in de eerste twee weken

na de operatie. Deze uitkomst wijst erop dat het ruimtelijk geheugen, geassocieerd

met het functioneren van de hippocampus, het meest gevoelig is voor een operatie.

In de hippocampus en de prefrontale cortex werden tekenen van neuroinflammatie

gevonden. Echter, alleen in de hippocampus werd een afname gezien van markers

voor het functioneren van zenuwcellen. Het lijkt dus zo te zijn dat neuroinflammatie

alleen niet voldoende is om tot cognitieve achteruitgang te leiden, maar dat cognitieve

veranderingen gemedieerd worden door veranderingen in neuronaal functioneren.

Deze bevindingen worden ondersteund door overeenkomstige resultaten in gezonde

ratten van middelbare leeftijd, in Hoofdstuk 6.

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SAMENVATTING

Vervolgens onderzochten wij de invloed van veroudering op cognitieve

problemen, twee (Hoofdstuk 4) en zes (Hoofdstuk 5) weken na een operatie. Wij

vonden dat veroudering in ratten, net zoals bij mensen, gepaard gaat met een

afname in de cognitieve prestaties en verandering van gedrag. Op de kortere termijn

na een operatie observeerden wij dat oude ratten ten opzichte van jonge ratten een

meer algemene achteruitgang vertoonden, waarbij naast het ruimtelijk geheugen

ook objectherkenning en exploratiegedrag aangedaan waren. Deze uitkomsten zijn

meer overeenkomstig met de cognitieve problematiek van POCD dan de geïsoleerde

geheugen problemen van jonge ratten. Er werden geen langere termijn effecten van

een operatie op het cognitief functioneren gevonden. Echter, oude ratten vertoonden

tot tenminste zes weken na de operatie een afname in het exploratie gedrag, terwijl

deze afname niet gevonden werd bij jonge ratten. Daarnaast vonden we een hogere

en langer aanhoudende microglia-activiteit na een operatie in oude ratten dan in

jonge ratten. Cognitief functioneren en exploratiegedrag waren gecorreleerd aan

microglia-activiteit in gerelateerde hersengebieden. Deze bevindingen suggereren

dat neuroinflammatie een rol zou kunnen spelen in de ontwikkeling van POCD en dat

een ernstigere neuroinflammatoire respons na een operatie kan bijdragen aan het

verhoogd risico op POCD in ouderen.

Bovenstaande uitkomsten verklaren niet waarom sommige ouderen POCD

krijgen en anderen niet. In Hoofdstuk 6 bediscussiëren we dat gebeurtenissen die

gepaard gaan met een ontstekingsreactie, zoals operaties, infecties en chronische

ontstekingsziektes, bij kunnen dragen aan een heviger ontstekingsrespons bij

veroudering. Als een eerste stap om deze hypothese te testen onderzochten we

de invloed van een longinfectie in de periode voorafgaande aan een operatie op

het ontstaan van postoperatieve cognitieve problemen in ratten. De uitkomsten

van dit experiment wijzen erop dat een infectie in ratten geassocieerd is met

langdurige veranderingen in neuroinflammatie die kunnen leiden tot een ernstiger

en gegeneraliseerde postoperatieve verandering in cognitie en gedrag. Dit

lijkt hypothese te ondersteunen dat gebeurtenissen die gepaard gaan met een

ontstekingsreactie bepalend kunnen zijn voor de ontwikkeling van POCD in ouderen.

248

Er wordt gedacht dat microglia een belangrijke rol spelen in POCD. In Hoofdstuk

7 wordt een nieuwe beeldanalyse methode beschreven die we ontwikkelden

om microglia-activiteit te kwantificeren in hersenplakjes van ratten. Deze snelle

gemakkelijke methode methode geeft naast een gevoelige uitkomst voor microglia-

activiteit extra informatie over de grootte van het cellichaam en de uitlopers van

microglia.

Postoperatieve cognitieve prestaties en inflammatie in oudere

operatie patiënten

In Hoofdstuk 8 worden de uitkomsten van een analyse op gegevens uit de “PICNIC –

postoperatieve cognitieve disfunctie in oudere kankerpatiënten” studie beschreven.

In deze studie zijn gegevens verzameld van patiënten bij wie een tumor operatief werd

verwijderd. We onderzochten de invloed van veranderingen van ontstekingswaarden

in het bloed en de risicofactoren leeftijd, operatieduur, educatieniveau en

preoperatief cognitief functioneren op de cognitieve domeinen geheugen, planning

en informatieverwerking. Zoals verwacht werden de postoperatieve uitkomsten in

alle domeinen sterk beïnvloedt door de leeftijd, preoperatief cognitief functioneren en

educatieniveau. Een verhoging van ontstekingsfactor C-reactief proteïne (CRP) was

gerelateerd aan een afname in informatieverwerking, maar dan alleen in patiënten

die cognitief goed presteerden voor de operatie. Deze uitkomsten suggereren

de invloed van ontstekingsfactoren op het cognitief functioneren na een operatie

verschilt per cognitief domein en per individu.

Ter conclusie

In eerder onderzoek is weinig aandacht besteedt aan welke cognitieve functies en

hersengebieden betrokken zijn bij POCD. De uitkomsten van dit proefschrift laten juist

zien dat de effecten van een operatie op specifieke hersengebieden en de hieraan

gerelateerde cognitieve functies sterk kunnen verschillen per individu, en beïnvloed

worden door risicofactoren zoals leeftijd, preoperatieve infecties en preoperatieve

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SAMENVATTING

cognitieve status. Daarnaast vonden wij aanwijzingen dat ontstekingsprocessen

betrokken zijn bij de ontwikkeling van en gevoeligheid voor postoperatieve cognitieve

problemen. In toekomstige studies willen we onderzoeken of het dempen van de

ontstekingsrespons geschikt is om POCD te voorkomen.

CURRICULUM VITAE

252

Iris Bertha Hovens is currently a postdoctoral researcher at the departments of

Surgery and Surgical Oncology (University Medical Center Groningen, University

of Groningen, The Netherlands) and Neurobiology (University of Groningen, the

Netherlands). She was born on the 12th of June 1984 in Leek, the Netherlands, where

she completed her secondary education. Hovens earned her Bachelor’s Life Science

and Technology (cum laude), with the specialization Molecular Physiology and

Pharmacology at the University of Groningen, the Netherlands, in 2005. She went on

to study Physiotherapy at the Hanze University of Applied Sciences, Groningen, the

Netherlands, and obtained her Bachelor’s degree (cum laude) in 2008. After working

for a year as a physiotherapist, Hovens enrolled in the Master’s Biomedical Sciences

at the University of Groningen. During this Master’s study she completed three

research internships at the Univeristy of Groningen, the first at the department of

Neuroendocrinology on personality and metabolism, the second at the department of

Epidemiology on an novel blood glucose kinetics test and the third at the department

of Molecular Neurobiology on postoperative cognitive dysfunction. After obtaining

her Master’s degree (cum laude), Hovens continued her research on postoperative

cognitive dysfunction as a PhD at the departments of Surgery and Surgical Oncology

and Neurobiology. She was supervised by prof. dr. E. Heineman, prof. dr. E.A. van der

Zee, dr. B.L. van Leeuwen en dr. R.G.Schoemaker. During her PhD Hovens combined

research in an animal model with analysis of clinical study results. The results of her

PhD are presented in this thesis, entitled ‘Characterizing Postoperative Cognitive

Dysfucntion in the Elderly’

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CURRICULUM VITAE

List of Publications

1. Hovens IB, van Leeuwen BL, Nyakas C, Heineman E, van der Zee EA, Schoemaker RG. Prior

infection exacerbates postoperative cognitive dysfunction in aged rats. In press: Am J Physiol Regul

Integr Comp Physiol

2. Hovens IB, van Leeuwen BL, Nyakas C, Heineman E, van der Zee EA, Schoemaker RG (2015).

Postoperative cognitive dysfunction and microglial activation in associated brain regions in old rats.

Neurobiol Learn Mem 118; 74-9

3. Hovens IB, Nyakas C, Schoemaker RG (2014). A novel method for evaluating microglial activation

using ionized calcium-binding adaptor protein-1 staining: cell body to cell size ratio. Neuroimmunol

neuroinflammation 1; 82-8.

4. Hovens IB, Schoemaker RG, van der Zee EA, Absalom AR, Heineman E and van Leeuwen BL. (2014).

Postoperative cognitive dysfunction: involvement of neuroinflammation and neuronal functioning.

Brain, Behavior, and Immunity 38: 201-10.

5. Hovens IB, Schoemaker RG, van der Zee EA, Heineman E, Nyakas C, van Leeuwen BL. (2013).

Surgery-induced behavioral changes in aged rats. Experimental gerontology 48: 1204–11.

6. Hovens IB, Schoemaker RG, van der Zee EA, Heineman E, Izaks GJ and van Leeuwen BL. (2012).

Thinking through postoperative cognitive dysfunction: How to bridge the gap between clinical and

pre-clinical perspectives. Brain, behavior, and immunity 26: 1169–79.

7. Hovens IB, van Wilgen CP en van Ittersum MW. (2009) Normscores en psychometrische

eigenschappen van de Fibromyalgia Impact Questionnaire in een Nederlandse populatie

fibromyalgiepatiënten, Nederlands Tijdschrift voor Fysiotherapie, 119, 3-9.

8. Schaafsma D, Boterman M, de Jong AR, Hovens IB, Penninks JM, Nelemans SA, Meurs H and

Zaagsma J.(2006) Differential Rho-kinase dependency of full and partial muscarinic receptor

agonists in airway smooth muscle contraction, British Journal of Pharmacology, 147: 737–743

Conference proceedings

9. Hovens IB, Schoemaker RG, van der Zee EA, van Leeuwen BL. Unraveling the role of

neuroinflammation in surgery-induced cognitive impairment. Extended abstract Measuring behavior

2014. (http://www.measuringbehavior.org/mb2014/proceedings)

10. Van Leeuwen BL, Hovens IB, Schoemaker RG, van der Zee EA, Heieman E, Nyakas C (2013) Effects

of surgery on cognition and affective behavior in aged rats. J Geriatr Oncol, 4, S71-72

DANKWOORD

256

Het is een enorme klus om een promotieonderzoek tot een goed einde te brengen. Het

is een leuke, intensieve, spannende, soms vreselijk frustrerende klus, en vooral ook

een klus die onmogelijk alleen geklaard kan worden. Gelukkig stond ik er niet alleen

voor. Ik heb van ontzettend veel mensen helpende handen, advies en vriendschap

ontvangen. Daarom wil ik dit dankwoord beginnen met een groot en welgemeend

“DANKJEWEL!!!” voor al deze mensen. Er zijn teveel mensen om allemaal te noemen.

Als je je naam hieronder niet terugvindt, weet dan dat ook jouw bijdrage ontzettend

door mij wordt gewaardeerd!

Uiteraard zijn er een aantal mensen die ik graag specifiek wil bedanken. Ten

eerste mijn promotoren en copromotoren, zonder wie dit promotieonderzoek niet

mogelijk was geweest. Mijn eerste promotor Prof. Erik Heineman: Erik, jouw enorme

enthousiasme en positieve instelling gaven mij altijd een boost en het vertrouwen dat

het allemaal wel goed zou komen.

Mijn tweede promotor Prof. Eddy van der Zee: Eddy, ik heb ontzettend veel gehad aan

jouw kennis op het gebied van leren en geheugen en je vragen die me uitdaagden

om toch nog eens kritisch naar mijn uitkomsten of manuscript te kijken.

Co-promotor en projectleider Dr. Barbara van Leeuwen: Barbara, dit onderzoek is

ontstaan uit jouw wens om te doorgronden waarom oudere operatiepatiënten

cognitieve problemen ondervinden en hoe we hier verandering in kunnen brengen.

Bedankt dat je de preklinische tak van je onderzoek aan mij hebt toevertrouwd. Ik

vind het fijn dat je me altijd veel ruimte hebt gegeven om dingen uit te proberen

en mezelf te ontwikkelen. Of ik nu een cursus wilde doen, naar een buitenlandse

conferentie wilde of een nieuw plan had voor een experiment, je stond altijd open

voor mijn ideeën.

Co-promotor Dr. Regien Schoemaker: Regien, jij was letterlijk mijn dagelijks begeleider.

Ik denk dat er weinig promovendi zijn die tijdens hun promotietraject op zoveel steun

van hun begeleider kunnen rekenen. Je deur stond altijd voor me open. Of het nu

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DANKWOORD

ging om een praktische vraag, een wild idee of gewoon een gezellig babbeltje,

je maakte altijd tijd voor me vrij. Ook heb ik veel geleerd van jouw vermogen om

onderzoeksresultaten om te zetten tot een verhaal (structuur!) en om onverwachte

(ongewilde) situaties en uitkomsten te zien als een kans in plaats van een falen.

Prof. Paul Luiten, bedankt dat je mij hebt aangedragen als kandidaat voor dit

promotieonderzoek. Hoewel je uiteindelijk niet mijn promotor bent geworden ben

je, zeker in de eerste jaren van mijn aanstelling, sterk betrokken geweest bij het

onderzoek. Ik heb je input altijd erg gewaardeerd, net zoals je regelmatige bezoeken

aan de PhD kamer voor een praatje.

Prof. Joris Sleats en Prof. Erik Boddeke, bedankt voor het plaatsnemen in de

beoordelingscommissie en het kritisch doornemen van mijn proefschrift. Prof.

Christopher Pryce, thank you for joining the reading committee and your willingness

to travel to the Netherlands to be an opponent at my defense.

Naast mijn promotoren, wil ik graag alle andere medeauteurs bedanken die

meegewerkt hebben aan het tot stand komen van dit proefschrift. Dr. Prof. Gerbrand

Izaks, Prof. Tony Absalom, Monique Huisman en Jelle Dalenberg bedankt voor de

fijne samenwerking. Prof. Csaba Nyakas, thanks for all the nice talks on your visits to

the Netherlands, and of course for providing us with all the aged rats that we used in

the research.

Waar zouden onderzoekers zijn zonder analisten en ander ondersteunend personeel.

Jan B, ja, eens zal ik moeten leren om net zo goed als jij vena jugularis canules te

plaatsen, maar ik ben heel blij dat jij altijd voor me klaar stond (en staat) om dit te doen.

Wanda, jij bent een rots in de branding voor alle promovendi op onze afdeling. Voor

mij was je naast een grote hulp bij de dierstudies ook een eerste aanspreekpunt voor

alle praktische vragen en problemen. Heel erg bedankt daarvoor. Kunja, Jan, Christa,

Folkert, Bert, Willem, Willeke, Petra, Michel, Andre, Annemieke, Pleuni, Marlies, Maria,

Henk en Richard, ook jullie bedankt voor alle hulp!

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Martijn, bedankt voor alle ondersteuning in de dierfaciliteit. Ik vind het heel fijn dat

je met alle verbouwingen altijd onze dierexperimenten voorop hebt gesteld. Linda,

Diana, Saskia, Roelie, Brendan, Wendy, Auke, Jaap, Ar, en alle andere dierverzorgers

van de Linnaeusborg en het CDP bedankt voor alle hulp. Miriam en Catriene,

jullie hebben nogal wat te stellen gehad met mijn oude ratten. Bedankt voor jullie

oplossingsgerichte houding en het meedenken met de experimenten.

Iets wat ik altijd als erg positief heb ervaren is de bereidheid van andere onderzoekers

en afdelingen om vragen te beantwoorden, adviezen te geven en te helpen met het

onder de knie krijgen van nieuwe technieken. De open sfeer onder onderzoekers

binnen het onderzoeksinstituut CBN, inmiddels gefuseerd in het overkoepelend

instituut GELIFES, vind ik ontzettend prettig. Met mijn vragen, en dat waren er nogal

wat, kon ik altijd bij iedereen binnen stappen en andersom kwamen anderen naar

mij toe met vragen over de technieken waar ik veel mee werk. Dit heeft me enorm

geholpen in mijn ontwikkeling als onderzoeker. Uli, Ad, Bauke, Anton, Gertjan, Peter,

Jocelien, Jaap en alle andere onderzoekers van voormalig CBN, bedankt.

Binnen de afdeling Chirurgie en Chirurgische Oncologie wil ik Hanneke bedanken

voor al het verzette werk voor het PICNIC-onderzoek en alle hulp bij het tot stand

komen van Hoofdstuk 8. Ook alle andere medewerkers van het PICNIC-onderzoek,

bedankt voor alle inzet.

Prof. Henri Leuvenink, Petra Ottens, Lydia Visser, Prof. Eliane Popa, Prof. Mathijs

Blankesteijn, Karola Jansen en Ellis Mulder, bedankt voor de mogelijkheid om

technieken te leren en uit te voeren in jullie labs. Masum Mia, Raffaele Altara, and

Kèvin Knoops thank you for helping me with my analysis.

Bij mijn onderzoek heb ik van veel studenten hulp gekregen. Alex, Priscilla,

Anouska, Nynke, Hidde, Bernard, Wouter, Tinka, Jahlisa, Adrie, Anna-Nynke en alle

bachelorstudenten die door de jaren heen hebben bijgedragen, bedankt.

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DANKWOORD

Niki, Pieter, Marcello, Kees and Martijn, thank you for making me feel at home in our

PhD room when I started my project. Vibeke, Yun, Priscila, Erin, Kata, Doortje, Peter,

Ewelina, and Leonie, thank you for your help and advice and even more so for the

great times spent gossiping in our room, having dinner together and jogging (or at

least attempting to do so). Leonie, bedankt voor de gezellige tijden op reis. Ook aan

alle andere PhD’s die ik door de jaren heen tegen ben gekomen binnen voormalig

CBN en research school BCN en GSMS dank voor de gezellige tijden.

Martha en Fiona, ik ben erg blij dat jullie mijn paranimfen zijn. Martha, na een slow

start zijn we de afgelopen jaren steeds meer naar elkaar toe gegroeid. We kunnen

uren over van alles en niets met elkaar kletsen. Ik bewonder je betrokkenheid bij

anderen en je enorme hart. Fiona, achter jouw rustige houding zit veel warmte en

humor. Je betrouwbaarheid en behulpzaamheid waardeer ik enorm. Jij en Jan zijn

naast collega’s ook goede vrienden geworden. Ik ben heel blij dat ik jullie heb leren

kennen.

Tot slot, mogen in dit dankwoord mijn vrienden en familie natuurlijk niet ontbreken.

Lieve vrienden en familie, bedankt voor alle steun, luisterende oren en gezelligheid.

Pap, mam en Kim, bedankt dat jullie er altijd voor mij waren. Jelle, bedankt voor je

interesse, humor en relativeringsvermogen. Ik vond het erg fijn om iemand naast me

te hebben die wist hoe het is om the promoveren. Jij was er altijd om mijn ideeën te

testen, mijn enthousiasme te delen en me op te beuren als het minder mee zat. Of we

nu in Nederland blijven of naar het buitenland afreizen, ik ben blij dat we samen zijn.