Publications by authors named "Frederik Barkhof"

822 Publications

Modifiable risk factors for dementia and dementia risk profiling. A user manual for Brain Health Services-part 2 of 6.

Alzheimers Res Ther 2021 Oct 11;13(1):169. Epub 2021 Oct 11.

College of Medicine and Health, University of Exeter, Exeter, UK.

We envisage the development of new Brain Health Services to achieve primary and secondary dementia prevention. These services will complement existing memory clinics by targeting cognitively unimpaired individuals, where the focus is on risk profiling and personalized risk reduction interventions rather than diagnosing and treating late-stage disease. In this article, we review key potentially modifiable risk factors and genetic risk factors and discuss assessment of risk factors as well as additional fluid and imaging biomarkers that may enhance risk profiling. We then outline multidomain measures and risk profiling and provide practical guidelines for Brain Health Services, with consideration of outstanding uncertainties and challenges. Users of Brain Health Services should undergo risk profiling tailored to their age, level of risk, and availability of local resources. Initial risk assessment should incorporate a multidomain risk profiling measure. For users aged 39-64, we recommend the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) Dementia Risk Score, whereas for users aged 65 and older, we recommend the Brief Dementia Screening Indicator (BDSI) and the Australian National University Alzheimer's Disease Risk Index (ANU-ADRI). The initial assessment should also include potentially modifiable risk factors including sociodemographic, lifestyle, and health factors. If resources allow, apolipoprotein E ɛ4 status testing and structural magnetic resonance imaging should be conducted. If this initial assessment indicates a low dementia risk, then low intensity interventions can be implemented. If the user has a high dementia risk, additional investigations should be considered if local resources allow. Common variant polygenic risk of late-onset AD can be tested in middle-aged or older adults. Rare variants should only be investigated in users with a family history of early-onset dementia in a first degree relative. Advanced imaging with 18-fluorodeoxyglucose positron emission tomography (FDG-PET) or amyloid PET may be informative in high risk users to clarify the nature and burden of their underlying pathologies. Cerebrospinal fluid biomarkers are not recommended for this setting, and blood-based biomarkers need further validation before clinical use. As new technologies become available, advances in artificial intelligence are likely to improve our ability to combine diverse data to further enhance risk profiling. Ultimately, Brain Health Services have the potential to reduce the future burden of dementia through risk profiling, risk communication, personalized risk reduction, and cognitive enhancement interventions.
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http://dx.doi.org/10.1186/s13195-021-00895-4DOI Listing
October 2021

Amyloid-driven disruption of default mode network connectivity in cognitively healthy individuals.

Brain Commun 2021 6;3(4):fcab201. Epub 2021 Sep 6.

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Location VUmc, 1081 HZ Amsterdam, The Netherlands.

Cortical accumulation of amyloid beta is one of the first events of Alzheimer's disease pathophysiology, and has been suggested to follow a consistent spatiotemporal ordering, starting in the posterior cingulate cortex, precuneus and medio-orbitofrontal cortex. These regions overlap with those of the default mode network, a brain network also involved in memory functions. Aberrant default mode network functional connectivity and higher network sparsity have been reported in prodromal and clinical Alzheimer's disease. We investigated the association between amyloid burden and default mode network connectivity in the preclinical stage of Alzheimer's disease and its association with longitudinal memory decline. We included 173 participants, in which amyloid burden was assessed both in CSF by the amyloid beta 42/40 ratio, capturing the soluble part of amyloid pathology, and in dynamic PET scans calculating the non-displaceable binding potential in early-stage regions. The default mode network was identified with resting-state functional MRI. Then, we calculated functional connectivity in the default mode network, derived from independent component analysis, and eigenvector centrality, a graph measure recursively defining important nodes on the base of their connection with other important nodes. Memory was tested at baseline, 2- and 4-year follow-up. We demonstrated that higher amyloid burden as measured by both CSF amyloid beta 42/40 ratio and non-displaceable binding potential in the posterior cingulate cortex was associated with lower functional connectivity in the default mode network. The association between amyloid burden (CSF and non-displaceable binding potential in the posterior cingulate cortex) and aberrant default mode network connectivity was confirmed at the voxel level with both functional connectivity and eigenvector centrality measures, and it was driven by voxel clusters localized in the precuneus, cingulate, angular and left middle temporal gyri. Moreover, we demonstrated that functional connectivity in the default mode network predicts longitudinal memory decline synergistically with regional amyloid burden, as measured by non-displaceable binding potential in the posterior cingulate cortex. Taken together, these results suggest that early amyloid beta deposition is associated with aberrant default mode network connectivity in cognitively healthy individuals and that default mode network connectivity markers can be used to identify subjects at risk of memory decline.
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http://dx.doi.org/10.1093/braincomms/fcab201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490784PMC
September 2021

Opportunities for Understanding MS Mechanisms and Progression With MRI Using Large-Scale Data Sharing and Artificial Intelligence.

Neurology 2021 Oct 4. Epub 2021 Oct 4.

MS Center Amsterdam, Amsterdam Neuroscience, Department of Radiology and Nuclear Medicine, Amsterdam UMC, Amsterdam, the Netherlands.

Multiple sclerosis (MS) patients have heterogeneous clinical presentations, symptoms and progression over time, making MS difficult to assess and comprehend in vivo. The combination of large-scale data-sharing and artificial intelligence creates new opportunities for monitoring and understanding MS using magnetic resonance imaging (MRI).First, development of validated MS-specific image analysis methods can be boosted by verified reference, test and benchmark imaging data. Using detailed expert annotations, artificial intelligence algorithms can be trained on such MS-specific data. Second, understanding disease processes could be greatly advanced through shared data of large MS cohorts with clinical, demographic and treatment information. Relevant patterns in such data that may be imperceptible to a human observer could be detected through artificial intelligence techniques. This applies from image analysis (lesions, atrophy or functional network changes) to large multi-domain datasets (imaging, cognition, clinical disability, genetics, etc.).After reviewing data-sharing and artificial intelligence, this paper highlights three areas that offer strong opportunities for making advances in the next few years: crowdsourcing, personal data protection, and organized analysis challenges. Difficulties as well as specific recommendations to overcome them are discussed, in order to best leverage data sharing and artificial intelligence to improve image analysis, imaging and the understanding of MS.
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http://dx.doi.org/10.1212/WNL.0000000000012884DOI Listing
October 2021

A deep learning algorithm for white matter hyperintensity lesion detection and segmentation.

Neuroradiology 2021 Oct 2. Epub 2021 Oct 2.

Department of Radiology, Beijing Tiantan Hospital, Fengtai District, Capital Medical University, No. 119 the West Southern 4th Ring Road, Beijing, 100070, China.

Purpose: White matter hyperintensity (WMHI) lesions on MR images are an important indication of various types of brain diseases that involve inflammation and blood vessel abnormalities. Automated quantification of the WMHI can be valuable for the clinical management of patients, but existing automated software is often developed for a single type of disease and may not be applicable for clinical scans with thick slices and different scanning protocols. The purpose of the study is to develop and validate an algorithm for automatic quantification of white matter hyperintensity suitable for heterogeneous MRI data with different disease types.

Methods: We developed and evaluated "DeepWML", a deep learning method for fully automated white matter lesion (WML) segmentation of multicentre FLAIR images. We used MRI from 507 patients, including three distinct white matter diseases, obtained in 9 centres, with a wide range of scanners and acquisition protocols. The automated delineation tool was evaluated through quantitative parameters of Dice similarity, sensitivity and precision compared to manual delineation (gold standard).

Results: The overall median Dice similarity coefficient was 0.78 (range 0.64 ~ 0.86) across the three disease types and multiple centres. The median sensitivity and precision were 0.84 (range 0.67 ~ 0.94) and 0.81 (range 0.64 ~ 0.92), respectively. The tool's performance increased with larger lesion volumes.

Conclusion: DeepWML was successfully applied to a wide spectrum of MRI data in the three white matter disease types, which has the potential to improve the practical workflow of white matter lesion delineation.
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http://dx.doi.org/10.1007/s00234-021-02820-wDOI Listing
October 2021

Glioblastoma Surgery Imaging-Reporting and Data System: Validation and Performance of the Automated Segmentation Task.

Cancers (Basel) 2021 Sep 17;13(18). Epub 2021 Sep 17.

Department of Clinical Epidemiology and Biostatistics, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands.

For patients with presumed glioblastoma, essential tumor characteristics are determined from preoperative MR images to optimize the treatment strategy. This procedure is time-consuming and subjective, if performed by crude eyeballing or manually. The standardized GSI-RADS aims to provide neurosurgeons with automatic tumor segmentations to extract tumor features rapidly and objectively. In this study, we improved automatic tumor segmentation and compared the agreement with manual raters, describe the technical details of the different components of GSI-RADS, and determined their speed. Two recent neural network architectures were considered for the segmentation task: nnU-Net and AGU-Net. Two preprocessing schemes were introduced to investigate the tradeoff between performance and processing speed. A summarized description of the tumor feature extraction and standardized reporting process is included. The trained architectures for automatic segmentation and the code for computing the standardized report are distributed as open-source and as open-access software. Validation studies were performed on a dataset of 1594 gadolinium-enhanced T1-weighted MRI volumes from 13 hospitals and 293 T1-weighted MRI volumes from the BraTS challenge. The glioblastoma tumor core segmentation reached a Dice score slightly below 90%, a patientwise F1-score close to 99%, and a 95th percentile Hausdorff distance slightly below 4.0 mm on average with either architecture and the heavy preprocessing scheme. A patient MRI volume can be segmented in less than one minute, and a standardized report can be generated in up to five minutes. The proposed GSI-RADS software showed robust performance on a large collection of MRI volumes from various hospitals and generated results within a reasonable runtime.
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http://dx.doi.org/10.3390/cancers13184674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465753PMC
September 2021

Visual Function and Brief Cognitive Assessment for Multiple Sclerosis in Optic Neuritis Clinically Isolated Syndrome Patients.

J Neuroophthalmol 2021 Sep 23. Epub 2021 Sep 23.

NMR Research Unit (SC, BK, LH, NC, FP, OC, and AT), Queen Square MS Centre, Department of Neuroinflammation, Queen Square Institute of Neurology, Faculty of Brain Sciences, UCL, London, United Kingdom; Department of Medical Physics and Biomedical Engineering (BK, FP, and FB), Centre for Medical Image Computing (CMIC), University College London, London, United Kingdom; Universitat Oberta de Catalunya (FP), Barcelona, Spain; Department of Brain Repair and Rehabilitation (ID and FB), University College London Institute of Neurology, Faculty of Brain Sciences, UCL, London, United Kingdom; National Institute for Health Research (FB and OC), University College London Hospitals, Biomedical Research Centre, London, United Kingdom; and Department of Radiology and Nuclear Medicine (FB), Amsterdam University Medical Centers, Vrije Universiteit, the Netherlands.

Background: In this study, we hypothesized that clinically isolated syndrome-optic neuritis patients may have disturbances in neuropsychological functions related to visual processes.

Methods: Forty-two patients with optic neuritis within 3 months from onset and 13 healthy controls were assessed at baseline and 6 months with MRI (brain volumes, lesion load, and optic radiation lesion volume) and optical coherence tomography (OCT) (peripapillary retinal nerve fiber layer [RNFL], ganglion cell and inner plexiform layers [GCIPLs], and inner nuclear layer). Patients underwent the brief cognitive assessment for multiple sclerosis, high-contrast and low-contrast letter acuity, and color vision.

Results: At baseline, patients had impaired visual function, had GCIPL thinning in both eyes, and performed below the normative average in the visual-related tests: Symbol Digit Modalities Test and Brief Visuospatial Memory Test-Revised (BVMT-R). Over time, improvement in visual function in the affected eye was predicted by baseline GCIPL (P = 0.015), RNFL decreased, and the BVMT-R improved (P = 0.001). Improvement in BVMT-R was associated with improvement in the high-contrast letter acuity of the affected eye (P = 0.03), independently of OCT and MRI metrics.

Conclusion: Cognitive testing, assessed binocularly, of visuospatial processing is affected after unilateral optic neuritis and improves over time with visual recovery. This is not related to structural markers of the visual or central nervous system.
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http://dx.doi.org/10.1097/WNO.0000000000001280DOI Listing
September 2021

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

Neuroradiology 2021 Sep 24. Epub 2021 Sep 24.

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

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

Fetal Familial Cerebral Cavernous Malformation With a Novel Heterozygous Pathogenic Variant.

Neurology 2021 Sep 23. Epub 2021 Sep 23.

Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

Objectives: To identify fetal familial cerebral cavernous malformation (CCMs) and a novel mutation.

Methods: A 37-year-old pregnant woman (G4P0) presented right-handed numbness since two weeks at 31 weeks of gestation. Evaluation with brain magnetic resonance imaging (MRI) revealed multiple CCMs. As a result, fetal MRI, fetal Whole Exome Sequencing (WES), and maternal Sanger sequencing were performed.

Results: The mother's brain MRI demonstrated numerous CCMs involving the brain stem, cerebral hemispheres, and cerebellum. Fetal MRI showed a CCM located in the left frontal lobe in SWI. The neuroimaging characteristics of the mother and the fetus suggested that their CCMs may be familial. Genetic analysis revealed a novel mutation in KRIT1 (c.1A>G, p.0?), also called CCM1, in the mother and the baby. The mother delivered a daughter at 32 weeks of gestation with an Apgar score of 10 by cesarean section.

Discussion: This mutation of the initial codon in the gene leads to a phenotype with an early-onset. To our knowledge, this is the first-ever reported case of fetal familial CCM and this novel mutation. Brain MRI has excellent sensitivity and specificity, providing the best option for detecting CCMs, even , primarily when SWI is used.
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http://dx.doi.org/10.1212/WNL.0000000000012852DOI Listing
September 2021

Risk of dementia in ε4 carriers is mitigated by a polygenic risk score.

Alzheimers Dement (Amst) 2021 14;13(1):e12229. Epub 2021 Sep 14.

Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands.

Introduction: We investigated relationships among genetic determinants of Alzheimer's disease (AD), amyloid/tau/neurodegenaration (ATN) biomarkers, and risk of dementia.

Methods: We studied cognitively normal individuals with subjective cognitive decline (SCD) from the Amsterdam Dementia Cohort and SCIENCe project. We examined associations between genetic variants and ATN biomarkers, and evaluated their predictive value for incident dementia. A polygenic risk score (PRS) was calculated based on 39 genetic variants. The was not included in the PRS and was analyzed separately.

Results: The PRS and ε4 were associated with amyloid-positive ATN profiles, and ε4 additionally with isolated increased tau (A-T+N-). A high PRS and ε4 separately predicted AD dementia. Combined, a high PRS increased while a low PRS attenuated the risk associated with ε4 carriers.

Discussion: Genetic variants beyond are clinically relevant and contribute to the pathophysiology of AD. In the future, a PRS might be used in individualized risk profiling.
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http://dx.doi.org/10.1002/dad2.12229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438688PMC
September 2021

Serum Neurofilament Light Association With Progression in Natalizumab-Treated Patients With Relapsing-Remitting Multiple Sclerosis.

Neurology 2021 Sep 9. Epub 2021 Sep 9.

Clinical Chemistry Laboratory, Amsterdam UMC.

ObjectiveThe objective of this study was to investigate the potential of serum neurofilament light (NfL) to reflect or predict progression mostly independent of acute inflammatory disease activity in patients with relapsing remitting multiple sclerosis (RRMS) treated with natalizumab.MethodsPatients were selected from a prospective observational cohort study initiated in 2006 at the VU University Medical Center Amsterdam, The Netherlands, including patients with RRMS treated with natalizumab. Selection criteria included an age of 18 years or older and a minimum follow-up of 3 years from natalizumab initiation. Clinical and MRI assessments were performedon a yearly basis, and serum NfL was measured at 5 time-points during the follow-up, including on the day of natalizumab initiation (baseline), 3 months, 1 year and 2 years after natalizumab initiation, and on last follow-up visit. Using general linear regression models, we compared the longitudinal dynamics of NfL between patients with and without confirmed EDSS progression between year 1 visit and last follow-up, and between individuals with and without EDSS progression, a composite endpoint including the EDSS, 9 hole peg test and timed 25 foot-walk.ResultsEighty-nine natalizumab-treated patients with RRMS were included. Median follow-up time was 5.2 years (IQR 4.3-6.7, range 3.0-11.0) after natalizumab initiation, mean age at time of natalizumab initiation was 36.9 (SD: 8.5), and median disease duration was 7.4 years (IQR 3.8-12.1). Between year 1 and the last follow-up, 28/89 (31.5%) individuals showed confirmed EDSS progression. Data for the EDSS endpoint was available for 73 out of the 89 patients and 35/73 (47.9%) showed confirmed EDSS progression.We observed a significant reduction in NfL levels 3 months after natalizumab initiation, which reached its nadir of close to 50% of baseline levels 1 year after treatment initiation. We found no difference in the longitudinal dynamics of NfL in progressors versus non-progressors. NfL levels at baseline and 1 year after natalizumab initiation did not predict progression at last follow-up.DiscussionIn our cohort of natalizumab-treated patients with RRMS, NfL fails to capture or predict progression that occurs largely independently of clinical or radiological signs of acute focal inflammatory disease activity. Additional biomarkers may thus be needed to monitor progression in these patients.Classification of EvidenceThis study provides Class II evidence that serum NfL levels are not associated with disease progression in natalizumab-treated patients with RRMS.
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http://dx.doi.org/10.1212/WNL.0000000000012752DOI Listing
September 2021

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

Neuroradiology 2021 Sep 3. Epub 2021 Sep 3.

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

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

Quantification of Cervical Cord Cross-Sectional Area: Which Acquisition, Vertebra Level, and Analysis Software? A Multicenter Repeatability Study on a Traveling Healthy Volunteer.

Front Neurol 2021 4;12:693333. Epub 2021 Aug 4.

Department of Radiology and Nuclear Medicine, Multiple Sclerosis Center Amsterdam, Amsterdam Neuroscience Amsterdam University Medical Centers (UMC), Vrije Universiteit Medical Center (VUmc), Amsterdam, Netherlands.

Considerable spinal cord (SC) atrophy occurs in multiple sclerosis (MS). While MRI-based techniques for SC cross-sectional area (CSA) quantification have improved over time, there is no common agreement on whether to measure at single vertebral levels or across larger regions and whether upper SC CSA can be reliably measured from brain images. To compare in a multicenter setting three CSA measurement methods in terms of repeatability at different anatomical levels. To analyze the agreement between measurements performed on the cervical cord and on brain MRI. One healthy volunteer was scanned three times on the same day in six sites (three scanner vendors) using a 3T MRI protocol including sagittal 3D T1-weighted imaging of the brain (covering the upper cervical cord) and of the SC. Images were analyzed using two semiautomated methods [NeuroQLab (NQL) and the Active Surface Model (ASM)] and the fully automated Spinal Cord Toolbox (SCT) on different vertebral levels (C1-C2; C2/3) on SC and brain images and the entire cervical cord (C1-C7) on SC images only. CSA estimates were significantly smaller using SCT compared to NQL and ASM ( < 0.001), regardless of the cord level. Inter-scanner repeatability was best in C1-C7: coefficients of variation for NQL, ASM, and SCT: 0.4, 0.6, and 1.0%, respectively. CSAs estimated in brain MRI were slightly lower than in SC MRI (all ≤ 0.006 at the C1-C2 level). Despite protocol harmonization between the centers with regard to image resolution and use of high-contrast 3D T1-weighted sequences, the variability of CSA was partly scanner dependent probably due to differences in scanner geometry, coil design, and details of the MRI parameter settings. For CSA quantification, dedicated isotropic SC MRI should be acquired, which yielded best repeatability in the entire cervical cord. In the upper part of the cervical cord, use of brain MRI scans entailed only a minor loss of CSA repeatability compared to SC MRI. Due to systematic differences between scanners and the CSA quantification software, both should be kept constant within a study. The MRI dataset of this study is available publicly to test new analysis approaches.
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http://dx.doi.org/10.3389/fneur.2021.693333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371197PMC
August 2021

Tau-related grey matter network breakdown across the Alzheimer's disease continuum.

Alzheimers Res Ther 2021 08 13;13(1):138. Epub 2021 Aug 13.

Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.

Background: Changes in grey matter covariance networks have been reported in preclinical and clinical stages of Alzheimer's disease (AD) and have been associated with amyloid-β (Aβ) deposition and cognitive decline. However, the role of tau pathology on grey matter networks remains unclear. Based on previously reported associations between tau pathology, synaptic density and brain structural measures, tau-related connectivity changes across different stages of AD might be expected. We aimed to assess the relationship between tau aggregation and grey matter network alterations across the AD continuum.

Methods: We included 533 individuals (178 Aβ-negative cognitively unimpaired (CU) subjects, 105 Aβ-positive CU subjects, 122 Aβ-positive patients with mild cognitive impairment, and 128 patients with AD dementia) from the BioFINDER-2 study. Single-subject grey matter networks were extracted from T1-weighted images and graph theory properties including degree, clustering coefficient, path length, and small world topology were calculated. Associations between tau positron emission tomography (PET) values and global and regional network measures were examined using linear regression models adjusted for age, sex, and total intracranial volume. Finally, we tested whether the association of tau pathology with cognitive performance was mediated by grey matter network disruptions.

Results: Across the whole sample, we found that higher tau load in the temporal meta-ROI was associated with significant changes in degree, clustering, path length, and small world values (all p < 0.001), indicative of a less optimal network organisation. Already in CU Aβ-positive individuals associations between tau burden and lower clustering and path length were observed, whereas in advanced disease stages elevated tau pathology was progressively associated with more brain network abnormalities. Moreover, the association between higher tau load and lower cognitive performance was only partly mediated (9.3 to 9.5%) through small world topology.

Conclusions: Our data suggest a close relationship between grey matter network disruptions and tau pathology in individuals with abnormal amyloid. This might reflect a reduced communication between neighbouring brain areas and an altered ability to integrate information from distributed brain regions with tau pathology, indicative of a more random network topology across different AD stages.
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http://dx.doi.org/10.1186/s13195-021-00876-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364121PMC
August 2021

Cognitive Functioning and Hippocampal Connectivity in Patients With Longstanding Type 1 Diabetes and Apolipoprotein E ε4.

Diabetes Care 2021 Aug 11. Epub 2021 Aug 11.

Department of Medical Psychology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

Objective: While the apolipoprotein E 4 allele (ApoE-4) is related to cognitive and brain decline in the general population, its effect on the brain in type 1 diabetes mellitus (T1DM) remains unclear. Therefore, the aim was to determine the interaction between ApoE-4 and T1DM on cognitive performance and hippocampal structure and connectivity as the brain area most vulnerable to ApoE-4 effects in adult patients with T1DM.

Research Design And Methods: Blood sampling was performed in 104 patients with T1DM and 49 control subjects for ApoE genotyping, neuropsychology, and neuroimaging to determine hippocampal volume and resting-state connectivity. The interaction between T1DM status and ApoE-4 presence was investigated and adjusted for age and mean systolic blood pressure.

Results: ApoE genotyping could not be performed for three patients with T1DM. Significant interaction effects, indicating a differential effect of ApoE-ε4 between both groups, were found for overall cognitive functioning and for the subdomains of information processing speed and attention. Additionally, interaction effects were present for right hippocampal connectivity with the right posterior cingulate and supramarginal gyri. Subsequent group analysis showed that patients with T1DM with ApoE-4 performed worse on these cognitive domains with increased connectivity, relative to their counterparts without ApoE-4. In contrast, no cognitive effects, but decreased connectivity, were observed in control subjects with ApoE-4. In patients with T1DM, higher right hippocampus connectivity with the posterior cingulate gyrus was related to poorer overall cognitive functioning.

Conclusions: The results may suggest that ApoE-ε4 presence leaves our patients with T1DM more susceptible to cognitive decrements at a younger age, possibly through vascular pathways, warranting further longitudinal studies.
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http://dx.doi.org/10.2337/dc21-0483DOI Listing
August 2021

Structural and functional hippocampal alterations in Multiple sclerosis and neuromyelitis optica spectrum disorder.

Mult Scler 2021 Aug 11:13524585211032800. Epub 2021 Aug 11.

Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Background: Hippocampal involvement may differ between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD).

Objective: To investigate the morphometric, diffusion and functional alterations in hippocampus in MS and NMOSD and the clinical significance.

Methods: A total of 752 participants including 236 MS, 236 NMOSD and 280 healthy controls (HC) were included in this retrospective multi-center study. The hippocampus and subfield volumes, fractional anisotropy (FA) and mean diffusivity (MD), amplitude of low frequency fluctuation (ALFF) and degree centrality (DC) were analyzed, and their associations with clinical variables were investigated.

Results: The hippocampus showed significantly lower volume, FA and greater MD in MS compared to NMOSD and HC ( < 0.05), while no abnormal ALFF or DC was identified in any group. Hippocampal subfields were affected in both diseases, though subiculum, presubiculum and fimbria showed significantly lower volume only in MS ( < 0.05). Significant correlations between diffusion alterations, several subfield volumes and clinical variables were observed in both diseases, especially in MS ( = -0.444 to 0.498, < 0.05). FA and MD showed fair discriminative power between MS and HC, NMOSD and HC (AUC > 0.7).

Conclusions: Hippocampal atrophy and diffusion abnormalities were identified in MS and NMOSD, partly explaining how clinical disability and cognitive impairment are differentially affected.
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http://dx.doi.org/10.1177/13524585211032800DOI Listing
August 2021

Regional amyloid accumulation predicts memory decline in initially cognitively unimpaired individuals.

Alzheimers Dement (Amst) 2021 2;13(1):e12216. Epub 2021 Aug 2.

Amsterdam UMC Department of Radiology and Nuclear Medicine Vrije Universiteit Amsterdam Amsterdam Netherlands.

Introduction: The value of quantitative longitudinal and regional amyloid beta (Aβ) measurements in predicting cognitive decline in initially cognitively unimpaired (CU) individuals remains to be determined.

Methods: We selected 133 CU individuals with two or more [C]Pittsburgh compound B ([C]PiB) scans and neuropsychological data from Open Access Series of Imaging Studies (OASIS-3). Baseline and annualized distribution volume ratios were computed for a global composite and four regional clusters. The predictive value of Aβ measurements (baseline, slope, and interaction) on longitudinal cognitive performance was examined.

Results: Global performance could only be predicted by Aβ burden in an early cluster (precuneus, lateral orbitofrontal, and insula) and the precuneus region of interest (ROI) by itself significantly improved the model. Precuneal Aβ burden was also predictive of immediate and delayed episodic memory performance. In Aβ subjects at baseline (= 93), lateral orbitofrontal Aβ burden predicted working and semantic memory performance.

Discussion: Quantifying longitudinal and regional changes in Aβ can improve the prediction of cognitive functioning in initially CU individuals.
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http://dx.doi.org/10.1002/dad2.12216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327468PMC
August 2021

Plasma Proteomic Biomarkers Relating to Alzheimer's Disease: A Meta-Analysis Based on Our Own Studies.

Front Aging Neurosci 2021 21;13:712545. Epub 2021 Jul 21.

Department of Psychiatry, University of Oxford, Oxford, United Kingdom.

: Plasma biomarkers for the diagnosis and stratification of Alzheimer's disease (AD) are intensively sought. However, no plasma markers are well established so far for AD diagnosis. Our group has identified and validated various blood-based proteomic biomarkers relating to AD pathology in multiple cohorts. The study aims to conduct a meta-analysis based on our own studies to systematically assess the diagnostic performance of our previously identified blood biomarkers. : To do this, we included seven studies that our group has conducted during the last decade. These studies used either Luminex xMAP or ELISA to measure proteomic biomarkers. As proteins measured in these studies differed, we selected protein based on the criteria that it must be measured in at least four studies. We then examined biomarker performance using random-effect meta-analyses based on the mean difference between biomarker concentrations in AD and controls (CTL), AD and mild cognitive impairment (MCI), MCI, and CTL as well as MCI converted to dementia (MCIc) and non-converted (MCInc) individuals. : An overall of 2,879 subjects were retrieved for meta-analysis including 1,053 CTL, 895 MCI, 882 AD, and 49 frontotemporal dementia (FTD) patients. Six proteins were measured in at least four studies and were chosen for meta-analyses for AD diagnosis. Of them, three proteins had significant difference between AD and controls, among which alpha-2-macroglobulin (A2M) and ficolin-2 (FCN2) increased in AD while fibrinogen gamma chain (FGG) decreased in AD compared to CTL. Furthermore, FGG significantly increased in FTD compared to AD. None of the proteins passed the significance between AD and MCI, or MCI and CTL, or MCIc and MCInc, although complement component 4 (CC4) tended to increase in MCIc individuals compared to MCInc. : The results suggest that A2M, FCN2, and FGG are promising biomarkers to discriminate AD patients from controls, which are worthy of further validation.
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http://dx.doi.org/10.3389/fnagi.2021.712545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335587PMC
July 2021

Right temporal variant frontotemporal dementia is pathologically heterogeneous: a case-series and a systematic review.

Acta Neuropathol Commun 2021 08 3;9(1):131. Epub 2021 Aug 3.

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, De Boelelaan 1118, 1081 HZ, Amsterdam, The Netherlands.

Although the right temporal variant frontotemporal dementia (rtvFTD) is characterised by distinct clinical and radiological features, its underlying histopathology remains elusive. Being considered a right-sided variant of semantic variant primary progressive aphasia (svPPA), TDP-43 type C pathology has been linked to the syndrome, but this has not been studied in detail in large cohorts. In this case report and systematic review, we report the autopsy results of five subjects diagnosed with rtvFTD from our cohort and 44 single rtvFTD subjects from the literature. Macroscopic pathological evaluation of the combined results revealed that rtvFTD demonstrated either a frontotemporal or temporal evolution, even if the degeneration started in the right temporal lobe initially. FTLD-TDP type C was the most common underlying pathology in rtvFTD, however, in 64% of rtvFTD, other underlying pathologies than FTLD-TDP type C were present, such as Tau-MAPT and FTLD-TDP type A and B. Additionally, accompanying motor neuron or corticospinal tract degeneration was observed in 28% of rtvFTD patients. Our results show that in contrast to the general assumption, rtvFTD might not be a pure FTLD-TDP type C disorder, unlike its left temporal counterpart svPPA. Large sample size pathological studies are warranted to understand the diverse pathologies of the right and left temporal variants of frontotemporal dementia.
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http://dx.doi.org/10.1186/s40478-021-01229-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330072PMC
August 2021

Measuring Resilience and Resistance in Aging and Alzheimer Disease Using Residual Methods: A Systematic Review and Meta-analysis.

Neurology 2021 09 15;97(10):474-488. Epub 2021 Jul 15.

From the Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience (D.I.B., A.C.v.L., C.G., W.M.v.d.F., R.O.), and Department of Radiology and Nuclear Medicine (F.B.), Vrije Universiteit Amsterdam, Amsterdam UMC, the Netherlands; Institutes of Neurology and Healthcare Engineering (F.B.), University College London, UK; Department of Epidemiology and Biostatistics (W.M.v.d.F.), VU University Medical Center, Amsterdam, the Netherlands; and Clinical Memory Research Unit (R.O.), Lund University, Sweden.

Background And Objective: There is a lack of consensus on how to optimally define and measure resistance and resilience in brain and cognitive aging. Residual methods use residuals from regression analysis to quantify the capacity to avoid (resistance) or cope (resilience) "better or worse than expected" given a certain level of risk or cerebral damage. We reviewed the rapidly growing literature on residual methods in the context of aging and Alzheimer disease (AD) and performed meta-analyses to investigate associations of residual method-based resilience and resistance measures with longitudinal cognitive and clinical outcomes.

Methods: A systematic literature search of PubMed and Web of Science databases (consulted until March 2020) and subsequent screening led to 54 studies fulfilling eligibility criteria, including 10 studies suitable for the meta-analyses.

Results: We identified articles using residual methods aimed at quantifying resistance (n = 33), cognitive resilience (n = 23), and brain resilience (n = 2). Critical examination of the literature revealed that there is considerable methodologic variability in how the residual measures were derived and validated. Despite methodologic differences across studies, meta-analytic assessments showed significant associations of levels of resistance (hazard ratio [HR] [95% confidence interval (CI)] 1.12 [1.07-1.17]; < 0.0001) and levels of resilience (HR [95% CI] 0.46 [0.32-0.68]; < 0.001) with risk of progression to dementia/AD. Resilience was also associated with rate of cognitive decline (β [95% CI] 0.05 [0.01-0.08]; < 0.01).

Discussion: This review and meta-analysis supports the usefulness of residual methods as appropriate measures of resilience and resistance, as they capture clinically meaningful information in aging and AD. More rigorous methodologic standardization is needed to increase comparability across studies and, ultimately, application in clinical practice.
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http://dx.doi.org/10.1212/WNL.0000000000012499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448552PMC
September 2021

On the cutting edge of glioblastoma surgery: where neurosurgeons agree and disagree on surgical decisions.

J Neurosurg 2021 Jul 9:1-11. Epub 2021 Jul 9.

1Department of Neurosurgery, Amsterdam UMC, Vrije Universiteit, Cancer Center Amsterdam.

Objective: The aim of glioblastoma surgery is to maximize the extent of resection while preserving functional integrity. Standards are lacking for surgical decision-making, and previous studies indicate treatment variations. These shortcomings reflect the need to evaluate larger populations from different care teams. In this study, the authors used probability maps to quantify and compare surgical decision-making throughout the brain by 12 neurosurgical teams for patients with glioblastoma.

Methods: The study included all adult patients who underwent first-time glioblastoma surgery in 2012-2013 and were treated by 1 of the 12 participating neurosurgical teams. Voxel-wise probability maps of tumor location, biopsy, and resection were constructed for each team to identify and compare patient treatment variations. Brain regions with different biopsy and resection results between teams were identified and analyzed for patient functional outcome and survival.

Results: The study cohort consisted of 1087 patients, of whom 363 underwent a biopsy and 724 a resection. Biopsy and resection decisions were generally comparable between teams, providing benchmarks for probability maps of resections and biopsies for glioblastoma. Differences in biopsy rates were identified for the right superior frontal gyrus and indicated variation in biopsy decisions. Differences in resection rates were identified for the left superior parietal lobule, indicating variations in resection decisions.

Conclusions: Probability maps of glioblastoma surgery enabled capture of clinical practice decisions and indicated that teams generally agreed on which region to biopsy or to resect. However, treatment variations reflecting clinical dilemmas were observed and pinpointed by using the probability maps, which could therefore be useful for quality-of-care discussions between surgical teams for patients with glioblastoma.
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http://dx.doi.org/10.3171/2020.11.JNS202897DOI Listing
July 2021

Efficacy and safety of temelimab in multiple sclerosis: Results of a randomized phase 2b and extension study.

Mult Scler 2021 Jul 9:13524585211024997. Epub 2021 Jul 9.

Nuclear Magnetic Resonance (NMR) Research Unit, Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, University College London, London, UK/Centre for Medical Image Computing (CMIC), Department of Medical Physics and Biomedical Engineering, University College London, London, UK/Department of Radiology and Nuclear Medicine, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.

Background: The envelope protein of human endogenous retrovirus W (HERV-W-Env) is expressed by macrophages and microglia, mediating axonal damage in chronic active MS lesions.

Objective And Methods: This phase 2, double-blind, 48-week trial in relapsing-remitting MS with 48-week extension phase assessed the efficacy and safety of temelimab; a monoclonal antibody neutralizing HERV-W-Env. The primary endpoint was the reduction of cumulative gadolinium-enhancing T1-lesions in brain magnetic resonance imaging (MRI) scans at week 24. Additional endpoints included numbers of T2 and T1-hypointense lesions, magnetization transfer ratio, and brain atrophy. In total, 270 participants were randomized to receive monthly intravenous temelimab (6, 12, or 18 mg/kg) or placebo for 24 weeks; at week 24 placebo-treated participants were re-randomized to treatment groups.

Results: The primary endpoint was not met. At week 48, participants treated with 18 mg/kg temelimab had fewer new T1-hypointense lesions ( = 0.014) and showed consistent, however statistically non-significant, reductions in brain atrophy and magnetization transfer ratio decrease, as compared with the placebo/comparator group. These latter two trends were sustained over 96 weeks. No safety issues emerged.

Conclusion: Temelimab failed to show an effect on features of acute inflammation but demonstrated preliminary radiological signs of possible anti-neurodegenerative effects. Current data support the development of temelimab for progressive MS.

Trial Registration: CHANGE-MS: ClinicalTrials.gov: NCT02782858, EudraCT: 2015-004059-29; ANGEL-MS: ClinicalTrials.gov: NCT03239860, EudraCT: 2016-004935-18.
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http://dx.doi.org/10.1177/13524585211024997DOI Listing
July 2021

The natural history of primary progressive aphasia: beyond aphasia.

J Neurol 2021 Jul 3. Epub 2021 Jul 3.

Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, De Boelelaan 1118, 1081 HZ, Amsterdam, The Netherlands.

Introduction: Primary progressive aphasia (PPA) is divided into three prototypical subtypes that are all characterized by their single core symptom of aphasia. Although later in their course, other cognitive, behavioral, and motor domains may become involved, little is known about the progression profile of each subtype relative to the other subtypes.

Methods: In this longitudinal retrospective cohort study, based on the recent biomarker-supported diagnostic criteria, 24 subjects diagnosed with semantic variant (svPPA), 22 with non-fluent variant (nfvPPA), and 18 with logopenic variant (lvPPA) were collected and followed up for 1-6 years. Symptom distribution, cognitive test and neuropsychiatric inventory scores, and progression into another syndrome were assessed.

Results: Over time, lvPPA progressed with broader language problems (PPA-extended) and nfvPPA progressed to mutism, whereas semantic impairment remained the major problem in svPPA. Apart from linguistic problems, svPPA developed pronounced behavioral disturbances, whereas lvPPA exhibited a greater cognitive decline. By contrast, in nfvPPA motor deficits were more common. Furthermore, within 5 years (IQR = 2.5) after clinical onset, 65.6% of the patients additionally fulfilled the clinical criteria for another neurodegenerative syndrome (PPA-plus). Fourteen out of 24 (58%) svPPA patients additionally met the diagnostic criteria of behavioral variant frontotemporal dementia (5.1 years, IQR = 1.1), whereas the clinical features of 15/18 (83%) lvPPA patients were consistent with Alzheimer disease dementia (4.5 years IQR = 3.4). Furthermore, 12/22 (54%) of the subjects with the nfvPPA progressed to meet the diagnostic criteria of corticobasal syndrome, progressive supranuclear palsy, or motor neuron disease (5.1 years IQR = 3.4).

Discussion: Despite aphasia being the initial and unique hallmark of the syndrome, our longitudinal results showed that PPA is not a language limited disorder and progression differs widely for each subtype, both with respect to the nature of symptoms and disease duration.
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http://dx.doi.org/10.1007/s00415-021-10689-1DOI Listing
July 2021

[F]Flortaucipir PET Across Various Mutations in Presymptomatic and Symptomatic Carriers.

Neurology 2021 09 1;97(10):e1017-e1030. Epub 2021 Jul 1.

From the Department of Radiology & Nuclear Medicine (E.E.W., S.C.J.V., D.V., E.W., H.T., T.T., R.B., M.Y., F.B., A.D.W., B.N.M.v.B.) and Alzheimer Center Amsterdam, Department of Neurology (E.E.W., C.G., W.M.v.d.F., Y.A.L.P., P.S., R.O.), Amsterdam Neuroscience, and Department of Epidemiology and Biostatistics (W.M.v.d.F.), Vrije Universiteit Amsterdam, Amsterdam UMC; Department of Neurology, Alzheimer Center (J.M.P., E.L.v.d.E., L.A.A.G., J.C.v.S., H.S.), and Department of Radiology & Nuclear Medicine (D.M.E.v.A., D.A.K., M.S.), Erasmus MC University Medical Center, Rotterdam; Department of Pathology (A.J.M.R.), Amsterdam Neuroscience, Amsterdam UMC, location VUmc, the Netherlands; Institutes of Neurology & Healthcare Engineering (F.B.), UCL, London, UK; and Clinical Memory Research Unit (R.O.), Lund University, Sweden.

Objective: To assess the [F]flortaucipir binding distribution across mutations in presymptomatic and symptomatic carriers.

Methods: We compared regional [F]flortaucipir binding potential (BP) derived from a 130-minute dynamic [F]flortaucipir PET scan in 9 (pre)symptomatic mutation carriers (4 with P301L [1 symptomatic], 2 with R406W [1 symptomatic], 1 presymptomatic L315R, 1 presymptomatic S320F, and 1 symptomatic G272V carrier) with 30 cognitively normal controls and 52 patients with Alzheimer disease.

Results: [F]Flortaucipir BP images showed overall highest binding in the symptomatic carriers. This was most pronounced in the symptomatic R406W carrier in whom tau binding exceeded the normal control range in the anterior cingulate cortex, insula, amygdala, temporal, parietal, and frontal lobe. Elevated medial temporal lobe BP was observed in a presymptomatic R406W carrier. The single symptomatic carrier and 1 of the 3 presymptomatic P301L carriers showed elevated [F]flortaucipir BP in the insula, parietal, and frontal lobe compared to controls. The symptomatic G272V carrier exhibited a widespread elevated cortical BP, with at neuropathologic examination a combination of 3R pathology and encephalitis. The L315R presymptomatic mutation carrier showed higher frontal BP compared to controls. The BP values of the S320F presymptomatic mutation carrier fell within the range of controls.

Conclusion: Presymptomatic mutation carriers already showed subtle elevated tau binding, whereas symptomatic mutation carriers showed a more marked increase in [F]flortaucipir BP. Tau deposition was most pronounced in R406W (pre)symptomatic mutation carriers, which is associated with both 3R and 4R tau accumulation. Thus, [F]flortaucipir may serve as an early biomarker for mutation carriers in mutations that cause 3R/4R tauopathies.
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http://dx.doi.org/10.1212/WNL.0000000000012448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448551PMC
September 2021

Glioblastoma Surgery Imaging-Reporting and Data System: Standardized Reporting of Tumor Volume, Location, and Resectability Based on Automated Segmentations.

Cancers (Basel) 2021 Jun 8;13(12). Epub 2021 Jun 8.

Department of Neurosurgery, Amsterdam University Medical Centers, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands.

Treatment decisions for patients with presumed glioblastoma are based on tumor characteristics available from a preoperative MR scan. Tumor characteristics, including volume, location, and resectability, are often estimated or manually delineated. This process is time consuming and subjective. Hence, comparison across cohorts, trials, or registries are subject to assessment bias. In this study, we propose a standardized Glioblastoma Surgery Imaging Reporting and Data System (GSI-RADS) based on an automated method of tumor segmentation that provides standard reports on tumor features that are potentially relevant for glioblastoma surgery. As clinical validation, we determine the agreement in extracted tumor features between the automated method and the current standard of manual segmentations from routine clinical MR scans before treatment. In an observational consecutive cohort of 1596 adult patients with a first time surgery of a glioblastoma from 13 institutions, we segmented gadolinium-enhanced tumor parts both by a human rater and by an automated algorithm. Tumor features were extracted from segmentations of both methods and compared to assess differences, concordance, and equivalence. The laterality, contralateral infiltration, and the laterality indices were in excellent agreement. The native and normalized tumor volumes had excellent agreement, consistency, and equivalence. Multifocality, but not the number of foci, had good agreement and equivalence. The location profiles of cortical and subcortical structures were in excellent agreement. The expected residual tumor volumes and resectability indices had excellent agreement, consistency, and equivalence. Tumor probability maps were in good agreement. In conclusion, automated segmentations are in excellent agreement with manual segmentations and practically equivalent regarding tumor features that are potentially relevant for neurosurgical purposes. Standard GSI-RADS reports can be generated by open access software.
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http://dx.doi.org/10.3390/cancers13122854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229389PMC
June 2021

MRI Natural History of the Leukodystrophy Vanishing White Matter.

Radiology 2021 09 29;300(3):671-680. Epub 2021 Jun 29.

From the Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam 1081 HV, the Netherlands (M.D.S., M.L.A., M.S.v.d.K.); Department of Epidemiology and Data Science, Amsterdam University Medical Centers, Amsterdam, the Netherlands (T.v.d.B.); Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center, Vrije Universiteit and Amsterdam Neuroscience, Amsterdam, the Netherlands (F.B., P.J.W.P.); Institutes of Neurology and Health Care Engineering, University College London, London, England (F.B.); and Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, the Netherlands (M.S.v.d.K.).

Background In vanishing white matter (VWM), a form of leukodystrophy, earlier onset is associated with faster clinical progression. MRI typically shows rarefaction and cystic destruction of the cerebral white matter. Information on the evolution of VWM according to age at onset is lacking. Purpose To determine whether nature and progression of cerebral white matter abnormalities in VWM differ according to age at onset. Materials and Methods Patients with genetically confirmed VWM were stratified into six groups according to age at onset: younger than 1 year, 1 year to younger than 2 years, 2 years to younger than 4 years, 4 years to younger than 8 years, 8 years to younger than 18 years, and 18 years or older. With institutional review board approval, all available MRI scans obtained between 1985 and 2019 were retrospectively analyzed with three methods: ratio of the width of the lateral ventricles over the skull (ventricle-to-skull ratio [VSR]) was measured to estimate brain atrophy; cerebral white matter was visually scored as percentage normal, hyperintense, rarefied, or cystic on fluid-attenuated inversion recovery (FLAIR) images and converted into a white matter decay score; and the intracranial volume was segmented into normal-appearing white and gray matter, abnormal but structurally present (FLAIR-hyperintense) and rarefied or cystic (FLAIR-hypointense) white matter, and ventricular and extracerebral cerebrospinal fluid (CSF). Multilevel regression analyses with patient as a clustering variable were performed to account for the nested data structure. Results A total of 461 examinations in 270 patients (median age, 7 years [interquartile range, 3-18 years]; 144 female patients) were evaluated; 112 patients had undergone serial imaging. Patients with later onset had higher VSR [F(5) = 8.42; < .001] and CSF volume [F(5) = 21.7; < .001] and lower white matter decay score [F(5) = 4.68; < .001] and rarefied or cystic white matter volume [F(5) = 13.3; < .001]. Rate of progression of white matter decay scores [b = -1.6, t(109) = -3.9; < .001] and VSRs [b = -0.05, t (109) = -3.7; < .001] were lower with later onset. Conclusion A radiologic spectrum based on age at onset exists in vanishing white matter. The earlier the onset, the faster and more cystic the white matter decay, whereas with later onset, white matter atrophy and gliosis predominate. © RSNA, 2021.
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http://dx.doi.org/10.1148/radiol.2021210110DOI Listing
September 2021

Differential trajectories of hypometabolism across cognitively-defined Alzheimer's disease subgroups.

Neuroimage Clin 2021 12;31:102725. Epub 2021 Jun 12.

Department of Medicine, University of Washington, Seattle, WA, USA.

Disentangling biologically distinct subgroups of Alzheimer's disease (AD) may facilitate a deeper understanding of the neurobiology underlying clinical heterogeneity. We employed longitudinal [F]FDG-PET standardized uptake value ratios (SUVRs) to map hypometabolism across cognitively-defined AD subgroups. Participants were 384 amyloid-positive individuals with an AD dementia diagnosis from ADNI who had a total of 1028 FDG-scans (mean time between first and last scan: 1.6 ± 1.8 years). These participants were categorized into subgroups on the basis of substantial impairment at time of dementia diagnosis in a specific cognitive domain relative to the average across domains. This approach resulted in groups of AD-Memory (n = 135), AD-Executive (n = 8), AD-Language (n = 22), AD-Visuospatial (n = 44), AD-Multiple Domains (n = 15) and AD-No Domains (for whom no domain showed substantial relative impairment; n = 160). Voxelwise contrasts against controls revealed that all AD-subgroups showed progressive hypometabolism compared to controls across temporoparietal regions at time of AD diagnosis. Voxelwise and regions-of-interest (ROI)-based linear mixed model analyses revealed there were also subgroup-specific hypometabolism patterns and trajectories. The AD-Memory group had more pronounced hypometabolism compared to all other groups in the medial temporal lobe and posterior cingulate, and faster decline in metabolism in the medial temporal lobe compared to AD-Visuospatial. The AD-Language group had pronounced lateral temporal hypometabolism compared to all other groups, and the pattern of metabolism was also more asymmetrical (left < right) than all other groups. The AD-Visuospatial group had faster decline in metabolism in parietal regions compared to all other groups, as well as faster decline in the precuneus compared to AD-Memory and AD-No Domains. Taken together, in addition to a common pattern, cognitively-defined subgroups of people with AD dementia show subgroup-specific hypometabolism patterns, as well as differences in trajectories of metabolism over time. These findings provide support to the notion that cognitively-defined subgroups are biologically distinct.
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http://dx.doi.org/10.1016/j.nicl.2021.102725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238088PMC
September 2021

2021 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis.

Lancet Neurol 2021 08 14;20(8):653-670. Epub 2021 Jun 14.

Section of Neuroradiology, Department of Radiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address:

The 2015 Magnetic Resonance Imaging in Multiple Sclerosis and 2016 Consortium of Multiple Sclerosis Centres guidelines on the use of MRI in diagnosis and monitoring of multiple sclerosis made an important step towards appropriate use of MRI in routine clinical practice. Since their promulgation, there have been substantial relevant advances in knowledge, including the 2017 revisions of the McDonald diagnostic criteria, renewed safety concerns regarding intravenous gadolinium-based contrast agents, and the value of spinal cord MRI for diagnostic, prognostic, and monitoring purposes. These developments suggest a changing role of MRI for the management of patients with multiple sclerosis. This 2021 revision of the previous guidelines on MRI use for patients with multiple sclerosis merges recommendations from the Magnetic Resonance Imaging in Multiple Sclerosis study group, Consortium of Multiple Sclerosis Centres, and North American Imaging in Multiple Sclerosis Cooperative, and translates research findings into clinical practice to improve the use of MRI for diagnosis, prognosis, and monitoring of individuals with multiple sclerosis. We recommend changes in MRI acquisition protocols, such as emphasising the value of three dimensional-fluid-attenuated inversion recovery as the core brain pulse sequence to improve diagnostic accuracy and ability to identify new lesions to monitor treatment effectiveness, and we provide recommendations for the judicious use of gadolinium-based contrast agents for specific clinical purposes. Additionally, we extend the recommendations to the use of MRI in patients with multiple sclerosis in childhood, during pregnancy, and in the post-partum period. Finally, we discuss promising MRI approaches that might deserve introduction into clinical practice in the near future.
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http://dx.doi.org/10.1016/S1474-4422(21)00095-8DOI Listing
August 2021

Prediction of H3K27M-mutant brainstem glioma by amide proton transfer-weighted imaging and its derived radiomics.

Eur J Nucl Med Mol Imaging 2021 Jun 16. Epub 2021 Jun 16.

Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.

Purpose: H3K27M-mutant associated brainstem glioma (BSG) carries a very poor prognosis. We aimed to predict H3K27M mutation status by amide proton transfer-weighted (APTw) imaging and radiomic features.

Methods: Eighty-one BSG patients with APTw imaging at 3T MR and known H3K27M status were retrospectively studied. APTw values (mean, median, and max) and radiomic features within manually delineated 3D tumor masks were extracted. Comparison of APTw measures between H3K27M-mutant and wildtype groups was conducted by two-sample Student's T/Mann-Whitney U test and receiver operating characteristic curve (ROC) analysis. H3K27M-mutant prediction using APTw-derived radiomics was conducted using a machine learning algorithm (support vector machine) in randomly selected train (n = 64) and test (n = 17) sets. Sensitivity analysis with additional random splits of train and test sets, 2D tumor masks, and other classifiers were conducted. Finally, a prospective cohort including 29 BSG patients was acquired for validation of the radiomics algorithm.

Results: BSG patients with H3K27M-mutant were younger and had higher max APTw values than those with wildtype. APTw-derived radiomic measures reflecting tumor heterogeneity could predict H3K27M mutation status with an accuracy of 0.88, sensitivity of 0.92, and specificity of 0.80 in the test set. Sensitivity analysis confirmed the predictive ability (accuracy range: 0.71-0.94). In the independent prospective validation cohort, the algorithm reached an accuracy of 0.86, sensitivity of 0.88, and specificity of 0.85 for predicting H3K27M-mutation status.

Conclusion: BSG patients with H3K27M-mutant had higher max APTw values than those with wildtype. APTw-derived radiomics could accurately predict a H3K27M-mutant status in BSG patients.
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http://dx.doi.org/10.1007/s00259-021-05455-4DOI Listing
June 2021

Cerebrovascular disease, neurodegeneration, and clinical phenotype in dementia with Lewy bodies.

Neurobiol Aging 2021 09 14;105:252-261. Epub 2021 May 14.

Department of Radiology, Mayo Clinic, Rochester, MN, USA. Electronic address:

We investigated whether cerebrovascular disease contributes to neurodegeneration and clinical phenotype in dementia with Lewy bodies (DLB). Regional cortical thickness and subcortical gray matter volumes were estimated from structural magnetic resonance imaging (MRI) in 165 DLB patients. Cortical and subcortical infarcts were recorded and white matter hyperintensities (WMHs) were assessed. Subcortical only infarcts were more frequent (13.3%) than cortical only infarcts (3.1%) or both subcortical and cortical infarcts (2.4%). Infarcts, irrespective of type, were associated with WMHs. A higher WMH volume was associated with thinner orbitofrontal, retrosplenial, and posterior cingulate cortices, smaller thalamus and pallidum, and larger caudate volume. A higher WMH volume was associated with the presence of visual hallucinations and lower global cognitive performance, and tended to be associated with the absence of probable rapid eye movement sleep behavior disorder. Presence of infarcts was associated with the absence of parkinsonism. We conclude that cerebrovascular disease is associated with gray matter neurodegeneration in patients with probable DLB, which may have implications for the multifactorial treatment of probable DLB.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338792PMC
September 2021

Longitudinal Network Changes and Conversion to Cognitive Impairment in Multiple Sclerosis.

Neurology 2021 08 7;97(8):e794-e802. Epub 2021 Jun 7.

From the Department of Anatomy and Neurosciences (M.H., A.J.C.E., T.A.A.B., J.P., J.J.G.G., H.E.H., M.M.S.), Department of Neurology (I.D., B.M.J.U.), and Department of Radiology and Nuclear Medicine (I.D., F.B., A.-M.W.), MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, the Netherlands; and UCL Institutes of Neurology and Healthcare Engineering (F.B.), London, UK.

Objective: To characterize functional network changes related to conversion to cognitive impairment in a large sample of patients with multiple sclerosis (MS) over a period of 5 years.

Methods: Two hundred twenty-seven patients with MS and 59 healthy controls of the Amsterdam MS cohort underwent neuropsychological testing and resting-state fMRI at 2 time points (time interval 4.9 ± 0.9 years). At both baseline and follow-up, patients were categorized as cognitively preserved (CP; n = 123), mildly impaired (MCI; < -1.5 on ≥2 cognitive tests, n = 32), or impaired (CI; < -2 on ≥2 tests, n = 72), and longitudinal conversion between groups was determined. Network function was quantified with eigenvector centrality, a measure of regional network importance, which was computed for individual resting-state networks at both time points.

Results: Over time, 18.9% of patients converted to a worse phenotype; 22 of 123 patients who were CP (17.9%) converted from CP to MCI, 10 of 123 from CP to CI (8.1%), and 12 of 32 patients with MCI converted to CI (37.5%). At baseline, default-mode network (DMN) centrality was higher in CI individuals compared to controls ( = 0.05). Longitudinally, ventral attention network (VAN) importance increased in CP, driven by stable CP and CP-to-MCI converters ( < 0.05).

Conclusions: Of all patients, 19% worsened in their cognitive status over 5 years. Conversion from intact cognition to impairment is related to an initial disturbed functioning of the VAN, then shifting toward DMN dysfunction in CI. Because the VAN normally relays information to the DMN, these results could indicate that in MS normal processes crucial for maintaining overall network stability are progressively disrupted as patients clinically progress.
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http://dx.doi.org/10.1212/WNL.0000000000012341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397585PMC
August 2021
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