Pharmacological fMRI; a clinical exploration

Dit proefschrift beschrijft de resultaten van een verkennend onderzoek naar een nieuwe techniek die gebruikt kan worden om de effecten van geneesmiddelen op hersenaktiviteit af te beelden: pharmacologische functionele magnetic resonance imaging (farmacologische fMRI of phMRI). Met behulp van deze techniek werden de effecten onderzocht van drie verschillende medicijnen (de bètablokker propranolol, de selectieve oestrogeen-receptor modulator (SERM) raloxifene en de cholinesteraseremmer galantamine) op hersenaktiviteit van respectievelijk gezonde jongere en oudere controles, en patiënten met geheugenklachten. Aan de hand van de resultaten van dit onderzoek werd nagegaan in hoeverre phMRI toepasbaar zou kunnen zijn in een klinische context. De MRI scanner is al bijna 30 jaar een vast onderdeel van het instrumentarium van radiologen. MRI is een volledig non-invasieve scantechniek die artsen in staat stelt om haarscherpe, driedimensionale afbeeldingen te maken van de verschillende organen van levende patiënten en de eventuele ziekteprocessen die zich daarin afspelen. fMRI is een meer recente toepassing van MRI, waarbij de wisselende magnetische eigenschappen van de rode bloedkleurstof ‘hemoglobine’ worden benut om zwart-wit contrast te geven aan MR plaatjes (Jezzard et al., 2001). Afhankelijk van de mate waarin hersengebieden aktief zijn wordt een sterker of minder sterk bloed-oxygenatie afhankelijk (BOLD) MR signaal gemeten. De meeste fMRI studies vergelijken de gemiddelde signaalintensiteiten van hersengebieden tussen actieve en een minder actieve condities van een bepaalde taak, die tijdens het scannen wordt uitgevoerd. Dit levert driedimensionaal plaatjes op van het hele brein, waarin de gemiddelde intensiteitsverschillen tussen twee taak-condities zijn af te lezen (“contrast plaatjes”). phMRI is een verdere nuancering van fMRI, waarbij contrastplaatjes worden onderzocht op toenames of afnames van intensiteitsverschillen als gevolg van blootstelling aan een bepaalde farmacologische stof. Aangezien de meeste psychotrope geneesmiddelen aangrijpen in specifieke neurotransmittersystemen zou phMRI gebruikt kunnen worden om de toestand van deze systemen te onderzoeken in de gezonde en de zieke situatie. phMRI zou dus eventueel als klinisch-diagnostisch instrument kunnen worden gebruikt. Er is echter nog maar weinig onderzoek gedaan naar de klinische waarde van phMRI (Honey and Bullmore, 2004). Dit proefschrift had tot doel dit terrein verder te verkennen. Patiënten en proefpersonen werden gescand met behulp van fMRI tijdens het uitvoeren van speciaal voor dit onderzoek ontwikkelde geheugentestjes (paradigmata). Hierdoor waren we in staat om hersengebieden zichtbaar te maken die betrokken zijn bij verschillende aspecten van geheugenfunctie. De effecten van geneesmiddelen werden onderzocht op hersenfunctie zoals die werd opgeroepen door bovengenoemde taken. We gebruikten achtereenvolgens een ‘face-encoding’ taak (onthouden van onbekende menselijke gezichten (Small et al., 1999)), een ‘face-recognition’ taak (herkennen van eerder getoonde gezichten), en een n-letter back werkgeheugen taak (tijdelijke opslag van nieuwe informatie (Owen et al., 2005)). Verder werd in samenwerking met Dr. A.H. van Stegeren and Prof. Dr. W.TA.M. Everaerd van de afdeling Klinische en Experimentele Psychologie van de Universiteit van Amsterdam het International Affective Picture System (IAPS) (Lang and Bradley, 1997), aangepast voor gebruik in de MR scanner. Deze taak had tot doel hersengebieden te aktiveren die betrokken zijn bij de opslag van emotioneel negatief geladen (onprettige) informatie. fMRI analyses werden gedaan met de fMRI expert analysis tool (FEAT) uit het data-analyse pakket fMRIB software library (FSL) (Smith et al., 2004). Ons onderzoek leverde de volgende bevindingen op: 1. Effecten van verschillende geneesmiddelen op hersenfunctie bij mensen kunnen worden gemeten met behulp van fMRI, maar zijn vrij klein. 2. Onze bevindingen sluiten aan bij die van ander fMRI onderzoek waaruit blijkt dat de effecten van geneesmiddelen op hersenfunctie regio-specifiek en proces-specifiek kunnen zijn (Honey and Bullmore, 2004). 3. De effecten van geneesmiddelen op hersenfunctie zijn tevens geslachts- en ziekte-(stadium)-specifiek. 4. Deze effecten zijn afhankelijk van de duur van blootstelling aan het farmacologische agens. 5. In het geval van cholinerge stimulatie leidde een éénmalige stootdosis galantamine al tot regio- proces- en ziektespecifieke effecten. 6. We hebben een methode ontwikkeld om de effecten van geneesmiddelen op hersenfunctie tijdens geheugenfunctie te onderzoeken in relatie tot gedragsveranderingen en specifieke hersenprocessen. 7. Indien grote groepen patiënten geïncludeerd worden zijn uitgebreide studies naar de klinische (vroegdiagnostische en predictieve) waarde van de gemeten effecten zeer goed mogelijk. phMRI is voorlopig nog een onderzoeksinstrument. Vanuit klinisch oogpunt kunnen de bevindingen van phMRI studies echter erg interessant zijn. Studies van de regio- en proces-specificiteit van geneesmiddelen kunnen helpen bij het ontwikkelen van geneesmiddelen die meer gericht inwerken op specifieke hersenprocessen. Dit zou mogelijk de effectiviteit van geneesmiddelen kunnen verhogen en het aantal bijwerkingen kunnen verminderen. phMRI kan verder worden ingezet om het werkingsmechanisme van psychotrope geneesmiddelen te onderzoeken. phMRI provokatietests laten bovendien zien dat de onmiddellijke effecten van geneesmiddelen een vroeg-diagnostische waarde kunnen hebben, en misschien zelfs het succes van farmacotherapie kunnen voorspellen (Fu et al., 2004). Toekomstig onderzoek zal moeten uitwijzen in hoeverre phMRI in staat is om klinisch relevante functionele biomarkers aan te tonen in individuele patiënten. Ondertussen kunnen groepsstudies al resultaten leveren die van klinisch belang zouden kunnen zijn voor individuele patiënten. Met phMRI provokatietests kunnen relaties worden gelegd tussen bepaalde klinische verschijnselen en een afwijkende reactiviteit van centrale neurotransmittersystemen. Zijn zulke relaties eenmaal gelegd, dan kunnen patiënten die zich presenteren met de bewuste symptomen of afwijkingen worden behandeld met een gerichte farmacotherapie. De ontwikkelingen in de methodologie van fMRI staan ondertussen niet stil. Er is inmiddels een arsenaal aan nieuwe analysemethoden beschikbaar gekomen, die van belang zouden kunnen zijn voor toekomstig phMRI onderzoek. Ook al staat farmacologische fMRI nog in de kinderschoenen, er wordt met grote stappen vooruitgang geboekt. Het is dus waarschijnlijk dat phMRI, in combinatie met andere technieken, een belangrijk bijdrage zal gaan leveren aan de zoektocht naar biologische markers met een bruikbare klinische waarde. Reference List Fu CHY, Williams SCR, Cleare AJ, Brammer MJ, Walsh ND, Kim J, Andrew CM, Pich EM, Williams PM, Reed LJ, Mitterschiffthaler MT, Suckling J, Bullmore ET. Attenuation of the neural response to sad faces in major depression by antidepressant treatment - A prospective, event-related functional magnetic resonance imaging study. Archives of General Psychiatry 2004; 61:877-889. Honey G, Bullmore E. Human pharmacological MRI. Trends in Pharmacological Sciences 2004; 25:366-374. Jezzard P, Matthews PM, Smith SM. Functional MRI - An introduction to methods. New York: Oxford University Press, 2001. Lang PJ, Bradley MM. International affective picture system (IAPS); Technical manual and affective ratings. NIMH Center for the study of emotion and attention 1997. Owen AM, McMillan KM, Laird AR, Bullmore E. N-back working memory paradigm: A meta-analysis of normative functional neuroimaging. Hum.Brain Mapp. 2005; 25:46-59. Small SA, Perera GM, DeLaPaz R, Mayeux R, Stern Y. Differential regional dysfunction of the hippocampal formation among elderly with memory decline and Alzheimer's disease. Annals of Neurology 1999; 45:466-472. Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TEJ, Johansen-Berg H, Bannister PR, De Luca M, Drobnjak I, Flitney DE, Niazy RK, Saunders J, Vickers J, Zhang YY, De Stefano N, Brady JM, Matthews PM. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 2004; 23:S208-S219.Barkhof, F. [Promotor]Scheltens, P. [Promotor]Rombouts, S.A.R.B. [Copromotor

An integrated network model of psychotic symptoms

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Construct validity and responsiveness of feasible composite disease activity measures for use in daily clinical practice in patients with psoriatic arthritis

OBJECTIVE: There is a need for a widely accepted comprehensive disease activity measure for use in daily practice in patients with psoriatic arthritis (PsA). For this reason, the 3-item Visual Analogue Scale (3VAS) and 4-item Visual Analogue Scale (4VAS) were developed. This study aimed to test construct validity and responsiveness of the 3VAS and 4VAS in a population of patients with newly diagnosed PsA receiving usual care. METHODS: Components of the 3VAS (physician global, patient global, patient skin) and 4VAS (physician global, patient pain, patient joint, patient skin) were scored on 0-10 VAS scales. Agreement of low disease activity (LDA) state between 3VAS/4VAS and other composite measures was tested using Venn diagrams. Construct validity and responsiveness (3-month interval) were assessed using Spearman correlation coefficients and standardised response means (SRM) with effect sizes (ES), respectively, following hypothesis generation. Both 3VAS/4VAS were also compared with several patient-reported outcome measures. RESULTS: Data from 629 patients were used. Both 3VAS (ES=0.48, SRM 0.52) and 4VAS (ES=0.48, SRM=0.50) showed responsiveness similar to Disease Activity in PSoriatic Arthritis (DAPSA) and Disease Activity Score-28 (DAS28). Both measures had a strong correlation with DAPSA (r=0.80-0.87), Psoriatic Arthritis Disease Activity Score (PASDAS) (r=0.89) and Routine Assessment of Patient Index Data 3 (RAPID3) (r=0.84-0.92). 3VAS and 4VAS had the highest agreement with PASDAS in categorising patients to LDA at 12 months. CONCLUSION: This is the first study assessing the performance of the 3VAS and 4VAS in an observational cohort of patients with early PsA. Both measures have promising performance characteristics, showing strong correlations and good discrimination with existing composite measures. The 4VAS may be the preferred version with better face validity.</p

Health-related quality of life and functional ability in patients with early arthritis during remission steered treatment: results of the IMPROVED study

INTRODUCTION: The aim of this study was to investigate patient reported outcomes (PROs) of functional ability and health related quality of life (HRQoL) in patients with early (rheumatoid) arthritis during one year of remission steered treatment. METHODS: In this study, 610 patients with early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and tapered high dose of prednisone. Patients in early remission (Disease Activity Score (DAS) <1.6 after 4 months) tapered prednisone to zero and when in persistent remission, also tapered MTX. Patients not in early remission were randomized to either MTX + hydroxychloroquine + sulphasalazine + prednisone (arm 1) or to MTX + adalimumab (arm 2). Every 4 months, patients filled out the Health Assessment Questionnaire (HAQ) and the McMaster Toronto Arthritis Patient Preference Questionnaire (MACTAR), the Short Form 36 (SF-36) and visual analogue scales (VAS). Change scores were compared between treatment groups. The association with achieving remission was analyzed using linear mixed models. RESULTS: During year 1, patients who achieved early remission had the most improvement in PROs with scores comparable to the general population. Patients in the randomization arms showed less improvement. Scores were comparable between the arms. There was a significant association between achieving remission and scores of HAQ, MACTAR and physical HRQoL. CONCLUSIONS: In early arthritis, PROs of functional ability and HRQoL after one year of remission steered treatment reach normal values in patients who achieved early remission. In patients not in early remission, who were randomized to two strategy arms, PROs improved less, with similar scores in both treatment arms. TRIAL REGISTRATIONS: ISRCTN11916566 and EudraCT2006-006186-1

Determinants of radiographic progression in early psoriatic arthritis:Insights from a real-world cohort

Objective Persistent articular inflammation in psoriatic arthritis (PsA) is associated with radiographic damage. Despite advances in diagnosis and therapy, radiographic structural damage remains prevalent in PsA. To elucidate this topic, we studied which baseline clinical characteristics determine radiographic progression. Methods For this analysis, data were used from DEPAR (Dutch South West Psoriatic Arthritis) Study, a real-world cohort of patients with newly diagnosed PsA. Radiographic changes were assessed using the modified Total Sharp/van der Heijde Score (mTSS) for PsA. Univariable-multivariable mixed-effects negative binomial regression analysis was applied to define baseline predictors for radiographic progression over time. Results The study included 476 patients with early PsA with 1660 hand and feet radiographs from four different time points (baseline, first, second and third year). The progressive group (n=71) had a higher mTSS compared with the non-progressive group (n=405) at diagnosis (17 (3-36) vs 0 (0-1)). A comparison of the two groups revealed that the progressive group had significantly older (59 (12) vs 49 (13)) and a higher rate of the presence of swollen joints (93% vs 78%) at diagnosis. Multivariable analysis identified age (incidence rate ratio (IRR)=1.10, p=0.000), sex (female) (IRR=0.48, p=0.043) and baseline mTSS (IRR=1.11, p=0.000) as significant determinants of radiographic change over time. For the progressive subset, additionally, the multivariable analysis highlighted baseline Disease Activity in PSoriatic Arthritis (IRR=1.05, p=0.006) and swollen joint count (IRR=1.07, p=0.034) as predictors. Conclusions According to this real-world cohort, patients with early PsA exhibit minimal radiographic progression under current treatment protocols. This study indicates that while old age and initial radiographic damage predict progression, female sex confers a protective effect on it. Furthermore, disease activity score and swollen joints emerged as predictors for radiographic changes during the follow-up in progressive patients.</p

Determinants of radiographic progression in early psoriatic arthritis:Insights from a real-world cohort

Objective Persistent articular inflammation in psoriatic arthritis (PsA) is associated with radiographic damage. Despite advances in diagnosis and therapy, radiographic structural damage remains prevalent in PsA. To elucidate this topic, we studied which baseline clinical characteristics determine radiographic progression. Methods For this analysis, data were used from DEPAR (Dutch South West Psoriatic Arthritis) Study, a real-world cohort of patients with newly diagnosed PsA. Radiographic changes were assessed using the modified Total Sharp/van der Heijde Score (mTSS) for PsA. Univariable-multivariable mixed-effects negative binomial regression analysis was applied to define baseline predictors for radiographic progression over time. Results The study included 476 patients with early PsA with 1660 hand and feet radiographs from four different time points (baseline, first, second and third year). The progressive group (n=71) had a higher mTSS compared with the non-progressive group (n=405) at diagnosis (17 (3-36) vs 0 (0-1)). A comparison of the two groups revealed that the progressive group had significantly older (59 (12) vs 49 (13)) and a higher rate of the presence of swollen joints (93% vs 78%) at diagnosis. Multivariable analysis identified age (incidence rate ratio (IRR)=1.10, p=0.000), sex (female) (IRR=0.48, p=0.043) and baseline mTSS (IRR=1.11, p=0.000) as significant determinants of radiographic change over time. For the progressive subset, additionally, the multivariable analysis highlighted baseline Disease Activity in PSoriatic Arthritis (IRR=1.05, p=0.006) and swollen joint count (IRR=1.07, p=0.034) as predictors. Conclusions According to this real-world cohort, patients with early PsA exhibit minimal radiographic progression under current treatment protocols. This study indicates that while old age and initial radiographic damage predict progression, female sex confers a protective effect on it. Furthermore, disease activity score and swollen joints emerged as predictors for radiographic changes during the follow-up in progressive patients.</p

Retreatment with rituximab based on a treatment-to-target approach provides better disease control than treatment as needed in patients with rheumatoid arthritis: a retrospective pooled analysis

Objective. To assess the efficacy and safety profiles of two different rituximab retreatment regimens in patients with RA

Paternal inflammatory arthritis is associated with a higher risk of miscarriage:results of a large multicentre study (iFAME-Fertility)

OBJECTIVES: Paternal preconception health is recognized as an important contributor to pregnancy outcomes. Nonetheless, pregnancy outcomes of partners of men with inflammatory arthritis (IA) have never been studied. Our objective was to describe the pregnancy outcomes of partners of men diagnosed with IA.METHODS: We performed a multicentre cross-sectional retrospective study conducted in the Netherlands. Men with IA who were over 40 years old that reported at least one positive pregnancy test were included. To analyse the impact of IA on pregnancy outcomes, pregnancies were classified into two groups: pregnancies conceived after the diagnosis of IA and before the diagnosis of IA.RESULTS: In total, 408 male participants diagnosed with IA reported 897 singleton pregnancies that resulted in 794 live births. Pregnancies conceived after the diagnosis of IA had higher rate of miscarriage (12.27 vs 7.53%, P = &lt;0.05). This increased risk was still present after adjusting for confounders [OR 2.03 (95% CI 1.12, 3.69) P = 0.015].CONCLUSIONS: This is the largest study to describe the pregnancy outcomes of partners of men diagnosed with IA and the first to demonstrate that paternal IA is associated with a higher risk of miscarriage. Notwithstanding, the overall rate of miscarriage reported in our study could be comparable to previously reported population estimates.</p

Excluding pulmonary embolism in primary care using the Wells-rule in combination with a point-of care D-dimer test: a scenario analysis

ABSTRACT: BACKGROUND: In secondary care the Wells clinical decision rule (CDR) combined with a quantitative D-dimer test can exclude pulmonary embolism (PE) safely. The introduction of point-of-care (POC) D-dimer tests facilitates a similar diagnostic strategy in primary care. We estimated failure-rate and efficiency of a diagnostic strategy using the Wells-CDR combined with a POC-D-dimer test for excluding PE in primary care. We considered ruling out PE safe if the failure rate was <2% with a maximum upper confidence limit of 2.7%. METHODS: We performed a scenario-analysis on data of 2701 outpatients suspected of PE. We used test characteristics of two qualitative POC-D-dimer tests, as derived from a meta-analysis and combined these with the Wells-CDR-score. RESULTS: In scenario 1 (SimpliRed-D-dimer sensitivity 85%, specificity 74%) PE was excluded safely in 23.8% of patients but only by lowering the cut-off value of the Wells rule to <2. (failure rate: 1.4%, 95% CI 0.6-2.6%) In scenario 2 (Simplify-D-dimer sensitivity 87%, specificity 62%) PE was excluded safely in 12.4% of patients provided that the Wells-cut-off value was set at 0. (failure rate: 0.9%, 95% CI 0.2-2.6%) CONCLUSION: Theoretically a diagnostic strategy using the Wells-CDR combined with a qualitative POC-D-dimer test can be used safely to exclude PE in primary care albeit with only moderate efficienc