Accurate prediction of the unbound drug concentration-time profile at the CNS target site is crucial for the assessment of the right drug concentration-effect relationship. PBPK models have... Show moreAccurate prediction of the unbound drug concentration-time profile at the CNS target site is crucial for the assessment of the right drug concentration-effect relationship. PBPK models have supported the PK prediction of the CNS target sites and the translation of PK data between species and between populations, given their mechanistic, physiology-based structure. In this thesis, we have developed a CNS PBPK model which could predict adequately the brainECF, brainICF, and CSF unbound PK profiles and provide important insights into the brain unbound pharmacokinetics of patients with CNS diseases. Early prediction of the brain target site pharmacokinetics of the right patient population can prioritize drugs with the favored brain PK profiles, which might optimize and accelerate the CNS drug development process. Show less
This thesis describes studies of individuals with systemic lupus erythematosus (SLE) presenting with neuropsychiatric (NP) symptoms at the Leiden NPSLE clinic. A diverse range of studies, including... Show moreThis thesis describes studies of individuals with systemic lupus erythematosus (SLE) presenting with neuropsychiatric (NP) symptoms at the Leiden NPSLE clinic. A diverse range of studies, including laboratory, radiological, clinical and patient´s reported outcomes are presented.The Leiden NPSLE clinic is a tertiary referral center for patients with SLE and neuropsychiatric (NP) symptoms. In the NPSLE clinic, patients are assessed by a multidisciplinary team. Thereafter, clinical, radiological and laboratory measures are weighed in a consensus meeting to correctly attribute the NP symptoms: related to lupus activity (NPSLE) or not. This extensive and standardized assessment of NPSLE, a rare and heterogenous disease lacking a gold standard, is unique and creates the opportunity to explore many aspects of NPSLE in well-defined phenotypes.In the first part of this thesis, we evaluate both classification and treatment of patients withSLE and NP symptoms. The second part of this thesis focuses on a diverse range of clinicaloutcomes of NPSLE, including both morbidity and mortality. The last part of this thesisassesses potential biomarkers for (specific manifestations of) NPSLE. Show less
The general aim of this thesis was to study the frequency, causes and consequences of pathologic brain aging specifically focusing on sub-clinical and clinical MRI manifestations of vascular (small... Show moreThe general aim of this thesis was to study the frequency, causes and consequences of pathologic brain aging specifically focusing on sub-clinical and clinical MRI manifestations of vascular (small vessel disease) and neurodegenerative (brain atrophy) disease. A second aim was to improve the accuracy of the tools to quantify brain tissue so to better reflect the imaging characteristics of older people. All data presented in this thesis are from the AGES-Reykjavik Study including 5764 elderly men and women. The data is based on cross-sectional and longitudinal assessments of the brain with MRI measures. Show less
MR fingerprinting (MRF) is a promising method for quantitative characterization of tissues. Often, voxel-wise measurements are made, assuming a single tissue-type per voxel. Alternatively, the... Show moreMR fingerprinting (MRF) is a promising method for quantitative characterization of tissues. Often, voxel-wise measurements are made, assuming a single tissue-type per voxel. Alternatively, the Sparsity Promoting Iterative Joint Non-negative least squares Multi-Component MRF method (SPIJN-MRF) facilitates tissue parameter estima-tion for identified components as well as partial volume segmentations. The aim of this paper was to evaluate the accuracy and repeatability of the SPIJN-MRF parameter estimations and partial volume segmentations. This was done (1) through numerical simulations based on the BrainWeb phantoms and (2) using in vivo acquired MRF data from 5 subjects that were scanned on the same week-day for 8 consecutive weeks. The partial volume segmen-tations of the SPIJN-MRF method were compared to those obtained by two conventional methods: SPM12 and FSL. SPIJN-MRF showed higher accuracy in simulations in comparison to FSL-and SPM12-based segmentations: Fuzzy Tanimoto Coefficients (FTC) comparing these segmentations and Brainweb references were higher than 0.95 for SPIJN-MRF in all the tissues and between 0.6 and 0.7 for SPM12 and FSL in white and gray matter and between 0.5 and 0.6 in CSF. For the in vivo MRF data, the estimated relaxation times were in line with literature and minimal variation was observed. Furthermore, the coefficient of variation (CoV) for estimated tissue volumes with SPIJN-MRF were 10.5% for the myelin water, 6.0% for the white matter, 5.6% for the gray matter, 4.6% for the CSF and 1.1% for the total brain volume. CoVs for CSF and total brain volume measured on the scanned data for SPIJN-MRF were in line with those obtained with SPM12 and FSL. The CoVs for white and gray mat-ter volumes were distinctively higher for SPIJN-MRF than those measured with SPM12 and FSL. In conclusion, the use of SPIJN-MRF provides accurate and precise tissue relaxation parameter estimations taking into account intrinsic partial volume effects. It facilitates obtaining tissue fraction maps of prevalent tissues including myelin water which can be relevant for evaluating diseases affecting the white matter. Show less
Background Pre-stroke dependent patients (modified Rankin Scale score (mRS) >= 3) were excluded from most trials on endovascular treatment (EVT) for acute ischemic stroke (AIS) in the anterior... Show moreBackground Pre-stroke dependent patients (modified Rankin Scale score (mRS) >= 3) were excluded from most trials on endovascular treatment (EVT) for acute ischemic stroke (AIS) in the anterior circulation. Therefore, little evidence exists for EVT in those patients. We aimed to investigate the safety and benefit of EVT in pre-stroke patients with mRS score 3. Methods We used data from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic stroke in the Netherlands (MR CLEAN) Registry. All patients treated with EVT for anterior circulation AIS with pre-stroke mRS 3 were included. We assessed causes for dependence and compared patients with successful reperfusion (defined as expanded Thrombolysis in Cerebral Ischemia scale (eTICI) 2b-3) to patients without successful reperfusion. We used regression analyses with pre-specified adjustments. Our primary outcome was 90-day mRS 0-3 (functional improvement or return to baseline). Results A total of 192 patients were included, of whom 82 (43%) had eTICI <2b and 108 (56%) eTICI >= 2b. The median age was 80 years (IQR 73-87). Fifty-one of the 192 patients (27%) suffered from previous stroke and 36/192 (19%) had cardiopulmonary disease. Patients with eTICI >= 2b more often returned to their baseline functional state or improved (n=26 (26%) vs n=15 (19%); adjusted odds ratio (aOR) 2.91 (95% CI 1.08 to 7.82)) and had lower mortality rates (n=49 (49%) vs n=50 (64%); aOR 0.42 (95% CI 0.19 to 0.93)) compared with patients with eTICI Conclusions Although patients with AIS with pre-stroke mRS 3 comprise a heterogenous group of disability causes, we observed improved outcomes when patients achieved successful reperfusion after EVT. Show less
More than 45 years of research on the effects of glucocorticoids on brain function has yielded many insights, but also left a number of longstanding questions. One conundrum has been how activation... Show moreMore than 45 years of research on the effects of glucocorticoids on brain function has yielded many insights, but also left a number of longstanding questions. One conundrum has been how activation of the structurally comparable mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) can lead to very different, or even opposite effects. It also remained unclear how the consequence of activation of a single receptor, GR, can differ from cell to cell and from situation to situation. In this thesis we have investigated two aspects of transcriptional regulation in response to glucocorticoids: the cause of MR/GR specificity, and the role of crosstalk with other transcription factors. Within the hippocampus, we found NeuroD factors to drive the specificity in corticosteroid receptor DNA binding and subsequent gene regulation, i.e. by stimulating MR signaling. We identified Jun dimerization protein 2 (Jdp2) as a stress-responsive MR-specific target gene. In a stress hormone relevant memory task, GR was suggested to act context-dependently and several novel GR target genes were detected. Further elucidation of distinct MR/GR downstream pathways will enable us to better understand the stress physiology and more specifically target aspects of glucocorticoid signaling for treatment of stress-related disorders. Show less
Su, R.S.; Cornelissen, S.A.P.; Sluijs, M. van der; Es, A.C.G.M. van; Zwam, W.H. van; Dippel, D.W.J.; ... ; Walsum, T. van 2021
The Thrombolysis in Cerebral Infarction (TICI) score is an important metric for reperfusion therapy assessment in acute ischemic stroke. It is commonly used as a technical outcome measure after... Show moreThe Thrombolysis in Cerebral Infarction (TICI) score is an important metric for reperfusion therapy assessment in acute ischemic stroke. It is commonly used as a technical outcome measure after endovascular treatment (EVT). Existing TICI scores are defined in coarse ordinal grades based on visual inspection, leading to inter- and intra-observer variation. In this work, we present autoTICI, an automatic and quantitative TICI scoring method. First, each digital subtraction angiography (DSA) acquisition is separated into four phases (non-contrast, arterial, parenchymal and venous phase) using a multi-path convolutional neural network (CNN), which exploits spatio-temporal features. The network also incorporates sequence level label dependencies in the form of a state-transition matrix. Next, a minimum intensity map (MINIP) is computed using the motion corrected arterial and parenchymal frames. On the MINIP image, vessel, perfusion and background pixels are segmented. Finally, we quantify the autoTICI score as the ratio of reperfused pixels after EVT. On a routinely acquired multi-center dataset, the proposed autoTICI shows good correlation with the extended TICI (eTICI) reference with an average area under the curve (AUC) score of 0.81. The AUC score is 0.90 with respect to the dichotomized eTICI. In terms of clinical outcome prediction, we demonstrate that autoTICI is overall comparable to eTICI. Show less
Neuroplasticity is the capacity of the central nervous system to adapt to external or internal stimuli. It is being increasingly recognized as an important factor which contributes to the... Show moreNeuroplasticity is the capacity of the central nervous system to adapt to external or internal stimuli. It is being increasingly recognized as an important factor which contributes to the successful outcome of nerve transfers. Other much more well-known factors are the number of axons that cross the coaptation site, the interval between trauma and repair, and age. Neuroplasticity is mediated by synaptic and neurotransmitter changes which underlie activation of previously existing but low-active connections in the brain. Dendritic sprouting and axonal elongation might also take place but is likely less prominent. We review different factors that play a role in neuroplasticity and functional regeneration after specific nerve transfers. These factors include, amongst others, the distance between cortical areas of the donor and receptor neurons; the presence versus absence of pre-existing low-active inter-neuronal connections; gross versus fine movement restoration; rehabilitation; brain trauma and very important: the age. The potential for plastic adaptation should be taken into consideration if the surgical strategy and postoperative rehabilitation are planned, as its influence on results cannot be denied. Show less
Background and purpose: To update the digital online atlas for organs at risk (OARs) delineation in neurooncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging... Show moreBackground and purpose: To update the digital online atlas for organs at risk (OARs) delineation in neurooncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging with new OARs. Materials and methods: In this planned update of the neurological contouring atlas published in 2018, ten new clinically relevant OARs were included, after thorough discussion between experienced neuroradiation oncologists (RTOs) representing 30 European radiotherapy-oncology institutes. Inclusion was based on daily practice and research requirements. Consensus was reached for the delineation after critical review. Contouring was performed on registered CT with intravenous (IV) contrast (soft tissue & bone window setting) and 3 Tesla (T) MRI (T1 with gadolinium & T2 FLAIR) images of one patient (1 mm slices). For illustration purposes, delineation on a 7 T MRI without IV contrast from a healthy volunteer was added. OARs were delineated by three experienced RTOs and a neuroradiologist based on the relevant literature. Results: The presented update of the neurological contouring atlas was reviewed and approved by 28 experts in the field. The atlas is available online and includes in total 25 OARs relevant to neurooncology, contoured on CT , MRI T1 and FLAIR (3 T , 7 T). Three-dimensional (3D) rendered films are also available online. Conclusion: In order to further decrease inter-and intra-observer OAR delineation variability in the field of neuro-oncology, we propose the use of this contouring atlas in photon and particle therapy, in clinical practice and in the research setting. The updated atlas is freely available on www.cancerdata.org. (c) 2021 Published by Elsevier B.V. Radiotherapy and Oncology 160 (2021) 259-265 Show less
Inglese, F.; Kant, I.M.J.; Monahan, R.C.; Steup-Beekman, G.M.; Huizinga, T.W.J.; Buchem, M.A. van; ... ; Bresser, J. de 2021
Objectives The underlying structural brain correlates of neuropsychiatric involvement in systemic lupus erythematosus (NPSLE) remain unclear, thus hindering correct diagnosis. We compared brain... Show moreObjectives The underlying structural brain correlates of neuropsychiatric involvement in systemic lupus erythematosus (NPSLE) remain unclear, thus hindering correct diagnosis. We compared brain tissue volumes between a clinically well-defined cohort of patients with NPSLE and SLE patients with neuropsychiatric syndromes not attributed to SLE (non-NPSLE). Within the NPSLE patients, we also examined differences between patients with two distinct disease phenotypes: ischemic and inflammatory. Methods In this prospective (May 2007 to April 2015) cohort study, we included 38 NPSLE patients (26 inflammatory and 12 ischemic) and 117 non-NPSLE patients. All patients underwent a 3-T brain MRI scan that was used to automatically determine white matter, grey matter, white matter hyperintensities (WMH) and total brain volumes. Group differences in brain tissue volumes were studied with linear regression analyses corrected for age, gender, and total intracranial volume and expressed as B values and 95% confidence intervals. Results NPSLE patients showed higher WMH volume compared to non-NPSLE patients (p = 0.004). NPSLE inflammatory patients showed lower total brain (p = 0.014) and white matter volumes (p = 0.020), and higher WMH volume (p = 0.002) compared to non-NPSLE patients. Additionally, NPSLE inflammatory patients showed lower white matter (p = 0.020) and total brain volumes (p = 0.038) compared to NPSLE ischemic patients. Conclusion We showed that different phenotypes of NPSLE were related to distinct patterns of underlying structural brain MRI changes. Especially the inflammatory phenotype of NPSLE was associated with the most pronounced brain volume changes, which might facilitate the diagnostic process in SLE patients with neuropsychiatric symptoms. Show less
Verwer, E.E.; Golla, S.S.V.; Kaalep, A.; Lubberink, M.; Velden, F.H.P. van; Bettinardi, V.; ... ; Boellaard, R. 2021
Purpose In order to achieve comparability of image quality, harmonisation of PET system performance is imperative. In this study, prototype harmonisation criteria for PET brain studies were... Show morePurpose In order to achieve comparability of image quality, harmonisation of PET system performance is imperative. In this study, prototype harmonisation criteria for PET brain studies were developed.Methods Twelve clinical PET/CT systems (4 GE, 4 Philips, 4 Siemens, including SiPM-based "digital" systems) were used to acquire 30-min PET scans of a Hoffman 3D Brain phantom filled with similar to 33 kBq.mL(-1) [F-18]FDG. Scan data were reconstructed using various reconstruction settings. The images were rigidly coregistered to a template (voxel size 1.17 x 1.17 x 2.00 mm(3)) onto which several volumes of interest (VOIs) were defined. Recovery coefficients (RC) and grey matter to white matter ratios (GMWMr) were derived for eroded (denoted in the text by subscript e) and non-eroded grey (GM) and white (WM) matter VOIs as well as a mid-phantom cold spot (VOIcold) and VOIs from the Hammers atlas. In addition, left-right hemisphere differences and voxel-by-voxel differences compared to a reference image were assessed.Results Systematic differences were observed for reconstructions with and without point-spread-function modelling (PSFON and PSFOFF, respectively). Normalising to image-derived activity, upper and lower limits ensuring image comparability were as follows: for PSFON, RCGMe = [0.97-1.01] and GMWMr(e) = [3.51-3.91] for eroded VOI and RCGM = [0.78-0.83] and GMWMr = [1.77-2.06] for non-eroded VOI, and for PSFOFF, RCGMe = [0.92-0.99] and GMWMr(e) = [3.14-3.68] for eroded VOI and RCGM = [0.75-0.81] and GMWMr = [1.72-1.95] for non-eroded VOI.Conclusions To achieve inter-scanner comparability, we propose selecting reconstruction settings based on RCGMe and GMWMr(e) as specified in "Results". These proposed standards should be tested prospectively to validate and/or refine the harmonisation criteria. Show less
Kleij, L.A. van der; Vis, J.B. de; Bresser, J. de; Hendrikse, J.; Siero, J.C.W. 2020
The Monro-Kellie hypothesis (MKH) states that volume changes in any intracranial component (blood, brain tissue, cerebrospinal fluid) should be counterbalanced by a co-occurring opposite change to... Show moreThe Monro-Kellie hypothesis (MKH) states that volume changes in any intracranial component (blood, brain tissue, cerebrospinal fluid) should be counterbalanced by a co-occurring opposite change to maintain intracranial pressure within the fixed volume of the cranium. In this feasibility study, we investigate the MKH application to structural magnetic resonance imaging (MRI) in observing compensating intracranial volume changes during hypercapnia, which causes an increase in cerebral blood volume. Seven healthy subjects aged from 24 to 64 years (median 32), 4 males and 3 females, underwent a 3-T three-dimensional T1-weighted MRI under normocapnia and under hypercapnia. Intracranial tissue volumes were computed. According to the MKH, the significant increase in measured brain parenchymal volume (median 6.0 mL; interquartile range 4.5, 8.5; p = 0.016) during hypercapnia co-occurred with a decrease in intracranial cerebrospinal fluid (median -10.0 mL; interquartile range -13.5, -6.5; p = 0.034). These results convey several implications: (i) blood volume changes either caused by disorders, anaesthesia, or medication can affect outcome of brain volumetric studies; (ii) besides probing tissue displacement, this approach may assess the brain cerebrovascular reactivity. Future studies should explore the use of alternative sequences, such as three-dimensional T2-weighted imaging, for improved quantification of hypercapnia-induced volume changes. Show less
Spoel, E. van der; Vliet, N.A. van; Heemst, D. van 2019
Specific hallmarks are thought to underlie the ageing process and age-related functional decline. In this viewpoint, we put forward the hypothesis that disturbances in the process of tissue... Show moreSpecific hallmarks are thought to underlie the ageing process and age-related functional decline. In this viewpoint, we put forward the hypothesis that disturbances in the process of tissue maintenance are an important common denominator that may lie in between specific hallmarks of ageing (i.e. damage and responses to damage) and their ultimate (patho)physiological consequences (i.e. functional decline and age-related disease). As a first step towards verifying or falsifying this hypothesis, it will be important to measure biomarkers of tissue maintenance in future studies in different study populations. The main aim of the current paper is to discuss potential biomarkers of tissue maintenance that could be used in such future studies. Among the many tissues that could have been chosen to explore our hypothesis, to keep the paper manageable, we chose to focus on a selected number of tissues, namely bone, cartilage, muscle, and the brain, which are important for mobility and cognition and affected in several common age-related diseases, including osteoporosis, osteoarthritis, sarcopenia, and neurodegenerative diseases. Furthermore, we discuss the advantages and limitations of potential biomarkers for use in (pre)clinical studies. The proposed biomarkers should be validated in future research, for example by measuring these in humans with different rates of ageing. Show less
In this thesis we have analyzed an important number of laboratory, radiological, clinical and patient´s reported outcomes in systemic lupus erythematosus (SLE) patients presenting with... Show moreIn this thesis we have analyzed an important number of laboratory, radiological, clinical and patient´s reported outcomes in systemic lupus erythematosus (SLE) patients presenting with neuropsychiatric (NP) manifestations. Our studies are among the most robust to date in this field due to the large number of patients included, the prospective character and the standard assessment followed by a multidisciplinary expert consensus.Furthermore our studies include the novelty of a phenotypic characterization of all NP manifestations according to the suspected underlying pathophysiological mechanism (inflammation or immune-mediated vs. ischemic or thrombotic). These studies give more light to the understanding of the underlying pathophysiological mechanisms of nervous involvement in SLE. Show less
Palombo, M.; Shemesh, N.; Ronen, I.; Valette, J. 2018
This thesis describes the longitudinal population-based CAMERA-study on the association between migraine and brain changes (e.g. white matter hyperintensities, infarct-like and other lesions) and... Show moreThis thesis describes the longitudinal population-based CAMERA-study on the association between migraine and brain changes (e.g. white matter hyperintensities, infarct-like and other lesions) and possible causes and consequences of those brain changes. Women with migraine showed higher incidence of deep white matter hyperintensities after nine years of follow-up. Infratentorial hyperintensities were also found more often among migraine women compared to controls. Migraine severity characteristics were not associated with progression of lesions. By using voxel based morphometry region-of-interest analyses, migraineurs showed decreased grey matter volume in visual areas of the right occipital cortex compared to controls. The occurrence of ischemia during attacks seems a logical explanation for the development of lesions. One other possible explanation for brain lesions is recurrent paradoxical (micro-)emboli as a result of right-to-left shunting (RLS). In our study, RLS are also more prevalent among migraineurs than among controls. As for the possible consequences: migraine patients and controls showed similar performance on all cerebellar functioning tests. In addition, cognitive functioning was similar for migraine patients and controls, deep white matter hyperintensities were not related to impaired cognitive performance, and migraine had no influence on this association. Our findings are reassuring for migraine patients and their doctors. Show less
The prevalence of obesity, defined as a body mass index (BMI) > 30 kg/m2, is increasing to epidemic proportions. In 2014, 11% of men and 15% of women worldwide were obese. Thus, more than... Show moreThe prevalence of obesity, defined as a body mass index (BMI) > 30 kg/m2, is increasing to epidemic proportions. In 2014, 11% of men and 15% of women worldwide were obese. Thus, more than half a billion adults worldwide are classed as obese. The fundamental cause of obesity is an imbalance between energy intake (excessive intake of energy-dense foods) and energy expenditure (reduced physical activity). People with obesity are at risk for a range of chronic conditions including cardiovascular disease (CVD) and nonalcoholic fatty liver disease (NAFLD). Furthermore, obesity is a major risk factor for the development of type 2 diabetes, which is one of the most common chronic diseases in nearly all countries. According to the World Health Organization, the global prevalence of diabetes in 2014 was estimated to be 9%, of which 90% was comprised of type 2 diabetes. This thesis focuses on cardiovascular and cerebral dimensions and function in people with obesity and type 2 diabetes. State-of-the-art imaging techniques are used to investigate links between the heart, liver, abdominal fat, and brain to elucidate parts of the complex relationships between these organs. Show less
