Grey matter (GM) atrophy is a prominent aspect of multiple sclerosis pathology and an important o... more Grey matter (GM) atrophy is a prominent aspect of multiple sclerosis pathology and an important outcome in studies. GM atrophy measurement requires accurate GM segmentation. Several methods are used in vivo for measuring GM volumes in MS, but assessing their validity in vivo remains challenging. In this postmortem study, we evaluated the correlation between postmortem MRI cortical volume or thickness and the cortical thickness measured on histological sections. Sixteen MS brains were scanned in situ using 3DT1-weighted MRI and these images were used to measure regional cortical volume using FSL-SIENAX, FreeSurfer, and SPM, and regional cortical thickness using FreeSurfer. Subsequently, cortical thickness was measured histologically in 5 systematically sampled cortical areas. Linear regression analyses were used to evaluate the relation between MRI regional cortical volume or thickness and histological cortical thickness to determine which postprocessing technique was most valid. Aft...
Studies disagree on the location of grey matter (GM) atrophy in the multiple sclerosis (MS) brain... more Studies disagree on the location of grey matter (GM) atrophy in the multiple sclerosis (MS) brain. To examine the consistency between FSL, FreeSurfer, SPM for GM atrophy measurement (for volumes, patient/control discrimination, and correlations with cognition). 127 MS patients and 50 controls were included and cortical and deep grey matter (DGM) volumetrics were performed. Consistency of volumes was assessed with Intraclass Correlation Coefficient/ICC. Consistency of patients/controls discrimination was assessed with Cohen's d, t-tests, MANOVA and a penalized double-loop logistic classifier. Consistency of association with cognition was assessed with Pearson correlation coefficient and ANOVA. Voxel-based morphometry (SPM-VBM and FSL-VBM) and vertex-wise FreeSurfer were used for group-level comparisons. The highest volumetry ICC were between SPM and FreeSurfer for cortical regions, and the lowest between SPM and FreeSurfer for DGM. The caudate nucleus and temporal lobes had high consistency between all software, while amygdala had lowest volumetric consistency. Consistency of patients/controls discrimination was largest in the DGM for all software, especially for thalamus and pallidum. The penalized double-loop logistic classifier most often selected the thalamus, pallidum and amygdala for all software. FSL yielded the largest number of significant correlations. DGM yielded stronger correlations with cognition than cortical volumes. Bilateral putamen and left insula volumes correlated with cognition using all methods. GM volumes from FreeSurfer, FSL and SPM are different, especially for cortical regions. While group-level separation between MS and controls is comparable, correlations between regional GM volumes and clinical/cognitive variables in MS should be cautiously interpreted.
Journal of neurology, neurosurgery, and psychiatry, 2015
To examine the temporal evolution of spinal cord (SC) atrophy in multiple sclerosis (MS), and its... more To examine the temporal evolution of spinal cord (SC) atrophy in multiple sclerosis (MS), and its association with clinical progression in a large MS cohort. A total of 352 patients from two centres with MS (relapsing remitting MS (RRMS): 256, secondary progressive MS (SPMS): 73, primary progressive MS (PPMS): 23) were included. Clinical and MRI parameters were obtained at baseline, after 12 months and 24 months of follow-up. In addition to conventional brain and SC MRI parameters, the annualised percentage brain volume change and the annualised percentage upper cervical cord cross-sectional area change (aUCCA) were quantified. Main outcome measure was disease progression, defined by expanded disability status scale increase after 24 months. UCCA was lower in SPMS and PPMS compared with RRMS for all time points. aUCCA over 24 months was highest in patients with SPMS (-2.2% per year) and was significantly higher in patients with disease progression (-2.3% per year) than in stable pat...
Multiple sclerosis (Houndmills, Basingstoke, England), Jan 12, 2015
Cortical atrophy, assessed with magnetic resonance imaging (MRI), is an important outcome measure... more Cortical atrophy, assessed with magnetic resonance imaging (MRI), is an important outcome measure in multiple sclerosis (MS) studies. However, the underlying histopathology of cortical volume measures is unknown. We investigated the histopathological substrate of MRI-measured cortical volume in MS using combined post-mortem imaging and histopathology. MS brain donors underwent post-mortem whole-brain in-situ MRI imaging. After MRI, tissue blocks were systematically sampled from the superior and inferior frontal gyrus, anterior cingulate gyrus, inferior parietal lobule, and superior temporal gyrus. Histopathological markers included neuronal, axonal, synapse, astrocyte, dendrite, myelin, and oligodendrocyte densities. Matched cortical volumes from the aforementioned anatomical regions were measured on the MRI, and used as outcomes in a nested prediction model. Forty-five tissue blocks were sampled from 11 MS brain donors. Mean age at death was 68±12 years, post-mortem interval 4±1 ho...
The back-to-back (BTB) acquisition of MP-RAGE MRI scans of the Alzheimer׳s Disease Neuroimaging I... more The back-to-back (BTB) acquisition of MP-RAGE MRI scans of the Alzheimer׳s Disease Neuroimaging Initiative (ADNI1) provides an excellent data set with which to check the reproducibility of brain atrophy measures. As part of ADNI1, 131 subjects received BTB MP-RAGEs at multiple time points and two field strengths of 3T and 1.5 T. As a result, high quality data from 200 subject-visit-pairs was available to compare the reproducibility of brain atrophies measured with FSL/SIENA over 12 to 18 month intervals at both 3T and 1.5 T. Although several publications have reported on the differing performance of brain atrophy measures at 3T and 1.5 T, no formal comparison of reproducibility has been published to date. Another goal was to check whether tuning SIENA options, including -B, -S, -R and the fractional intensity threshold (f) had a significant impact on the reproducibility. The BTB reproducibility for SIENA was quantified by the 50th percentile of the absolute value of the difference in the percentage brain volume change (PBVC) for the BTB MP-RAGES. At both 3T and 1.5 T the SIENA option combination of "-B f=0.2", which is different from the default values of f=0.5, yielded the best reproducibility as measured by the 50th percentile yielding 0.28 (0.23-0.39)% and 0.26 (0.20-0.32)%. These results demonstrated that in general 3T had no advantage over 1.5 T for the whole brain atrophy measure - at least for SIENA. While 3T MRI is superior to 1.5 T for many types of measurements, and thus worth the additional cost, brain atrophy measurement does not seem to be one of them.
Gray matter (GM) atrophy is common in multiple sclerosis (MS), as is cognitive dysfunction. Under... more Gray matter (GM) atrophy is common in multiple sclerosis (MS), as is cognitive dysfunction. Understanding the exact relationship between atrophy and cognition requires further investigation. The aim of this study was to investigate the relationship between subcortical GM atrophy and cognition in early relapsing onset MS. Structural MRI and neuropsychological evaluations were performed in 120 patients (80 women) and 50 controls (30 women), part of an early inception cohort, 6 years postdiagnosis. Deep GM volumes were segmented automatically. Cognition was assessed in 7 domains. Stepwise linear regression was used to predict average cognition in the patient group. Most deep GM volumes were reduced in patients, with larger effects on average in men (-11%) than in women (-6.3%). Only the bilateral hippocampus, amygdala, and right nucleus accumbens in men, and right hippocampus and nucleus accumbens, bilateral amygdala, and putamen in women, showed no atrophy compared to controls. All cognitive domains except visuospatial memory were affected in men; none were significantly affected in women. In the MS group, average cognition was best predicted by thalamic volume, sex, and education (adjusted R(2) = 0.31), while lesion volume was not a significant predictor in the model. Six years postdiagnosis, almost all subcortical structures were affected by MS, especially in men. Cognition was most severely affected in male patients. Thalamic volume, sex, and education best predicted average cognition. These results underline the relevance of specific subcortical structures to cognition, as well as the relevance of (sex-specific) atrophy in MS.
Body fluid biomarkers for clinical subtyping and monitoring of disease progression are of conside... more Body fluid biomarkers for clinical subtyping and monitoring of disease progression are of considerable interest in multiple sclerosis (MS). Proteomics tools are optimal for the unbiased simultaneous detection of large series of peptides and proteins. To identify novel candidate biomarkers discriminating patients with MS from patients with other neurological diseases (OND), and for subtyping of relapsing-remitting (RR), secondary progressive (SP) and primary progressive (PP) MS patients using a high-throughput MALDI-TOF-based mass spectrometry method. Paired cerebrospinal fluid (CSF) and serum samples of 41 RRMS, 30 SPMS, 13 PPMS patients and 25 patients with OND were analysed. Out of a total of 100 detected peptides in CSF and 200 peptides in serum, 11 peptides were differentially regulated in serum and two in CSF between patients with MS and the OND control group. Eleven peptides were differentially regulated in both serum and CSF between relapse-onset MS and PPMS patients. Lastly, four peptides were differentially regulated in serum and two in CSF between RRMS and SPMS patients. Specific peaks regulated in MS were tentatively identified as fragments of secretogranin III and complement C3. The peak intensity of the CSF peptide ion with m/z value 8607.7 correlated to atrophy (r = -0.27, p < 0.005), black hole volumes (r = 0.31, p < 0.008) and total lesion load (r = 0.34, p < 0.003). A serum peptide with m/z value of 872.4 elevated in SPMS correlated to Expanded Disability Status Scale (r = 0.341, p < 0.005) and atrophy (r = -0.286, p < 0.028). Using high-throughput body fluid profiling by MALDI-TOF mass spectrometry, small proteins and peptides were detected as promising candidate biomarkers for diagnosis and disease progression of MS.
Cholesterol homeostasis is important for formation and maintenance of myelin and axonal membranes... more Cholesterol homeostasis is important for formation and maintenance of myelin and axonal membranes in the central nervous system (CNS). The concentrations of the brain specific cholesterol metabolite 24S-hydroxycholesterol (24OHC) and cholesterol precursors have been shown to be altered in multiple sclerosis (MS). However, how changes in sterol levels relate to the pathological processes in MS is not clear. In this study, we compared serum and cerebrospinal fluid (CSF) sterol levels between 105 MS (51 relapsing-remitting (RR); 39 secondary progressive (SP) and 15 primary progressive (PP)) and 49 control patients. Sterol levels were correlated to magnetic resonance imaging (MRI) markers of disease activity. We found decreased serum 24OHC and 27-hydroxycholesterol (27OHC) and increased CSF lathosterol in MS patients compared to control patients (p=0.018, p=0.002 and p=0.002, respectively). Subgroup analysis showed that serum 24OHC levels were negatively correlated to normalized brain volume measurements in relapse-onset MS patients (r= -0.326, p=0.004). These results confirm that cholesterol homeostasis is disturbed in MS and suggest that changes in cholesterol synthesis are related to neurodegenerative pathological processes as seen on the MRI. The data seem to be in line with the recently reported observation that high dose statins may have a positive effect on clinical disability in secondary progressive MS.
Grey matter (GM) atrophy is a prominent aspect of multiple sclerosis pathology and an important o... more Grey matter (GM) atrophy is a prominent aspect of multiple sclerosis pathology and an important outcome in studies. GM atrophy measurement requires accurate GM segmentation. Several methods are used in vivo for measuring GM volumes in MS, but assessing their validity in vivo remains challenging. In this postmortem study, we evaluated the correlation between postmortem MRI cortical volume or thickness and the cortical thickness measured on histological sections. Sixteen MS brains were scanned in situ using 3DT1-weighted MRI and these images were used to measure regional cortical volume using FSL-SIENAX, FreeSurfer, and SPM, and regional cortical thickness using FreeSurfer. Subsequently, cortical thickness was measured histologically in 5 systematically sampled cortical areas. Linear regression analyses were used to evaluate the relation between MRI regional cortical volume or thickness and histological cortical thickness to determine which postprocessing technique was most valid. Aft...
Studies disagree on the location of grey matter (GM) atrophy in the multiple sclerosis (MS) brain... more Studies disagree on the location of grey matter (GM) atrophy in the multiple sclerosis (MS) brain. To examine the consistency between FSL, FreeSurfer, SPM for GM atrophy measurement (for volumes, patient/control discrimination, and correlations with cognition). 127 MS patients and 50 controls were included and cortical and deep grey matter (DGM) volumetrics were performed. Consistency of volumes was assessed with Intraclass Correlation Coefficient/ICC. Consistency of patients/controls discrimination was assessed with Cohen's d, t-tests, MANOVA and a penalized double-loop logistic classifier. Consistency of association with cognition was assessed with Pearson correlation coefficient and ANOVA. Voxel-based morphometry (SPM-VBM and FSL-VBM) and vertex-wise FreeSurfer were used for group-level comparisons. The highest volumetry ICC were between SPM and FreeSurfer for cortical regions, and the lowest between SPM and FreeSurfer for DGM. The caudate nucleus and temporal lobes had high consistency between all software, while amygdala had lowest volumetric consistency. Consistency of patients/controls discrimination was largest in the DGM for all software, especially for thalamus and pallidum. The penalized double-loop logistic classifier most often selected the thalamus, pallidum and amygdala for all software. FSL yielded the largest number of significant correlations. DGM yielded stronger correlations with cognition than cortical volumes. Bilateral putamen and left insula volumes correlated with cognition using all methods. GM volumes from FreeSurfer, FSL and SPM are different, especially for cortical regions. While group-level separation between MS and controls is comparable, correlations between regional GM volumes and clinical/cognitive variables in MS should be cautiously interpreted.
Journal of neurology, neurosurgery, and psychiatry, 2015
To examine the temporal evolution of spinal cord (SC) atrophy in multiple sclerosis (MS), and its... more To examine the temporal evolution of spinal cord (SC) atrophy in multiple sclerosis (MS), and its association with clinical progression in a large MS cohort. A total of 352 patients from two centres with MS (relapsing remitting MS (RRMS): 256, secondary progressive MS (SPMS): 73, primary progressive MS (PPMS): 23) were included. Clinical and MRI parameters were obtained at baseline, after 12 months and 24 months of follow-up. In addition to conventional brain and SC MRI parameters, the annualised percentage brain volume change and the annualised percentage upper cervical cord cross-sectional area change (aUCCA) were quantified. Main outcome measure was disease progression, defined by expanded disability status scale increase after 24 months. UCCA was lower in SPMS and PPMS compared with RRMS for all time points. aUCCA over 24 months was highest in patients with SPMS (-2.2% per year) and was significantly higher in patients with disease progression (-2.3% per year) than in stable pat...
Multiple sclerosis (Houndmills, Basingstoke, England), Jan 12, 2015
Cortical atrophy, assessed with magnetic resonance imaging (MRI), is an important outcome measure... more Cortical atrophy, assessed with magnetic resonance imaging (MRI), is an important outcome measure in multiple sclerosis (MS) studies. However, the underlying histopathology of cortical volume measures is unknown. We investigated the histopathological substrate of MRI-measured cortical volume in MS using combined post-mortem imaging and histopathology. MS brain donors underwent post-mortem whole-brain in-situ MRI imaging. After MRI, tissue blocks were systematically sampled from the superior and inferior frontal gyrus, anterior cingulate gyrus, inferior parietal lobule, and superior temporal gyrus. Histopathological markers included neuronal, axonal, synapse, astrocyte, dendrite, myelin, and oligodendrocyte densities. Matched cortical volumes from the aforementioned anatomical regions were measured on the MRI, and used as outcomes in a nested prediction model. Forty-five tissue blocks were sampled from 11 MS brain donors. Mean age at death was 68±12 years, post-mortem interval 4±1 ho...
The back-to-back (BTB) acquisition of MP-RAGE MRI scans of the Alzheimer׳s Disease Neuroimaging I... more The back-to-back (BTB) acquisition of MP-RAGE MRI scans of the Alzheimer׳s Disease Neuroimaging Initiative (ADNI1) provides an excellent data set with which to check the reproducibility of brain atrophy measures. As part of ADNI1, 131 subjects received BTB MP-RAGEs at multiple time points and two field strengths of 3T and 1.5 T. As a result, high quality data from 200 subject-visit-pairs was available to compare the reproducibility of brain atrophies measured with FSL/SIENA over 12 to 18 month intervals at both 3T and 1.5 T. Although several publications have reported on the differing performance of brain atrophy measures at 3T and 1.5 T, no formal comparison of reproducibility has been published to date. Another goal was to check whether tuning SIENA options, including -B, -S, -R and the fractional intensity threshold (f) had a significant impact on the reproducibility. The BTB reproducibility for SIENA was quantified by the 50th percentile of the absolute value of the difference in the percentage brain volume change (PBVC) for the BTB MP-RAGES. At both 3T and 1.5 T the SIENA option combination of "-B f=0.2", which is different from the default values of f=0.5, yielded the best reproducibility as measured by the 50th percentile yielding 0.28 (0.23-0.39)% and 0.26 (0.20-0.32)%. These results demonstrated that in general 3T had no advantage over 1.5 T for the whole brain atrophy measure - at least for SIENA. While 3T MRI is superior to 1.5 T for many types of measurements, and thus worth the additional cost, brain atrophy measurement does not seem to be one of them.
Gray matter (GM) atrophy is common in multiple sclerosis (MS), as is cognitive dysfunction. Under... more Gray matter (GM) atrophy is common in multiple sclerosis (MS), as is cognitive dysfunction. Understanding the exact relationship between atrophy and cognition requires further investigation. The aim of this study was to investigate the relationship between subcortical GM atrophy and cognition in early relapsing onset MS. Structural MRI and neuropsychological evaluations were performed in 120 patients (80 women) and 50 controls (30 women), part of an early inception cohort, 6 years postdiagnosis. Deep GM volumes were segmented automatically. Cognition was assessed in 7 domains. Stepwise linear regression was used to predict average cognition in the patient group. Most deep GM volumes were reduced in patients, with larger effects on average in men (-11%) than in women (-6.3%). Only the bilateral hippocampus, amygdala, and right nucleus accumbens in men, and right hippocampus and nucleus accumbens, bilateral amygdala, and putamen in women, showed no atrophy compared to controls. All cognitive domains except visuospatial memory were affected in men; none were significantly affected in women. In the MS group, average cognition was best predicted by thalamic volume, sex, and education (adjusted R(2) = 0.31), while lesion volume was not a significant predictor in the model. Six years postdiagnosis, almost all subcortical structures were affected by MS, especially in men. Cognition was most severely affected in male patients. Thalamic volume, sex, and education best predicted average cognition. These results underline the relevance of specific subcortical structures to cognition, as well as the relevance of (sex-specific) atrophy in MS.
Body fluid biomarkers for clinical subtyping and monitoring of disease progression are of conside... more Body fluid biomarkers for clinical subtyping and monitoring of disease progression are of considerable interest in multiple sclerosis (MS). Proteomics tools are optimal for the unbiased simultaneous detection of large series of peptides and proteins. To identify novel candidate biomarkers discriminating patients with MS from patients with other neurological diseases (OND), and for subtyping of relapsing-remitting (RR), secondary progressive (SP) and primary progressive (PP) MS patients using a high-throughput MALDI-TOF-based mass spectrometry method. Paired cerebrospinal fluid (CSF) and serum samples of 41 RRMS, 30 SPMS, 13 PPMS patients and 25 patients with OND were analysed. Out of a total of 100 detected peptides in CSF and 200 peptides in serum, 11 peptides were differentially regulated in serum and two in CSF between patients with MS and the OND control group. Eleven peptides were differentially regulated in both serum and CSF between relapse-onset MS and PPMS patients. Lastly, four peptides were differentially regulated in serum and two in CSF between RRMS and SPMS patients. Specific peaks regulated in MS were tentatively identified as fragments of secretogranin III and complement C3. The peak intensity of the CSF peptide ion with m/z value 8607.7 correlated to atrophy (r = -0.27, p < 0.005), black hole volumes (r = 0.31, p < 0.008) and total lesion load (r = 0.34, p < 0.003). A serum peptide with m/z value of 872.4 elevated in SPMS correlated to Expanded Disability Status Scale (r = 0.341, p < 0.005) and atrophy (r = -0.286, p < 0.028). Using high-throughput body fluid profiling by MALDI-TOF mass spectrometry, small proteins and peptides were detected as promising candidate biomarkers for diagnosis and disease progression of MS.
Cholesterol homeostasis is important for formation and maintenance of myelin and axonal membranes... more Cholesterol homeostasis is important for formation and maintenance of myelin and axonal membranes in the central nervous system (CNS). The concentrations of the brain specific cholesterol metabolite 24S-hydroxycholesterol (24OHC) and cholesterol precursors have been shown to be altered in multiple sclerosis (MS). However, how changes in sterol levels relate to the pathological processes in MS is not clear. In this study, we compared serum and cerebrospinal fluid (CSF) sterol levels between 105 MS (51 relapsing-remitting (RR); 39 secondary progressive (SP) and 15 primary progressive (PP)) and 49 control patients. Sterol levels were correlated to magnetic resonance imaging (MRI) markers of disease activity. We found decreased serum 24OHC and 27-hydroxycholesterol (27OHC) and increased CSF lathosterol in MS patients compared to control patients (p=0.018, p=0.002 and p=0.002, respectively). Subgroup analysis showed that serum 24OHC levels were negatively correlated to normalized brain volume measurements in relapse-onset MS patients (r= -0.326, p=0.004). These results confirm that cholesterol homeostasis is disturbed in MS and suggest that changes in cholesterol synthesis are related to neurodegenerative pathological processes as seen on the MRI. The data seem to be in line with the recently reported observation that high dose statins may have a positive effect on clinical disability in secondary progressive MS.
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Papers by Veronica Popescu