Introduction: Cardiac magnetic resonance (CMR) is of diagnostic and prognostic value in a range of cardiopulmonary conditions. Current methods for evaluating CMR studies are laborious and time... Show moreIntroduction: Cardiac magnetic resonance (CMR) is of diagnostic and prognostic value in a range of cardiopulmonary conditions. Current methods for evaluating CMR studies are laborious and time-consuming, contributing to delays for patients. As the demand for CMR increases, there is a growing need to automate this process. The application of artificial intelligence (AI) to CMR is promising, but the evaluation of these tools in clinical practice has been limited. This study assessed the clinical viability of an automatic tool for measuring cardiac volumes on CMR. Methods: Consecutive patients who underwent CMR for any indication between January 2022 and October 2022 at a single tertiary centre were included prospectively. For each case, short-axis CMR images were segmented by the AI tool and manually to yield volume, mass and ejection fraction measurements for both ventricles. Automated and manual measurements were compared for agreement and the quality of the automated contours was assessed visually by cardiac radiologists. Results: 462 CMR studies were included. No statistically significant difference was demonstrated between any automated and manual measurements (p > 0.05; independent T-test). Intraclass correlation coefficient and BlandAltman analysis showed excellent agreement across all metrics (ICC > 0.85). The automated contours were evaluated visually in 251 cases, with agreement or minor disagreement in 229 cases (91.2%) and failed segmentation in only a single case (0.4%). The AI tool was able to provide automated contours in under 90 s. Conclusions: Automated segmentation of both ventricles on CMR by an automatic tool shows excellent agreement with manual segmentation performed by CMR experts in a retrospective real-world clinical cohort. Implementation of the tool could improve the efficiency of CMR reporting and reduce delays between imaging and diagnosis. Show less
Groot, D.M.G. de; Linders, L.; Kayser, R.; Nederlof, R.; Esch, C. de; Slieker, R.C.; ... ; Vries, E.F.J. de 2023
Disruption of the immune system during embryonic brain development by environmental chemicals was proposed as a possible cause of neurodevelopmental disorders. We previously found adverse effects... Show moreDisruption of the immune system during embryonic brain development by environmental chemicals was proposed as a possible cause of neurodevelopmental disorders. We previously found adverse effects of di-n-octyltin dichloride (DOTC) on maternal and developing immune systems of rats in an extended one-generation reproductive toxicity study according to the OECD 443 test guideline. We hypothesize that the DOTC-induced changes in the immune system can affect neurodevelopment. Therefore, we used in-vivo MRI and PET imaging and genomics, in addition to behavioral testing and neuropathology as proposed in OECD test guideline 443, to investigate the effect of DOTC on structural and functional brain development. Male rats were exposed to DOTC (0, 3, 10, or 30 mg/kg of diet) from 2 weeks prior to mating of the F0-generation until sacrifice of F1-animals. The brains of rats, exposed to DOTC showed a transiently enlarged volume of specific brain regions (MRI), altered specific gravity, and transient hyper-metabolism ([18F]FDG PET). The alterations in brain development concurred with hyper-responsiveness in auditory startle response and slight hyperactivity in young adult animals. Genomics identified altered transcription of key regulators involved in neurodevelopment and neural function (e.g. Nrgrn, Shank3, Igf1r, Cck, Apba2, Foxp2); and regulators involved in cell size, cell proliferation, and organ development, especially immune system development and functioning (e.g. LOC679869, Itga11, Arhgap5, Cd47, Dlg1, Gas6, Cml5, Mef2c). The results suggest the involvement of immunotoxicity in the impairment of the nervous system by DOTC and support the hypothesis of a close connection between the immune and nervous systems in brain development. Show less
Boeren, A.M.P.; Khidir, S.J.H.; Jong, P.H.P. de; Helm-van Mil, A.H.M. van der; Mulligen, E. van 2023
ObjectivePatients with clinically suspect arthralgia (CSA) are at risk for developing rheumatoid arthritis (RA). These patients often report joint swelling while this is not objectified by physical... Show moreObjectivePatients with clinically suspect arthralgia (CSA) are at risk for developing rheumatoid arthritis (RA). These patients often report joint swelling while this is not objectified by physical examination. To explore the value of patient-reported swelling in CSA, we aimed to determine its association with subclinical joint inflammation on imaging and RA development.MethodsIn two independent, similarly designed CSA cohorts from the Netherlands, symptomatic patients at risk for RA were studied. At baseline, patients indicated whether they had experienced swelling in hand joints. Subclinical joint inflammation was assessed with MRI or US. Patients were followed for inflammatory arthritis development.ResultsIn total, 534 CSA patients from two independent cohorts were studied, and patient-reported swelling was present in 57% in cohort 1 and in 43% in cohort 2. In both cohorts patient-reported swelling was associated with subclinical joint inflammation. Using MRI, it associated specifically with tenosynovitis (odds ratio [OR] 3.7 [95% CI: 2.0, 6.9]) and when using US with synovitis (OR 2.3 [95% CI: 1.04, 5.3]). CSA patients with self-reported swelling at baseline developed arthritis more often, with hazard ratios of 3.7 (95% CI: 2.0, 6.9) and 3.4 (95% CI: 1.4, 8.4) in cohort 1 and 2, respectively. This was independent of clinical predictors (e.g. morning stiffness), autoantibody positivity and US-detected subclinical joint inflammation. However, when corrected for MRI-detected subclinical joint inflammation, self-reported swelling was no longer an independent predictor.ConclusionPatient-reported joint swelling in CSA relates to subclinical joint inflammation and is an independent risk factor for RA development, but it is less predictive than the presence of MRI-detected subclinical joint inflammation. Show less
BACKGROUND:Surgical removal of thromboembolic material by pulmonary endarterectomy (PEA) leads within months to the improvement of right ventricular (RV) function in the majority of patients with... Show moreBACKGROUND:Surgical removal of thromboembolic material by pulmonary endarterectomy (PEA) leads within months to the improvement of right ventricular (RV) function in the majority of patients with chronic thromboembolic pulmonary hypertension. However, RV mass does not always normalize. It is unknown whether incomplete reversal of RV remodeling results from extracellular matrix expansion (diffuse interstitial fibrosis) or cellular hypertrophy, and whether residual RV remodeling relates to altered diastolic function.METHODS:We prospectively included 25 patients with chronic thromboembolic pulmonary hypertension treated with PEA. Structured follow-up measurements were performed before, and 6 and 18 months after PEA. With single beat pressure-volume loop analyses, we determined RV end-systolic elastance (Ees), arterial elastance (Ea), RV–arterial coupling (Ees/Ea), and RV end-diastolic elastance (stiffness, Eed). The extracellular volume fraction of the RV free wall was measured by cardiac magnetic resonance imaging and used to separate the myocardium into cellular and matrix volume. Circulating collagen biomarkers were analyzed to determine the contribution of collagen metabolism.RESULTS:RV mass significantly decreased from 43±15 to 27±11g/m2 (−15.9 g/m2 [95% CI, −21.4 to –10.5]; P<0.0001) 6 months after PEA but did not normalize (28±9 versus 22±6 g/m2 in healthy controls [95% CI, 2.1 to 9.8]; P<0.01). On the contrary, Eed normalized after PEA. Extracellular volume fraction in the right ventricular free wall increased after PEA from 31.0±3.8 to 33.6±3.5% (3.6% [95% CI, 1.2–6.1]; P=0.013) as a result of a larger reduction in cellular volume than in matrix volume (Pinteraction=0.0013). Levels of MMP-1 (matrix metalloproteinase-1), TIMP-1 (tissue inhibitor of metalloproteinase-1), and TGF-β (transforming growth factor-β) were elevated at baseline and remained elevated post-PEA.CONCLUSIONS:Although cellular hypertrophy regresses and diastolic stiffness normalizes after PEA, a relative increase in extracellular volume remains. Incomplete regression of diffuse RV interstitial fibrosis after PEA is accompanied by elevated levels of circulating collagen biomarkers, suggestive of active collagen turnover. Show less
Keller, J.A.; Sigurdsson, S.; Klaassen, K.; Hirschler, L.; Buchem, M.A. van; Launer, L.J.; ... ; Bresser, J.H.J.M. de 2023
INTRODUCTIONWe aimed to investigate the association between white matter hyperintensity (WMH) shape and volume and the long-term dementia risk in community-dwelling older adults. METHODSThree... Show moreINTRODUCTIONWe aimed to investigate the association between white matter hyperintensity (WMH) shape and volume and the long-term dementia risk in community-dwelling older adults. METHODSThree thousand seventy-seven participants (mean age: 75.6 +/- 5.2 years) of the Age Gene/Environment Susceptibility (AGES)-Reykjavik study underwent baseline 1.5T brain magnetic resonance imaging and were followed up for dementia (mean follow-up: 9.9 +/- 2.6 years). RESULTSMore irregular shape of periventricular/confluent WMH (lower solidity (hazard ratio (95% confidence interval) 1.34 (1.17 to 1.52), p < .001) and convexity 1.38 (1.28 to 1.49), p < .001); higher concavity index 1.43 (1.32 to 1.54), p < .001) and fractal dimension 1.45 (1.32 to 1.58), p < .001)), higher total WMH volume (1.68 (1.54 to 1.87), p < .001), higher periventricular/confluent WMH volume (1.71 (1.55 to 1.89), p < .001), and higher deep WMH volume (1.17 (1.08 to 1.27), p < .001) were associated with an increased long-term dementia risk. DISCUSSIONWMH shape markers may in the future be useful in determining patient prognosis and may aid in patient selection for future preventive treatments in community-dwelling older adults. Show less
Fernandes, C.D.; Schaap, A.; Kant, J.; Houdt, P. van; Wijkstra, H.; Bekers, E.; ... ; Turco, S. 2023
Prostate cancer (PCa) is a highly prevalent cancer type with a heterogeneous prognosis. An accurate assessment of tumor aggressiveness can pave the way for tailored treatment strategies,... Show moreProstate cancer (PCa) is a highly prevalent cancer type with a heterogeneous prognosis. An accurate assessment of tumor aggressiveness can pave the way for tailored treatment strategies, potentially leading to better outcomes. While tumor aggressiveness is typically assessed based on invasive methods (e.g., biopsy), radiogenomics, combining diagnostic imaging with genomic information can help uncover aggressive (imaging) phenotypes, which in turn can provide non-invasive advice on individualized treatment regimens. In this study, we carried out a parallel analysis on both imaging and transcriptomics data in order to identify features associated with clinically significant PCa (defined as an ISUP grade ≥ 3), subsequently evaluating the correlation between them. Textural imaging features were extracted from multi-parametric MRI sequences (T2W, DWI, and DCE) and combined with DCE-derived parametric pharmacokinetic maps obtained using magnetic resonance dispersion imaging (MRDI). A transcriptomic analysis was performed to derive functional features on transcription factors (TFs), and pathway activity from RNA sequencing data, here referred to as transcriptomic features. For both the imaging and transcriptomic features, different machine learning models were separately trained and optimized to classify tumors in either clinically insignificant or significant PCa. These models were validated in an independent cohort and model performance was used to isolate a subset of relevant imaging and transcriptomic features to be further investigated. A final set of 31 imaging features was correlated to 33 transcriptomic features obtained on the same tumors. Five significant correlations (p < 0.05) were found, of which, three had moderate strength (|r| ≥ 0.5). The strongest significant correlations were seen between a perfusion-based imaging feature—MRDI A median—and the activities of the TFs STAT6 (−0.64) and TFAP2A (−0.50). A higher-order T2W textural feature was also significantly correlated to the activity of the TF STAT6 (−0.58). STAT6 plays an important role in controlling cell proliferation and migration. Loss of the AP2alpha protein expression, quantified by TFAP2A, has been strongly associated with aggressiveness and progression in PCa. According to our findings, a combination of texture features extracted from T2W and DCE, as well as perfusion-based pharmacokinetic features, can be considered for the prediction of clinically significant PCa, with the pharmacokinetic MRDI A feature being the most correlated with the underlying transcriptomic information. These results highlight a link between quantitative imaging features and the underlying transcriptomic landscape of prostate tumors. Show less
Chemaly, M.; Marlevi, D.; Iglesias, M.J.; Lengquist, M.; Kronqvist, M.; Bos, D.; ... ; Hedin, U. 2023
Background: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid... Show moreBackground: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid atherosclerosis and functionally associated with IPH. Objective: We explored the biomarker potential of plasma BLVRB through (1) its correlation with IPH in carotid plaques assessed by magnetic resonance imaging (MRI), and with recurrent ischemic stroke, and (2) its use for monitoring pharmacotherapy targeting IPH in a preclinical setting. Methods: Plasma BLVRB levels were measured in patients with symptomatic carotid atherosclerosis from the PARISK study (n = 177, 5 year follow-up) with and without IPH as indicated by MRI. Plasma BLVRB levels were also measured in a mouse vein graft model of IPH at baseline and following antiangiogenic therapy targeting vascular endothelial growth factor receptor 2 (VEGFR-2). Results: Plasma BLVRB levels were significantly higher in patients with IPH (737.32 & PLUSMN; 693.21 vs. 520.94 & PLUSMN; 499.43 mean fluorescent intensity (MFI), p = 0.033), but had no association with baseline clinical and biological parameters. Plasma BLVRB levels were also significantly higher in patients who developed recurrent ischemic stroke (1099.34 & PLUSMN; 928.49 vs. 582.07 & PLUSMN; 545.34 MFI, HR = 1.600, CI [1.092-2.344]; p = 0.016). Plasma BLVRB levels were significantly reduced following prevention of IPH by anti-VEGFR-2 therapy in mouse vein grafts (1189 & PLUSMN; 258.73 vs. 1752 & PLUSMN; 366.84 MFI; p = 0.004). Conclusions: Plasma BLVRB was associated with IPH and increased risk of recurrent ischemic stroke in patients with symptomatic low- to moderate-grade carotid stenosis, indicating the capacity to monitor the efficacy of IPH-preventive pharmacotherapy in an animal model. Together, these results suggest the utility of plasma BLVRB as a biomarker for atherosclerotic plaque instability. Show less
Purpose: Activated brown adipose tissue (BAT) enhances lipid catabolism and improves cardiometabolic health. Quantitative MRI of the fat fraction (FF) of supraclavicular BAT (scBAT) is a promising... Show morePurpose: Activated brown adipose tissue (BAT) enhances lipid catabolism and improves cardiometabolic health. Quantitative MRI of the fat fraction (FF) of supraclavicular BAT (scBAT) is a promising noninvasive measure to assess BAT activity but suffers from high scan variability. We aimed to test the effects of coregistration and mutual thresholding on the scan variability in a fast (1 min) time-resolution MRI protocol for assessing scBAT FF changes during cold exposure. Methods: Ten volunteers (age 24.8 +/- 3.0 years; body mass index 21.2 +/- 2.1 kg/m(2)) were scanned during thermoneutrality (32 degrees C; 10 min) and mild cold exposure (18 degrees C; 60 min) using a 12-point gradient-echo sequence (70 consecutive scans with breath-holds, 1.03 min per dynamic). Dynamics were coregistered to the first thermoneutral scan, which enabled drawing of single regions of interest in the scBAT depot. Voxel-wise FF changes were calculated at each time point and averaged across regions of interest. We applied mutual FF thresholding, in which voxels were included if their FF was greater than 30% FF in the reference scan and the registered dynamic. The efficacy of the coregistration was determined by using a moving average and comparing the mean squared error of residuals between registered and nonregistered data. Registered scBAT Delta FF was compared with single-scan thresholding using the moving average method. Results: Registered scBAT Delta FF had lower mean square error values than nonregistered data (0.07 +/- 0.05% vs. 0.16 +/- 0.14%; p<0.05), and mutual thresholding reduced the scBAT Delta FF variability by 30%. Conclusion: We demonstrate that coregistration and mutual thresholding improve stability of the data 2-fold, enabling assessment of small changes in FF following cold exposure. Show less
Background:Prion-like transmission of amyloid-ss through cadaveric dura, decades after neurosurgical procedures, has been hypothesized as an iatrogenic cause of cerebral amyloid angiopathy (CAA).... Show moreBackground:Prion-like transmission of amyloid-ss through cadaveric dura, decades after neurosurgical procedures, has been hypothesized as an iatrogenic cause of cerebral amyloid angiopathy (CAA). We investigated new and previously described patients to assess the clinical profile, radiological features, and outcome of this presumed iatrogenic CAA-subtype (iCAA). Methods:Patients were collected from our prospective lobar hemorrhage and CAA database (n=251) with patients presenting to our hospital between 2008 and 2022. In addition, we identified patients with iCAA from 2 other Dutch CAA-expertise hospitals and performed a systematic literature-search for previously described patients. We classified patients according to the previously proposed diagnostic criteria for iCAA, assessed clinical and radiological disease features, and calculated intracerebral hemorrhage (ICH)-recurrence rates. We evaluated the spatial colocalization of cadaveric dura placement and CAA-associated magnetic resonance imaging markers. Results:We included 49 patients (74% men, mean age 43 years [range, 27-84]); 15 from our database (6% [95% CI, 3%-10%]; 45% of patients <55 years), 3 from the 2 other CAA-expertise hospitals, and 31 from the literature. We classified 43% (n=21; 1 newly identified patient) as probable and 57% (n=28) as possible iCAA. Patients presented with lobar ICH (57%), transient focal neurological episodes (12%), or seizures (8%). ICH-recurrence rate in the new patients (16/100 person-years [95% CI, 7-32], median follow-up 18 months) was lower than in the previously described patients (77/100 person-years [95% CI, 59-99], median follow-up 18 months). One patient had a 10 year interlude without ICH-recurrence. We identified no clear spatial relationship between dura placement and CAA-associated magnetic resonance imaging markers. During follow-up (median, 18 months), 20% of the patients developed transient focal neurological episodes and 20% cognitively declined. Conclusions:iCAA seems common in patients presenting with nonhereditary CAA under the age of 55. Clinical and radiological features are comparable with sCAA. After diagnosis, multiple ICH-recurrences but also long symptom-free intervals can occur. Harmonized registries are necessary to identify and understand this potentially underrecognized CAA-subtype. Show less
Magnetic resonance imaging (MRI) of the axial skeleton, spine, and sacroiliac (SI) joints is critical for the early detection and follow-up of inflammatory rheumatologic disorders such as axial... Show moreMagnetic resonance imaging (MRI) of the axial skeleton, spine, and sacroiliac (SI) joints is critical for the early detection and follow-up of inflammatory rheumatologic disorders such as axial spondyloarthritis, rheumatoid arthritis, and SAPHO/CRMO (synovitis, acne, pustulosis, hyperostosis, and osteitis/chronic recurrent multifocal osteomyelitis). To offer a valuable report to the referring physician, disease-specific knowledge is essential. Certain MRI parameters can help the radiologist provide an early diagnosis and lead to effective treatment. Awareness of these hallmarks may help avoid misdiagnosis and unnecessary biopsies. A bone marrow edema-like signal plays an important role in reports but is not disease specific. Age, sex, and history should be considered in interpreting MRI to prevent overdiagnosis of rheumatologic disease. Differential diagnoses-degenerative disk disease, infection, and crystal arthropathy-are addressed here. Whole-body MRI may be helpful in diagnosing SAPHO/CRMO. Show less
Hulst, H.J. van der; Vos, J.L.; Tissier, R.; Smit, L.A.; Martens, R.M.; Beets-Tan, R.G.H.; ... ; Castelijns, J.A. 2022
Simple Summary Immunotherapy may induce early treatment response in head and neck squamous cell carcinoma (HNSCC) for some patients. Routine imaging parameters fail to diagnose these responses;... Show moreSimple Summary Immunotherapy may induce early treatment response in head and neck squamous cell carcinoma (HNSCC) for some patients. Routine imaging parameters fail to diagnose these responses; however, magnetic resonance (MR) diffusion-weighted imaging (DWI) may be able to do so. This study sought to correlate DWI parameters with treatment response early after immunotherapy treatment in HNSCC. We analyzed 24 patients with advanced HNSCC with imaging before and after the immunotherapy. We found that rounder tumors that were smaller in diameter before treatment were more likely to respond. A decrease in skewness of the tumor after treatment compared to before treatment, as well as an overall low skewness post-treatment, were linked to better treatment response. Though this study was explorative in nature, these results are promising for the predictive use of MR-DWI in HNSCC treated with immunotherapy. Background: Neoadjuvant immune checkpoint blockade (ICB) prior to surgery may induce early pathological responses in head and neck squamous cell carcinoma (HNSCC) patients. Routine imaging parameters fail to diagnose these responses early on. Magnetic resonance (MR) diffusion-weighted imaging (DWI) has proven to be useful for detecting HNSCC tumor mass after (chemo)radiation therapy. METHODS: 32 patients with stage II-IV, resectable HNSCC, treated at a phase Ib/IIa IMCISION trial (NCT03003637), were retrospectively analyzed using MR-imaging before and after two doses of single agent nivolumab (anti-PD-1) (n = 6) or nivolumab with ipilimumab (anti-CTLA-4) ICB (n = 26). The primary tumors were delineated pre- and post-treatment. A total of 32 features were derived from the delineation and correlated with the tumor regression percentage in the surgical specimen. Results: MR-DWI data was available for 24 of 32 patients. Smaller baseline tumor diameter (p = 0.01-0.04) and higher sphericity (p = 0.03) were predictive of having a good pathological response to ICB. Post-treatment skewness and the change in skewness between MRIs were negatively correlated with the tumor's regression (p = 0.04, p = 0.02). Conclusion: Pre-treatment DWI tumor diameter and sphericity may be quantitative biomarkers for the prediction of an early pathological response to ICB. Furthermore, our data indicate that ADC skewness could be a marker for individual response evaluation. Show less
Bakels, H.S.; Duinen, S.G. van; Bresser, J. de; Roon-Mom, W.M.C. van; Weerd, L. van der; Bot, S.T. de 2022
Objective: Blood-brain barrier (BBB) dysfunction is implicated in the pathophysiology of cerebral small vessel disease (cSVD)-related intracerebral hemorrhage (ICH). The formation of perihematomal... Show moreObjective: Blood-brain barrier (BBB) dysfunction is implicated in the pathophysiology of cerebral small vessel disease (cSVD)-related intracerebral hemorrhage (ICH). The formation of perihematomal edema (PHE) is presumed to reflect acute BBB permeability following ICH. We aimed to assess the association between cSVD burden and PHE formation in patients with spontaneous ICH. Methods: We selected patients with spontaneous ICH who underwent 3T MRI imaging within 21 days after symptom onset from a prospective observational multicenter cohort study. We rated markers of cSVD (white matter hyperintensities, enlarged perivascular spaces, lacunes and cerebral microbleeds) and calculated the composite score as a measure of the total cSVD burden. Perihematomal edema formation was measured using the edema extension distance (EED). We assessed the association between the cSVD burden and the EED using a multivariable linear regression model adjusting for age, (log-transformed) ICH volume, ICH location (lobar vs. non-lobar), and interval between symptom onset and MRI. Results: We included 85 patients (mean age 63.5 years, 75.3% male). Median interval between symptom onset and MRI imaging was 6 days (IQR 1-19). Median ICH volume was 17.0 mL (IQR 1.4-88.6), and mean EED was 0.54 cm (SD 0.17). We found no association between the total cSVD burden and EED (B = -0.003, 95% CI -0.003-0.03, p = 0.83), nor for any of the individual radiological cSVD markers. Conclusion: We found no association between the cSVD burden and PHE formation. This implies that mechanisms other than BBB dysfunction are involved in the pathophysiology of PHE. Show less
Heijde, D. van der; Deodhar, A.; Maksymowych, W.P.; Sieper, J.; Bosch, F. van den; Kim, T.H.; ... ; Song, I.H. 2022
Introduction Long-term safety and efficacy of upadacitinib in patients with active ankylosing spondylitis (AS) has not been previously reported. Methods In SELECT-AXIS 1, patients receiving placebo... Show moreIntroduction Long-term safety and efficacy of upadacitinib in patients with active ankylosing spondylitis (AS) has not been previously reported. Methods In SELECT-AXIS 1, patients receiving placebo were switched to upadacitinib 15 mg once daily at week 14 while patients initially randomised to upadacitinib continued their regimen through week 104. Efficacy was assessed using as-observed (AO) and non-responder imputation (NRI). Results Of 187 patients randomised, 144 patients (77%) completed week 104. Among patients receiving continuous upadacitinib, 85.9% (AO) and 65.6% (NRI) achieved Assessment of SpondyloArthritis international Society 40 response (ASAS40) at week 104. Similar magnitude of ASAS40 responses were observed among patients who switched from placebo to upadacitinib (88.7% and 63.8%, respectively). The mean change from baseline to week 104 in Spondyloarthritis Research Consortium of Canada MRI spine and sacroiliac joint inflammation scores were -7.3 and -5.3, respectively, in the continuous upadacitinib group and -7.9 and -4.9 in the placebo-to-upadacitinib switch group. The mean (95% CI) change from baseline to week 104 in the modified Stoke Ankylosing Spondylitis Spine Score was 0.7 (0.3, 1.1) in the total group. Adverse event rate was 242.7/100 patient-years. No serious infections, adjudicated major adverse cardiovascular events, lymphoma, non-melanoma skin cancer, or gastrointestinal perforations were observed. Conclusions Upadacitinib 15 mg once daily showed sustained and consistent efficacy over 2 years for ASAS40 and other clinically relevant endpoints. A low rate of radiographic progression was observed and no new safety findings were observed. Show less
Boeren, A.M.P.; Oei, E.H.G.; Helm-van Mil, A.H.M. van der 2022
In the last decade, much research has focused on the development of rheumatoid arthritis (RA) and the symptomatic phase preceding the onset of clinical arthritis. Observational studies on imaging... Show moreIn the last decade, much research has focused on the development of rheumatoid arthritis (RA) and the symptomatic phase preceding the onset of clinical arthritis. Observational studies on imaging have revealed that subclinical joint inflammation in patients with arthralgia at risk for RA precedes and predicts the onset of clinically apparent arthritis. Moreover, the results of two placebo-controlled randomised proof-of-concept trials in patients with arthralgia and MRI-detected subclinical inflammation studies will soon be available. The initial results are encouraging and suggest a beneficial effect of DMARD treatment on subclinical inflammation. Since this may increase the necessity to detect subclinical joint inflammation in persons with arthralgia that are at risk for RA, we will here review what has been learnt about subclinical inflammation in at-risk individuals by means of imaging. We will focus on MRI as this method has the best sensitivity and reproducibility. We evaluate the prognostic value of MRI-detected subclinical inflammation and assess the lessons learnt from MRIs about the tissues that are inflamed early on and are associated with the clinical phenotype in arthralgia at risk for RA, for example, subclinical tenosynovitis underlying pain and impaired hand function. Finally, because long scan times and the need for intravenous-contrast agent contribute to high costs and limited feasibility of current MRI protocols, we discuss progress that is being made in the field of MRI and that can result in a future-proof way of imaging that is useful for assessment of joint inflammation on a large scale, also in a society with social distancing due to COVID-19 restrictions. Show less
Stal, R.; Baraliakos, X.; Heijde, D. van der; Gaalen, F. van; Ramiro, S.; Berg, R. van den; ... ; Sepriano, A. 2022
Objectives To investigate the associations between MRI detected vertebral corner inflammation (VCI) and vertebral corner fat deposition (VCFD) on whole spine low-dose CT scan (ldCT) detected... Show moreObjectives To investigate the associations between MRI detected vertebral corner inflammation (VCI) and vertebral corner fat deposition (VCFD) on whole spine low-dose CT scan (ldCT) detected syndesmophyte formation and growth. Methods Patients from the Sensitive Imaging in Ankylosing Spondylitis cohort underwent MRI (baseline, 1 year and 2 years) and ldCT (baseline and 2 years). MR images were scored by three readers for VCI and VCFD, MRI patterns were defined by presence of VCI and/or VCFD over 2 years. LdCT images were scored by two central readers for presence and size of syndesmophytes and change was calculated for new or new/grown syndesmophytes. Multilevel generalised estimated equations were used to test the associations between VCI and VCFD and syndesmophyte development. Results Fifty radiographic patients with axial spondyloarthritis were included (mean age 49 years, 86% male, 78% HLA-B27+). Absence of both VCI and VCFD protected against syndesmophyte development (ORs 0.36-0.37). Presence of VCI and/or VCFD increased the risk of syndesmophyte development (ORs 1.73-2.60). Out of all corners with a new or new/grown syndesmophyte, 47% of corners according to reader 1 and 44% according to reader 2 had neither VCI nor VCFD preceding the bone formation. Conclusions VCI and VCFD were positively associated with syndesmophyte development. This has been shown for the first time for syndesmophytes detected on ldCT and also in the thoracic spine. However, almost half of all bone formation occurred in corners without VCI or VCFD, suggesting the presence of these lesions in yearly MRIs does not fully clarify the development of syndesmophytes. Show less
Heijde, D. van der; Deodhar, A.; Maksymowych, W.P.; Sieper, J.; Bosch, F. van den; Kim, T.H.; ... ; Song, I.H. 2022
Introduction Long-term safety and efficacy of upadacitinib in patients with active ankylosing spondylitis (AS) has not been previously reported. Methods In SELECT-AXIS 1, patients receiving placebo... Show moreIntroduction Long-term safety and efficacy of upadacitinib in patients with active ankylosing spondylitis (AS) has not been previously reported. Methods In SELECT-AXIS 1, patients receiving placebo were switched to upadacitinib 15 mg once daily at week 14 while patients initially randomised to upadacitinib continued their regimen through week 104. Efficacy was assessed using as-observed (AO) and non-responder imputation (NRI). Results Of 187 patients randomised, 144 patients (77%) completed week 104. Among patients receiving continuous upadacitinib, 85.9% (AO) and 65.6% (NRI) achieved Assessment of SpondyloArthritis international Society 40 response (ASAS40) at week 104. Similar magnitude of ASAS40 responses were observed among patients who switched from placebo to upadacitinib (88.7% and 63.8%, respectively). The mean change from baseline to week 104 in Spondyloarthritis Research Consortium of Canada MRI spine and sacroiliac joint inflammation scores were -7.3 and -5.3, respectively, in the continuous upadacitinib group and -7.9 and -4.9 in the placebo-to-upadacitinib switch group. The mean (95% CI) change from baseline to week 104 in the modified Stoke Ankylosing Spondylitis Spine Score was 0.7 (0.3, 1.1) in the total group. Adverse event rate was 242.7/100 patient-years. No serious infections, adjudicated major adverse cardiovascular events, lymphoma, non-melanoma skin cancer, or gastrointestinal perforations were observed. Conclusions Upadacitinib 15 mg once daily showed sustained and consistent efficacy over 2 years for ASAS40 and other clinically relevant endpoints. A low rate of radiographic progression was observed and no new safety findings were observed. Show less
Gool, J.K.; Fronczek, R.; Bosma, P.; Meer, J.N. van der; Werf, Y.D. van der; Lammers, G.J. 2022
The brain activation patterns related to sleep resistance remain to be discovered in health and disease. The maintenance of wakefulness test (MWT) is an objective neuropsychological assessment... Show moreThe brain activation patterns related to sleep resistance remain to be discovered in health and disease. The maintenance of wakefulness test (MWT) is an objective neuropsychological assessment often used to assess an individual's ability to resist sleep. It is frequently used in narcolepsy type 1, a disorder characterized by impaired sleep-wake control and the inability to resist daytime sleep. We investigated the neural correlates of active sleep resistance in 12 drug-free people with narcolepsy type 1 and 12 healthy controls. Simultaneous fMRI-EEG measurements were recorded during five cycles of two alternating conditions of active sleep resistance and waking rest. Cleaned EEG signals were used to verify wakefulness and task adherence. Pooling both subject groups, significantly higher fMRI activation when actively resisting sleep was seen in the brainstem, superior cerebellum, bilateral thalamus and visual cortices. In controls the activation clusters were generally smaller compared to patients and no significant activation was seen in the brainstem. Formal comparison between groups only found a significantly higher left primary visual cortex activation in patients during active sleep resistance. The active sleep resistance paradigm is a feasible fMRI task to study sleep resistance and induces evident arousal- and visual-related activity. Significantly higher left primary visual cortical activation in patients could be caused by an enhanced need of visual focus to resist sleep, or reflecting a more rapid descent in their level of alertness when resting. Show less
The current study aimed to investigate whether diffusion-weighted imaging-positive (DWI+) lesions after acute intracerebral hemorrhage (ICH) are associated with underlying small vessel disease (SVD... Show moreThe current study aimed to investigate whether diffusion-weighted imaging-positive (DWI+) lesions after acute intracerebral hemorrhage (ICH) are associated with underlying small vessel disease (SVD) or linked to the acute ICH. We included patients >= 18 years with spontaneous ICH confirmed on neuroimaging and performed 3T MRIs after a median of 11 days (interquartile range [IQR] 6-43). DWI+ lesions were assessed in relation to the hematoma (perihematomal vs. distant and ipsilateral vs. contralateral). Differences in clinical characteristics, ICH characteristics, and MRI markers of SVD between participants with or without DWI+ lesions were investigated using non-parametric tests. We observed 54 DWI+ lesions in 30 (22%) of the 138 patients (median age [IQR] 65 [55-73] years; 71% men, 59 lobar ICH) with available DWI images. We found DWI+ lesions ipsilateral (54%) and contralateral (46%) to the ICH, and 5 (9%) DWI+ lesions were located in the immediate perihematomal region. DWI+ lesion presence was associated with probable CAA diagnosis (38 vs. 15%, p = 0.01) and larger ICH volumes (37 [8-47] vs. 12 [6-24] ml, p = 0.01), but not with imaging features of SVD. Our findings suggest that DWI+ lesions after ICH are a feature of both the underlying SVD and ICH-related mechanisms. Show less
Dijk, S.E. van; Grond, J. van der; Lak, J.; Berg-Huysmans, A. van den; Labadie, G.; Terwindt, G.M.; ... ; Rooden, S. van 2022
Background: Hemorrhagic and ischemic magnetic resonance imaging lesions as well as the more recently described decrease in vasomotor reactivity have been suggested as possible biomarkers for... Show moreBackground: Hemorrhagic and ischemic magnetic resonance imaging lesions as well as the more recently described decrease in vasomotor reactivity have been suggested as possible biomarkers for cerebral amyloid angiopathy (CAA). Analyses of these markers have been primarily cross-sectional during the symptomatic phase of the disease, with little data on their longitudinal progression, particularly in the presymptomatic phase of the disease when it may be most responsive to treatment. We used the unique opportunity provided by studying Dutch-type hereditary cerebral amyloid angiopathy (D-CAA) to determine longitudinal progression of CAA biomarkers during the presymptomatic as well as the symptomatic phase of the disease. Methods: In this longitudinal case-control study, magnetic resonance imaging markers and cognitive performance were assessed at baseline and after approximate to 4 years in 10 presymptomatic and 6 symptomatic D-CAA mutation carriers and 20 control subjects. These magnetic resonance imaging markers included hemorrhagic and ischemic manifestations, measurements of cerebral blood flow, and vasomotor reactivity to visual stimulation. Results: In presymptomatic D-CAA mutations carriers, vasomotor reactivity showed a decline over time for blood-oxygen-level-dependent amplitude (P=0.011) and prolongation of time to peak (P<0.001). In contrast, no significant changes in hemorrhagic markers, ischemic markers, cerebral blood flow, and cognition were found. In symptomatic D-CAA mutation carriers, the number of intracerebral hemorrhages increased over the 4-year period (P=0.007). Conclusions: Our findings indicate that in the presymptomatic phase of D-CAA, cerebrovascular reactivity measured by the blood-oxygen-level-dependent amplitude and time to peak to visual stimulation progressively worsens and can thus be regarded as a disease progression marker. In the symptomatic phase, the most salient marker of progression appears to be recurrent intracerebral hemorrhage. Show less