Publications by authors named "Meike W Vernooij"

290 Publications

Thyroid status and brain circulation: The Rotterdam Study.

J Clin Endocrinol Metab 2021 Oct 11. Epub 2021 Oct 11.

Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

Context: Whether thyroid dysfunction is related to altered brain circulation in the general population remains unknown.

Objective: We determined the association of thyroid hormones with different markers of brain circulation within community-dwelling elderly.

Design: Three subcohorts of the Rotterdam Study, starting in 1989, 2000 and 2006 respectively.

Setting: Population-based.

Patients Or Other Participants: A total of 5,142 participants (mean age, 63.8 years; 55.4% women), underwent venapuncture to measure serum thyroid-stimulating hormone (TSH), free thyroxine (FT4).

Main Outcome Measures: Between 2005 and 2015, all participants underwent phase-contrast brain magnetic resonance imaging to assess global brain perfusion (mL of blood flow/100 mL of brain/min). Arteriolar retinal calibers were assessed using digitized images of stereoscopic fundus color transparencies in 3,105 participants as markers of microcirculation. We investigated associations of TSH, FT4 with brain circulation measures using (non-)linear regression models. Results. FT4 (in pmol/L) levels had an inverse u-shaped association with global brain perfusion, such that high and low levels of FT4 were associated with lower global brain perfusion compared to middle levels of FT4. The difference in global brain perfusion between high FT4 levels (25 pmol/L) and middle FT4 levels (FT4 = 15 pmol/L; P non-linearity = 0.002) was up to -2.44 mL (95% confidence interval (95%CI)= -4.31; -0.56). Similarly, higher and lower levels of FT4, compared with middle FT4 levels, were associated with arteriolar retinal vessels (mean difference up to -2.46 µm, 95%CI -4.98; 0.05 for lower FT4).

Conclusions: These results suggest that thyroid dysfunction could lead to brain diseases such as stroke or dementia through a suboptimal brain circulation that is potentially modifiable.
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http://dx.doi.org/10.1210/clinem/dgab744DOI Listing
October 2021

Automated Segmentation and Volume Measurement of Intracranial Internal Carotid Artery Calcification at Noncontrast CT.

Radiol Artif Intell 2021 Sep 30;3(5):e200226. Epub 2021 Jun 30.

Biomedical Imaging Group Rotterdam, Department of Radiology and Nuclear Medicine (G.B., M.d.B.), Department of Epidemiology (D.B., M.W.V., M.K.I.), and Department of Radiology and Nuclear Medicine (M.W.V.), Erasmus MC, PO Box 2040, 3000 CA Rotterdam, the Netherlands; Department of Biomedical Data Science, Stanford University, Stanford, Calif (F.D.); Faculty of Science, Radboud University, Nijmegen, the Netherlands (G.v.T.); and Machine Learning Section, Department of Computer Science, University of Copenhagen, Copenhagen, Denmark (M.d.B.).

Purpose: To develop and evaluate a fully-automated deep learning-based method for assessment of intracranial internal carotid artery calcification (ICAC).

Materials And Methods: This was a secondary analysis of prospectively collected data from the Rotterdam study (2003-2006) to develop and validate a deep learning-based method for automated ICAC delineation and volume measurement. Two observers manually delineated ICAC on noncontrast CT scans of 2319 participants (mean age, 69 years ± 7 [standard deviation]; 1154 women [53.2%]), and a deep learning model was trained to segment ICAC and quantify its volume. Model performance was assessed by comparing manual and automated segmentations and volume measurements to those produced by an independent observer (available on 47 scans), comparing the segmentation accuracy in a blinded qualitative visual comparison by an expert observer, and comparing the association with first stroke incidence from the scan date until 2016. All method performance metrics were computed using 10-fold cross-validation.

Results: The automated delineation of ICAC reached a sensitivity of 83.8% and positive predictive value (PPV) of 88%. The intraclass correlation between automatic and manual ICAC volume measures was 0.98 (95% CI: 0.97, 0.98; computed in the entire dataset). Measured between the assessments of independent observers, sensitivity was 73.9%, PPV was 89.5%, and intraclass correlation coefficient was 0.91 (95% CI: 0.84, 0.95; computed in the 47-scan subset). In the blinded visual comparisons of 294 regions, automated delineations were judged as more accurate than manual delineations in 131 regions, less accurate in 94 regions, and equally accurate in the rest of the regions (131 of 225, 58.2%; = .01). The association of ICAC volume with incident stroke was similarly strong for both automated (hazard ratio, 1.38 [95% CI: 1.12, 1.75]) and manually measured volumes (hazard ratio, 1.48 [95% CI: 1.20, 1.87]).

Conclusion: The developed model was capable of automated segmentation and volume quantification of ICAC with accuracy comparable to human experts. CT, Neural Networks, Carotid Arteries, Calcifications/Calculi, Arteriosclerosis, Segmentation, Vision Application Domain, Stroke © RSNA, 2021.
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http://dx.doi.org/10.1148/ryai.2021200226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489463PMC
September 2021

Correction to: Technical and clinical validation of commercial automated volumetric MRI tools for dementia diagnosis-a systematic review.

Neuroradiology 2021 Sep 24. Epub 2021 Sep 24.

Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

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http://dx.doi.org/10.1007/s00234-021-02818-4DOI Listing
September 2021

Sleep and perivascular spaces in the middle-aged and elderly population.

J Sleep Res 2021 Sep 22:e13485. Epub 2021 Sep 22.

Department of Epidemiology, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands.

Sleep has been hypothesised to facilitate waste clearance from the brain. We aimed to determine whether sleep is associated with perivascular spaces on brain magnetic resonance imaging (MRI), a potential marker of impaired brain waste clearance, in a population-based cohort of middle-aged and elderly people. In 559 participants (mean [SD] age 62 [6] years, 52% women) from the population-based Rotterdam Study, we measured total sleep time, sleep onset latency, wake after sleep onset and sleep efficiency with actigraphy and polysomnography. Perivascular space load was determined with brain MRI in four regions (centrum semiovale, basal ganglia, hippocampus, and midbrain) via a validated machine learning algorithm using T2-weighted MR images. Associations between sleep characteristics and perivascular space load were analysed with zero-inflated negative binomial regression models adjusted for various confounders. We found that higher actigraphy-estimated sleep efficiency was associated with a higher perivascular space load in the centrum semiovale (odds ratio 1.10, 95% confidence interval 1.04-1.16, p = 0.0008). No other actigraphic or polysomnographic sleep characteristics were associated with perivascular space load in other brain regions. We conclude that, contrary to our hypothesis, associations of sleep with perivascular space load in this middle-aged and elderly population remained limited to an association of a high actigraphy-estimated sleep efficiency with a higher perivascular space load in the centrum semiovale.
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http://dx.doi.org/10.1111/jsr.13485DOI Listing
September 2021

Technical and clinical validation of commercial automated volumetric MRI tools for dementia diagnosis-a systematic review.

Neuroradiology 2021 Sep 3. Epub 2021 Sep 3.

Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Developments in neuroradiological MRI analysis offer promise in enhancing objectivity and consistency in dementia diagnosis through the use of quantitative volumetric reporting tools (QReports). Translation into clinical settings should follow a structured framework of development, including technical and clinical validation steps. However, published technical and clinical validation of the available commercial/proprietary tools is not always easy to find and pathways for successful integration into the clinical workflow are varied. The quantitative neuroradiology initiative (QNI) framework highlights six necessary steps for the development, validation and integration of quantitative tools in the clinic. In this paper, we reviewed the published evidence regarding regulatory-approved QReports for use in the memory clinic and to what extent this evidence fulfils the steps of the QNI framework. We summarize unbiased technical details of available products in order to increase the transparency of evidence and present the range of reporting tools on the market. Our intention is to assist neuroradiologists in making informed decisions regarding the adoption of these methods in the clinic. For the 17 products identified, 11 companies have published some form of technical validation on their methods, but only 4 have published clinical validation of their QReports in a dementia population. Upon systematically reviewing the published evidence for regulatory-approved QReports in dementia, we concluded that there is a significant evidence gap in the literature regarding clinical validation, workflow integration and in-use evaluation of these tools in dementia MRI diagnosis.
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http://dx.doi.org/10.1007/s00234-021-02746-3DOI Listing
September 2021

The Global Reading Room: Imaging of Post-Traumatic Headache.

AJR Am J Roentgenol 2021 Jul 28. Epub 2021 Jul 28.

Department of Radiology & Nuclear Medicine; Department of Epidemiology, Rotterdan, The Netherlands.

A 19-year-old man presents to the emergency room with migraine headaches seven days after a blow to the head during martial arts competition. His neurologic examination is normal. The patient wishes to resume normal activities, including martial arts practice. As the radiologist, what imaging test, if any, do you recommend?
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http://dx.doi.org/10.2214/AJR.21.26587DOI Listing
July 2021

Resistance to developing brain pathology due to vascular risk factors: the role of educational attainment.

Neurobiol Aging 2021 10 24;106:197-206. Epub 2021 Jun 24.

Department of Radiology and Nuclear Medicine, Erasmus MC-University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, the Netherlands. Electronic address:

Brain pathology develops at different rates between individuals with similar burden of risk factors, possibly explained by brain resistance. We examined if education contributes to brain resistance by studying its influence on the association between vascular risk factors and brain pathology. In 4111 stroke-free and dementia-free community-dwelling participants (62.9 ± 10.7 years), we explored the association between vascular risk factors (hypertension and the Framingham Stroke Risk Profile [FRSP]) and imaging markers of brain pathology (markers of cerebral small vessel disease and brain volumetry), stratified by educational attainment level. Associations of hypertension and FSRP with markers of brain pathology were not significantly different between levels of educational attainment. Certain associations appeared weaker in those with higher compared to lower educational attainment, particularly for white matter hyperintensities (WMH). Supplementary residual analyses showed significant associations between higher educational attainment and stronger resistance to WMH among others. Our results suggest a role for educational attainment in resistance to vascular brain pathology. Yet, further research is needed to better characterize determinants of brain resistance.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.06.006DOI Listing
October 2021

C-factor: a summary measure for systemic arterial calcifications.

BMC Cardiovasc Disord 2021 06 29;21(1):317. Epub 2021 Jun 29.

Departments of Epidemiology, Erasmus MC, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.

Background: Arterial calcification, the hallmark of arteriosclerosis, has a widespread distribution in the human body with only moderate correlation among sites. Hitherto, a single measure capturing the systemic burden of arterial calcification was lacking. In this paper, we propose the C-factor as an overall measure of calcification burden.

Methods: To quantify calcification in the coronary arteries, aortic arch, extra- and intracranial carotid arteries, and vertebrobasilar arteries, 2384 Rotterdam Study participants underwent cardiac and extra-cardiac non-enhanced CT. We performed principal component analyses on the calcification volumes of all twenty-six possible combinations of these vessel beds. Each analysis' first principal component represents the C-factor. Subsequently, we determined the correlation between the C-factor derived from all vessel beds and the other C-factors with intraclass correlation coefficient (ICC) analyses. Finally, we examined the association of the C-factor and calcification in the separate vessel beds with cardiovascular, non-cardiovascular, and overall mortality using Cox-regression analyses.

Results: The ICCs ranged from 0.80 to 0.99. Larger calcification volumes and a higher C-factor were all individually associated with higher risk of cardiovascular, non-cardiovascular, and overall mortality. When included simultaneously in a model, the C-factor was still associated with all three mortality types (adjusted hazard ratio per standard deviation increase (HR) > 1.52), whereas associations of the separate vessel beds with mortality attenuated substantially (HR < 1.26).

Conclusions: The C-factor summarizes the systemic component of arterial calcification on an individual level and appears robust among different combinations of vessel beds. Importantly, when mutually adjusted, the C-factor retains its strength of association with mortality while the site-specific associations attenuate.
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http://dx.doi.org/10.1186/s12872-021-02126-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243490PMC
June 2021

Progression along data-driven disease timelines is predictive of Alzheimer's disease in a population-based cohort.

Neuroimage 2021 09 4;238:118233. Epub 2021 Jun 4.

Department of Radiology & Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands; Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, The Netherlands. Electronic address:

Data-driven disease progression models have provided important insight into the timeline of brain changes in AD phenotypes. However, their utility in predicting the progression of pre-symptomatic AD in a population-based setting has not yet been investigated. In this study, we investigated if the disease timelines constructed in a case-controlled setting, with subjects stratified according to APOE status, are generalizable to a population-based cohort, and if progression along these disease timelines is predictive of AD. Seven volumetric biomarkers derived from structural MRI were considered. We estimated APOE-specific disease timelines of changes in these biomarkers using a recently proposed method called co-initialized discriminative event-based modeling (co-init DEBM). This method can also estimate a disease stage for new subjects by calculating their position along the disease timelines. The model was trained and cross-validated on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, and tested on the population-based Rotterdam Study (RS) cohort. We compared the diagnostic and prognostic value of the disease stage in the two cohorts. Furthermore, we investigated if the rate of change of disease stage in RS participants with longitudinal MRI data was predictive of AD. In ADNI, the estimated disease timeslines for ϵ4 non-carriers and carriers were found to be significantly different from one another (p<0.001). The estimate disease stage along the respective timelines distinguished AD subjects from controls with an AUC of 0.83 in both APOEϵ4 non-carriers and carriers. In the RS cohort, we obtained an AUC of 0.83 and 0.85 in ϵ4 non-carriers and carriers, respectively. Progression along the disease timelines as estimated by the rate of change of disease stage showed a significant difference (p<0.005) for subjects with pre-symptomatic AD as compared to the general aging population in RS. It distinguished pre-symptomatic AD subjects with an AUC of 0.81 in APOEϵ4 non-carriers and 0.88 in carriers, which was better than any individual volumetric biomarker, or its rate of change, could achieve. Our results suggest that co-init DEBM trained on case-controlled data is generalizable to a population-based cohort setting and that progression along the disease timelines is predictive of the development of AD in the general population. We expect that this approach can help to identify at-risk individuals from the general population for targeted clinical trials as well as to provide biomarker based objective assessment in such trials.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118233DOI Listing
September 2021

Intracranial arteriosclerosis is related to cerebral small vessel disease: a prospective cohort study.

Neurobiol Aging 2021 09 22;105:16-24. Epub 2021 Apr 22.

Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address:

Intracranial arteriosclerosis has been increasingly recognized as a risk factor for cognitive impairment and even dementia. A possible mechanism linking intracranial arteriosclerosis to cognitive impairment and dementia involves structural brain changes including cerebral small vessel disease (CSVD). To assess whether intracranial carotid artery calcification (ICAC) and vertebrobasilar artery calcification (VBAC), as proxies for intracranial arteriosclerosis, are related to CSVD. Within the population-based Rotterdam Study, between 2003 and 2006 a computed tomography (CT)-based measurement of ICAC and VBAC and at least one magnetic resonance imaging (MRI) measurement of structural brain changes were performed from 2005 onwards in 1,489 participants. To estimate the burden of calcification independent of age, we computed age-adjusted percentile curves for ICAC and VBAC separately, based on the calcification volumes. Using the longitudinal MRI data, we assessed whether a larger calcification burden accelerates structural brain changes using appropriate statistical models for repeated outcome measures. A larger burden of ICAC and VBAC was associated with an increase of CSVD markers accelerating over time. A larger burden of ICAC and VBAC was not significantly (p > 0.05) associated with accelerated brain atrophy. Arteriosclerosis is related to accelerating structural brain changes over time.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.005DOI Listing
September 2021

Season of birth and the risk of dementia in the population-based Rotterdam Study.

Eur J Epidemiol 2021 May 17;36(5):497-506. Epub 2021 May 17.

Department of Epidemiology, Erasmus MC University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.

Early-life environmental factors have been suggested in the pathophysiology of dementia. Season of birth has previously been used as a proxy for these external exposures. We investigated the link between season of birth and the risk of dementia and further explored underlying pathways by studying structural brain changes on MRI. From the Dutch, population-based Rotterdam Study, 12,964 participants born between 1887 and 1960 were followed between 1990 and 2018 for dementia. Cox regression was conducted to assess the association between season of birth and dementia. In addition, we distinguished between mild and cold winters. The association of season of birth with structural brain markers on MRI was examined in 5237 participants. The risk of dementia in participants born in winter and fall was higher than of those born in summer (hazard ratio (HR) 1.15 [95% confidence interval (CI) 1.01-1.31] for winter and HR 1.17 [95% CI 1.01-1.33] for fall), especially for Alzheimer's disease (HR 1.23 [1.06-1.43] for winter and HR 1.15 [95% CI 0.99-1.35] for fall). The risk was particularly increased for participants born in a cold winter. Except for slightly lower hippocampus in fall born participants (β - 0.03; 95% CI - 0.06 to 0.00), we did not find associations with brain imaging markers. In conclusion, winter and fall births were associated with a higher incidence of dementia, especially of AD. We did not find evidence for structural brain changes as an underlying mechanism.
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http://dx.doi.org/10.1007/s10654-021-00755-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159812PMC
May 2021

Tinnitus and Its Central Correlates: A Neuroimaging Study in a Large Aging Population.

Ear Hear 2021 Mar 26;42(5):1428-1435. Epub 2021 Mar 26.

Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.

Objectives: To elucidate the association between tinnitus and brain tissue volumes and white matter microstructural integrity.

Design: Two thousand six hundred sixteen participants (mean age, 65.7 years [SD: 7.5 years]; 53.9% female) of the population-based Rotterdam Study underwent tinnitus assessment (2011 to 2014) and magnetic resonance imaging of the brain (2011 to 2014). Associations between tinnitus (present versus absent) and total, gray, and white matter volume and global white matter microstructure were assessed using multivariable linear regression models adjusting for demographic factors, cardiovascular risk factors, depressive symptoms, Mini-Mental State Examination score, and hearing loss. Finally, potential regional gray matter density and white matter microstructural volume differences were assessed on a voxel-based level again using multivariable linear regression.

Results: Participants with tinnitus (21.8%) had significantly larger brain tissue volumes (difference in SD, 0.09; 95% confidence interval, 0.06 to 0.13), driven by larger white matter volumes (difference, 0.12; 95% confidence interval, 0.04 to 0.21) independent of hearing loss. There was no association between tinnitus and gray matter volumes nor with global white matter microstructure. On a lobar level, tinnitus was associated with larger white matter volumes in each lobe, not with gray matter volume. Voxel-based results did not show regional specificity.

Conclusions: We found that tinnitus in older adults was associated with larger brain tissue volumes, driven by larger white matter volumes, independent of age, and hearing loss. Based on these results, it may be hypothesized that tinnitus potentially has a neurodevelopmental origin in earlier life independent of aging processes.
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http://dx.doi.org/10.1097/AUD.0000000000001042DOI Listing
March 2021

Lipoprotein(a) is robustly associated with aortic valve calcium.

Heart 2021 Sep 7;107(17):1422-1428. Epub 2021 May 7.

Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

Objectives: To investigate the prevalence and quantity of aortic valve calcium (AVC) in two large cohorts, stratified according to age and lipoprotein(a) (Lp(a)), and to assess the association between Lp(a) and AVC.

Methods: We included 2412 participants from the population-based Rotterdam Study (52% women, mean age=69.6±6.3 years) and 859 apparently healthy individuals from the Amsterdam University Medical Centers (UMC) outpatient clinic (57% women, mean age=45.9±11.6 years). All individuals underwent blood sampling to determine Lp(a) concentration and non-enhanced cardiac CT to assess AVC. Logistic and linear regression analyses were performed to investigate the associations of Lp(a) with the presence and amount of AVC.

Results: The prevalence of AVC was 33.1% in the Rotterdam Study and 5.4% in the Amsterdam UMC cohort. Higher Lp(a) concentrations were independently associated with presence of AVC in both cohorts (OR per 50 mg/dL increase in Lp(a): 1.54 (95% CI 1.36 to 1.75) in the Rotterdam Study cohort and 2.02 (95% CI 1.19 to 3.44) in the Amsterdam UMC cohort). In the Rotterdam Study cohort, higher Lp(a) concentrations were also associated with increase in aortic valve Agatston score (β 0.19, 95% CI 0.06 to 0.32 per 50 mg/dL increase).

Conclusions: Lp(a) is robustly associated with presence of AVC in a wide age range of individuals. These results provide further rationale to assess the effect of Lp(a) lowering interventions in individuals with early AVC to prevent end-stage aortic valve stenosis.
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http://dx.doi.org/10.1136/heartjnl-2021-319044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372399PMC
September 2021

Clinical characteristics of subsequent histologically confirmed meningiomas in long-term childhood cancer survivors: A Dutch LATER study.

Eur J Cancer 2021 06 30;150:240-249. Epub 2021 Apr 30.

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Background: Meningiomas are the most frequent brain tumours occurring after pediatric cranial radiotherapy (CrRT). Data on course of disease, to inform clinical management of meningiomas, are sparse. This study reports the clinical characteristics of histologically confirmed meningiomas in childhood cancer survivors (CCS) in the Netherlands.

Methods: In total, 6015 CCS from the Dutch Long-Term Effects After Childhood Cancer (LATER) cohort were eligible, including 1551 with prior CrRT. These CCS were diagnosed with cancer age <18 y (between 1963 and 2002) and are not subject to brain tumour screening. We identified histologically confirmed meningiomas by record linkage with the Dutch Pathology Registry (PALGA; 1991-2018), and in the Dutch LATER registry. We extracted details regarding diagnosis, treatment, and follow-up from medical records.

Results: We described 93 CCS with meningioma, of whom 89 (95.7%) were treated with CrRT (5.7% of 1551 with prior CrRT; OR = 68). Median age at diagnosis was 31.8 y (range: 13.2-50.5). Thirty survivors (32.3%) had synchronous meningiomas; 84 (90.3%) presented with symptoms. Only 16.1% of meningioma was detected at late effects clinics. Over time, all survivors had surgery; one-third also received radiotherapy. During follow-up 38 (40.9%), survivors developed new meningiomas, 22(23.7%) recurrences and at least four died due to the meningioma.

Conclusions: Histologically confirmed meningiomas after childhood cancer are mostly diagnosed with symptoms and not during routine follow-up at late effects clinics. The meningiomas occur at a median of 20-25 y younger age than incidental meningiomas, are frequently multiple and recurrence after treatment is high. It is crucial to inform CCS and healthcare providers about risk and symptoms of subsequent meningiomas.
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http://dx.doi.org/10.1016/j.ejca.2021.03.021DOI Listing
June 2021

Visit-to-Visit Blood Pressure Variability, Neuropathology, and Cognitive Decline.

Neurology 2021 06 26;96(23):e2812-e2823. Epub 2021 Apr 26.

From the Department of Epidemiology (Y.M., D. Blacker, A.H.), Harvard T.H. Chan School of Public Health; Departments of Neurology (Y.M., A.V., S.J.v.V., B.T.H., S.D.) and Psychiatry (D. Blacker), Massachusetts General Hospital, Harvard Medical School, Boston; Departments of Epidemiology (D. Bos, M.W.V., A.H.) and Radiology and Nuclear Medicine (D. Bos, M.W.V.), Erasmus MC University Medical Center, Rotterdam, the Netherlands; and University of Bordeaux (C.T.), Inserm, Bordeaux Population Health Research Center, UMR 1219, CHU Bordeaux, France.

Objective: Large systolic blood pressure (SBP) variability has been proposed as a novel risk factor for dementia above and beyond SBP levels, but the underlying neuropathology is largely unknown. We investigated the relationship among visit-to-visit SBP variability, cognitive deterioration, and underlying neuropathologic changes.

Methods: We used longitudinal data (between 2005 and 2019) from the National Alzheimer's Coordinating Center. A total of 13,284 dementia-free participants ≥50 years of age were followed up over a median of 5.0 (interquartile range 3.1-7.6) years. Neuropathology data were available in 1,400 autopsied participants. Visit-to-visit SBP variability was quantified from repeated annual SBP measurements. Cognitive deterioration was defined as conversion from normal cognition to mild cognitive impairment (MCI) or dementia or from MCI to dementia.

Results: Larger visit-to-visit SBP variability was associated with cognitive deterioration (adjusted odds ratio comparing extreme quintiles 2.64, 95% confidence interval 2.29-3.04, < 0.001). It was also associated with a higher burden of vascular pathology (including microinfarcts, white matter lesions, atherosclerosis of the circle of Willis, and arteriolosclerosis) and with neurofibrillary tangle pathology assessed by Braak staging (all < 0.05). The association with cognitive deterioration and vascular pathology appeared stronger among those with normal cognition vs those with MCI at baseline. These findings were observed after adjustment for age, sex, mean SBP, and other confounding variables. Similar results were observed for diastolic blood pressure variability.

Conclusion: Larger visit-to-visit SBP variability was associated with cognitive deterioration. It was also associated with cerebrovascular pathology and neurofibrillary tangles. These results suggest the intertwined role of vascular and Alzheimer disease pathology in the etiology of dementia.
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http://dx.doi.org/10.1212/WNL.0000000000012065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205457PMC
June 2021

A machine learning approach to distinguish between knees without and with osteoarthritis using MRI-based radiomic features from tibial bone.

Eur Radiol 2021 Apr 21. Epub 2021 Apr 21.

Department of Radiology & Nuclear Medicine, Erasmus MC University Medical Center, P.O. Box 2040, CA, 3000, Rotterdam, The Netherlands.

Objectives: Our aim was to assess the ability of semi-automatically extracted magnetic resonance imaging (MRI)-based radiomic features from tibial subchondral bone to distinguish between knees without and with osteoarthritis.

Methods: The right knees of 665 females from the population-based Rotterdam Study scanned with 1.5T MRI were analyzed. A fast imaging employing steady-state acquisition sequence was used for the quantitative bone analyses. Tibial bone was segmented using a method that combines multi-atlas and appearance models. Radiomic features related to the shape and texture were calculated from six volumes of interests (VOIs) in the proximal tibia. Machine learning-based Elastic Net models with 10-fold cross-validation were used to distinguish between knees without and with MRI Osteoarthritis Knee Score (MOAKS)-based tibiofemoral osteoarthritis. Performance of the covariate (age and body mass index), image features, and combined covariate + image features models were assessed using the area under the receiver operating characteristic curve (ROC AUC).

Results: Of 665 analyzed knees, 76 (11.4%) had osteoarthritis. An ROC AUC of 0.68 (95% confidence interval (CI): 0.60-0.75) was obtained using the covariate model. The image features model yielded an ROC AUC of 0.80 (CI: 0.73-0.87). The model that combined image features from all VOIs and covariates yielded an ROC AUC of 0.80 (CI: 0.73-0.87).

Conclusion: Our results suggest that radiomic features are useful imaging biomarkers of subchondral bone for the diagnosis of osteoarthritis. An advantage of assessing bone on MRI instead of on radiographs is that other tissues can be assessed simultaneously.

Key Points: • Subchondral bone plays a role in the osteoarthritis disease processes. • MRI radiomics is a potential method for quantifying changes in subchondral bone. • Semi-automatically extracted radiomic features of tibia differ between subjects without and with osteoarthritis.
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http://dx.doi.org/10.1007/s00330-021-07951-5DOI Listing
April 2021

Longitudinal diffusion MRI analysis using Segis-Net: A single-step deep-learning framework for simultaneous segmentation and registration.

Neuroimage 2021 07 29;235:118004. Epub 2021 Mar 29.

Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands.

This work presents a single-step deep-learning framework for longitudinal image analysis, coined Segis-Net. To optimally exploit information available in longitudinal data, this method concurrently learns a multi-class segmentation and nonlinear registration. Segmentation and registration are modeled using a convolutional neural network and optimized simultaneously for their mutual benefit. An objective function that optimizes spatial correspondence for the segmented structures across time-points is proposed. We applied Segis-Net to the analysis of white matter tracts from N=8045 longitudinal brain MRI datasets of 3249 elderly individuals. Segis-Net approach showed a significant increase in registration accuracy, spatio-temporal segmentation consistency, and reproducibility compared with two multistage pipelines. This also led to a significant reduction in the sample-size that would be required to achieve the same statistical power in analyzing tract-specific measures. Thus, we expect that Segis-Net can serve as a new reliable tool to support longitudinal imaging studies to investigate macro- and microstructural brain changes over time.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118004DOI Listing
July 2021

Atherosclerotic Carotid Plaque Composition and Incident Stroke and Coronary Events.

J Am Coll Cardiol 2021 03;77(11):1426-1435

Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.

Background: Increasing evidence suggests that atherosclerotic plaque composition rather than plaque size is linked to ischemic cardiovascular events, yet largescale population-based data in asymptomatic individuals remain scarce.

Objectives: This study sought to investigate carotid plaque composition in relation to incident stroke and coronary heart disease (CHD) in a population-based setting.

Methods: Between 2007 and 2012, 1,349 persons (mean age 72 years, 49.5% women) from the population-based Rotterdam Study who were free from a history of stroke or CHD, in whom carotid ultrasonography showed subclinical atherosclerosis, and who underwent high-resolution magnetic resonance imaging of the carotid arteries to assess plaque characteristics. These included the presence of specific plaque components (intraplaque hemorrhage [IPH], lipid-rich necrotic core, and calcification), and measures of plaque size (maximum plaque thickness and presence of stenosis of more than 30%). Individuals were continuously followed for the occurrence of stroke or CHD until January 1, 2015. The authors used Cox regression models to assess the association of the plaque characteristics with the incidence of stroke and CHD, with adjustments for age, sex, and cardiovascular risk factors.

Results: During a median of 5.1 years' follow-up for stroke and 4.8 years for CHD, 51 individuals had a stroke and 83 developed CHD. Independent of maximum plaque thickness and cardiovascular risk factors, the presence of IPH was associated with incident stroke and CHD (fully adjusted hazard ratio: 2.42 [95% confidence interval: 1.30 to 4.50], and 1.95 [95% confidence interval: 1.20 to 3.14]). Presence of a lipid-rich necrotic core and calcification were not associated with stroke or CHD.

Conclusions: The presence of IPH in the carotid atherosclerotic plaque is an independent risk factor for stroke and CHD. These findings indicate the promise of IPH as a marker of plaque vulnerability in healthy persons with subclinical atherosclerosis.
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http://dx.doi.org/10.1016/j.jacc.2021.01.038DOI Listing
March 2021

Social Health Is Associated With Structural Brain Changes in Older Adults: The Rotterdam Study.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Feb 5. Epub 2021 Feb 5.

Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address:

Background: Social health markers have been linked to the development of dementia. We hypothesize that social health affects brain structure and consequently influences cognitive function. We aim to elucidate the cross-sectional and longitudinal associations between social health markers and structural brain changes in older adults in the general population.

Methods: Social health markers (loneliness, perceived social support, marital status) were assessed in the Rotterdam Study from 2002 to 2008. Magnetic resonance imaging of the brain was performed repeatedly between 2005 and 2015 for 3737 participants to obtain brain volumetrics, cerebral small vessel disease markers, and white matter microstructural integrity as measures of brain structure. Cross-sectional associations between social health and brain structure were studied using multivariable linear and logistic regression models. Longitudinal associations between baseline social health and changes in brain structure were examined using linear mixed models and generalized estimating equations.

Results: Loneliness was associated with smaller white matter volume at baseline (mean difference = -4.63 mL, 95% confidence interval = -8.46 to -0.81). Better perceived social support was associated with larger total brain volume and gray matter volume at baseline and a less steep decrease in total brain volume over time. Better social support was associated with higher global fractional anisotropy and lower mean diffusivity at baseline. Participants who had never been married had a smaller total brain volume (mean difference = -8.27 mL, 95% confidence interval = -13.16 to -3.39) at baseline than married peers.

Conclusions: Social health is associated with brain structure. Better perceived social support at baseline was associated with better brain structure over time.
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http://dx.doi.org/10.1016/j.bpsc.2021.01.009DOI Listing
February 2021

Clinical Relevance of Cortical Cerebral Microinfarcts on 1.5T Magnetic Resonance Imaging in the Late-Adult Population.

Stroke 2021 Mar 4;52(3):922-930. Epub 2021 Feb 4.

Department of Radiology and Nuclear Medicine (S.H., M.A.I., M.W.V.), Erasmus Medical Center, Rotterdam, the Netherlands.

Background And Purpose: Cortical cerebral microinfarcts (CMIs) have been linked with dementia and impaired cognition in cross-sectional studies. However, the clinical relevance of CMIs in a large population-based setting is lacking. We examine the association of cortical CMIs detected on 1.5T magnetic resonance imaging with cardiovascular risk factors, cerebrovascular disease, and brain tissue volumes. We further explore the association between cortical CMIs with cognitive decline and risk of stroke, dementia, and mortality in the general population.

Methods: Two thousand one hundred fifty-six participants (age: 75.7±5.9 years, women: 55.6%) with clinical history and baseline magnetic resonance imaging (January 2009-December 2013) were included from the Rotterdam Study. Cortical CMIs were graded based on a previously validated method. Markers of cerebrovascular disease and brain tissue volumes were assessed on magnetic resonance imaging. Cognition was assessed using a detailed neuropsychological test at baseline and at 5 years of follow-up. Data on incident stroke, dementia, and mortality were included until January 2016.

Results: Two hundred twenty-seven individuals (10.5%) had ≥1 cortical CMIs. The major risk factors of cortical CMIs were male sex, current smoking, history of heart disease, and stroke. Furthermore, presence of cortical CMIs was associated with infarcts and smaller brain volume. Persons with cortical CMIs showed cognitive decline in Stroop tests (color-naming and interference subtasks; β for color-naming, 0.18 [95% CI, 0.04-0.33], interaction ≤0.001 and β for interference subtask, 1.74, [95% CI, 0.66-2.82], interaction ≤0.001). During a mean follow-up of 5.2 years, 73 (4.3%) individuals developed incident stroke, 95 (5.1%) incident dementia, and 399 (19.2%) died. People with cortical CMIs were at an increased risk of stroke (hazard ratio, 1.18 [95% CI, 1.09-1.28]) and mortality (hazard ratio, 1.09 [95% CI, 1.00-1.19]).

Conclusions: Cortical CMIs are highly prevalent in a population-based setting and are associated with cardiovascular disease, cognitive decline, and increased risk of stroke and mortality. Future investigations will have to show whether cortical CMIs are a useful biomarker to intervene upon to reduce the burden of stroke.
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http://dx.doi.org/10.1161/STROKEAHA.120.032085DOI Listing
March 2021

Cortical superficial siderosis in the general population: The Framingham Heart and Rotterdam studies.

Int J Stroke 2021 Oct 21;16(7):798-808. Epub 2021 Jan 21.

Erasmus MC, Rotterdam, The Netherlands.

Objective: We aimed to characterize cortical superficial siderosis, its determinants and sequel, in community-dwelling older adults.

Methods: The sample consisted of Framingham ( = 1724; 2000-2009) and Rotterdam ( = 4325; 2005-2013) study participants who underwent brain MRI. In pooled individual-level analysis, we compared baseline characteristics in patients with cortical superficial siderosis to two reference groups: (i) persons without hemorrhagic MRI markers of cerebral amyloid angiopathy (no cortical superficial siderosis and no microbleeds) and (ii) those with presumed cerebral amyloid angiopathy based on the presence of strictly lobar microbleeds but without cortical superficial siderosis.

Results: Among a total of 6049 participants, 4846 did not have any microbleeds or cortical superficial siderosis (80%), 401 had deep/mixed microbleeds (6.6%), 776 had strictly lobar microbleeds without cortical superficial siderosis (12.8%) and 26 had cortical superficial siderosis with/without microbleeds (0.43%). In comparison to participants without microbleeds or cortical superficial siderosis and to those with strictly lobar microbleeds but without cortical superficial siderosis, participants with cortical superficial siderosis were older (OR 1.09 per year, 95% CI 1.05, 1.14;  < 0.001 and 1.04, 95% CI 1.00, 1.09;  = 0.058, respectively), had overrepresentation of the APOE ɛ4 allele (5.19, 2.04, 13.25;  = 0.001 and 3.47, 1.35, 8.92;  = 0.01), and greater prevalence of intracerebral hemorrhage (72.57, 9.12, 577.49;  < 0.001 and 81.49, 3.40, >999.99;  = 0.006). During a mean follow-up of 5.6 years, 42.4% participants with cortical superficial siderosis had a stroke (five intracerebral hemorrhage, two ischemic strokes and four undetermined strokes), 19.2% had transient neurological deficits and 3.8% developed incident dementia.

Conclusion: Our study adds supporting evidence to the association between cortical superficial siderosis and cerebral amyloid angiopathy within the general population. Community-dwelling persons with cortical superficial siderosis may be at high risk for intracerebral hemorrhage and future neurological events.
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http://dx.doi.org/10.1177/1747493020984559DOI Listing
October 2021

Harsh Parenting and Child Brain Morphology: A Population-Based Study.

Child Maltreat 2021 Jan 18:1077559520986856. Epub 2021 Jan 18.

Department of Child and Adolescent Psychiatry/Psychology, 6993Erasmus University Medical Center, Rotterdam, The Netherlands.

Evidence suggests that maltreatment shapes the child's brain. Little is known, however, about how normal variation in parenting influences the child neurodevelopment. We examined whether harsh parenting is associated with the brain morphology in 2,410 children from a population-based cohort. Mothers fathers independently reported harsh parenting at child age 3 years. Structural and diffusion-weighted brain morphological measures were acquired with MRI scans at age 10 years. We explored whether associations between parenting and brain morphology were explained by co-occurring adversities, and whether there was a joint effect of both parents' harsh parenting. Maternal harsh parenting was associated with smaller total gray (β = -0.05 (95%CI = -0.08; -0.01)), cerebral white matter and amygdala volumes (β = -0.04 (95%CI = -0.07; 0)). These associations were also observed with the combined harsh parenting measure and were robust to the adjustment for multiple confounding factors. Similar associations, although non-significant, were found between paternal parenting and these brain outcomes. Maternal and paternal harsh parenting were not associated with the hippocampus or the white matter microstructural metrics. We found a long-term association between harsh parenting and the global brain and amygdala volumes in preadolescents, suggesting that adverse rearing environments common in the general population are related to child brain morphology.
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http://dx.doi.org/10.1177/1077559520986856DOI Listing
January 2021

Automated quantitative MRI volumetry reports support diagnostic interpretation in dementia: a multi-rater, clinical accuracy study.

Eur Radiol 2021 Jul 15;31(7):5312-5323. Epub 2021 Jan 15.

Centre for Medical Image Computing (CMIC), Department of Medical Physics and Bioengineering, University College London, London, UK.

Objectives: We examined whether providing a quantitative report (QReport) of regional brain volumes improves radiologists' accuracy and confidence in detecting volume loss, and in differentiating Alzheimer's disease (AD) and frontotemporal dementia (FTD), compared with visual assessment alone.

Methods: Our forced-choice multi-rater clinical accuracy study used MRI from 16 AD patients, 14 FTD patients, and 15 healthy controls; age range 52-81. Our QReport was presented to raters with regional grey matter volumes plotted as percentiles against data from a normative population (n = 461). Nine raters with varying radiological experience (3 each: consultants, registrars, 'non-clinical image analysts') assessed each case twice (with and without the QReport). Raters were blinded to clinical and demographic information; they classified scans as 'normal' or 'abnormal' and if 'abnormal' as 'AD' or 'FTD'.

Results: The QReport improved sensitivity for detecting volume loss and AD across all raters combined (p = 0.015* and p = 0.002*, respectively). Only the consultant group's accuracy increased significantly when using the QReport (p = 0.02*). Overall, raters' agreement (Cohen's κ) with the 'gold standard' was not significantly affected by the QReport; only the consultant group improved significantly (κ 0.41➔0.55, p = 0.04*). Cronbach's alpha for interrater agreement improved from 0.886 to 0.925, corresponding to an improvement from 'good' to 'excellent'.

Conclusion: Our QReport referencing single-subject results to normative data alongside visual assessment improved sensitivity, accuracy, and interrater agreement for detecting volume loss. The QReport was most effective in the consultants, suggesting that experience is needed to fully benefit from the additional information provided by quantitative analyses.

Key Points: • The use of quantitative report alongside routine visual MRI assessment improves sensitivity and accuracy for detecting volume loss and AD vs visual assessment alone. • Consultant neuroradiologists' assessment accuracy and agreement (kappa scores) significantly improved with the use of quantitative atrophy reports. • First multi-rater radiological clinical evaluation of visual quantitative MRI atrophy report for use as a diagnostic aid in dementia.
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http://dx.doi.org/10.1007/s00330-020-07455-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213665PMC
July 2021

Modelling the cascade of biomarker changes in -related frontotemporal dementia.

J Neurol Neurosurg Psychiatry 2021 May 15;92(5):494-501. Epub 2021 Jan 15.

Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

Objective: Progranulin-related frontotemporal dementia (FTD-) is a fast progressive disease. Modelling the cascade of multimodal biomarker changes aids in understanding the aetiology of this disease and enables monitoring of individual mutation carriers. In this cross-sectional study, we estimated the temporal cascade of biomarker changes for FTD-, in a data-driven way.

Methods: We included 56 presymptomatic and 35 symptomatic mutation carriers, and 35 healthy non-carriers. Selected biomarkers were neurofilament light chain (NfL), grey matter volume, white matter microstructure and cognitive domains. We used discriminative event-based modelling to infer the cascade of biomarker changes in FTD- and estimated individual disease severity through cross-validation. We derived the biomarker cascades in non-fluent variant primary progressive aphasia (nfvPPA) and behavioural variant FTD (bvFTD) to understand the differences between these phenotypes.

Results: Language functioning and NfL were the earliest abnormal biomarkers in FTD-. White matter tracts were affected before grey matter volume, and the left hemisphere degenerated before the right. Based on individual disease severities, presymptomatic carriers could be delineated from symptomatic carriers with a sensitivity of 100% and specificity of 96.1%. The estimated disease severity strongly correlated with functional severity in nfvPPA, but not in bvFTD. In addition, the biomarker cascade in bvFTD showed more uncertainty than nfvPPA.

Conclusion: Degeneration of axons and language deficits are indicated to be the earliest biomarkers in FTD-, with bvFTD being more heterogeneous in disease progression than nfvPPA. Our data-driven model could help identify presymptomatic mutation carriers at risk of conversion to the clinical stage.
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http://dx.doi.org/10.1136/jnnp-2020-323541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053353PMC
May 2021

Brain structure prior to non-central nervous system cancer diagnosis: A population-based cohort study.

Neuroimage Clin 2020 13;28:102466. Epub 2020 Oct 13.

Department of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Brain and Cognition, Department of Psychology, University of Amsterdam, Amsterdam, the Netherlands. Electronic address:

Purpose: Many studies have shown that patients with non-central nervous system (CNS) cancer can have brain abnormalities, such as reduced gray matter volume and cerebral microbleeds. These abnormalities can sometimes be present even before start of treatment, suggesting a potential detrimental effect of non-CNS cancer itself on the brain. In these previous studies, psychological factors associated with a cancer diagnosis and selection bias may have influenced results. To overcome these limitations, we investigated brain structure with magnetic resonance imaging (MRI) prior to cancer diagnosis.

Patients And Methods: Between 2005 and 2014, 4,622 participants from the prospective population-based Rotterdam Study who were free of cancer, dementia, and stroke, underwent brain MRI and were subsequently followed for incident cancer until January 1st, 2015. We investigated the association between brain MRI measurements, including cerebral small vessel disease, volumes of global brain tissue, lobes, and subcortical structures, and global white matter microstructure, and the risk of non-CNS cancer using Cox proportional hazards models. Age was used as time scale. Models were corrected for e.g. sex, intracranial volume, educational level, body mass index, hypertension, diabetes mellitus, smoking status, alcohol use, and depression sum-score.

Results: During a median (interquartile range) follow-up of 7.0 years (4.9-8.1), 353 participants were diagnosed with non-CNS cancer. Results indicated that persons who develop cancer do not have more brain abnormalities before clinical manifestation of the disease than persons who remain free of cancer. The largest effect estimates were found for the relation between presence of lacunar infarcts and the risk of cancer (hazard ratio [HR] 95% confidence interval [CI] = 1.39 [0.97-1.98]) and for total brain volume (HR [95%CI] per standard deviation increase in total brain volume = 0.76 [0.55-1.04]).

Conclusion: We did not observe associations between small vessel disease, brain tissue volumes, and global white matter microstructure, and subsequent cancer risk in an unselected population. These findings deviate from previous studies indicating brain abnormalities among patients shortly after cancer diagnosis.
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http://dx.doi.org/10.1016/j.nicl.2020.102466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578754PMC
June 2021

Silent cerebral infarcts in patients with sickle cell disease: a systematic review and meta-analysis.

BMC Med 2020 12 22;18(1):393. Epub 2020 Dec 22.

Department of Pediatric Haematology and Oncology, Erasmus MC - Sophia Children's Hospital, NC-825, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.

Background And Purpose: Silent cerebral infarcts (SCIs) are the most common neurological complication in children and adults with sickle cell disease (SCD). In this systematic review, we provide an overview of studies that have detected SCIs in patients with SCD by cerebral magnetic resonance imaging (MRI). We focus on the frequency of SCIs, the risk factors involved in their development and their clinical consequences.

Methods: The databases of Embase, MEDLINE ALL via Ovid, Web of Science Core Collection, Cochrane Central Register of Trials via Wiley and Google Scholar were searched from inception to June 1, 2019.

Results: The search yielded 651 results of which 69 studies met the eligibility criteria. The prevalence of SCIs in patients with SCD ranges from 5.6 to 80.6% with most studies reported in the 20 to 50% range. The pooled prevalence of SCIs in HbSS and HbSβ SCD patients is 29.5%. SCIs occur more often in patients with the HbSS and HbSβ genotype in comparison with other SCD genotypes, as SCIs are found in 9.2% of HbSC and HbSβ patients. Control subjects showed a mean pooled prevalence of SCIs of 9.8%. Data from included studies showed a statistically significant association between increasing mean age of the study population and mean SCI prevalence. Thirty-three studies examined the risk factors for SCIs. The majority of the risk factors show no clear association with prevalence, since more or less equal numbers of studies give evidence for and against the causal association.

Conclusions: This systematic review and meta-analysis shows SCIs are common in patients with SCD. No clear risk factors for their development were identified. Larger, prospective and controlled clinical, neuropsychological and neuroimaging studies are needed to understand how SCD and SCIs affect cognition.
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http://dx.doi.org/10.1186/s12916-020-01864-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754589PMC
December 2020

Design and overview of the Origins of Alzheimer's Disease Across the Life course (ORACLE) study.

Eur J Epidemiol 2021 Jan 16;36(1):117-127. Epub 2020 Dec 16.

Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.

Brain development and deterioration across the lifespan are integral to the etiology of late-life neurodegenerative disease. Factors that influence the health of the adult brain remain to be elucidated and include risk factors, protective factors, and factors related to cognitive and brain reserve. To address this knowledge gap we designed a life-course study on brain health, which received funding through the EU ERC Programme under the name Origins of Alzheimer's Disease Across the Life course (ORACLE) Study. The ORACLE Study is embedded within Generation R, a prospective population-based cohort study of children and their parents, and links this with the Rotterdam Study, a population-based study in middle-aged and elderly persons. The studies are based in Rotterdam, the Netherlands. Generation R focuses on child health from fetal life until adolescence with repeated in-person examinations, but has also included data collection on the children's parents. The ORACLE Study aims to extend the parental data collection in nearly 2000 parents with extensive measures on brain health, including neuroimaging, cognitive testing and motor testing. Additionally, questionnaires on migraine, depressive symptoms, sleep, and neurological family history were completed. These data allow for the investigation of longitudinal influences on adult brain health as well as intergenerational designs involving children and parents. As a secondary focus, the sampling is enriched by mothers (n = 356) that suffered from hypertensive disorders during pregnancy in order to study brain health in this high-risk population. This article provides an overview of the rationale and the design of the ORACLE Study.
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http://dx.doi.org/10.1007/s10654-020-00696-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847463PMC
January 2021

Cerebral small vessel disease genomics and its implications across the lifespan.

Nat Commun 2020 12 8;11(1):6285. Epub 2020 Dec 8.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35233, USA.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
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http://dx.doi.org/10.1038/s41467-020-19111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722866PMC
December 2020

Air pollution exposure during pregnancy and childhood and brain morphology in preadolescents.

Environ Res 2021 07 19;198:110446. Epub 2020 Nov 19.

ISGlobal, Barcelona, Spain; Pompeu Fabra University, Barcelona, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Spain; Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands. Electronic address:

Background: Studies investigating the relationship between exposure to air pollution and brain development using magnetic resonance images are emerging. However, most studies have focused only on prenatal exposures, and have included a limited selection of pollutants. Here, we aim to expand the current knowledge by studying pregnancy and childhood exposure to a wide selection of pollutants, and brain morphology in preadolescents.

Methods: We used data from 3133 preadolescents from a birth cohort from Rotterdam, the Netherlands (enrollment: 2002-2006). Concentrations of nitrogen oxides, coarse, fine, and ultrafine particles, and composition of fine particles were estimated for participant's home addresses in pregnancy and childhood, using land use regression models. Structural brain images were obtained at age 9-12 years. We assessed the relationships of air pollution exposure, with brain volumes, and surface-based morphometric data, adjusting for socioeconomic and life-style characteristics, using single as well as multi-pollutant approach.

Results: No associations were observed between air pollution exposures and global volumes of total brain, and cortical and subcortical grey matter. However, we found associations between higher pregnancy and childhood air pollution exposures with smaller corpus callosum, smaller hippocampus, larger amygdala, smaller nucleus accumbens, and larger cerebellum (e.g. -69.2mm hippocampal volume [95%CI -129.1 to -9.3] per 1ng/m increase in pregnancy exposure to polycyclic aromatic hydrocarbons). Higher pregnancy exposure to air pollution was associated with smaller cortical thickness while higher childhood exposure was associated with predominantly larger cortical surface area.

Conclusion: Higher pregnancy or childhood exposure to several air pollutants was associated with altered volume of several brain structures, as well as with cortical thickness and surface area. Associations showed some similarity to delayed maturation and effects of early-life stress.
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http://dx.doi.org/10.1016/j.envres.2020.110446DOI Listing
July 2021
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