Parelsnoer Institute Research Articles

Small vessel disease burden and functional brain connectivity in mild cognitive impairment

BackgroundThe role of small vessel disease in the development of dementia is not yet completely understood. Functional brain connectivity has been shown to differ between individuals with and without cerebral small vessel disease. However, a comprehensive measure of small vessel disease quantifying the overall damage on the brain is not consistently used and studies using such measure in mild cognitive impairment individuals are missing. MethodFunctional brain connectivity differences were analyzed between mild cognitive impairment individuals with absent or low (n = 34) and high (n = 34) small vessel disease burden using data from the Parelsnoer Institute, a Dutch multicenter study. Small vessel disease was characterized using an ordinal scale considering: lacunes, microbleeds, perivascular spaces in the basal ganglia, and white matter hyperintensities. Resting state functional MRI data using 3 Tesla scanners was analyzed with group-independent component analysis using the CONN toolbox. ResultsFunctional connectivity between areas of the cerebellum and between the cerebellum and the thalamus and caudate nucleus was higher in the absent or low small vessel disease group compared to the high small vessel disease group. ConclusionThese findings might suggest that functional connectivity of mild cognitive impairment individuals with low or absent small vessel disease burden is more intact than in mild cognitive impairment individuals with high small vessel disease. These brain areas are mainly responsible for motor, attentional and executive functions, domains which in previous studies were found to be mostly associated with small vessel disease markers. Our results support findings on the involvement of the cerebellum in cognitive functioning.

Functional Brain Activation in Mild Cognitive Impairment With Defined Small Vessel Disease Burden

AbstractBackgroundVascular dysregulations and changes in functional brain network integrity play a fundamental role in the pathogenesis of dementia. While often identified in individuals with dementia, the role of small vessel disease (SVD) in the development of dementia is not completely understood yet. Previously, structural and functional brain connectivity was shown to be different between individuals with and without cerebral SVD, but a comprehensive measure of SVD has not been used consistently. We aim to analyze functional brain activation differences in mild cognitive impairment (MCI) individuals with defined SVD burden.MethodFunctional brain activation differences were analyzed in MCI individuals with absent or low (n = 34) or high (n = 34) SVD burden using data from the Parelsnoer Institute, a multicenter study involving eight Dutch medical centers. SVD burden was characterized using an ordinal scale ranging from 0 to 4 (Klarenbeek et al., 2013) considering the following markers: lacunes; microbleeds; perivascular spaces in the basal ganglia; white matter hyperintensities based on the Fazekas score. Two groups were identified: the absent or low SVD burden group with a score of 0 or 1 and the high SVD group with a score between 2 and 4. Activation differences were calculated using resting state fMRI data acquired using 3Tesla scanners and analyzed with group‐independent component analysis using the CONN toolbox.ResultActivation of two clusters in the high SVD burden group was lower than in the absent or low SVD group: the cerebellum (p‐FDR >. 001, F = 1.49) and the brainstem (p‐FDR >. 001, F = 2.79). The cerebellar cluster (4541 voxels, +20 ‐74 ‐38) consisted of the left cerebellum crus II, right cerebellum crus II, and left cerebellum lobule VIII. The brainstem cluster (218 voxels, +22 ‐28 +20) involved the right thalamus and the right caudate nucleus.ConclusionBrain activation differences between groups of individuals with MCI and absent or low or high SVD burden were found in the cerebellum and brainstem. These brain areas are mainly responsible for motor, attentional and executive functions, domains which were found in previous studies to be mostly associated with SVD markers.

Sex Differences in Risk Profile, Stroke Cause and Outcome in Ischemic Stroke Patients With and Without Migraine.

Background: An increased risk of stroke in patients with migraine has been primarily found for women. The sex-dependent mechanisms underlying the migraine–stroke association, however, remain unknown. This study aims to explore these sex differences to improve our understanding of pathophysiological mechanisms behind the migraine–stroke association.Methods: We included 2,492 patients with ischemic stroke from the prospective multicenter Dutch Parelsnoer Institute Initiative study, 425 (17%) of whom had a history of migraine. Cardiovascular risk profile, stroke cause (TOAST classification), and outcome [modified Rankin scale (mRS) at 3 months] were compared with both sexes between patients with and without migraine.Results: A history of migraine was not associated with sex differences in the prevalence of conventional cardiovascular risk factors. Women with migraine had an increased risk of stroke at young age (onset < 50 years) compared with women without migraine (RR: 1.7; 95% CI: 1.3–2.3). Men with migraine tended to have more often stroke in the TOAST category other determined etiology (RR: 1.7; 95% CI: 1.0–2.7) in comparison with men without migraine, whereas this increase was not found in women with migraine. Stroke outcome was similar for women with or without migraine (mRS ≥ 3 RR 1.1; 95% CI 0.7–1.5), whereas men seemed to have a higher risk of poor outcome compared with their counterparts without migraine (mRS ≥ 3 RR: 1.5; 95% CI: 1.0–2.1).Conclusion: Our results indicate possible sex differences in the pathophysiology underlying the migraine–stroke association, which are unrelated to conventional cardiovascular risk factors. Further research in larger cohorts is needed to validate these findings.

A nationwide database study on colectomy and colorectal cancer in ulcerative colitis: what is the role of appendectomy?

Although has been suggested that an appendectomy has a positive effect on the disease course in patients with ulcerative colitis (UC), recent studies indicate a potential increase in risk of colectomy and colorectal cancer (CRC). This study aimed to evaluate the rates of colectomy and CRC after appendectomy in UC patients using a nationwide prospective database [the Initiative on Crohn and Colitis Parelsnoer Institute - Inflammatory Bowel Disease (ICC PSI-IBD) database]. All UC patients were retrieved from the ICC PSI-IBD database between January 2007 and May 2018. Primary outcomes were colectomy and CRC. Outcomes were compared in patients with and without appendectomy, with a separate analysis for timing of appendectomy (before or after UC diagnosis). A total of 826 UC patients (54.7% female; median age 46years, range 18-89 years) were included. Sixty-three (7.6%) patients had previously undergone appendectomy: 24 (38.1%) before and 33 (52.4%) after their diagnosis of UC. In multivariate analysis, appendectomy after UC diagnosis was associated with a significantly lower colectomy rate compared with no appendectomy [hazard ratio (HR) 0.16, 95% C: 0.04-0.66, P=0.011], and the same nonsignificant trend was seen in patients with an appendectomy before UC diagnosis (HR 0.35, 95% CI 0.08-1.41, P=0.138). Appendectomy was associated with delayed colectomy, particularly when it was performed after diagnosis of UC (P=0.009). No significant differences were found in the CRC rate between patients with and without appendectomy (1.6% vs 1.2%; P=0.555). Appendectomy in established UC is associated with an 84% decreased risk of colectomy and a delay in surgery. Since the colon is in situ for longer, the risk of developing CRC remains, which underscores the importance of endoscopic surveillance programmes.

Establishing and Coordinating a Nationwide Multidisciplinary Study Group: Lessons Learned by the Dutch Pancreatic Cancer Group.

Establishing and Coordinating a Nationwide Multidisciplinary Study Group: Lessons Learned by the Dutch Pancreatic Cancer Group.

The Association Between Biomarkers and Neuropsychiatric Symptoms Across the Alzheimer's Disease Spectrum

To investigate the relationship between Alzheimer's disease biomarkers and neuropsychiatric symptoms. Data from two large cohort studies, the Dutch Parelsnoer Institute - Neurodegenerative Diseases and the Alzheimer's Disease Neuroimaging Initiative was used, including subjects with subjective cognitive decline (N = 650), mild cognitive impairment (N = 887), and Alzheimer's disease dementia (N = 626). Cerebrospinal fluid (CSF) levels of Aβ42, t-tau, p-tau, and hippocampal volume were associated with neuropsychiatric symptoms (measured with the Neuropsychiatric Inventory) using multiple logistic regression analyses. The effect of the Mini-Mental State Examination (as proxy for cognitive functioning) on these relationships was assessed with mediation analyses. Alzheimer's disease biomarkers were not associated with depression, agitation, irritability, and sleep disturbances. Lower levels of CSF Aβ42, higher levels of t- and p-tau were associated with presence of anxiety. Lower levels of CSF Aβ42 and smaller hippocampal volumes were associated with presence of apathy. All associations were mediated by cognitive functioning. The association between Alzheimer's disease pathology and anxiety and apathy is partly due to impairment in cognitive functioning.

The Dutch Parelsnoer Institute Cerebrovascular Disease Initiative: a retrospective study of the effects of integrating clinical care and research on costs and quality of care in patients with ischaemic stroke

IntroductionThe Dutch Parelsnoer Institute (PSI) is a collaboration between all university medical centres in which clinical data, imaging and biomaterials are prospectively and uniformly collected for research purposes. The PSI...

Design and protocol of a comprehensive multicentre biobank for abdominal aortic aneurysms

IntroductionThe pathophysiology and natural course of abdominal aortic aneurysms (AAAs) are insufficiently understood. In order to improve our understanding, it is imperative to carry out longitudinal research that combines biomarkers...

Sa1772 – Prevalence of Cervical Dysplasia in Women with Inflammatory Bowel Disease: Data from the Parelsnoer Institute (PSI) and Palga Database (PAP-IBD Study)

Sa1772 – Prevalence of Cervical Dysplasia in Women with Inflammatory Bowel Disease: Data from the Parelsnoer Institute (PSI) and Palga Database (PAP-IBD Study)

Parelsnoer Institute Biobank Hereditary Colorectal Cancer: A Joint Infrastructure for Patient Data and Biomaterial on Hereditary Colorectal Cancer in the Netherlands

Each year approximately 15,000 patients are diagnosed with colorectal cancer (CRC) in the Netherlands, of whom 5-10% are associated with a hereditary syndrome. To enable future research into hereditary CRC, we established a collaborative biobank for hereditary CRC in all eight University Medical Centers (UMCs) in the Netherlands in 2009. This Biobank Hereditary CRC is part of the Parelsnoer Institute (PSI), which is funded by the Dutch Federation of UMCs and the Dutch Government. Besides the multicenter collaboration, the multidisciplinary nature of this biobank - involving Gastroenterology, Genetics and Surgery - is essential for its functionality and value.Patients at increased risk of hereditary CRC and/or Polyposis, or with a proven germline mutation causing CRC and/or Polyposis are included. Both clinical data (demographic data, details on medical and family history, information on surveillance, endoscopy and surgery, results of microsatellite instability and molecular genetic tests) and biomaterial (DNA, plasma, serum and tissue) are collected in a standardized manner.

P784 Prevalence of cervical dysplasia in women with inflammatory bowel disease: data from the Parelsnoer Institute (PSI) and PALGA database (PAP-IBD study)

P784 Prevalence of cervical dysplasia in women with inflammatory bowel disease: data from the Parelsnoer Institute (PSI) and PALGA database (PAP-IBD study)

P593 A national database study on colectomy and colorectal cancer in ulcerative colitis: what is the role of appendectomy?

Appendectomy prevents the development of ulcerative colitis (UC), and might have a positive effect on the disease course of UC. However, several studies indicated an increased risk of colectomy and colorectal cancer (CRC) after appendectomy in UC, and discourage the use of an experimental appendectomy. Nonetheless, it seems premature to draw strong conclusions, as these retrospective studies did not correct for possible confounding factors. The aim of this study was to evaluate the risk of colectomy and CRC after appendectomy in UC patients, while correcting for relevant confounders. All included patients were retrieved from the prospective national Initiative on Crohns and Colitis Parelsnoer Institute – inflammatory bowel disease (IBD) database. From 2007, consecutive IBD patients were continuously invited to participate. For inclusion in the current study, patients had to have UC, and data on both appendectomy and colectomy and/or CRC rate had to be available. Primary outcomes were the risk of colectomy and CRC. Outcomes were compared in patients with and without appendectomy, with a separate analysis for timing of appendectomy (before or after UC diagnosis). In total, 826 UC patients (54.7% female) with a median age of 46 (range 18–89) years were included from 2007 until May 2018. Sixty-three (7.6%) patients previously had an appendectomy: 24 (38.1%) before UC diagnosis, 33 (52.3%) after diagnosis, and in 6 (9.5%) patients the timing was unknown. On baseline characteristics, patients with an appendectomy had a significantly lower rate of colectomy (19.0% vs. 37.6%; p = 0.003) and tended to have more often PSC (11.8% vs. 5.7%; p = 0.090). In multi-variate analysis, appendectomy after UC diagnosis was associated with a significantly lower risk of colectomy compared with no appendectomy (HR 0.15, 95% CI 0.04–0.59; p = 0.007), and the same trend was seen in patients with appendectomy before UC (HR 0.36, 95% CI 0.09–1.47; p = 0.156). Kaplan–Meier analysis demonstrated that appendectomy was associated with a significantly postponed colectomy, in particular when performed after UC diagnosis (p = 0.009). No significant differences were found in the CRC rate for patients with and without an appendectomy (1.6% vs. 1.2%; p = 0.555). An appendectomy during the course of UC is associated with an 85% decreased risk of colectomy and a postponed resection in patients who did undergo colectomy. As the colon is longer in situ the risk of developing CRC remains, emphasising the importance of endoscopic surveillance.

Dutch Parelsnoer Institute-Cerebrovascular Accident (CVA) Study: A Large Multicenter Clinical Biobank with Standardized Collection and Storage

The Dutch Parelsnoer Institute-Cerebrovascular accident (CVA) Study is part of the Parelsnoer Institute (PSI), initiated in 2007 by the Netherlands Federation of University Medical Centers (NFU). PSI is a cooperation of all eight Dutch University Medical Centers (UMCs) and aims at building large prospectively collected datasets with uniformly and standardized storage of biomaterials for complex diseases. Currently, PSI covers 18 disease-specific cohorts called ‘Pearls’, and this number is still growing. One of these cohorts is the Stroke or CVA Pearl. For each of the cohorts, PSI offers the UMCs an infrastructure and standard procedures for storing the specific biomaterials in their certified biobanks. Clinical data are stored in a central database after being pseudonymized to ensure patient privacy. For the Parelsnoer Institute-CVA Study, blood for genetic analysis, serum and plasma are collected according to nationally agreed standards. Currently (November 2017) the Stroke Pearl has stored blood samples with prospectively obtained clinical data of around 6000 patients in all UMCs combined. Blood samples and data are available for all researchers with a methodologically valid research proposal. Funding statement: PSI was founded in 2007 with a five year grant from the Dutch Government. From 2011 until now PSI is funded and facilitated by the Netherlands Federation of University Medical Centers (NFU) and its member institutions, independent of external funds. Additional funds from governmental sources, industry sponsors and charity are used for the analysis on the existing data and the expansion of PSI with new diseases.

The Dutch Pancreas Biobank Within the Parelsnoer Institute: A Nationwide Biobank of Pancreatic and Periampullary Diseases.

Large biobanks with uniform collection of biomaterials and associated clinical data are essential for translational research. The Netherlands has traditionally been well organized in multicenter clinical research on pancreatic diseases, including the nationwide multidisciplinary Dutch Pancreatic Cancer Group and Dutch Pancreatitis Study Group. To enable high-quality translational research on pancreatic and periampullary diseases, these groups established the Dutch Pancreas Biobank. The Dutch Pancreas Biobank is part of the Parelsnoer Institute and involves all 8 Dutch university medical centers and 5 nonacademic hospitals. Adult patients undergoing pancreatic surgery (all indications) are eligible for inclusion. Preoperative blood samples, tumor tissue from resected specimens, pancreatic cyst fluid, and follow-up blood samples are collected. Clinical parameters are collected in conjunction with the mandatory Dutch Pancreatic Cancer Audit. Between January 2015 and May 2017, 488 patients were included in the first 5 participating centers: 4 university medical centers and 1 nonacademic hospital. Over 2500 samples were collected: 1308 preoperative blood samples, 864 tissue samples, and 366 follow-up blood samples. Prospective collection of biomaterials and associated clinical data has started in the Dutch Pancreas Biobank. Subsequent translational research will aim to improve treatment decisions based on disease characteristics.

A Stepwise Procedure to Define a Data Collection Framework for a Clinical Biobank.

Current guidelines for clinical biobanking have a strong focus on obtaining, handling, and storage of biospecimens. However, to allow for research tying biomarker analysis to clinical decision making, there should be more focus on collection of data on donor characteristics. Therefore, our aim was to develop a stepwise procedure to define a framework as a tool to help start the data collection process in clinical biobanking. The Radboud Biobank (RB) is a central clinical biobanking facility designed in accordance with the standards set by the Parelsnoer Institute, a Dutch national biobank originally initiated with eight different disease cohorts. To organize the information of these cohorts, we used our experience and knowledge in the field of biobanking and translational research to identify research domains and information categories to classify data. We extended this classification system to a stepwise procedure for defining a data collection framework and examined its utility for existing RB biobanks. Our approach resulted in the definition of a three-step procedure: (1) Identification of research domains and relevant questions within the field that may benefit from biobank samples. (2) Identification of information categories and accompanying subcategories that are relevant for answering questions in identified research domains. (3) Reduction to an efficient framework based on essentiality and quality criteria. We showed the utility of the procedure for three existing RB biobanks. We developed guidelines for the definition of a framework that supports the standardization of the biobank data collection process. Connecting the biobank database to pertinent information collected from the electronic health record will improve data quality and efficiency for both care and research. This is crucial when using the corresponding biospecimens for scientific research. Further, it also facilitates the combination of different clinical biobanks for a specific disease.

Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease.

Background:Abnormal insulin signaling in the brain has been linked to Alzheimer’s disease (AD).Objective:To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype.Methods:From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42, total (t-)Tau, and phosphorylated (p-)Tau.Results:CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient –0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029).Conclusion:Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin.

The Parelsnoer Institute: A National Network of Standardized Clinical Biobanks in the Netherlands

The Parelsnoer Institute (PSI) is a collaborative biobanking project of all eight University Medical Centers in the Netherlands which was launched in 2007. Basically, PSI consists of three dimensions: participating institutions, disease entities and a central organization. An executive board for operational management instigates collective strategic and tactic policies and a central team of PSI experts and advisors supports the researchers and the board in establishing and implementing standards and procedures. PSI offers researchers an infrastructure and standard procedures for the establishment, expansion and optimisation of clinical biobanks for scientific research. To ensure patient privacy clinical data is pseudomized and carefully stored in a central database. Human biomaterials are collected according to nationally agreed standards. Currently PSI covers fifteen large disease specific cohorts (the so-called ‘Parels’ or ‘Pearls’) and new ‘Pearls’ are being developed. The Parelsnoer Institute currently (December 2016) has stored more than 538,000 biospecimens with annotated clinical data of more than 30,000 patients. All these materials and data are available for anyone with a bona fide research proposal.

Patients to learn from: on the need for systematic integration of research and care in academic health care

Integrating research and care in academic medicine in a more systematic fashion offers a promising perspective to current and future patients. In order to live up to these promises, research and care should be integrated more systematically in academic health science, with patients being included as research participants by default. Data and tissue infrastructures and facilities can provide a platform for doing so. At the same time, many issues remain to be settled. New ethical ways and means for protecting and respecting patient-participants in such a double role are also needed in this respect. In this way a deeper transformation is at stake as well: a change towards a setting in which patients fully take center stage in debate and action on the future of biomedicine.

Mo1838 First Results and Information Model From the Parelsnoer Institute IBD Biobank: A Nationwide Standardized Inflammatory Bowel Disease Collection by All University Medical Centers in the Netherlands

Mo1838 First Results and Information Model From the Parelsnoer Institute IBD Biobank: A Nationwide Standardized Inflammatory Bowel Disease Collection by All University Medical Centers in the Netherlands

P696. First results and information model from the Parelsnoer Institute IBD biobank: a nationwide standardised inflammatory bowel disease collection by all university medical centres in the Netherlands

P696. First results and information model from the Parelsnoer Institute IBD biobank: a nationwide standardised inflammatory bowel disease collection by all university medical centres in the Netherlands