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F. Barkhof

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YNICL Journal 2021 Journal Article

FLAIR-only joint volumetric analysis of brain lesions and atrophy in clinically isolated syndrome (CIS) suggestive of multiple sclerosis

  • O. Goodkin
  • F. Prados
  • S.B. Vos
  • H. Pemberton
  • S. Collorone
  • M.H.J. Hagens
  • M.J. Cardoso
  • T.A. Yousry

BACKGROUND: MRI assessment in multiple sclerosis (MS) focuses on the presence of typical white matter (WM) lesions. Neurodegeneration characterised by brain atrophy is recognised in the research field as an important prognostic factor. It is not routinely reported clinically, in part due to difficulty in achieving reproducible measurements. Automated MRI quantification of WM lesions and brain volume could provide important clinical monitoring data. In general, lesion quantification relies on both T1 and FLAIR input images, while tissue volumetry relies on T1. However, T1-weighted scans are not routinely included in the clinical MS protocol, limiting the utility of automated quantification. OBJECTIVES: We address an aspect of this important translational challenge by assessing the performance of FLAIR-only lesion and brain segmentation, against a conventional approach requiring multi-contrast acquisition. We explore whether FLAIR-only grey matter (GM) segmentation yields more variability in performance compared with two-channel segmentation; whether this is related to field strength; and whether the results meet a level of clinical acceptability demonstrated by the ability to reproduce established biological associations. METHODS: We used a multicentre dataset of subjects with a CIS suggestive of MS scanned at 1.5T and 3T in the same week. WM lesions were manually segmented by two raters, 'manual 1' guided by consensus reading of CIS-specific lesions and 'manual 2' by any WM hyperintensity. An existing brain segmentation method was adapted for FLAIR-only input. Automated segmentation of WM hyperintensity and brain volumes were performed with conventional (T1/T1 + FLAIR) and FLAIR-only methods. RESULTS: = 0.998, SE = 0.006). Age-associated change in cortical GM volume was a significant covariate in both T1 (p = 0.001) and FLAIR-only (p = 0.005) methods, confirming the expected relationship between age and GM volume for FLAIR-only segmentations. CONCLUSIONS: FLAIR-only automated segmentation of WM lesions and brain volumes were consistent with results obtained through conventional methods and had the ability to demonstrate biological effects in our study population. Imaging protocol harmonisation and validation with other MS phenotypes could facilitate the integration of automated WM lesion volume and brain atrophy analysis as clinical tools in radiological MS reporting.

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YNICL Journal 2020 Journal Article

Tau PET and relative cerebral blood flow in dementia with Lewy bodies: A PET study

  • E.E. Wolters
  • M. van de Beek
  • R. Ossenkoppele
  • S.S.V. Golla
  • S.C.J. Verfaillie
  • E.M. Coomans
  • T Timmers
  • D. Visser

PURPOSE: F]flortaucipir PET scan we derived measures of both tau binding and relative cerebral blood flow (rCBF). We tested whether regional tau binding or rCBF differed between DLB patients and AD patients and controls and examined their association with clinical characteristics of DLB. METHODS: and performance on ten neuropsychological tests. RESULTS: was associated to worse performance on VOSP fragmented letters (stβ = 0.61), all p < 0.05. CONCLUSION: The amount of tau binding in DLB was minimal and did not differ from controls. However, there were DLB-specific occipital and lateral parietal relative cerebral blood flow reductions compared to both controls and AD patients. Regional rCBF, but not tau binding, was related to cognitive impairment. This indicates that assessment of rCBF may give more insight into disease mechanisms in DLB than tau PET.

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YNICL Journal 2019 Journal Article

Comparing lesion segmentation methods in multiple sclerosis: Input from one manually delineated subject is sufficient for accurate lesion segmentation

  • M.M. Weeda
  • I. Brouwer
  • M.L. de Vos
  • M.S. de Vries
  • F. Barkhof
  • P.J.W. Pouwels
  • H. Vrenken

PURPOSE: Accurate lesion segmentation is important for measurements of lesion load and atrophy in subjects with multiple sclerosis (MS). International MS lesion challenges show a preference of convolutional neural networks (CNN) strategies, such as nicMSlesions. However, since the software is trained on fairly homogenous training data, we aimed to test the performance of nicMSlesions in an independent dataset with manual and other automatic lesion segmentations to determine whether this method is suitable for larger, multi-center studies. METHODS: Manual lesion segmentation was performed in fourteen subjects with MS on sagittal 3D FLAIR images from a 3T GE whole-body scanner with 8-channel head coil. We compared five different categories of automated lesion segmentation methods for their volumetric and spatial agreement with manual segmentation: (i) unsupervised, untrained (LesionTOADS); (ii) supervised, untrained (LST-LPA and nicMSlesions with default settings); (iii) supervised, untrained with threshold adjustment (LST-LPA optimized for current data); (iv) supervised, trained with leave-one-out cross-validation on fourteen subjects with MS (nicMSlesions and BIANCA); and (v) supervised, trained on a single subject with MS (nicMSlesions). Volumetric accuracy was determined by the intra-class correlation coefficient (ICC) and spatial accuracy by Dice's similarity index (SI). Volumes and SI were compared between methods using repeated measures ANOVA or Friedman tests with post-hoc pairwise comparison. RESULTS: The best volumetric and spatial agreement with manual was obtained with the supervised and trained methods nicMSlesions and BIANCA (ICC absolute agreement > 0.968 and median SI > 0.643) and the worst with the unsupervised, untrained method LesionTOADS (ICC absolute agreement = 0.140 and median SI = 0.444). Agreement with manual in the single-subject network training of nicMSlesions was poor for input with low lesion volumes (i.e. two subjects with lesion volumes ≤ 3.0 ml). For the other twelve subjects, ICC varied from 0.593 to 0.973 and median SI varied from 0.535 to 0.606. In all cases, the single-subject trained nicMSlesions segmentations outperformed LesionTOADS, and in almost all cases it also outperformed LST-LPA. CONCLUSION: Input from only one subject to re-train the deep learning CNN nicMSlesions is sufficient for adequate lesion segmentation, with on average higher volumetric and spatial agreement with manual than obtained with the untrained methods LesionTOADS and LST-LPA.

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YNICL Journal 2019 Journal Article

Inter-rater agreement in glioma segmentations on longitudinal MRI

  • M. Visser
  • D.M.J. Müller
  • R.J.M. van Duijn
  • M. Smits
  • N. Verburg
  • E.J. Hendriks
  • R.J.A. Nabuurs
  • J.C.J. Bot

BACKGROUND: Tumor segmentation of glioma on MRI is a technique to monitor, quantify and report disease progression. Manual MRI segmentation is the gold standard but very labor intensive. At present the quality of this gold standard is not known for different stages of the disease, and prior work has mainly focused on treatment-naive glioblastoma. In this paper we studied the inter-rater agreement of manual MRI segmentation of glioblastoma and WHO grade II-III glioma for novices and experts at three stages of disease. We also studied the impact of inter-observer variation on extent of resection and growth rate. METHODS: In 20 patients with WHO grade IV glioblastoma and 20 patients with WHO grade II-III glioma (defined as non-glioblastoma) both the enhancing and non-enhancing tumor elements were segmented on MRI, using specialized software, by four novices and four experts before surgery, after surgery and at time of tumor progression. We used the generalized conformity index (GCI) and the intra-class correlation coefficient (ICC) of tumor volume as main outcome measures for inter-rater agreement. RESULTS: For glioblastoma, segmentations by experts and novices were comparable. The inter-rater agreement of enhancing tumor elements was excellent before surgery (GCI 0.79, ICC 0.99) poor after surgery (GCI 0.32, ICC 0.92), and good at progression (GCI 0.65, ICC 0.91). For non-glioblastoma, the inter-rater agreement was generally higher between experts than between novices. The inter-rater agreement was excellent between experts before surgery (GCI 0.77, ICC 0.92), was reasonable after surgery (GCI 0.48, ICC 0.84), and good at progression (GCI 0.60, ICC 0.80). The inter-rater agreement was good between novices before surgery (GCI 0.66, ICC 0.73), was poor after surgery (GCI 0.33, ICC 0.55), and poor at progression (GCI 0.36, ICC 0.73). Further analysis showed that the lower inter-rater agreement of segmentation on postoperative MRI could only partly be explained by the smaller volumes and fragmentation of residual tumor. The median interquartile range of extent of resection between raters was 8.3% and of growth rate was 0.22 mm/year. CONCLUSION: Manual tumor segmentations on MRI have reasonable agreement for use in spatial and volumetric analysis. Agreement in spatial overlap is of concern with segmentation after surgery for glioblastoma and with segmentation of non-glioblastoma by non-experts.

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YNICL Journal 2019 Journal Article

Non-linear registration improves statistical power to detect hippocampal atrophy in aging and dementia

  • F. Bartel
  • M. Visser
  • M. de Ruiter
  • J. Belderbos
  • F. Barkhof
  • H. Vrenken
  • J.C. de Munck
  • M. van Herk

OBJECTIVE: To compare the performance of different methods for determining hippocampal atrophy rates using longitudinal MRI scans in aging and Alzheimer's disease (AD). BACKGROUND: Quantifying hippocampal atrophy caused by neurodegenerative diseases is important to follow the course of the disease. In dementia, the efficacy of new therapies can be partially assessed by measuring their effect on hippocampal atrophy. In radiotherapy, the quantification of radiation-induced hippocampal volume loss is of interest to quantify radiation damage. We evaluated plausibility, reproducibility and sensitivity of eight commonly used methods to determine hippocampal atrophy rates using test-retest scans. MATERIALS AND METHODS: was used to determine the agreement between different methods. RESULTS: = 12.39%). Atrophy rates of non-linear registration methods also agreed best with each other. DISCUSSION AND CONCLUSION: Non-linear registration methods were most consistent in determining hippocampal atrophy and because of their better reproducibility, methods, such as ANTs, Elastix and NiftyReg, are preferred for determining hippocampal atrophy rates on longitudinal MRI. Since performances of non-linear registration methods are well comparable, the preferred method would mostly depend on computational efficiency.

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YNICL Journal 2019 Journal Article

Validation of mean upper cervical cord area (MUCCA) measurement techniques in multiple sclerosis (MS): High reproducibility and robustness to lesions, but large software and scanner effects

  • M.M. Weeda
  • S.M. Middelkoop
  • M.D. Steenwijk
  • M. Daams
  • H. Amiri
  • I. Brouwer
  • J. Killestein
  • B.M.J. Uitdehaag

INTRODUCTION: Atrophy of the spinal cord is known to occur in multiple sclerosis (MS). The mean upper cervical cord area (MUCCA) can be used to measure this atrophy. Currently, several (semi-)automated methods for MUCCA measurement exist, but validation in clinical magnetic resonance (MR) images is lacking. METHODS: Five methods to measure MUCCA (SCT-PropSeg, SCT-DeepSeg, NeuroQLab, Xinapse JIM and ITK-SNAP) were investigated in a predefined upper cervical cord region. First, within-scanner reproducibility and between-scanner robustness were assessed using intra-class correlation coefficient (ICC) and Dice's similarity index (SI) in scan-rescan 3DT1-weighted images (brain, including cervical spine using a head coil) performed on three 3 T MR machines (GE MR750, Philips Ingenuity, Toshiba Vantage Titan) in 21 subjects with MS and 6 healthy controls (dataset A). Second, sensitivity of MUCCA measurement to lesions in the upper cervical cord was assessed with cervical 3D T1-weighted images (3 T GE HDxT using a head-neck-spine coil) in 7 subjects with MS without and 14 subjects with MS with cervical lesions (dataset B), using ICC and SI with manual reference segmentations. RESULTS: In dataset A, MUCCA differed between MR machines (p 0.176). However, there was an effect of method for both volumetric and voxel wise agreement of the segmentations (both p < 0.001). Highest volumetric and voxel wise agreement was obtained with Xinapse JIM (ICC absolute agreement = 0.940 and median SI = 0.962). CONCLUSION: Although MUCCA is highly reproducible within a scanner for each individual measurement method, MUCCA differs between scanners and between methods. Cervical cord lesions do not affect MUCCA measurement performance.

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YNICL Journal 2014 Journal Article

Accurate GM atrophy quantification in MS using lesion-filling with co-registered 2D lesion masks

  • V. Popescu
  • N.C.G. Ran
  • F. Barkhof
  • D.T. Chard
  • C.A. Wheeler-Kingshott
  • H. Vrenken

BACKGROUND: In multiple sclerosis (MS), brain atrophy quantification is affected by white matter lesions. LEAP and FSL-lesion_filling, replace lesion voxels with white matter intensities; however, they require precise lesion identification on 3DT1-images. AIM: To determine whether 2DT2 lesion masks co-registered to 3DT1 images, yield grey and white matter volumes comparable to precise lesion masks. METHODS: 2DT2 lesion masks were linearly co-registered to 20 3DT1-images of MS patients, with nearest-neighbor (NNI), and tri-linear interpolation. As gold-standard, lesion masks were manually outlined on 3DT1-images. LEAP and FSL-lesion_filling were applied with each lesion mask. Grey (GM) and white matter (WM) volumes were quantified with FSL-FAST, and deep gray matter (DGM) volumes using FSL-FIRST. Volumes were compared between lesion mask types using paired Wilcoxon tests. RESULTS: Lesion-filling with gold-standard lesion masks compared to native images reduced GM overestimation by 1.93 mL (p < .001) for LEAP, and 1.21 mL (p = .002) for FSL-lesion_filling. Similar effects were achieved with NNI lesion masks from 2DT2. Global WM underestimation was not significantly influenced. GM and WM volumes from NNI, did not differ significantly from gold-standard. GM segmentation differed between lesion masks in the lesion area, and also elsewhere. Using the gold-standard, FSL-FAST quantified as GM on average 0.4% of the lesion area with LEAP and 24.5% with FSL-lesion_filling. Lesion-filling did not influence DGM volumes from FSL-FIRST. DISCUSSION: These results demonstrate that for global GM volumetry, precise lesion masks on 3DT1 images can be replaced by co-registered 2DT2 lesion masks. This makes lesion-filling a feasible method for GM atrophy measurements in MS.

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YNIMG Journal 2014 Journal Article

Functional brain network analysis using minimum spanning trees in Multiple Sclerosis: An MEG source-space study

  • P. Tewarie
  • A. Hillebrand
  • M.M. Schoonheim
  • B.W. Van Dijk
  • J.J.G. Geurts
  • F. Barkhof
  • C.H. Polman
  • C.J. Stam

Cognitive dysfunction in Multiple Sclerosis (MS) is closely related to altered functional brain network topology. Conventional network analyses to compare groups are hampered by differences in network size, density and suffer from normalization problems. We therefore computed the Minimum Spanning Tree (MST), a sub-graph of the original network, to counter these problems. We hypothesize that functional network changes analysed with MSTs are important for understanding cognitive changes in MS and that changes in MST topology also represent changes in the critical backbone of the original brain networks. Here, resting-state magnetoencephalography (MEG) recordings from 21 early MS patients and 17 age-, gender-, and education-matched controls were projected onto atlas-based regions-of-interest (ROIs) using beamforming. The phase lag index was applied to compute functional connectivity between regions, from which a graph and subsequently the MST was constructed. Results showed lower global integration in the alpha2 (10–13Hz) and beta (13–30Hz) bands in MS patients, whereas higher global integration was found in the theta band. Changes were most pronounced in the alpha2 band where a loss of hierarchical structure was observed, which was associated with poorer cognitive performance. Finally, the MST in MS patients as well as in healthy controls may represent the critical backbone of the original network. Together, these findings indicate that MST network analyses are able to detect network changes in MS patients, which may correspond to changes in the core of functional brain networks. Moreover, these changes, such as a loss of hierarchical structure, are related to cognitive performance in MS.

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YNIMG Journal 2014 Journal Article

Structural degree predicts functional network connectivity: A multimodal resting-state fMRI and MEG study

  • P. Tewarie
  • A. Hillebrand
  • E. van Dellen
  • M.M. Schoonheim
  • F. Barkhof
  • C.H. Polman
  • C. Beaulieu
  • G. Gong

Communication between neuronal populations in the human brain is characterized by complex functional interactions across time and space. Recent studies have demonstrated that these functional interactions depend on the underlying structural connections at an aggregate level. Multiple imaging modalities can be used to investigate the relation between the structural connections between brain regions and their functional interactions at multiple timescales. We investigated if consistent modality-independent functional interactions take place between brain regions, and whether these can be accounted for by underlying structural properties. We used functional MRI (fMRI) and magnetoencephalography (MEG) recordings from a population of healthy adults together with a previously described structural network. A high overlap in resting-state functional networks was found in fMRI and especially alpha band MEG recordings. This overlap was characterized by a strongly interconnected functional core network in temporo-posterior brain regions. Anatomically realistically coupled neural mass models revealed that this strongly interconnected functional network emerges near the threshold for global synchronization. Most importantly, this functional core network could be explained by a trade-off between the product of the degrees of structurally-connected regions and the Euclidean distance between them. For both fMRI and MEG, the product of the degrees of connected regions was the most important predictor for functional network connectivity. Therefore, irrespective of the modality, these results indicate that a functional core network in the human brain is especially shaped by communication between high degree nodes of the structural network.

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YNICL Journal 2013 Journal Article

Cognition in MS correlates with resting-state oscillatory brain activity: An explorative MEG source-space study

  • M.L. Van der Meer
  • P. Tewarie
  • M.M. Schoonheim
  • L. Douw
  • F. Barkhof
  • C.H. Polman
  • C.J. Stam
  • A. Hillebrand

Clinical and cognitive dysfunction in Multiple Sclerosis (MS) is insufficiently explained by structural damage as identified by traditional magnetic resonance imaging (MRI) of the brain, indicating the need for reliable functional measures in MS. We investigated whether altered resting-state oscillatory power could be related to clinical and cognitive dysfunction in MS. MEG recordings were acquired using a 151-channel whole-head MEG system from 21 relapsing remitting MS patients and 17 healthy age-, gender-, and education-matched controls, using an eyes-closed no-task condition. Relative spectral power was estimated for 78 regions of interest, using an atlas-based beamforming approach, for classical frequency bands; delta, theta, alpha1, alpha2, beta and gamma. These cortical power estimates were compared between groups by means of permutation analysis and correlated with clinical disability (Expanded Disability Status Scale: EDSS), cognitive performance and MRI measures of atrophy and lesion load. Patients showed increased power in the alpha1 band and decreased power in the alpha2 band, compared to controls, mainly in occipital, parietal and temporal areas, confirmed by a lower alpha peak-frequency. Increased power in the alpha1 band was associated with worse overall cognition and especially with information processing speed. Our quantitative relative power analysis of MEG recordings showed abnormalities in oscillatory brain dynamics in MS patients in the alpha band. By applying source-space analyses, this study provides a detailed topographical view of abnormal brain activity in MS patients, especially localized to occipital areas. Interestingly, poor cognitive performance was related to high resting-state alpha1 power indicating that changes in oscillatory activity might be of value as an objective measure of disease burden in MS patients.

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YNIMG Journal 2012 Journal Article

Optimizing parameter choice for FSL-Brain Extraction Tool (BET) on 3D T1 images in multiple sclerosis

  • V. Popescu
  • M. Battaglini
  • W.S. Hoogstrate
  • S.C.J. Verfaillie
  • I.C. Sluimer
  • R.A. van Schijndel
  • B.W. Van Dijk
  • K.S. Cover

Background Brain atrophy studies often use FSL-BET (Brain Extraction Tool) as the first step of image processing. Default BET does not always give satisfactory results on 3DT1 MR images, which negatively impacts atrophy measurements. Finding the right alternative BET settings can be a difficult and time-consuming task, which can introduce unwanted variability. Aim To systematically analyze the performance of BET in images of MS patients by varying its parameters and options combinations, and quantitatively comparing its results to a manual gold standard. Methods Images from 159 MS patients were selected from different MAGNIMS consortium centers, and 16 different 3DT1 acquisition protocols at 1. 5T or 3T. Before running BET, one of three pre-processing pipelines was applied: (1) no pre-processing, (2) removal of neck slices, or (3) additional N3 inhomogeneity correction. Then BET was applied, systematically varying the fractional intensity threshold (the “f” parameter) and with either one of the main BET options (“B” — bias field correction and neck cleanup, “R” — robust brain center estimation, or “S” — eye and optic nerve cleanup) or none. For comparison, intracranial cavity masks were manually created for all image volumes. FSL-FAST (FMRIB's Automated Segmentation Tool) tissue-type segmentation was run on all BET output images and on the image volumes masked with the manual intracranial cavity masks (thus creating the gold-standard tissue masks). The resulting brain tissue masks were quantitatively compared to the gold standard using Dice overlap coefficient (DOC). Normalized brain volumes (NBV) were calculated with SIENAX. NBV values obtained using for SIENAX other BET settings than default were compared to gold standard NBV with the paired t-test. Results The parameter/preprocessing/options combinations resulted in 20, 988 BET runs. The median DOC for default BET (f=0. 5, g=0) was 0. 913 (range 0. 321–0. 977) across all 159 native scans. For all acquisition protocols, brain extraction was substantially improved for lower values of “f” than the default value. Using native images, optimum BET performance was observed for f=0. 2 with option “B”, giving median DOC=0. 979 (range 0. 867–0. 994). Using neck removal before BET, optimum BET performance was observed for f=0. 1 with option “B”, giving median DOC 0. 983 (range 0. 844–0. 996). Using the above BET-options for SIENAX instead of default, the NBV values obtained from images after neck removal with f=0. 1 and option “B” did not differ statistically from NBV values obtained with gold-standard. Conclusion Although default BET performs reasonably well on most 3DT1 images of MS patients, the performance can be improved substantially. The removal of the neck slices, either externally or within BET, has a marked positive effect on the brain extraction quality. BET option “B” with f=0. 1 after removal of the neck slices seems to work best for all acquisition protocols.

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YNIMG Journal 2012 Journal Article

The spatial distribution of age-related white matter changes as a function of vascular risk factors—Results from the LADIS study

  • E. Rostrup
  • A.A. Gouw
  • H. Vrenken
  • E.C.W. van Straaten
  • S. Ropele
  • L. Pantoni
  • D. Inzitari
  • F. Barkhof

White matter hyperintensities (WMH) are a frequent finding on brain MRI of elderly subjects, and have been associated with various risk factors, as well as with development of cognitive and functional impairment. While an overall association between WMH load and risk factors is well described, possible spatially restricted vulnerability remains to be established. The aim of this study was to investigate the spatial distribution of WMH in normally functioning elderly subjects. We introduce a voxel-based approach in which lesion probability is mapped as a function of clinical risk factors using logistic regression, and validate the method using simulated datasets. The method was then applied in a total of 605 participants of the LADIS study (age 74±5years, all with WMH), and the location of manually delineated WMH was investigated after spatial normalisation. Particularly strong and widespread associations were found for age, gender and hypertension. Different distribution patterns were found for men and women. Further, increased probability was found in association with self-reported alcohol and tobacco consumption, as well as in those with a history of migraine. It is concluded that the location of WMH is dependent on the risk factors involved pointing towards a regionally different pathogenesis and/or vulnerability of the white matter.

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YNIMG Journal 2009 Journal Article

Short-term adaptation to a simple motor task: A physiological process preserved in multiple sclerosis

  • L. Mancini
  • O. Ciccarelli
  • F. Manfredonia
  • J.S. Thornton
  • F. Agosta
  • F. Barkhof
  • C. Beckmann
  • N. De Stefano

Short-term adaptation indicates the attenuation of the functional MRI (fMRI) response during repeated task execution. It is considered to be a physiological process, but it is unknown whether short-term adaptation changes significantly in patients with brain disorders, such as multiple sclerosis (MS). In order to investigate short-term adaptation during a repeated right-hand tapping task in both controls and in patients with MS, we analyzed the fMRI data collected in a large cohort of controls and MS patients who were recruited into a multi-centre European fMRI study. Four fMRI runs were acquired for each of the 55 controls and 56 MS patients at baseline and 33 controls and 26 MS patients at 1-year follow-up. The externally cued (1 Hz) right hand tapping movement was limited to 3 cm amplitude by using at all sites (7 at baseline and 6 at follow-up) identically manufactured wooden frames. No significant differences in cerebral activation were found between sites. Furthermore, our results showed linear response adaptation (i. e. reduced activation) from run 1 to run 4 (over a 25 minute period) in the primary motor area (contralateral more than ipsilateral), in the supplementary motor area and in the primary sensory cortex, sensory–motor cortex and cerebellum, bilaterally. This linear activation decay was the same in both control and patient groups, did not change between baseline and 1-year follow-up and was not influenced by the modest disease progression observed over 1 year. These findings confirm that the short-term adaptation to a simple motor task is a physiological process which is preserved in MS.

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YNIMG Journal 2008 Journal Article

Reproducibility of fMRI in the clinical setting: Implications for trial designs

  • R. Bosnell
  • C. Wegner
  • Z.T. Kincses
  • T. Korteweg
  • F. Agosta
  • O. Ciccarelli
  • N. De Stefano
  • A. Gass

With expanding potential clinical applications of functional magnetic resonance imaging (fMRI) it is important to test how reliable different measures of fMRI activation are between subjects and sessions and between centres. This study compared variability across 17 patients with multiple sclerosis (MS) and 22 age-matched healthy controls (HC) in 5 European centres performing an fMRI block design with hand tapping. We recruited subjects from sites using 1. 5 T scanners from different manufacturers. 5 healthy volunteers also were studied at each of 4 of the centres. We found that reproducibility between runs and sessions for single individuals was consistently much greater than between individuals. There was greater run-to-run variability for MS patients than for HC. Measurements of maximum signal change (MSC) appeared to provide higher reproducibility within individuals and greater sensitivity to differences between individuals than region of interest (ROI) suprathreshold voxel counts. The variability in measurements between centres was not as great as that between individuals. Consistent with these observations, we estimated that power should not be reduced substantially with use of multi-, as opposed to single-, centre study designs with similar numbers of subjects. Multi-centre interventional studies in which fMRI is used as an outcome measure thus appear practical even when implemented in conventional clinical environments.

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YNIMG Journal 2007 Journal Article

Improved reliability of hippocampal atrophy rate measurement in mild cognitive impairment using fluid registration

  • L.A. van de Pol
  • J. Barnes
  • R.I. Scahill
  • C. Frost
  • E.B. Lewis
  • R.G. Boyes
  • R.A. van Schijndel
  • P. Scheltens

MRI-derived rates of hippocampal atrophy may serve as surrogate markers of disease progression in mild cognitive impairment (MCI). Manual delineation is the gold standard in hippocampal volumetry; however, this technique is time-consuming and subject to errors. We aimed to compare regional non-linear (fluid) registration measurement of hippocampal atrophy rates against manual delineation in MCI. Hippocampi of 18 subjects were manually outlined twice on MRI scan-pairs (interval±SD: 2. 01±0. 11 years), and volumes were subtracted to calculate change over time. Following global affine and local rigid registration, regional fluid registration was performed from which atrophy rates were derived from the Jacobian determinants over the hippocampal region. Atrophy rates as derived by fluid registration were computed using both forward (repeat onto baseline) and backward (baseline onto repeat) registration. Reliability for both methods and agreement between methods was assessed. Mean±SD hippocampal atrophy rates (%/year) derived by manual delineation were: left: 2. 13±1. 62; right: 2. 36±1. 78 and for regional fluid registration: forward: left: 2. 39±1. 68; right: 2. 49±1. 52 and backward: left: 2. 21±1. 51; right: 2. 42±1. 49. Mean hippocampal atrophy rates did not differ between both methods. Reliability for manual hippocampal volume measurements (cross-sectional) was high (intraclass correlation coefficient (ICC): baseline and follow-up, left and right, >0. 99). However, the resulting ICC for manual measurements of hippocampal volume change (longitudinal) was considerably lower (left: 0. 798; right: 0. 850) compared with regional fluid registration (forward: left: 0. 985; right: 0. 988 and backward: left: 0. 975; right: 0. 989). We conclude that regional fluid registration is more reliable than manual delineation in assessing hippocampal atrophy rates, without sacrificing sensitivity to change. This method may be useful to quantify hippocampal volume change, given the reduction in operator time and improved precision.

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YNIMG Journal 2005 Journal Article

Raloxifene exposure enhances brain activation during memory performance in healthy elderly males; its possible relevance to behavior

  • R. Goekoop
  • E.J.J. Duschek
  • D.L. Knol
  • F. Barkhof
  • C. Netelenbos
  • Ph. Scheltens
  • S.A.R.B. Rombouts

Raloxifene is a selective estrogen receptor modulator (SERM) that is prescribed in females only, but its use in male subjects is increasingly considered. With a growing number of patients having potential benefit from raloxifene, the need for an assessment of its effects on brain function is growing. Effects of estrogens on brain function are very subtle and difficult to detect by neuropsychological assessment. Functional imaging techniques, however, have been relatively successful in detecting such changes. This study used functional magnetic resonance imaging (fMRI) to examine effects of raloxifene treatment on memory function. Healthy elderly males (n = 28; mean age 63. 6 years, SD 2. 4) were scanned during performance on a face encoding paradigm. Scans were made at baseline and after 3 months of treatment with either raloxifene (n = 14) or placebo (n = 14). Treatment effects were analyzed using mixed-effects statistical analysis (FSL). Activation during task performance involved bilateral parietal and prefrontal areas, anterior cingulate gyrus, and inferior prefrontal, occipital, and mediotemporal areas bilaterally. When compared to placebo, raloxifene treatment significantly enhanced activation in these structures (Z > 3. 1), except for mediotemporal areas. Task performance accuracy diminished in the placebo group (P = 0. 02), but remained constant in the raloxifene group (P = 0. 60). In conclusion, raloxifene treatment enhanced brain activation in areas spanning a number of different cognitive domains, suggesting an effect on cortical arousal. Such effects may translate into small effects on behavior, including effects on attention and working memory performance, executive functions, verbal skills, and episodic memory. Further neuropsychological assessment is necessary to test the validity of these predictions.

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YNIMG Journal 2004 Journal Article

Global and local gray matter loss in mild cognitive impairment and Alzheimer's disease

  • G.B. Karas
  • P. Scheltens
  • S.A.R.B. Rombouts
  • P.J. Visser
  • R.A. van Schijndel
  • N.C. Fox
  • F. Barkhof

Purpose Mild cognitive impairment (MCI) is thought to be the prodromal phase to Alzheimer's disease (AD). We analyzed patterns of gray matter (GM) loss to examine what characterizes MCI and what determines the difference with AD. Materials and methods Thirty-three subjects with AD, 14 normal elderly controls (NCLR), and 22 amnestic MCI subjects were included and underwent brain MR imaging. Global GM volume was assessed using segmentation and local GM volume was assessed using voxel-based morphometry (VBM); VBM was optimized for template mismatch and statistical mass. Results AD subjects had significantly (12. 3%) lower mean global GM volume when compared to controls (517 ± 58 vs. 590 ± 52 ml; P < 0. 001). Global GM volume in the MCI group (552 ± 52) was intermediate between these two: 6. 2% lower than AD and 6. 5% higher than the controls but not significantly different from either group. VBM showed that subjects with MCI had significant local reductions in gray matter in the medial temporal lobe (MTL), the insula, and thalamus compared to NCLR subjects. By contrast, when compared to subjects with AD, MCI subjects had more GM in the parietal association areas and the anterior and the posterior cingulate. Conclusion GM loss in the MTL characterizes MCI, while GM loss in the parietal and cingulate cortices might be a feature of AD.

Details DOI

YNIMG Journal 2002 Journal Article

Patterns of Cerebral Atrophy in Dementia with Lewy Bodies Using Voxel-Based Morphometry

  • E.J. Burton
  • G. Karas
  • S.M. Paling
  • R. Barber
  • E.D. Williams
  • C.G. Ballard
  • I.G. McKeith
  • P. Scheltens

Previouscross-sectional MRI studies based on region-of-interest analyses have shown that increased cerebral atrophy is a feature of both Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Relative preservation of the hippocampus and temporal lobe structures in DLB compared to AD has been reported in region-of-interest-based studies. Recently, image processing techniques such as voxel-based morphometry (VBM) have been developed to provide an unbiased, visually informative, and comprehensive means of studying patterns of cerebral atrophy. We report the first study to use the voxel-based approach to assess patterns of cerebral atrophy in DLB compared to control subjects and AD. Regional gray matter volume loss was observed bilaterally in the temporal and frontal lobes and insular cortex of patients with DLB compared to control subjects. Comparison of dementia groups showed preservation of the medial temporal lobe, hippocampus, and amygdala in DLB relative to AD. Significant gray matter loss was also observed in the thalamus of AD patients compared to DLB.

Details DOI

YNIMG Journal 2001 Journal Article

Anterior Medial Temporal Lobe Activation during Attempted Retrieval of Encoded Visuospatial Scenes: An Event-Related fMRI Study

  • S.A.R.B. Rombouts
  • F. Barkhof
  • M.P. Witter
  • W.C.M. Machielsen
  • Ph. Scheltens

Various studies have shown that the medial temporal lobe (MTL), which consists of the hippocampus and parahippocampal gyrus, is important for episodic memory. Earlier fMRI studies substantiated this role by showing activation upon encoding of visuospatial scenes. In this study we used event-related fMRI to study whether the cognitive process of retrieval of visuospatial scenes, tested with the use of a recognition paradigm, also activates the MTL. Nine subjects (mean age 24 years) were presented previously studied color pictures (old) and pictures they had never seen before (new) in a mixed trial design. Data analysis allowed calculation of the fMRI response of correct judgments on new pictures, old pictures, and false judgments. Since we used previously encoded color pictures as old stimuli, we also included an encoding paradigm in the current set of experiments. This allowed us to compare encoding and recognition activation in the MTL of exactly the same pictures in the same subjects. Correct judgments on new pictures showed an increased activation in the anterior parahippocampus bilaterally and the right anterior hippocampus compared to judgments on old pictures in the recognition experiment. The former judgments took significantly longer, indicating that retrieval of successfully stored information is less demanding than the effort to retrieve nonencoded information. A comparison of the two experimental data sets showed evidence for a functional segregation of encoding and retrieving color pictures. We conclude that the left posterior parahippocampal gyrus responds during encoding, while on the other hand the left anterior parahippocampal gyrus and the right anterior hippocampus were more strongly involved in retrieval.

Details DOI
v2026.09.13