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Frederik Barkhof

Publications and source records attributed to Frederik Barkhof.

At least 19 recordsLinked to original sources
PubMed2004

The spinal cord in multiple sclerosis: relationship of high-spatial-resolution quantitative MR imaging findings to histopathologic results.

PURPOSE: To correlate quantitative magnetic resonance (MR) imaging data (ie, relaxation times and magnetization transfer ratios [MTRs]) with histopathologic findings of demyelination and axonal disease in cervical spinal cord specimens from patients with multiple sclerosis (MS) and control subjects. MATERIALS AND METHODS: Formaldehyde-fixed cervical spinal cord specimens from 11 patients with MS-three men and eight women (mean age at death, 66 years +/- 11.3 [standard deviation])-and two female control subjects without neurologic disease (83 and 41 years of age at death) were examined at 4.7 T. Relaxation time measurements and MTR mapping were performed. Analyses included the whole cord area and region-of-interest measurements. Histopathologic analyses included semiquantitative myelin and quantitative axonal analysis. RESULTS: Compared with control specimens (P < .001, analysis of variance), specimens from patients with MS had smaller cord areas (mean area, 59.0 mm(2) +/- 12.5 vs 72.7 mm(2) +/- 10.0), significant prolongation of T1 (mean prolongation, 30%) and T2 (mean prolongation, 13%), and decreased MTRs (mean, 10.5%). Within MS specimens, 58% of the white matter area displayed signal intensity abnormalities on intermediate-weighted MR images. The number of axons in normal-appearing white matter in MS specimens was, on average, 46% lower than the number of axons in white matter in control specimens. All quantitative MR parameters correlated well with demyelination; the correlation with T2 relaxation time was the strongest (r = 0.77, Spearman and Kendall nonparametric correlations). By contrast, quantitative MR parameters correlated less well with axonal density; the correlation with T2 relaxation time was the strongest (r = -0.44, Spearman and Kendall nonparametric correlations). Multilevel analysis, corrected for age and MS phenotype, could not result in a model explaining axonal density on the basis of quantitative MR parameters when myelin density was included as a predictor. CONCLUSION: Changes in quantitative MR imaging parameters in the cervical spinal cord in MS are mainly determined by demyelination and do not reflect axonal disease well.

Adult↗
PubMed2004

White matter lesions and hippocampal atrophy in Alzheimer's disease.

White matter lesions (WML) and hippocampal atrophy (HA) on MRI commonly co-occur in Alzheimer's disease (AD) and are thought to play a role in the etiology of AD. It is still not known whether WML and HA are independent or related. The authors investigated the relation between WML and HA in 179 patients with probable AD who had a cerebral MRI. A linear relation was found between WML and HA, especially for WML in the frontal and parieto-occipital regions. The results suggest that vascular pathology and typical AD pathology (HA) are related.

Aged↗
PubMed2004

Thalamic lesions in vascular dementia: low sensitivity of fluid-attenuated inversion recovery (FLAIR) imaging.

BACKGROUND AND PURPOSE: The criteria of the National Institute of Neurological Disorders and Stroke (NINDS)-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) include thalamic lesions for the diagnosis of vascular dementia (VaD). Although studies concerning VaD and brain aging advocate the use of fluid-attenuated inversion recovery (FLAIR) or T2-weighted images (T2-WI) to detect ischemic lesions, none compared the sensitivity of these sequences to depict thalamic lesions. METHODS: We performed a blinded review of T2-WI and FLAIR images in 73 patients fulfilling the radiological part of the NINDS-AIREN criteria (mean age, 71 years; range, 49 to 83 years). This sample was drawn from a large multicenter trial on VaD and was expected to have a high prevalence of thalamic lesions. In a side-by-side review, including T1-weighted images as well, lesions were classified according to presumed underlying pathology. RESULTS: The total number of thalamic lesions was 214. Two hundred eight (97%) were detected on T2-WI, but only 117 (55%) were detected on FLAIR (chi(2)=5.1; P<0.05). Although the mean size of lesions detected on T2-WI and not on FLAIR (4.4 mm) was significantly lower than the mean size of lesions detected on both sequences (6.7 mm) (P<0.001), 5 of the 29 lesions >10 mm on T2-WI were not visible on FLAIR. FLAIR detected only 81 (51%) of the 158 probable ischemic lesions and 30 (60%) of the 50 probable microbleeds. CONCLUSIONS: FLAIR should not be used as the only T2-weighted sequence to detect thalamic lesions in patients suspected of having VaD.

Aged↗
PubMed2004

Quantitative 1H-MRS of healthy human cortex, hippocampus, and thalamus: metabolite concentrations, quantification precision, and reproducibility.

PURPOSE: To evaluate metabolite concentrations in cortical gray matter, hippocampus, and thalamus of healthy adults, and to investigate precision and reproducibility of quantitative proton magnetic resonance spectroscopy (1H-MRS) in these gray matter regions. MATERIALS AND METHODS: Quantitative single-voxel short echo-time spectra were obtained from healthy human cortex, hippocampus, and thalamus. Subjects were examined twice. Metabolite concentrations, quantification precision, and reproducibility were determined. RESULTS: There were no significant differences between test and retest measurements. Regional differences were observed with respect to metabolite concentrations, quantification precision, and reproducibility. Quantification precision and reproducibility of N-acetylaspartate and N-acetyl aspartylglutamate (tNAA), creatine and phosphocreatine (tCr), choline-containing compounds (Cho), and myo-inositol (myo-Ins), were better than those of glutamate (Glu) and glutamine (Gln). Generally, precision and reproducibility were better in cortex than in hippocampus or thalamus. The quantification precision was shown to correlate both with reproducibility and spectral linewidth. CONCLUSION: The reliability of quantitative MRS depends on the metabolite concerned, its concentration, and on the brain area studied. Moreover, the quantification precision of a metabolite in a single spectrum appears to be a reliable measure for its reproducibility in a longitudinal study.

Adult↗
PubMed2004

Assessing treatment effects on axonal loss--evidence from MRI monitored clinical trials.

Magnetic resonance imaging (MRI) is a collection of very sensitive and versatile techniques for detecting multiple sclerosis (MS) related damage in the central nervous system. Each technique is characterised by a particular combination of sensitivity, tissue and pathological specificity, and technical requirements that enable diverse aspects of MS to be explored.MRI techniques also offer the possibility of quantitatively assessing the effects of therapeutic interventions, and to correlate these effects to clinical outcomes. Of special interest are newer MR techniques that correlate more strongly with disability than gadolinium-enhancement and T2 lesion load, and this review focuses on T1 hypointense lesions, MR spectroscopy, and brain atrophy as surrogate markers of axonal loss, and their application in randomised clinical trials. Several disease-modifying therapies appear to have differential effects on inflammation, demyelination and axonal loss as judged by MRI, illustrating the unique capability of MRI to interrogate the pathophysiology of MS. At the same time it illustrates the difficulties in understanding the mechanisms leading to axonal loss and persistent clinical deficit.

Axons↗
PubMed2004

Monocyte activation and disease activity in multiple sclerosis. A longitudinal analysis of serum MRP8/14 levels.

In active multiple sclerosis (MS) lesions macrophages expressing myeloid related protein (MRP) 8/14 are present. The aim of this study was to determine whether serum levels of MRP8/14 complexes are related to disease activity in MS. In a longitudinal study of 16 relapsing remitting (RR) MS patients that underwent monthly gadolinium diethylentriaminepenta acid (Gd-DTPA) magnetic resonance imaging (MRI), the relation between serum MRP8/14 levels and disease activity was investigated. Patients were participating in a monoclonal antibody study targeting a specific T cell population (Vbeta5.2/5.3+ T-cells). In time, within patients large variations in serum MRP8/14 levels were observed. Serum MRP8/14 levels were not related to changes in clinical disease activity or increase in Gd-DTPA lesion enhancement. Neither did comparison of active (>1 relapse in follow-up period) with inactive (0-1 relapse) MS patients reveal any differences in MRP8/14 levels. Therefore, we conclude that although MRP8/14 expression is a good histopathological marker for monocyte activation, serum levels of these proteins do not correlate with disease activity in RR MS.

Adult↗
PubMed2004

Gender-related association between the TGFB1+869 polymorphism and multiple sclerosis.

Our objective was to investigate whether polymorphisms and haplotypes in the TGFB1 gene are associated with susceptibility or disease characteristics of multiple sclerosis (MS). In 247 MS patients and 194 controls, single nucleotide polymorphisms (SNPs) at position +869 (Leu10Pro) and position +915 (Arg25Pro) in the signaling sequence of the TGFB1 gene were determined, and the distribution of alleles, genotypes, and haplotypes was related to clinical data. In addition, magnetic resonance imaging (MRI) data were studied in a subgroup of patients (n = 96). The allele distribution of the two polymorphisms studied was in Hardy-Weinberg equilibrium in patients and in controls. No association was found with any of the three haplotypes found in the Dutch population, denoted as haplotype 1 (TGFB1+869T-TGFB1+915G), haplotype 2 (TGFB1+869C-TGFB1+915G), and haplotype 3 (TGFB1+869C-TGFB1+915C). However, the TGFB1+869 genotype CC was significantly more frequent in patients (p = 0.031, chi2 test). The highest frequency of the TGFB1+869 genotype CC was observed in male patients (25.2% vs. 10.0% in controls, p = 0.004, chi2 test), and carriership of TGFB1+869 allele C was correspondingly increased in male patients (74.8% vs. 56.7%, p = 0.008, chi2 test, OR 2.27, 95% CI 1.23-4.17). Although there was no association with clinical markers of disease progression, patients homozygous for TGFB1+869 allele C showed a significantly higher annual increase in two MRI parameters: ventricular fraction (central atrophy) and T1-hypointense lesion load (matrix destruction). The TGFB1 T+869C (Leu10Pro) gene polymorphism is associated with MS susceptibility, especially in males, and with a more destructive course of the disease as illustrated by MRI.

Adult↗
PubMed2004

Pattern of white matter abnormalities at MR imaging: use of polymerase chain reaction testing of Guthrie cards to link pattern with congenital cytomegalovirus infection.

PURPOSE: To define a magnetic resonance (MR) imaging pattern suggestive of congenital cytomegalovirus (CMV) infection by using polymerase chain reaction (PCR) testing to detect CMV DNA in neonatal blood on Guthrie cards for validation. MATERIALS AND METHODS: On the basis of findings in eight patients with documented congenital CMV infection, the authors developed MR imaging inclusion criteria, including multifocal lesions predominantly located in the deep parietal white matter. If gyral abnormalities were present, white matter lesions were either multifocal or diffuse. The criteria were applied to 152 patients with static leukoencephalopathy of unknown etiology. Guthrie cards for 22 of the 43 patients fulfilling the MR imaging criteria, 20 patients not fulfilling them, and 300 control subjects were analyzed. Fisher exact testing was used to evaluate the association between MR imaging characteristics and CMV status, and backward elimination linear discriminant analysis was used to identify MR imaging characteristics predictive of CMV infection in addition to the initial criteria. RESULTS: PCR test results were positive in 12 of 22 patients suspected of having congenital CMV infection, in no patient not suspected of having infection (P <.001), and in two of 300 control subjects (negative predictive value [NPV] of MR imaging criteria, 100% [95% CI: 83%, 100%]; positive predictive value [PPV], 55% [95% CI: 32%, 76%]). The most important additional MR imaging finding predicting a positive PCR result was abnormality of the anterior part of the temporal lobe, including abnormal white matter, cysts, and enlargement of inferior horns. Including this finding in the MR imaging criteria enhanced the PPV (89%; 95% CI: 52%, 99%) at the expense of the NPV (88%; 95% CI: 72%, 97%). CONCLUSION: In patients with static encephalopathy, an MR imaging pattern of multifocal lesions predominantly involving deep parietal white matter, with or without gyral abnormalities, is predictive of congenital CMV infection. When gyral abnormalities are present, leukoencephalopathy may also be diffuse. The presence of abnormalities in the anterior part of the temporal lobe increases the likelihood that CMV infection is present.

Brain↗
PubMed2004

An fMRI study of planning-related brain activity in patients with moderately advanced multiple sclerosis.

INTRODUCTION: Cognitive impairment occurs in a substantial number of multiple sclerosis (MS) patients and often includes frontal lobe dysfunction. We used functional magnetic resonance imaging (fMRI) to study planning, an executive function, in moderately impaired MS patients. METHODS: An fMRI version of the Tower of London (ToL) test was used to study patterns of brain activation in 23 MS patients and 18 healthy controls. The median score on the Expanded Disability Status Scale (EDSS) for the MS patients was 4. fMRI data were analysed using whole brain random effects analysis as well as region of interest (ROI)-based methods to assess group effects. Within the MS group, associations with behavioural data and measures of disease severity (lesion load from structural MRI) were examined. RESULTS: Test performance in MS patients was significantly worse than in controls. Group analysis for the MS patients and the controls showed for both groups globally the same areas of activation, located in the frontal and parietal lobes bilaterally and the cerebellum. Although visual inspection suggested a larger extent of activation in the MS group, no statistically significant differences between groups were found. In the ROI analysis, statistically significant larger extent of activation was only found in the cerebellum. No association between disease severity and brain activity could be determined in the MS group. CONCLUSION: In MS patients with moderate disability and structural damage, the pattern and extent of brain activation during planning were maintained despite poorer performance. In contrast to other studies showing increased activity, the failure to do so in our group may reflect exhaustion of adaptive mechanisms.

Adult↗
PubMed2003

A paced visual serial addition test for fMRI.

BACKGROUND AND PURPOSE: The Paced Auditory Serial Attention Task (PASAT) is an attention and information processing task used in patients with diffuse brain disorders, like cerebral trauma and multiple sclerosis (MS). Based on the PASAT we used a adapted version of the test to assess several cognitive functions with fMRI. In this study we investigated the activation pattern on a group and individual level and upon parametric stimulation. METHODS: Nine young, healthy, right-handed subjects (mean age 24 years) were studied. The test contrasts an adding-and-memory stage with a control stage in a block design, at two different speeds. Group average maps (random effects analysis, p=0.05) were created to identify the brain areas subserving this task. For each area found active in the group map, the percentage of individuals showing activation in that same anatomical area was calculated. RESULTS: Group activation was localized in the superior and inferior parietal lobe bilaterally, the superior frontal gyrus bilaterally, the left medial frontal gyrus, the left inferior frontal gyrus and adjacent part of the insula, the anterior part of the cingulate gyrus and some cerebellar areas. For the main activated areas, 78-100% of the individual subjects showed activation in that same area. Contrasting the low speed with the high speed condition yielded activation with a considerable individual variation. CONCLUSION: The group mean activated areas were located mainly in the frontal and parietal lobes and those areas were also activated in the majority of the subjects, indicating limited inter-individual variation, rendering this test suitable for clinical applications in a variety of neurological disorders.

Adult↗
PubMed2003

Thallium-201 single-photon emission computed tomography as an early predictor of outcome in recurrent glioma.

PURPOSE: With limited response rates and potential toxicity of chemotherapeutic treatment in patients with recurrent glioma, reliable response assessment is essential. Currently, the assessment of treatment response in glioma patients is based on the combination of radiologic and clinical findings. However, response monitoring with computed tomography (CT) or magnetic resonance imaging (MRI) is hampered by several pitfalls and is prone to interobserver variability. The aim of this study was to establish the value of thallium-201 single-photon emission computed tomography (201Tl-SPECT) as a predictor of overall survival and response to chemotherapy in recurrent glioma, and to compare the value of 201Tl-SPECT with that of CT and MRI. PATIENTS AND METHODS: We studied patients who underwent CT or MRI and 201Tl-SPECT before chemotherapy (n = 57), and patients who also had undergone CT or MRI and 201Tl-SPECT after two courses of chemotherapy (n = 44). The value of the radiologic variables (CT-MRI tumor size, 201Tl-SPECT tumor size, and maximal tumor intensity) at baseline and at follow-up in predicting overall survival, and the percentage of patients alive and progression-free at 6 months (APF6) were examined using Cox regression and logistic regression analysis. RESULTS: Both at baseline and at follow-up, 201Tl-SPECT maximal tumor intensity was the strongest predictive variable and was inversely related to overall survival and APF6. In particular, progression of maximal tumor intensity after two courses of chemotherapy was a powerful predictor of poor outcome. CONCLUSION: 201Tl-SPECT is superior to conventional CT-MRI in the early prediction of overall survival and response to chemotherapy in patients with recurrent glioma.

Adult↗
PubMed2003

Operational definitions for the NINDS-AIREN criteria for vascular dementia: an interobserver study.

BACKGROUND AND PURPOSE: Vascular dementia (VaD) is thought to be the most common cause of dementia after Alzheimer's disease. The commonly used International Workshop of the National Institute of Neurological Disorders and Stroke (NINDS) and the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) criteria for VaD necessitate evidence of vascular disease on CT or MRI of the brain. The purposes of our study were to operationalize the radiological part of the NINDS-AIREN criteria and to assess the effect of this operationalization on interobserver agreement. METHODS: Six experienced and 4 inexperienced observers rated a set of 40 MRI studies of patients with clinically suspected VaD twice using the NINDS-AIREN set of radiological criteria. After the first reading session, operational definitions were conceived, which were subsequently used in the second reading session. Interobserver reproducibility was measured by Cohen's kappa. RESULTS: Overall agreement at the first reading session was poor (kappa=0.29) and improved slightly after application of the additional definitions (kappa=0.38). Raters in the experienced group improved their agreement from almost moderate (kappa=0.39) to good (0.62). The inexperienced group started out with poor agreement (kappa=0.17) and did not improve (kappa=0.18). The experienced group improved in both the large- and small-vessel categories, whereas the inexperienced group improved generally in the extensive white matter hyperintensities categories. CONCLUSIONS: Considerable interobserver variability exists for the assessment of the radiological part of the NINDS-AIREN criteria. Use of operational definitions improves agreement but only for already experienced observers.

Brain↗
PubMed2003

Remyelinated lesions in multiple sclerosis: magnetic resonance image appearance.

BACKGROUND: Various types of pathologic mechanisms in multiple sclerosis (MS) can alter magnetic resonance imaging (MRI) signals, and the appearance of remyelinated lesions on MRI is largely unknown. OBJECTIVE: To describe the MRI appearance of remyelinated lesions in MS. DESIGN: Comparison of postmortem MRI findings with histopathologic findings. SETTING: Brain donations from a general community. Patients Magnetic resonance images from 36 rapid autopsies yielded 161 areas that could be matched with histologic characteristics, including 149 focal T2-weighted abnormalities, with a range of signal intensities on T1-weighted images. In a subset of 49 lesions, magnetization transfer ratio could be determined. MAIN OUTCOME MEASURES: An observer blinded to the MRI findings assessed the presence of remyelination using light microscopic criteria; in 25 areas, in situ hybridization was used to assess the presence of oligodendrocytes expressing proteolipid protein messenger RNA. RESULTS: Remyelinated areas were found in 67 lesions (42%): partial remyelination was present in 30 lesions (19%), whereas 37 lesions (23%) were fully remyelinated. Remyelinated lesions contained enhanced numbers of oligodendrocytes containing proteolipid protein messenger RNA. All areas with remyelination shown histopathologically were hyperintense on T2-weighted images. Strong hypointensity on T1-weighted images was significantly associated (chi2 = 29.8, P<.001) with demyelinated and partially remyelinated lesions compared with fully remyelinated lesions. The magnetization transfer ratio of remyelinated lesions (mean [SD], 27.6% [41%]) differed (F = 46.3, P<.001) from both normal-appearing white matter (35.2% [32%]) and demyelinated lesions (22.3% [48%]). CONCLUSIONS: Remyelinated lesions return an abnormal signal on T2-weighted images. Both T1-weighted images and magnetization transfer ratio may have (limited) additional value in separating lesions with and without remyelination.

Adult↗
PubMed2003

A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate.

We identified eight patients with a distinct magnetic resonance imaging pattern of inhomogeneous cerebral white matter abnormalities and selective involvement of brainstem and spinal tracts. Proton magnetic resonance imaging showed increased lactate in the abnormal white matter. Clinically, the patients had slowly progressive pyramidal, cerebellar, and dorsal column dysfunction. The uniform, highly characteristic magnetic resonance imaging pattern and the similarities in clinical and magnetic resonance spectroscopy findings provide evidence for a new disease entity. Autosomal recessive inheritance is likely.

Adolescent↗
PubMed2003

Validation of diagnostic magnetic resonance imaging criteria for multiple sclerosis and response to interferon beta1a.

In the recently proposed diagnostic criteria for multiple sclerosis (MS) by McDonald, the modified magnetic resonance imaging (MRI) Barkhof criteria have been incorporated. We examined the validity of this implementation in the Early Treatment of MS study, a randomized, double-blind, placebo-controlled study of 22 microg interferon beta1a given subcutaneously once weekly in 309 patients with a first episode consistent with demyelinating disease (and abnormal MRI). Conversion to clinically definite MS (CDMS) within 2 years of follow-up, as evidenced by a new clinical episode, occurred in 41% of patients (independent of treatment) with gadolinium enhancement or nine or more T2 lesions versus 11% of those without either finding (p = 0.017); similarly, proportions converting were 44% versus 31% for infratentorial lesions (p = 0.026), 40% versus 35% for juxtacortical lesions (p = 0.413), and 41% versus 17% for three or more periventricular lesions (p = 0.034). The rate of conversion to CDMS based on the number of modified Barkhof criteria was 22% for two or fewer positive criteria, increasing to 47% with four positive criteria. For a cutoff of three positive criteria, the hazard ratio for time to CDMS was 2.3 (95% confidence interval, 1.17-4.55; p = 0.016). Treatment effect seemed more evident as the number of positive criteria increased, and the number of patients needed to avoid one patient converting to CDMS decreased from 50 in patients with one or two positive criteria to 5.6 in patients with four positive criteria. However, the study was not powered to detect statistically significant treatment by variable interaction, and this remains an important issue for further study.

Adjuvants, Immunologic↗
PubMed2003

Guidelines for using quantitative magnetization transfer magnetic resonance imaging for monitoring treatment of multiple sclerosis.

Quantitative evaluation of brain magnetic resonance imaging (MRI) scans is now an accepted part of the trial of new putative treatments for multiple sclerosis (MS). However, conventional MRI is not pathologically specific, and it does not reveal the details of the pathological processes that underlie the progression of the disease. Magnetization transfer (MT) imaging is a relatively new quantitative technique that appears to offer some pathological specificity, and can be used to monitor the changes over time in both individual lesions and the central nervous system as a whole. This paper considers the case for incorporating MT imaging into new clinical trials, so that the utility of MT for monitoring the modification of MS progression by treatment can be assessed. Specific guidelines for implementing MT imaging as part of a large multicenter clinical trial are given, and practical considerations when planning such a trial are detailed. It is anticipated that MT imaging will be incorporated into many new trials in the near future.

Brain↗
PubMed2003

Multislice T1 relaxation time measurements in the brain using IR-EPI: reproducibility, normal values, and histogram analysis in patients with multiple sclerosis.

PURPOSE: To perform T(1) measurements using inversion recovery (IR) echoplanar imaging (EPI) to evaluate reproducibility, normal values, and T(1) histogram analysis as a measure of disease progression in multiple sclerosis (MS) patients. MATERIALS AND METHODS: Multislice IR-EPI was performed in 10 controls and 36 MS patients. Region-of-interest (ROI) and T(1) histogram analysis were performed on T(1) maps and compared to hypointense T(1) lesions and brain atrophy in MS patients. RESULTS: Coefficient of variation (COV) varied from 1.6% to 4.9%. Callosal normal (appearing) white matter (N(A)WM) showed the lowest and cortical gray matter the highest T(1) values. T(1) histogram analysis in controls showed a sharp WM peak centered on a T(1) value of 729 msec (range = 679-765) with extension into a shoulder of higher T(1) values. In MS patients, a shift toward higher T(1) values (mean = 788 msec, range = 700-957) with a lower relative peak amplitude was present, predominantly resulting from T(1) prolongation in NAWM. T(1) histogram parameters strongly related to hypointense T(1) lesion volume and brain atrophy in MS patients. CONCLUSIONS: IR-EPI provides a reproducible method to obtain T(1) values in the brain. Regional variation in T(1) values is present in N(A)WM of volunteers and MS patients. Since T(1) histogram parameters reflect changes in NAWM and correlate with conventional measures of disease burden in MS patients, T(1) histogram analysis may provide a global measure of disease progression in MS.

Adult↗