Publications by authors named "Matthan W A Caan"

74 Publications

Gray and white matter are both affected in classical galactosemia: An explorative study on the association between neuroimaging and clinical outcome.

Mol Genet Metab 2020 12 6;131(4):370-379. Epub 2020 Nov 6.

Department of Pediatrics, Division of Metabolic Disorders, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic address:

Background: Classical Galactosemia (CG) is an inherited disorder of galactose metabolism caused by a deficiency of the galactose-1-phosphate uridylyltransferase (GALT) enzyme resulting in neurocognitive complications. As in many Inborn Errors of Metabolism, the metabolic pathway of CG is well-defined, but the pathophysiology and high variability in clinical outcome are poorly understood. The aim of this study was to investigate structural changes of the brain of CG patients on MRI and their association with clinical outcome.

Methods: In this prospective cohort study an MRI protocol was developed to evaluate gray matter (GM) and white matter (WM) volume of the cerebrum and cerebellum, WM hyperintensity volume, WM microstructure and myelin content with the use of conventional MRI techniques, diffusion tensor imaging (DTI) and quantitative T1 mapping. The association between several neuroimaging parameters and both neurological and intellectual outcome was investigated.

Results: Twenty-one patients with CG (median age 22 years, range 8-47) and 24 controls (median age 30, range 16-52) were included. Compared to controls, the WM of CG patients was lower in volume and the microstructure of WM was impaired both in the whole brain and corticospinal tract (CST) and the lower R1 values of WM, GM and the CST were indicative of less myelin. The volume of WM lesions were comparable between patients and controls. The 9/16 patients with a poor neurological outcome (defined as the presence of a tremor and/or dystonia), demonstrated a lower WM volume, an impaired WM microstructure and lower R1 values of the WM indicative of less myelin content compared to 7/16 patients without movement disorders. In 15/21 patients with a poor intellectual outcome (defined as an IQ < 85) both GM and WM were affected with a lower cerebral and cerebellar WM and GM volume compared to 6/21 patients with an IQ ≥ 85. Both the severity of the tremor (as indicated by the Tremor Rating Scale) and IQ (as continuous measure) were associated with several neuroimaging parameters such as GM volume, WM volume, CSF volume, WM microstructure parameters and R1 values of GM and WM.

Conclusion: In this explorative study performed in patients with Classical Galactosemia, not only WM but also GM pathology was found, with more severe brain abnormalities on MRI in patients with a poor neurological and intellectual outcome. The finding that structural changes of the brain were associated with the severity of long-term complications indicates that quantitative MRI techniques could be of use to explain neurological and cognitive dysfunction as part of the disease spectrum. Based on the clinical outcome of patients, the absence of widespread WM lesions and the finding that both GM and WM are affected, CG could be primarily a GM disease with secondary damage to the WM as a result of neuronal degeneration. To investigate this further the course of GM and WM should be evaluated in longitudinal research, which could also clarify if CG is a neurodegenerative disease.
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http://dx.doi.org/10.1016/j.ymgme.2020.11.001DOI Listing
December 2020

Differences in location of cerebral white matter hyperintensities in children and adults living with a treated HIV infection: A retrospective cohort comparison.

PLoS One 2020 28;15(10):e0241438. Epub 2020 Oct 28.

Department of Pediatric Infectious Diseases, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Cerebral white matter hyperintensities (WMH) persist in children and adults living with HIV, despite effective combination antiretroviral therapy (cART). As age and principal routes of transmission differ between children (perinatally) and adults (behaviorally), comparing the characteristics and determinants of WMH between these populations may increase our understanding of the pathophysiology of WMH. From separate cohorts of 31 children (NOVICE) and 74 adults (AGEhIV), we cross-sectionally assessed total WMH volume and number of WMH per location (periventricular vs. deep) using fluid-attenuated inversion recovery (FLAIR) MRI images. WMH were either periventricular when within 10mm of the lateral ventricles, or deep otherwise. We assessed patient- or HIV-related determinants of total WMH volume (adjusted for intracranial volume) and location of WMH using logistic regression, while stratifying on children and adults. At enrollment, median age of participants was 13.8 years (IQR 11.4-15.9) for children and 53.4 years (IQR 48.3-60.8) for adults and 27/31 children (87%) and 74/74 adults (100%) had an HIV RNA viral load <200 copies/mL. WMH were present in 16/27 (52%) children and 74/74 adults (100%). The prevalence of deep WMH was not different between groups, (16/16 [100%] in children vs. 71/74 [96%] in adults, p = 0,999), yet periventricular WMH were more prevalent in adults (74/74 [100%]) compared to children (9/16; 56%) (p<0.001). Median WMH volume was higher in adults compared to children (1182 mm3 [425-2617] vs. 109 mm3 [61.7-625], p<0.001). In children, boys were more likely to have deep WMH compared to girls. In adults, older age was associated with higher total WMH volume, and age, hypertension and lower CD4+ T-lymphocyte nadir with a higher number of periventricular WMH. Our findings suggest that the location of WMH differs between children and adults living with HIV, hinting at a different underlying pathogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241438PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592958PMC
December 2020

Sharpness in motion corrected quantitative imaging at 7T.

Neuroimage 2020 11 8;222:117227. Epub 2020 Aug 8.

Amsterdam UMC, University of Amsterdam, Biomedical Engineering and Physics, Amsterdam, the Netherlands. Electronic address:

Sub-millimeter imaging at 7T has opened new possibilities for qualitatively and quantitatively studying brain structure as it evolves throughout the life span. However, subject motion introduces image blurring on the order of magnitude of the spatial resolution and is thus detrimental to image quality. Such motion can be corrected for, but widespread application has not yet been achieved and quantitative evaluation is lacking. This raises a need to quantitatively measure image sharpness throughout the brain. We propose a method to quantify sharpness of brain structures at sub-voxel resolution, and use it to assess to what extent limited motion is related to image sharpness. The method was evaluated in a cohort of 24 healthy volunteers with a wide and uniform age range, aiming to arrive at results that largely generalize to larger populations. Using 3D fat-excited motion navigators, quantitative R, R and Quantitative Susceptibility Maps and T-weighted images were retrospectively corrected for motion. Sharpness was quantified in all modalities for selected regions of interest (ROI) by fitting the sigmoidally shaped error function to data within locally homogeneous clusters. A strong, almost linear correlation between motion and sharpness improvement was observed, and motion correction significantly improved sharpness. Overall, the Full Width at Half Maximum reduced from 0.88 mm to 0.70 mm after motion correction, equivalent to a 2.0 times smaller voxel volume. Motion and sharpness were not found to correlate with the age of study participants. We conclude that in our data, motion correction using fat navigators is overall able to restore the measured sharpness to the imaging resolution, irrespective of the amount of motion observed during scanning.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117227DOI Listing
November 2020

Distance to white matter trajectories is associated with treatment response to internal capsule deep brain stimulation in treatment-refractory depression.

Neuroimage Clin 2020 25;28:102363. Epub 2020 Jul 25.

Amsterdam UMC, University of Amsterdam, Department of Psychiatry, Amsterdam Neuroscience, Meibergdreef 9, Amsterdam, Netherlands; Amsterdam Brain and Cognition, Nieuwe Achtergracht 129 B, Amsterdam, Netherlands.

Background: Deep brain stimulation (DBS) is an innovative treatment for treatment-refractory depression. DBS is usually targeted at specific anatomical landmarks, with patients responding to DBS in approximately 50% of cases. Attention has recently shifted to white matter tracts to explain DBS response, with initial open-label trials targeting white matter tracts yielding much higher response rates (>70%).

Objective/hypothesis: Our aim was to associate distance to individual white matter tracts around the stimulation target in the ventral anterior limb of the internal capsule to treatment response.

Methods: We performed diffusion magnetic resonance tractography of the superolateral branch of the medial forebrain bundle and the anterior thalamic radiation in fourteen patients that participated in our randomized clinical trial. We combined the tract reconstructions with the postoperative images to identify the DBS leads and estimated the distance between tracts and leads, which we subsequently associated with treatment response.

Results: Stimulation closer to both tracts was significantly correlated to a larger symptom decrease (r = 0.61, p = 0.02), suggesting that stimulation more proximal to the tracts was beneficial. Biophysical modelling indicated that 37.5% of tracts were even outside the volume of activated tissue. There was no difference in lead placement with respect to anatomical landmarks, which could mean that differences in treatment response were driven by individual differences in white matter anatomy.

Conclusions: Our results suggest that deep brain stimulation of the ventral anterior limb of the internal capsule could benefit from targeting white matter bundles. We recommend acquiring diffusion magnetic resonance data for each individual patient.
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http://dx.doi.org/10.1016/j.nicl.2020.102363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396898PMC
July 2020

The muscarinic M receptor modulates associative learning and memory in psychotic disorders.

Neuroimage Clin 2020 26;27:102278. Epub 2020 May 26.

Department of Psychiatry and Psychology, University of Maastricht, Maastricht, The Netherlands.

Background: Psychotic disorders are characterized by prominent deficits in associative learning and memory for which there are currently no effective treatments. Functional magnetic resonance imaging (fMRI) studies in psychotic disorders have identified deficits in fronto-temporal activation during associative learning and memory. The underlying pathology of these findings remains unclear. Postmortem data have suggested these deficits may be related to loss of muscarinic M receptor mediated signaling. This is supported by an in-vivo study showing improvements in these symptoms after treatment with the experimental M receptor agonist xanomeline. The current study tests whether reported deficits in fronto-temporal activation could be mediated by loss of M receptor signaling in psychotic disorders.

Methods: Twenty-six medication-free subjects diagnosed with a psychotic disorder and 29 age-, gender-, and IQ-matched healthy controls underwent two functional magnetic resonance imaging (fMRI) sessions, one under placebo and one under selective M antagonist biperiden, while performing the paired associated learning task. M binding potentials (BP) were measured in the dorsolateral prefrontal cortex (DLPFC) and hippocampus using I-IDEX single photon emission computed tomography.

Results: In the subjects with psychotic disorders DLPFC hypoactivation was only found in the memory phase of the task. In both learning and memory phases of the task, M antagonism by biperiden elicited significantly greater hyperactivation of the parahippocampal gyrus and superior temporal gyrus in subjects with a psychotic disorders compared to controls. Greater hyperactivation of these areas after biperiden was associated with greater hippocampal M receptor binding during learning, with no association found with M receptor binding in the DLPFC. M receptor binding in the DLPFC was related to greater functional sensitivity to biperiden of the cingulate gyrus during the memory phase.

Conclusion: The current study is the first to show differences in M receptor mediated functional sensitivity between subjects with a psychotic disorder and controls during a paired associate learning and memory task. Results point to subjects with psychotic disorders having a loss of M receptor reserve in temporal-limbic areas.
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http://dx.doi.org/10.1016/j.nicl.2020.102278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305431PMC
May 2020

ExploreASL: An image processing pipeline for multi-center ASL perfusion MRI studies.

Neuroimage 2020 10 8;219:117031. Epub 2020 Jun 8.

Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, Amsterdam University Medical Center, Location VUmc, Amsterdam, the Netherlands; UCL Queen Square Institute of Neurology, University College London, London, UK; Centre for Medical Image Computing (CMIC), Faculty of Engineering Science, University College London, London, UK.

Arterial spin labeling (ASL) has undergone significant development since its inception, with a focus on improving standardization and reproducibility of its acquisition and quantification. In a community-wide effort towards robust and reproducible clinical ASL image processing, we developed the software package ExploreASL, allowing standardized analyses across centers and scanners. The procedures used in ExploreASL capitalize on published image processing advancements and address the challenges of multi-center datasets with scanner-specific processing and artifact reduction to limit patient exclusion. ExploreASL is self-contained, written in MATLAB and based on Statistical Parameter Mapping (SPM) and runs on multiple operating systems. To facilitate collaboration and data-exchange, the toolbox follows several standards and recommendations for data structure, provenance, and best analysis practice. ExploreASL was iteratively refined and tested in the analysis of >10,000 ASL scans using different pulse-sequences in a variety of clinical populations, resulting in four processing modules: Import, Structural, ASL, and Population that perform tasks, respectively, for data curation, structural and ASL image processing and quality control, and finally preparing the results for statistical analyses on both single-subject and group level. We illustrate ExploreASL processing results from three cohorts: perinatally HIV-infected children, healthy adults, and elderly at risk for neurodegenerative disease. We show the reproducibility for each cohort when processed at different centers with different operating systems and MATLAB versions, and its effects on the quantification of gray matter cerebral blood flow. ExploreASL facilitates the standardization of image processing and quality control, allowing the pooling of cohorts which may increase statistical power and discover between-group perfusion differences. Ultimately, this workflow may advance ASL for wider adoption in clinical studies, trials, and practice.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117031DOI Listing
October 2020

Cognitive Improvement After Kidney Transplantation Is Associated With Structural and Functional Changes on MRI.

Transplant Direct 2020 Mar 10;6(3):e531. Epub 2020 Feb 10.

Department of Nephrology, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, the Netherlands.

Background: Several studies have reported improved cognitive outcomes after kidney transplantation, but most studies either did not include controls or lacked extensive neuroimaging. In addition, there is uncertainty whether kidney donation is a safe procedure in terms of cognitive outcomes.

Methods: We prospectively studied neurocognitive function in kidney transplant recipients. The primary outcome was change in neurocognitive function after 1 year compared with baseline, which was evaluated using the Amsterdam Neuropsychological Task battery and verbal fluency tests. Secondary outcomes included changes in depression and anxiety (measured by the Hospital Anxiety and Depression scale) and changes in fatigue (measured by the Checklist for Individual Strength). We included kidney donors to control for learning effects, socioeconomic status, and surgery. In addition, kidney transplant recipients were evaluated with MRI scans at baseline and at year 1. The MRI protocol included conventional MRI, automated volumetric measurement, diffusion tensor imaging, magnetic resonance spectroscopy, arterial spin labeling, and a resting state functional MRI.

Results: Twenty-seven recipients and 24 donors were included. For both recipients and donors, neuropsychologic testing scores improved 1 year after transplantation (donation). Recipient improvement significantly exceeded donor improvement on tasks measuring attention and working memory. These improvements were associated with increases in white matter volume and -acetylaspartate/creatine (a marker for neuronal integrity).

Conclusions: Attention and working memory improve significantly 1 year after kidney transplantation. Learning effects do not account for these improvements because recipient improvement in these areas exceeds donor improvement and correlates with an improvement in white matter integrity after transplantation. Kidney donation appears to be a safe procedure in terms of cognitive outcomes.
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http://dx.doi.org/10.1097/TXD.0000000000000976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056275PMC
March 2020

Spatial versus angular resolution for tractography-assisted planning of deep brain stimulation.

Neuroimage Clin 2020 9;25:102116. Epub 2019 Dec 9.

Spinoza Centre for Neuroimaging, Meibergdreef 75, Amsterdam, the Netherlands; Department of Biomedical Engineering and Physics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands.

Given the restricted total scanning time for clinical neuroimaging, it is unclear whether clinical diffusion MRI protocols would benefit more from higher spatial resolution or higher angular resolution. In this work, we investigated the relative benefit of improving spatial or angular resolution in diffusion MRI to separate two parallel running white matter tracts that are targets for deep brain stimulation: the anterior thalamic radiation and the supero-lateral branch of the medial forebrain bundle. Both these tracts are situated in the ventral anterior limb of the internal capsule, and recent studies suggest that targeting a specific tract could improve treatment efficacy. Therefore, we scanned 19 healthy volunteers at 3T and 7T according to three diffusion MRI protocols with respectively standard clinical settings, increased spatial resolution of 1.4 mm, and increased angular resolution (64 additional gradient directions at b = 2200s/mm). We performed probabilistic tractography for all protocols and quantified the separability of both tracts. The higher spatial resolution protocol improved separability by 41% with respect to the clinical standard, presumably due to decreased partial voluming. The higher angular resolution protocol resulted in increased apparent tract volumes and overlap, which is disadvantageous for application in precise treatment planning. We thus recommend to increase the spatial resolution for deep brain stimulation planning to 1.4 mm while maintaining angular resolution. This recommendation complements the general advice to aim for high angular resolution to resolve crossing fibers, confirming that the specific application and anatomical considerations are leading in clinical diffusion MRI protocol optimization.
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http://dx.doi.org/10.1016/j.nicl.2019.102116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928456PMC
January 2021

Diagnostic accuracy of MRI and ultrasound in chronic immune-mediated neuropathies.

Neurology 2020 01 11;94(1):e62-e74. Epub 2019 Dec 11.

From the Departments of Radiology and Nuclear Medicine (J.O., S.D.R., M.P.E., M.W.A.C., M.M., A.J.N.), Neurology (F.E., I.N.v.S., M.d.V., C.V.), and Biomedical Engineering and Physics (G.J.S., M.W.A.C.), Amsterdam UMC, University of Amsterdam; Departments of Radiology (J.J.S.) and Neurology (P.A.v.D.), Erasmus Medical Center, Rotterdam; and Departments of Radiology (M.F.) and Neurology (H.S.G.), University Medical Center Utrecht, the Netherlands.

Objective: To assess and compare the diagnostic performance of qualitative and (semi-)quantitative MRI and ultrasound for distinguishing chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) from segmental spinal muscular atrophy (sSMA).

Methods: Patients with CIDP (n = 13), MMN (n = 10), or sSMA (n = 12) and healthy volunteers (n = 30) were included. MRI of the brachial plexus, using short tau inversion recovery (STIR), nerve-specific T2-weighted (magnetic resonance neurography [MRN]), and diffusion tensor imaging (DTI) sequences, was evaluated. Furthermore, with ultrasound, cross-sectional areas of the nerves were evaluated. Three radiologists blinded for diagnosis qualitatively scored hypertrophy and increased signal intensity (STIR and MRN), and intraobserver and interobserver agreement was assessed. For the (semi-)quantitative modalities, group differences and receiver operator characteristics were calculated.

Results: Hypertrophy and increased signal intensity were found in all groups including healthy controls. Intraobserver and interobserver agreements varied considerably (intraclass correlation coefficients 0.00-0.811 and 0.101-0.491, respectively). DTI showed significant differences ( < 0.05) among CIDP, MMN, sSMA, and controls for fractional anisotropy, axial diffusivity, and radial diffusivity in the brachial plexus. Ultrasound showed significant differences in cross-sectional area ( < 0.05) among CIDP, MMN, and sSMA in upper arm and brachial plexus. For distinguishing immune-mediated neuropathies (CIDP and MMN) from sSMA, ultrasound yielded the highest area under the curve (0.870).

Conclusion: Qualitative assessment of hypertrophy and signal hyperintensity on STIR or MRN is of limited value. DTI measures may discriminate among CIDP, MMN, and sSMA. Currently, ultrasound may be the most appropriate diagnostic imaging aid in the clinical setting.
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http://dx.doi.org/10.1212/WNL.0000000000008697DOI Listing
January 2020

Brain structure of perinatally HIV-infected patients on long-term treatment: A systematic review.

Neurol Clin Pract 2019 Oct;9(5):433-442

Emma Children's Hospital (MVH, AMtH, DP), Amsterdam University Medical Center, location Academic Medical Center, University of Amsterdam, Pediatric Infectious Diseases, Amsterdam, the Netherlands; Biomedical Engineering and Physics (MWAC), Amsterdam University Medical Center, location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Medical Library (RS), Amsterdam University Medical Center, location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Cochrane Netherlands (RS), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; and Emma Children's Hospital (JHL), Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Pediatric Clinical Research Office, Amsterdam, the Netherlands.

Objective: We aim to give an overview of the available evidence on brain structure and function in PHIV-infected patients (PHIV+) using long-term combination antiretroviral therapy (cART) and how differences change over time.

Methods: We conducted an electronic search using MEDLINE, Embase, and PsycINFO. We used the following selection criteria: cohort and cross-sectional studies that reported on brain imaging differences between PHIV+ of all ages who used cART for at least six months before neuroimaging and HIV-negative controls. Two reviewers independently selected studies, performed data extraction, and assessed quality of studies.

Results: After screening 1500 abstracts and 343 full-text articles, we identified 19 eligible articles. All included studies had a cross-sectional design and used MRI with different modalities: structural MRI (n = 7), diffusion tensor imaging (DTI) (n = 6), magnetic resonance spectroscopy (n = 5), arterial spin labeling (n = 1), and resting-state functional neuroimaging (n = 1). Studies showed considerable methodological limitations and heterogeneity, preventing us to perform meta-analyses. DTI data on white matter microstructure suggested poorer directional diffusion in cART-treated PHIV+ compared with controls. Other modalities were inconclusive.

Conclusion: Evidence may suggest brain structure and function differences in the population of PHIV+ on long-term cART compared with the HIV-negative population. Because of a small study population, and considerable heterogeneity and methodological limitations, the extent of brain structure and function differences on neuroimaging between groups remains unknown.
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http://dx.doi.org/10.1212/CPJ.0000000000000637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814418PMC
October 2019

Longitudinal diffusion MRI as surrogate outcome measure for myelopathy in adrenoleukodystrophy.

Neurology 2019 12 12;93(23):e2133-e2143. Epub 2019 Nov 12.

From the Department of Paediatric Neurology, Emma Children's Hospital (I.C.H., W.J.C.v.B., J.M.B.W.V., M.E.), Laboratory Genetic Metabolic Diseases (S.K.), and Department of Biomedical Engineering & Physics (M.W.A.C.), Amsterdam UMC, University of Amsterdam, the Netherlands.

Objective: To prospectively determine the potential of diffusion MRI (dMRI) of the cervical spinal cord and the corticospinal tracts in brain as surrogate outcome measure for progression of myelopathy in men with adrenoleukodystrophy, as better outcome measures to quantify progression of myelopathy would enable clinical trials with fewer patients and shorter follow-up.

Methods: Clinical assessment of myelopathy included Expanded Disability Status Scale (EDSS), Severity Scoring System for Progressive Myelopathy (SSPROM), Timed Up-and-Go, and 6-Minute Walk Test. Applied dMRI metrics included fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity.

Results: Data were available for 33 controls and 52 patients. First, cross-sectionally, differences between groups (controls vs patients; controls vs asymptomatic patients vs symptomatic patients) were statistically significant for fractional anisotropy, mean diffusivity, and radial diffusivity in spinal cord and brain corticospinal tracts (effect size 0.31-0.68). Correlations between dMRI metrics and clinical measures were moderate to strong (correlation coefficient 0.35-0.60). Second, longitudinally (n = 36), change on clinical measures was significant after 2-year follow-up for EDSS, SSPROM, and Timed Up-and-Go ( ≤ 0.021, effect size ≤0.14). Change on brain fractional anisotropy and radial diffusivity was slightly larger ( ≤ 0.002, effect sizes 0.16-0.28). In addition, a statistically significant change was detectable in asymptomatic patients using brain dMRI and not using the clinical measures. Change on clinical measures did not correlate to change on dMRI metrics.

Conclusion: Although effect sizes were small, our prospective data illustrate the potential of dMRI as surrogate outcome measure for progression of myelopathy in men with adrenoleukodystrophy.
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http://dx.doi.org/10.1212/WNL.0000000000008572DOI Listing
December 2019

White Matter by Diffusion MRI Following Methylphenidate Treatment: A Randomized Control Trial in Males with Attention-Deficit/Hyperactivity Disorder.

Radiology 2019 10 13;293(1):186-192. Epub 2019 Aug 13.

From the Departments of Radiology and Nuclear Medicine and Biomedical Engineering and Physics, Amsterdam University Medical Centers, location AMC, University of Amsterdam, G1-222 Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands (C.B., A.S., M.W.A.C., F.M.V., L.R.); Department of Imaging Physics, Delft University of Technology, Delft, the Netherlands (O.G.F., F.M.V.); and Amsterdam Neuroscience, Amsterdam, the Netherlands (A.S., L.R.).

BackgroundMethylphenidate (MPH) is highly effective in treating attention-deficit/hyperactivity disorder (ADHD). However, not much is known about its effect on the development of human brain white matter (WM).PurposeTo determine whether MPH modulates WM microstructure in an age-dependent fashion in a randomized double-blind placebo-controlled trial (Effects of Psychotropic Medication on Brain Development-Methylphenidate, or ePOD-MPH) among ADHD referral centers between October 13, 2011, and June 15, 2015, by using diffusion-tensor imaging (DTI).Materials and MethodsIn this prospective study (NTR3103 and NL34509.000.10), 50 stimulant treatment-naive boys and 49 young adult men diagnosed with ADHD (all types) according to criteria were randomized to undergo treatment with MPH or placebo for 16 weeks. Before and 1 week after treatment cessation, study participants underwent MRI, including DTI. The outcome measure was change in fractional anisotropy (FA), which was assessed in three regions of interest (ROIs), as well as in a voxel-based analysis in brain WM. Data were analyzed by using intention-to-treat linear mixed models for ROI analysis and a permutation-based method for voxel-based analysis with family-wise error correction.ResultsFifty boys ( = 25 MPH group, = 25 placebo group; age range, 10-12 years) and 48 men ( = 24 MPH group, = 24 placebo group; age range, 23-40 years) were included. ROI analysis of FA yielded no main effect of time in any of the conditions. However, voxel-based analysis revealed significant ( < .05) time-by-medication-by-age interaction effects in several association tracts of the left hemisphere, as well as in the lateral aspect of the truncus of the corpus callosum, due to greater increase in FA (standardized effect size, 5.25) in MPH-treated boys. Similar changes were not present in boys receiving a placebo, nor in adult men.ConclusionFour months of treatment with methylphenidate affects specific tracts in brain white matter in boys with attention-deficit/hyperactivity disorder. These effects seem to be age dependent, because they were not observed in adults treated with methylphenidate.© RSNA, 2019
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http://dx.doi.org/10.1148/radiol.2019182528DOI Listing
October 2019

Late-life brain perfusion after prenatal famine exposure.

Neurobiol Aging 2019 10 8;82:1-9. Epub 2019 Jul 8.

Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, the Netherlands; Department of Obstetrics and Gynaecology, Amsterdam UMC, the Netherlands.

Early nutritional deprivation may cause irreversible damage to the brain and seems to affect cognitive function in older age. We investigated whether prenatal undernutrition was associated with brain perfusion differences in older age. We acquired Arterial spin labeling scans in 118 Dutch famine birth cohort members. Using linear regression analyses, cerebral blood flow was compared between exposed and unexposed groups in gray matter (GM) and white matter (WM), perfusion territories, the neurodegeneration-related regions anterior and posterior cingulate cortex and precuneus. Furthermore, we compared the GM/WM ratio and the spatial coefficient of variation as a proxy of overall cerebrovascular health. The WM arterial spin labeling signal and the GM/WM ratio were significantly lower and higher, respectively, among exposed participants (-2.5 mL/100 g/min [95% CI: -4.3 to -0.8; p = 0.01] and 0.48 [0.19 to 0.76; p = 0.002], respectively). Exposed men had lower cerebral blood flow in anterior and posterior cingulate cortices (-8.0 mL/100 g/min [-15.1 to -0.9; p = 0.03]; -11.4 mL/100 g/min [-19.6 to -3.2; p = 0.02]) and higher spatial coefficient of variation (0.05 [0.00 to 0.09; p = 0.05]). The latter seemed largely mediated by higher 2h-glucose levels at age 50. Our findings suggest that prenatal undernutrition affects brain perfusion parameters providing further evidence for life-long effects of undernutrition during early brain development.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.06.012DOI Listing
October 2019

Distance to white matter tracts is associated with deep brain stimulation motor outcome in Parkinson's disease.

J Neurosurg 2019 Jul 26:1-10. Epub 2019 Jul 26.

1Department of Neurology and Clinical Neurophysiology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience.

Objective: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates motor symptoms in patients with Parkinson's disease (PD). However, the underlying mechanism of tremor suppression is not well understood. Stimulation of white matter tracts, such as the dentatorubrothalamic tract (DRT), might be involved. Also, side effects, including dysarthria, might result from (unwanted) stimulation of white matter tracts in proximity to the STN. The aim of this study was to establish an association between stimulation effect on tremor and dysarthria and stimulation location relative to relevant white matter tracts.

Methods: In 35 PD patients in whom a bilateral STN DBS system was implanted, the authors established clinical outcome measures per electrode contact. The distance from each stimulation location to the center of the DRT, corticopontocerebellar tract, pyramidal tract (PT), and medial lemniscus was determined using diffusion-weighted MRI data. Clinical outcome measures were subsequently related to the distances to the white matter tracts.

Results: Patients with activated contacts closer to the DRT showed increased tremor improvement. Proximity of activated contacts to the PT was associated with dysarthria.

Conclusions: Proximity to specific white matter tracts is associated with tremor outcome and side effects in DBS. This knowledge can help to optimize both electrode placement and postsurgical electrode contact selection. Presurgical white matter tract visualization may improve targeting and DBS outcome. These findings are of interest not only for treatment in PD, but potentially also for other (movement) disorders.
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http://dx.doi.org/10.3171/2019.5.JNS1952DOI Listing
July 2019

Validation of a Novel Multivariate Method of Defining HIV-Associated Cognitive Impairment.

Open Forum Infect Dis 2019 Jun 3;6(6):ofz198. Epub 2019 May 3.

Division of Infectious Diseases, Imperial College London, UK.

Background: The optimum method of defining cognitive impairment in virally suppressed people living with HIV is unknown. We evaluated the relationships between cognitive impairment, including using a novel multivariate method (NMM), patient- reported outcome measures (PROMs), and neuroimaging markers of brain structure across 3 cohorts.

Methods: Differences in the prevalence of cognitive impairment, PROMs, and neuroimaging data from the COBRA, CHARTER, and POPPY cohorts (total n = 908) were determined between HIV-positive participants with and without cognitive impairment defined using the HIV-associated neurocognitive disorders (HAND), global deficit score (GDS), and NMM criteria.

Results: The prevalence of cognitive impairment varied by up to 27% between methods used to define impairment (eg, 48% for HAND vs 21% for NMM in the CHARTER study). Associations between objective cognitive impairment and subjective cognitive complaints generally were weak. Physical and mental health summary scores (SF-36) were lowest for NMM-defined impairment ( < .05).There were no differences in brain volumes or cortical thickness between participants with and without cognitive impairment defined using the HAND and GDS measures. In contrast, those identified with cognitive impairment by the NMM had reduced mean cortical thickness in both hemispheres ( < .05), as well as smaller brain volumes ( < .01). The associations with measures of white matter microstructure and brain-predicted age generally were weaker.

Conclusion: Different methods of defining cognitive impairment identify different people with varying symptomatology and measures of brain injury. Overall, NMM-defined impairment was associated with most neuroimaging abnormalities and poorer self-reported health status. This may be due to the statistical advantage of using a multivariate approach.
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http://dx.doi.org/10.1093/ofid/ofz198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590980PMC
June 2019

Recurrent inference machines for reconstructing heterogeneous MRI data.

Med Image Anal 2019 04 18;53:64-78. Epub 2019 Jan 18.

Informatics Institute at the University of Amsterdam, Amsterdam 1098 XH, the Netherlands; AMLab, Amsterdam, 1098 XH, the Netherlands.

Deep learning allows for accelerated magnetic resonance image (MRI) reconstruction, thereby shortening measurement times. Rather than using sparsifying transforms, a prerequisite in Compressed Sensing (CS), suitable MRI prior distributions are learned from data. In clinical practice, both the underlying anatomy as well as image acquisition settings vary. For this reason, deep neural networks must be able to reapply what they learn across different measurement conditions. We propose to use Recurrent Inference Machines (RIM) as a framework for accelerated MRI reconstruction. RIMs solve inverse problems in an iterative and recurrent inference procedure by repeatedly reassessing the state of their reconstruction, and subsequently making incremental adjustments to it in accordance with the forward model of accelerated MRI. RIMs learn the inferential process of reconstructing a given signal, which, in combination with the use of internal states as part of their recurrent architecture, makes them less dependent on learning the features pertaining to the source of the signal itself. This gives RIMs a low tendency to overfit, and a high capacity to generalize to unseen types of data. We demonstrate this ability with respect to anatomy by reconstructing brain and knee scans, as well as other MRI acquisition settings, by reconstructing scans of different contrast and resolution, at different field strength, subjected to varying acceleration levels. We show that RIMs outperform CS not only with respect to quality metrics, but also according to a rating given by an experienced neuroradiologist in a double blinded experiment. Finally, we show with qualitative results that our model can be applied to prospectively under-sampled raw data, as acquired by pre-installed acquisition protocols.
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http://dx.doi.org/10.1016/j.media.2019.01.005DOI Listing
April 2019

MP2RAGEME: T , T , and QSM mapping in one sequence at 7 tesla.

Hum Brain Mapp 2019 04 13;40(6):1786-1798. Epub 2018 Dec 13.

Spinoza Centre for Neuroimaging, Amsterdam, The Netherlands.

Quantitative magnetic resonance imaging generates images of meaningful physical or chemical variables measured in physical units that allow quantitative comparisons between tissue regions and among subjects scanned at the same or different sites. Here, we show that we can acquire quantitative T , T , and quantitative susceptibility mapping (QSM) information in a single acquisition, using a multi-echo (ME) extension of the second gradient-echo image of the MP2RAGE sequence. This combination is called MP2RAGE ME, or MP2RAGEME. The simultaneous acquisition results in large time savings, perfectly coregistered data, and minimal image quality differences compared to separately acquired data. Following a correction for residual transmit B -sensitivity, quantitative T , T , and QSM values were in excellent agreement with those obtained from separately acquired, also B -corrected, MP2RAGE data and ME gradient echo data. The quantitative values from reference regions of interests were also in very good correspondence with literature values. From the MP2RAGEME data, we further derived a multiparametric cortical parcellation, as well as a combined arterial and venous map. In sum, our MP2RAGEME sequence has the benefit in large time savings, perfectly coregistered data and minor image quality differences.
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http://dx.doi.org/10.1002/hbm.24490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590660PMC
April 2019

The 'COmorBidity in Relation to AIDS' (COBRA) cohort: Design, methods and participant characteristics.

PLoS One 2018 29;13(3):e0191791. Epub 2018 Mar 29.

Academisch Medisch Centrum, Universiteit van Amsterdam, Amsterdam, The Netherlands.

Background: Persons living with HIV on combination antiretroviral therapy (cART) may be at increased risk of the development of age-associated non-communicable comorbidities (AANCC) at relatively young age. It has therefore been hypothesised that such individuals, despite effective cART, may be prone to accelerated aging.

Objective: The COmorBidity in Relation to AIDS (COBRA) cohort study was designed to investigate the potential causal link between HIV and AANCC, amongst others, in a cohort of middle-aged individuals with HIV with sustained viral suppression on cART and otherwise comparable HIV-negative controls.

Methods: Longitudinal cohort study of HIV-positive subjects ≥45 years of age, with sustained HIV suppression on cART recruited from two large European HIV treatment centres and similarly-aged HIV-negative controls recruited from sexual health centres and targeted community groups. Both HIV-positive and HIV-negative subjects were assessed at study entry and again at follow-up after 2 years.

Results: Of the 134 HIV-positive individuals with a median (IQR) age of 56 (51, 62) years recruited, 93% were male, 88% of white ethnicity and 86% were men who have sex with men (MSM). Similarly, the 79 HIV-negative subjects had a median (IQR) age of 57 (52, 64) and 92% were male, 97% of white ethnicity and 80% were MSM.

Conclusions: The results from the COBRA study will be a significant resource to understand the link between HIV and AANCC and the pathogenic mechanisms underlying this link. COBRA will inform future development of novel prognostic tools for earlier diagnosis of AANCC and of novel interventions which, as an adjunct to cART, may prevent AANCC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191791PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875743PMC
June 2018

ADHD and maturation of brain white matter: A DTI study in medication naive children and adults.

Neuroimage Clin 2018 29;17:53-59. Epub 2017 Sep 29.

Department of Radiology and Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Brain Imaging Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, The Netherlands. Electronic address:

Several diffusion tensor imaging (DTI) studies in attention deficit hyperactivity disorder (ADHD) have shown a delay in brain white matter (WM) development. Because these studies were mainly conducted in children and adolescents, these WM abnormalities have been assumed, but not proven to progress into adulthood. To provide further insight in the natural history of WM maturation delay in ADHD, we here investigated the modulating effect of age on WM in children and adults. 120 stimulant-treatment naive male ADHD children (10-12 years of age) and adults (23-40 years of age) with ADHD (according to DSM-IV; all subtypes) were included, along with 23 age and gender matched controls. Fractional anisotropy (FA) values were compared throughout the WM by means of tract-based spatial statistics (TBSS) and in specific regions of interest (ROIs). On both TBSS and ROI analyses, we found that stimulant-treatment naive ADHD children did not differ in FA values from control children, whereas adult ADHD subjects had reduced FA values when compared to adult controls in several regions. Significant age × group interactions for whole brain FA (p = 0.015), as well as the anterior thalamic radiation (p = 0.015) suggest that ADHD affects the brain WM age-dependently. In contrast to prior studies conducted in medicated ADHD children, we did not find WM alterations in stimulant treatment naïve children, only treatment-naïve adults. Thus, our findings suggest that the reported developmental delay in WM might appear after childhood, and that previously reported differences between ADHD children and normal developing peers could have been attributed to prior ADHD medications, and/or other factors that affect WM development, such as age and gender.
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http://dx.doi.org/10.1016/j.nicl.2017.09.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842546PMC
February 2019

No Evidence for Accelerated Aging-Related Brain Pathology in Treated Human Immunodeficiency Virus: Longitudinal Neuroimaging Results From the Comorbidity in Relation to AIDS (COBRA) Project.

Clin Infect Dis 2018 06;66(12):1899-1909

Computational, Cognitive and Computational Neuroimaging Laboratory, Division of Brain Sciences, Imperial College London.

Background: Despite successful antiretroviral therapy, people living with human immunodeficiency virus (PLWH) experience higher rates of age-related morbidity, including abnormal brain structure, brain function, and cognitive impairment. This has raised concerns that PLWH may experience accelerated aging-related brain pathology.

Methods: We performed a multicenter longitudinal study of 134 virologically suppressed PLWH (median age, 56.0 years) and 79 demographically similar human immunodeficiency virus (HIV)-negative controls (median age, 57.2 years). To measure cognitive performance and brain pathology, we conducted detailed neuropsychological assessments and multimodality neuroimaging (T1-weighted, T2-weighted, diffusion magnetic resonance imaging [MRI], resting-state functional MRI, spectroscopy, arterial spin labeling) at baseline and at 2 years. Group differences in rates of change were assessed using linear mixed effects models.

Results: One hundred twenty-three PLWH and 78 HIV-negative controls completed longitudinal assessments (median interval, 1.97 years). There were no differences between PLWH and HIV-negative controls in age, sex, years of education, smoking or alcohol use. At baseline, PLWH had poorer global cognitive performance (P < .01), lower gray matter volume (P = .04), higher white matter hyperintensity load (P = .02), abnormal white matter microstructure (P < .005), and greater brain-predicted age difference (P = .01). Longitudinally, there were no significant differences in rates of change in any neuroimaging measure between PLWH and HIV-negative controls (P > .1). Cognitive performance was longitudinally stable in both groups.

Conclusions: We found no evidence that middle-aged PLWH, when receiving successful treatment, are at increased risk of accelerated aging-related brain changes or cognitive decline over 2 years.
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http://dx.doi.org/10.1093/cid/cix1124DOI Listing
June 2018

Structural Brain Abnormalities in Successfully Treated HIV Infection: Associations With Disease and Cerebrospinal Fluid Biomarkers.

J Infect Dis 2017 12;217(1):69-81

Department of Global Health, Academic Medical Center, and Amsterdam Institute for Global Health and Development, Amsterdam, the Netherlands.

Background: Brain structural abnormalities have been reported in persons living with human immunodeficiency virus (HIV; PLWH) who are receiving suppressive combination antiretroviral therapy (cART), but their pathophysiology remains unclear.

Methods: We investigated factors associated with brain tissue volumes and white matter microstructure (fractional anisotropy) in 134 PLWH receiving suppressive cART and 79 comparable HIV-negative controls, aged ≥45 years, from the Comorbidity in Relation to AIDS cohort, using multimodal neuroimaging and cerebrospinal fluid biomarkers.

Results: Compared with controls, PLWH had lower gray matter volumes (-13.7 mL; 95% confidence interval, -25.1 to -2.2) and fractional anisotropy (-0.0073; 95% confidence interval, -.012 to -.0024), with the largest differences observed in those with prior clinical AIDS. Hypertension and the soluble CD14 concentration in cerebrospinal fluid were associated with lower fractional anisotropy. These associations were independent of HIV serostatus (Pinteraction = .32 and Pinteraction = .59, respectively) and did not explain the greater abnormalities in brain structure in relation to HIV infection.

Conclusions: The presence of lower gray matter volumes and more white matter microstructural abnormalities in well-treated PLWH partly reflect a combination of historical effects of AIDS, as well as the more general influence of systemic factors, such as hypertension and ongoing neuroinflammation. Additional mechanisms explaining the accentuation of brain structure abnormalities in treated HIV infection remain to be identified.
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http://dx.doi.org/10.1093/infdis/jix553DOI Listing
December 2017

Predicting brain age with deep learning from raw imaging data results in a reliable and heritable biomarker.

Neuroimage 2017 12 29;163:115-124. Epub 2017 Jul 29.

Department of Biomedical Engineering, King's College London, London, UK; Department of Mathematics, Imperial College London, London, UK. Electronic address:

Machine learning analysis of neuroimaging data can accurately predict chronological age in healthy people. Deviations from healthy brain ageing have been associated with cognitive impairment and disease. Here we sought to further establish the credentials of 'brain-predicted age' as a biomarker of individual differences in the brain ageing process, using a predictive modelling approach based on deep learning, and specifically convolutional neural networks (CNN), and applied to both pre-processed and raw T1-weighted MRI data. Firstly, we aimed to demonstrate the accuracy of CNN brain-predicted age using a large dataset of healthy adults (N = 2001). Next, we sought to establish the heritability of brain-predicted age using a sample of monozygotic and dizygotic female twins (N = 62). Thirdly, we examined the test-retest and multi-centre reliability of brain-predicted age using two samples (within-scanner N = 20; between-scanner N = 11). CNN brain-predicted ages were generated and compared to a Gaussian Process Regression (GPR) approach, on all datasets. Input data were grey matter (GM) or white matter (WM) volumetric maps generated by Statistical Parametric Mapping (SPM) or raw data. CNN accurately predicted chronological age using GM (correlation between brain-predicted age and chronological age r = 0.96, mean absolute error [MAE] = 4.16 years) and raw (r = 0.94, MAE = 4.65 years) data. This was comparable to GPR brain-predicted age using GM data (r = 0.95, MAE = 4.66 years). Brain-predicted age was a heritable phenotype for all models and input data (h ≥ 0.5). Brain-predicted age showed high test-retest reliability (intraclass correlation coefficient [ICC] = 0.90-0.99). Multi-centre reliability was more variable within high ICCs for GM (0.83-0.96) and poor-moderate levels for WM and raw data (0.51-0.77). Brain-predicted age represents an accurate, highly reliable and genetically-influenced phenotype, that has potential to be used as a biomarker of brain ageing. Moreover, age predictions can be accurately generated on raw T1-MRI data, substantially reducing computation time for novel data, bringing the process closer to giving real-time information on brain health in clinical settings.
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http://dx.doi.org/10.1016/j.neuroimage.2017.07.059DOI Listing
December 2017

Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with -mutated or -mutated solid tumours.

BMJ Open 2017 06 10;7(6):e014961. Epub 2017 Jun 10.

Department of Medical Oncology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands.

Introduction: High-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome. This is due to the lack of effective treatment options, emphasising the need for novel therapies. Mutations in the genes and (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. -mutated cancer cells produce the oncometabolite -2-hydroxyglutarate (-2HG) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine.

Methods And Analysis: We describe a dose-finding phase Ib/II clinical trial, in which patients with -mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma are treated with a combination of metformin and chloroquine. Dose escalation is performed according to a 3+3 dose-escalation scheme. The primary objective is to determine the maximum tolerated dose to establish the recommended dose for a phase II clinical trial. Secondary objectives of the study include (1) determination of pharmacokinetics and toxic effects of the study therapy, for which metformin and chloroquine serum levels will be determined over time; (2) investigation of tumour responses to metformin plus chloroquine in -mutated cancers using CT/MRI scans; and (3) whether tumour responses can be measured by non-invasive -2HG measurements (mass spectrometry and magnetic resonance spectroscopy) of tumour tissue, serum, urine, and/or bile or next-generation sequencing of circulating tumour DNA (liquid biopsies). This study may open a novel treatment avenue for -mutated high-grade chondrosarcoma, glioma and intrahepatic cholangiocarcinoma by repurposing the combination of two inexpensive drugs that are already approved for other indications.

Ethics And Dissemination: This study has been approved by the medical-ethical review committee of the Academic Medical Center, Amsterdam, The Netherlands. The report will be submitted to a peer-reviewed journal.

Trial Registration Number: This article was registered at ClinicalTrials.gov identifier (NCT02496741): Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2016-014961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541450PMC
June 2017

Effect of Long-Term Vascular Care on Progression of Cerebrovascular Lesions: Magnetic Resonance Imaging Substudy of the PreDIVA Trial (Prevention of Dementia by Intensive Vascular Care).

Stroke 2017 07 8;48(7):1842-1848. Epub 2017 Jun 8.

From the Department of Neurology (J.W.v.D., W.A.v.G., E.R.), Department of General Practice (E.P.M.v.C.), and Department of Radiology (M.W.A.C., C.B.L.M.M., A.J.N.), Academic Medical Center, Amsterdam, the Netherlands; Department of Neurology, VU Medical Center, Alzheimer Center, Amsterdam, the Netherlands (P.S.); Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands (E.R.).

Background And Purpose: This study aimed to evaluate the effect of a nurse-led multidomain cardiovascular intervention on white matter hyperintensity (WMH) progression and incident lacunar infarcts in community-dwelling elderly with hypertension.

Methods: The preDIVA trial (Prevention of Dementia by Intensive Vascular Care) was an open-label, cluster-randomized controlled trial in community-dwelling individuals aged 70 to 78 years. General practices were assigned by computer-generated randomization to 6-year nurse-led, multidomain intensive vascular care or standard care. Of 3526 preDIVA participants, 195 nondemented participants with a systolic blood pressure ≥140 mm Hg were consecutively recruited to undergo magnetic resonance imaging at 2 to 3 and 5 to 6 years after baseline. WMH volumes were measured automatically, lacunar infarcts assessed visually, blinded to treatment allocation.

Results: One hundred and twenty-six participants were available for longitudinal analysis (64 intervention and 62 control). Annual WMH volume increase in milliliter was similar for intervention (mean=0.73, SD=0.84) and control (mean=0.70, SD=0.59) participants (adjusted mean difference, -0.08 mL; 95% confidence interval, -0.30 to 0.15; =0.50). Analyses suggested greater intervention effects with increasing baseline WMH volumes ( for interaction=0.03). New lacunar infarcts developed in 6 (9%) intervention and 2 (3%) control participants (odds ratio, 2.2; 95% confidence interval, 0.4-12.1; =0.36).

Conclusions: Nurse-led vascular care in hypertensive community-dwelling older persons did not diminish WMH accumulation over 3 years. However, our results do suggest this type of intervention could be effective in persons with high WMH volumes. There was no effect on lacunar infarcts incidence but numbers were low.

Clinical Trial Information: URL: http://www.isrctn.com/ISRCTN29711771. Unique identifier: ISRCTN29711771.
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http://dx.doi.org/10.1161/STROKEAHA.117.017207DOI Listing
July 2017

Impact of Structural Cerebral Damage in Adults With Tetralogy of Fallot.

Circulation 2017 05;135(19):1873-1875

From Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands (M.A.S., B.J.B., M.G., B.J.M.M.); Interuniversity Cardiology Institute of the Netherlands, Utrecht (M.A.S., B.J.M.M.); Department of Neurology, Academic Medical Center, Amsterdam, The Netherlands (E.R., J.W.v.D., L.L.v.W.); Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands (E.R.); Department of Medical Psychology, (L.L.v.W., B.A.S.), Department of Radiology (M.G., M.W.A.C., A.J.N., H.-J.M.M.M., C.B.L.M.M.), Academic Medical Center, Amsterdam, The Netherlands; Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Canada (H.-J.M.M.M.); and Department of Psychology, University of Amsterdam, The Netherlands (B.A.S.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.027865DOI Listing
May 2017

Increased brain-predicted aging in treated HIV disease.

Neurology 2017 Apr 3;88(14):1349-1357. Epub 2017 Mar 3.

From the Computational, Cognitive & Clinical Neuroimaging Laboratory, Division of Brain Sciences, Department of Medicine (J.H.C., R.L., D.J.S.), and Division of Infectious Diseases (J.U., A.W.), Imperial College London, UK; Departments of Radiology (M.W.A.C., C.B.L.M.M.), Global Health, Amsterdam Institute for Global Health and Development (AIGHD) (R.A.v.Z., F.W.N.M.W., P.R.), Neurology (P.P., B.A.S.), and Medical Psychology (G.J.G., B.A.S.), Academic Medical Center, Amsterdam, the Netherlands; Department of Infection & Population Health (D.D.F., C.A.S.), University College London, UK; Dutch HIV Monitoring Foundation (F.W.N.M.W., P.R.); Department of Neurology (P.P.), OLVG Hospital; Public Health Service of Amsterdam (M.F.S.v.d.L.), the Netherlands; and Alma Mater Studiorum (C.F.), University of Bologna, Italy.

Objective: To establish whether HIV disease is associated with abnormal levels of age-related brain atrophy, by estimating apparent brain age using neuroimaging and exploring whether these estimates related to HIV status, age, cognitive performance, and HIV-related clinical parameters.

Methods: A large sample of virologically suppressed HIV-positive adults (n = 162, age 45-82 years) and highly comparable HIV-negative controls (n = 105) were recruited as part of the Comorbidity in Relation to AIDS (COBRA) collaboration. Using T1-weighted MRI scans, a machine-learning model of healthy brain aging was defined in an independent cohort (n = 2,001, aged 18-90 years). Neuroimaging data from HIV-positive and HIV-negative individuals were then used to estimate brain-predicted age; then brain-predicted age difference (brain-PAD = brain-predicted brain age - chronological age) scores were calculated. Neuropsychological and clinical assessments were also carried out.

Results: HIV-positive individuals had greater brain-PAD score (mean ± SD 2.15 ± 7.79 years) compared to HIV-negative individuals (-0.87 ± 8.40 years; = 3.48, < 0.01). Increased brain-PAD score was associated with decreased performance in multiple cognitive domains (information processing speed, executive function, memory) and general cognitive performance across all participants. Brain-PAD score was not associated with age, duration of HIV infection, or other HIV-related measures.

Conclusion: Increased apparent brain aging, predicted using neuroimaging, was observed in HIV-positive adults, despite effective viral suppression. Furthermore, the magnitude of increased apparent brain aging related to cognitive deficits. However, predicted brain age difference did not correlate with chronological age or duration of HIV infection, suggesting that HIV disease may accentuate rather than accelerate brain aging.
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http://dx.doi.org/10.1212/WNL.0000000000003790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379929PMC
April 2017

Higher subcortical and white matter cerebral blood flow in perinatally HIV-infected children.

Medicine (Baltimore) 2017 Feb;96(7):e5891

Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital/Academic Medical Center, University of Amsterdam Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Cognitive Neurology Research Unit, Sunnybrook Health Sciences Center, Toronto, Canada Department of Global Health, Academic Medical Center, University of Amsterdam, and Amsterdam Institute for Global Health and Development Department of Internal Medicine, Division of Infectious Diseases, Center for Infection and Immunity Amsterdam, Academic Medical Center HIV Monitoring Foundation, Amsterdam, The Netherlands.

This study aimed to evaluate cerebral blood flow (CBF) in pediatric human immunodeficiency virus (HIV)-infection, and its role in HIV-related cerebral injury and cognitive impairment.This cross-sectional observational study compared 28 perinatally HIV-infected children (8-18 years) to 34 healthy controls matched for age, sex, ethnicity, and socio-economic status. All participants underwent 3-Tesla magnetic resonance imaging, using arterial spin labeling to assess CBF in gray matter (GM), white matter (WM), basal ganglia, and thalamus. We used linear regression analysis to evaluate group differences and associations with HIV disease and treatment characteristics, macrostructural (volume loss, WM lesions) or microstructural injury (increased WM diffusivity, neurometabolite alterations), or poorer cognitive performance.HIV-infected children had higher CBF in WM (+10.2%; P = 0.042), caudate nucleus (+4.8%; P = 0.002), putamen (+3.6%; P = 0.017), nucleus accumbens (+3.9%; P = 0.031), and thalamus (+5.5%; P = 0.032). Thalamus CBF was highest in children with a Centers for Disease Control and Prevention stage B (Coef. = 6.45; P = 0.005) or C (Coef. = 8.52; P = 0.001) diagnosis. Lower GM CBF was associated with higher WM lesion volume in HIV-infected children (Coef. = -0.053; P = 0.001). No further associations with HIV-related cognitive impairment or cerebral injury were found.CBF was higher in WM, basal ganglia, and thalamus in combination antiretroviral therapy (cART)-treated perinatally HIV-infected children, but this was not associated with cerebral injury or cognitive impairment. HIV-infected children with lower GM CBF had a higher volume of WM lesions, which could reflect vascular disease as potential contributing factor to white matter injury. Lifelong exposure to HIV and cART in this population warrants longitudinal assessment of CBF and how it relates to (neuro)inflammation, vascular dysfunction, and cerebral injury in pediatric HIV.
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http://dx.doi.org/10.1097/MD.0000000000005891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319495PMC
February 2017

Cerebral blood flow and cognitive function in HIV-infected men with sustained suppressed viremia on combination antiretroviral therapy.

AIDS 2017 03;31(6):847-856

aDepartment of Radiology bDepartment of Global Health, Academic Medical Center, Amsterdam Institute for Global Health and Development (AIGHD) cCenter for Infection and Immunity Amsterdam (CINIMA), Division of Infectious Diseases, Department of Internal Medicine dDepartment of Neurology eDepartment of Medical Psychology, Academic Medical Center, Amsterdam, The Netherlands fThe Computational, Cognitive, and Clinical Neuroimaging Laboratory, Department of Medicine, Imperial College London, London, UK gPublic Health Service Amsterdam, Infectious Diseases Research, Amsterdam hDepartment of Neurology, Radboud University Medical Centre, Nijmegen iDepartment of Neurology, Onze Lieve Vrouwe Gasthuis (OLVG Hospital) jHIV Monitoring Foundation, Amsterdam, The Netherlands.

Objective: To assess if HIV-infected patients on long-term successful combination antiretroviral therapy show cerebral blood flow (CBF) alterations in comparison with HIV-uninfected, otherwise similar controls. To explore whether such alterations are associated with HIV-associated cognitive impairment and to explore potential determinants of CBF alterations in HIV.

Design: Cross-sectional comparison of CBF in an observational cohort study.

Methods: Clinical, cognitive and MRI data of 100 middle-aged aviremic HIV-infected men on combination antiretroviral therapy and 69 HIV-uninfected controls were collected and compared. From pseudocontinuous arterial spin labeling MRI data, CBF-maps were calculated. The associations of mean gray matter CBF with clinical and cognitive parameters were explored in regression models, followed by a spatial delineation in a voxel-based analysis.

Results: CBF was decreased in HIV-infected patients compared with HIV-uninfected controls (P = 0.02), adjusted for age, ecstasy use and waist circumference. Spatially distinct and independent effects of total gray matter volume and HIV-serostatus on CBF were found. Within the HIV-infected group, decreased CBF was associated with increased triglyceride levels (P = 0.005) and prior clinical AIDS (P = 0.03). No association between CBF and cognitive impairment was found.

Conclusion: Decreased CBF was observed among HIV-infected patients, which was associated with both vascular risk factors as well as with measures of past immune deficiency. These results provide support for increased vascular disease in HIV-infected patients as represented by hemodynamic alteration, but without overt cognitive consequences within the current cohort of patients on long-term successful treatment.
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http://dx.doi.org/10.1097/QAD.0000000000001414DOI Listing
March 2017

Dynamic contrast-enhanced magnetic resonance imaging of the wrist in children with juvenile idiopathic arthritis.

Pediatr Radiol 2017 Feb 12;47(2):205-213. Epub 2016 Dec 12.

Department of Radiology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Background: Dynamic contrast-enhanced MRI provides information on the heterogeneity of the synovium, the primary target of disease in children with juvenile idiopathic arthritis (JIA).

Objective: To evaluate the feasibility of dynamic contrast-enhanced MRI in the wrist of children with JIA using conventional descriptive measures and time-intensity-curve shape analysis. To explore the association between enhancement characteristics and clinical disease status.

Materials And Methods: Thirty-two children with JIA and wrist involvement underwent dynamic contrast-enhanced MRI with movement-registration and were classified using validated criteria as clinically active (n = 27) or inactive (n = 5). Outcome measures included descriptive parameters and the classification into time-intensity-curve shapes, which represent the patterns of signal intensity change over time. Differences in dynamic contrast-enhanced MRI outcome measures between clinically active and clinically inactive disease were analyzed and correlation with the Juvenile Arthritis Disease Activity Score was determined.

Results: Comprehensive evaluation of disease status was technically feasible and the quality of the dynamic dataset was improved by movement registration. The conventional descriptive measure maximum enhancement differed significantly between clinically active and inactive disease (P = 0.019), whereas time-intensity-curve shape analysis showed no differences. Juvenile Arthritis Disease Activity Score correlated moderately with enhancing volume (P = 0.484).

Conclusion: Dynamic contrast-enhanced MRI is a promising biomarker for evaluating disease status in children with JIA and wrist involvement. Conventional descriptive dynamic contrast-enhanced MRI measures are better associated with clinically active disease than time-intensity-curve shape analysis.
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http://dx.doi.org/10.1007/s00247-016-3736-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5250661PMC
February 2017

Cortical Morphology Differences in Subjects at Increased Vulnerability for Developing a Psychotic Disorder: A Comparison between Subjects with Ultra-High Risk and 22q11.2 Deletion Syndrome.

PLoS One 2016 9;11(11):e0159928. Epub 2016 Nov 9.

Department of Psychiatry & Psychology, University of Maastricht, Maastricht, The Netherlands.

Introduction: Subjects with 22q11.2 deletion syndrome (22q11DS) and subjects with ultra-high risk for psychosis (UHR) share a risk of approximately 30% to develop a psychotic disorder. Studying these groups helps identify biological markers of pathophysiological processes involved in the development of psychosis. Total cortical surface area (cSA), total cortical grey matter volume (cGMV), cortical thickness (CT), and local gyrification index (LGI) of the cortical structure have a distinct neurodevelopmental origin making them important target markers to study in relation to the development of psychosis.

Materials And Methods: Structural T1-weighted high resolution images were acquired using a 3 Tesla Intera MRI system in 18 UHR subjects, 18 22q11DS subjects, and 24 matched healthy control (HC) subjects. Total cSA, total cGMV, mean CT, and regional vertex-wise differences in CT and LGI were assessed using FreeSurfer software. The Positive and Negative Syndrome Scale was used to assess psychotic symptom severity in UHR and 22q11DS subjects at time of scanning.

Results: 22q11DS subjects had lower total cSA and total cGMV compared to UHR and HC subjects. The 22q11DS subjects showed bilateral lower LGI in the i) prefrontal cortex, ii) precuneus, iii) precentral gyrus and iv) cuneus compared to UHR subjects. Additionally, lower LGI was found in the left i) fusiform gyrus and right i) pars opercularis, ii) superior, and iii) inferior temporal gyrus in 22q11DS subjects compared to HC. In comparison to 22q11DS subjects, the UHR subjects had lower CT of the insula. For both risk groups, positive symptom severity was negatively correlated to rostral middle frontal gyrus CT.

Conclusion: A shared negative correlation between positive symptom severity and rostral middle frontal gyrus CT in UHR and 22q11DS may be related to their increased vulnerability to develop a psychotic disorder. 22q11DS subjects were characterised by widespread lower degree of cortical gyrification linked to early and postnatal neurodevelopmental pathology. No implications for early neurodevelopmental pathology were found for the UHR subjects, although they did have distinctively lower insula CT which may have arisen from defective pruning processes during adolescence. Implications of these findings in relation to development of psychotic disorders are in need of further investigation in longitudinal studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0159928PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102447PMC
July 2017