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Svenningsson, Anders
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Publications (10 of 71) Show all publications
Bergman, J., Burman, J., Bergenheim, A. T. & Svenningsson, A. (2021). Intrathecal treatment trial of rituximab in progressive MS: results after a 2-year extension. Journal of Neurology, 268(2), 651-657
Open this publication in new window or tab >>Intrathecal treatment trial of rituximab in progressive MS: results after a 2-year extension
2021 (English)In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 268, no 2, p. 651-657Article in journal (Refereed) Published
Abstract [en]

Objectives: To evaluate the effect of intrathecally (IT) delivered rituximab as a therapeutic intervention for progressive multiple sclerosis (PMS) during a 3-year follow-up period.

Methods: Participants of a 1-year open-label phase 1b study of IT delivered rituximab to patients with PMS were offered extended treatment with follow-up for an additional 2 years. During the extension phase, treatment with 25 mg rituximab was administered every 6 months via a subcutaneous Ommaya reservoir connected to the right frontal horn with a ventricular catheter.

Results: Mild to moderate vertigo and nausea occurred in 4 out of 14 participants as temporary adverse events associated with IT rituximab infusion. During the entire 3-year period, two cases of low-virulent bacterial meningitis occurred, which were successfully treated. Walking speed deteriorated significantly during the study.

Conclusions: IT administration of rituximab via a ventricular catheter was well tolerated. Considering the meningitis cases, the risk of infection was not negligible. The continued loss of walking speed indicates that IT rituximab was not able to stop disease progression.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2021
Keywords
Multiple sclerosis, Rituximab, Intrathecal, Progressive MS, Treatment, Clinical trial
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-175373 (URN)10.1007/s00415-020-10210-0 (DOI)000567784200002 ()32901316 (PubMedID)2-s2.0-85090434104 (Scopus ID)
Funder
Region Västerbotten
Available from: 2020-09-29 Created: 2020-09-29 Last updated: 2022-05-03Bibliographically approved
Luna, G., Alping, P., Burman, J., Fink, K., Fogdell-Hahn, A., Gunnarsson, M., . . . Frisell, T. (2020). Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies. JAMA Neurology, 177(2), 184-191
Open this publication in new window or tab >>Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies
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2020 (English)In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 177, no 2, p. 184-191Article in journal (Refereed) Published
Abstract [en]

Importance: Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden.

Objective: To examine the risk of serious infections associated with disease-modifying treatments for MS.

Design, Setting, and Participants: This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included.

Exposures: Treatment with rituximab, natalizumab, fingolimod, and interferon beta and GA.

Main Outcomes and Measures: Serious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions.

Results: A total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42 645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 [95% CI, 6.4-12.1] vs 5.2 [95% CI, 4.8-5.5] per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 [95% CI, 10.8-18.5] per 1000 person-years), natalizumab (incidence rate, 11.4 [95% CI, 8.3-15.3] per 1000 person-years), and rituximab (incidence rate, 19.7 [95% CI, 16.4-23.5] per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 [95% CI, 1.11-2.61]) but not fingolimod (HR, 1.30 [95% CI, 0.84-2.03]) or natalizumab (HR, 1.12 [95% CI, 0.71-1.77]) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 [1.34-2.46]) and fingolimod (HR, 1.71 [95% CI, 1.27-2.32]).

Conclusions and Relevance: Patients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles should inform the risk-benefit assessments of these treatments.

Place, publisher, year, edition, pages
American Medial Association, 2020
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-167310 (URN)10.1001/jamaneurol.2019.3365 (DOI)000514922200008 ()31589278 (PubMedID)2-s2.0-85073032106 (Scopus ID)
Available from: 2020-01-15 Created: 2020-01-15 Last updated: 2020-03-17Bibliographically approved
Bergman, J., Svenningsson, A., Liv, P., Bergenheim, A. T. & Burman, J. (2020). Location matters: highly divergent protein levels in samples from diferent CNS compartments in a clinical trial of rituximab for progressive MS. Fluids and Barriers of the CNS (1), Article ID 49.
Open this publication in new window or tab >>Location matters: highly divergent protein levels in samples from diferent CNS compartments in a clinical trial of rituximab for progressive MS
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2020 (English)In: Fluids and Barriers of the CNS, E-ISSN 2045-8118, no 1, article id 49Article in journal (Refereed) Published
Abstract [en]

Background: The relationship between proteins in different CNS extracellular compartments is unknown. In this study the levels of selected proteins in three compartments in people with progressive multiple sclerosis (PMS) were compared.

Methods: During an open label, phase 1b study on intraventricular administration of rituximab for PMS, samples were collected from the interstitial space (ISS) of the brain through microdialysis. Samples were also obtained from ventricular and lumbar cerebrospinal fluid (CSF). These samples were analyzed with a multiplexed proximity extension assay, measuring the levels of 180 proteins split equally between two panels, detecting proteins associated with immunology and neurology, respectively.

Results: Considerable differences in concentrations were observed between the three analyzed compartments. Compared to ventricular CSF, ISS fluid contained statistically significant higher levels of 25 proteins (84% immunology panel and 16% neurology panel). Ventricular CSF contained significantly higher levels of 54 proteins (31% immunology panel and 69% neurology panel) compared to ISS fluid, and 17 proteins (76% immunology panel and 24% neurology panel) compared to lumbar CSF. Lumbar CSF showed significantly higher levels of 115 proteins (32% immunology panel and 68% neurology panel) compared to ventricular CSF. The three compartments displayed poor correlation with a median Spearman’s rho of -0.1 (IQR 0.4) between ISS and ventricular CSF and 0.3 (IQR 0.4) between ventricular and lumbar CSF.

Conclusion: A substantial heterogeneity in the protein levels of samples obtained from different CNS compartments was seen. Therefore, data obtained from analysis of lumbar CSF should be interpreted with caution when making conclusions about pathophysiological processes in brain tissue.

Place, publisher, year, edition, pages
BioMed Central, 2020
Keywords
Cerebrospinal fuid, Microdialysis, Ventricular CSF, Lumbar CSF, Interstitial fuid, CSF compartments, CSF proteins, Progressive MS
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-169319 (URN)10.1186/s12987-020-00205-4 (DOI)000557471600001 ()32727487 (PubMedID)2-s2.0-85088850911 (Scopus ID)
Funder
Region Västerbotten
Note

Originally included in thesis in manuscript form, with title: "Location matters: highly divergent protein levels in samples from different CNS compartments"

Available from: 2020-03-31 Created: 2020-03-31 Last updated: 2024-01-17Bibliographically approved
Salzer, J., Granåsen, G., Sundström, P., Vågberg, M. & Svenningsson, A. (2020). Prevention of post-dural puncture headache: a randomized controlled trial. European Journal of Neurology, 27(5), 871-877
Open this publication in new window or tab >>Prevention of post-dural puncture headache: a randomized controlled trial
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2020 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 27, no 5, p. 871-877Article in journal (Refereed) Published
Abstract [en]

Background and purpose: We investigated 952 subjects undergoing diagnostic lumbar puncture (LP) to study the effects of needle size, needle design and stylet reinsertion on the risk of post‐dural puncture headache (PDPH).

Methods: This randomized double‐blind study was performed at Umeå University Hospital in Sweden during 2013–2018. Subjects were randomly assigned one of three needles [22 gauge (G) atraumatic, 25G atraumatic and 25G cutting] and stylet reinsertion before needle withdrawal or not. The main outcome measure was PDPH assessed by standardized telephone interview(s) 5 days after the LP, repeated until headache cessation. We used logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CI) for PDPH.

Results: The mean (SD) age was 51.1 (16.7) years and 53.6% were females. The smaller bore (25G) atraumatic needle incurred a lower risk of headache compared with the larger bore (22G) atraumatic needle [22.0% (69/314) vs. 30.2% (98/324); OR, 0.65; 95% CI, 0.45–0.93] and compared with the cutting needle [32.8% (103/314); OR, 0.58; 95% CI, 0.40–0.82]. Reinserting the stylet before needle withdrawal did not reduce the risk of headache.

Conclusions: These data suggest that a 25G atraumatic needle is superior to a larger atraumatic needle, and to a same‐sized cutting needle, in preventing PDPH after diagnostic LP. In contrast to one earlier report, this study did not find that stylet reinsertion was effective in preventing PDPH. This study provides class I evidence that a small atraumatic needle decreases the risk of PDPH and that stylet reinsertion does not influence PDPH risk.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2020
Keywords
headache, lumbar puncture, post-dural puncture headache, randomized controlled trial
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-168838 (URN)10.1111/ene.14158 (DOI)000514599100001 ()31997481 (PubMedID)2-s2.0-85083689854 (Scopus ID)
Available from: 2020-03-19 Created: 2020-03-19 Last updated: 2023-05-26Bibliographically approved
de Flon, P., Laurell, K., Sundström, P., Blennow, K., Söderström, L., Zetterberg, H., . . . Svenningsson, A. (2019). Comparison of plasma and cerebrospinal fluid neurofilament light in a multiple sclerosis trial. Acta Neurologica Scandinavica, 139(5), 462-468
Open this publication in new window or tab >>Comparison of plasma and cerebrospinal fluid neurofilament light in a multiple sclerosis trial
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2019 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 139, no 5, p. 462-468Article in journal (Refereed) Published
Abstract [en]

Objective: The main objective of this study was to evaluate the axonal component neurofilament light protein (NFL) in plasma and cerebrospinal fluid (CSF) as an outcome measure in a clinical trial on disease-modifying treatments in multiple sclerosis.

Materials and methods: Seventy-five patients with clinically stable relapsing-remitting multiple sclerosis (RRMS) participating in the clinical trial "Switch-To RItuXimab in MS" (STRIX-MS) were switched to rituximab from first-line injectable therapy and then followed up for 2 years. Thirty patients from the extension trial (STRIX-MS extension), accepting repeated lumbar punctures, were followed up for an additional 3 years. Plasma and CSF samples were collected yearly during the follow-up. NFL concentration in plasma was measured by an in-house NF-light assay on the Simoa platform with a Homebrew kit. NFL concentration in CSF was measured by sandwich ELISA.

Results: The mean levels of NFL, in both CSF and plasma, were low. The reduction of CSF-NFL was 25% during the first year of follow-up (from a mean of 471 [SD 393] to 354 [SD 174] pg/mL; P = 0.006) and was statistically significant. The corresponding reduction in plasma NFL was 18% (from 9.73 [SD 7.04] to 7.94 [SD 3.10] pg/mL; P = 0.055) and did not reach statistical significance.

Conclusion: This study indicates that NFL in plasma is less sensitive as an endpoint in group comparisons than NFL in CSF. Given that plasma NFL is far easier to access, it is a promising and awaited method but further studies are needed to optimize the use in clinical trials.

Keywords
cerebrospinal fluid, clinical trial, multiple sclerosis, neurofilament light, plasma, rituximab, treatment
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-158568 (URN)10.1111/ane.13078 (DOI)000464338600008 ()30740668 (PubMedID)2-s2.0-85062548724 (Scopus ID)
Available from: 2019-05-27 Created: 2019-05-27 Last updated: 2023-03-24Bibliographically approved
de Flon, P., Söderström, L., Laurell, K., Dring, A., Sundström, P., Gunnarsson, M. & Svenningsson, A. (2018). Immunological profile in cerebrospinal fluid of patients with multiple sclerosis after treatment switch to rituximab and compared with healthy controls. PLOS ONE, 13(2), Article ID e0192516.
Open this publication in new window or tab >>Immunological profile in cerebrospinal fluid of patients with multiple sclerosis after treatment switch to rituximab and compared with healthy controls
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2018 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 13, no 2, article id e0192516Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To investigate changes in the cerebrospinal fluid (CSF) immunological profile after treatment switch from first-line injectables to rituximab in patients with relapsing-remitting MS (RRMS), and to compare the profile in MS patients with healthy controls (HC).

METHOD: Cerebrospinal fluid from 70 patients with clinically stable RRMS and 55 HC was analysed by a multiplex electrochemiluminescence method for a broad panel of cytokines and immunoactive substances before, and over a two-year period after, treatment switch to rituximab. After quality assessment of data, using a predefined algorithm, 14 analytes were included in the final analysis.

RESULTS: Ten of the 14 analytes differed significantly in MS patients compared with HC at baseline. Levels of IP-10 (CXCL10), IL-12/23p40, IL-6, sVCAM1, IL-15, sICAM1 and IL-8 (CXCL8) decreased significantly after treatment switch to rituximab. The cytokines IP-10 and IL-12/IL-23p40 displayed the largest difference versus HC at baseline and also the largest relative reduction after therapy switch to rituximab.

CONCLUSION: We found significant changes in the immunological profile after therapy switch to rituximab in RRMS in the direction towards the values of HC. IP-10 and IL12/IL-23p40 deserve further studies as part of the immunopathogenesis of MS as well as for the mode of action of rituximab in MS.

National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-145871 (URN)10.1371/journal.pone.0192516 (DOI)000424517900086 ()29420590 (PubMedID)2-s2.0-85041734965 (Scopus ID)
Available from: 2018-03-20 Created: 2018-03-20 Last updated: 2023-03-24Bibliographically approved
Bergman, J., Burman, J., Gilthorpe, J. D., Zetterberg, H., Jiltsova, E., Bergenheim, T. & Svenningsson, A. (2018). Intrathecal treatment trial of rituximab in progressive MS: An open-label phase 1b study. Neurology, 91(20), E1893-E1901
Open this publication in new window or tab >>Intrathecal treatment trial of rituximab in progressive MS: An open-label phase 1b study
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2018 (English)In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 91, no 20, p. E1893-E1901Article in journal (Refereed) Published
Abstract [en]

Objectives To perform a phase 1b assessment of the safety and feasibility of intrathecally delivered rituximab as a treatment for progressive multiple sclerosis (PMS) and to evaluate the effect of treatment on disability and CSF biomarkers during a1-year follow-up period. Methods Three doses of rituximab (25 mg with a 1-week interval) were administered in 23 patients with PMS via a ventricular catheter inserted into the right frontal horn and connected to a subcutaneous Ommaya reservoir. Follow-ups were performed at 1, 3, 6, 9, and 12 months. Results Mild to moderate vertigo and nausea were common but temporary adverse events associated with intrathecal rituximab infusion, which was otherwise well tolerated. The only severe adverse event was a case of low-virulent bacterial meningitis that was treated effectively. Of 7 clinical assessments, only 1 showed statistically significant improvement 1 year after treatment. No treatment effect was observed during the follow-up period among 6 CSF biomarkers. Conclusions Intrathecal administration of rituximab was well tolerated. However, it may involve a risk for injection-related infections. The lack of a control group precludes conclusions being drawn regarding treatment efficacy. ClinicalTrials.gov identifier NCT01719159. Classification of evidence This study provides Class IV evidence that intrathecal rituximab treatment is well tolerated and feasible in PMS but involves a risk of severe infections.

Place, publisher, year, edition, pages
Wolters Kluwer, 2018
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-154850 (URN)10.1212/WNL.0000000000006500 (DOI)000452514700006 ()30305449 (PubMedID)2-s2.0-85056314572 (Scopus ID)
Available from: 2019-01-04 Created: 2019-01-04 Last updated: 2020-03-31Bibliographically approved
Vågberg, M., Granåsen, G. & Svenningsson, A. (2017). Brain parenchymal fraction in healthy adults: a systematic review of the literature. PLOS ONE, 12(1), Article ID e0170018.
Open this publication in new window or tab >>Brain parenchymal fraction in healthy adults: a systematic review of the literature
2017 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 12, no 1, article id e0170018Article in journal (Refereed) Published
Abstract [en]

Brain atrophy is an important feature of many neurodegenerative disorders. It can be described in terms of change in the brain parenchymal fraction (BPF). In order to interpret the BPF in disease, knowledge on the BPF in healthy individuals is required. The aim of this study was to determine data on the BPF of healthy individuals via a systematic review of the literature. The databases PubMed and Scopus were searched and 95 articles, including a total of 9269 individuals, were identified including the required data. We present values of BPF from healthy individuals stratified by age and post-processing method. The BPF correlated with age and there were significant differences in age-adjusted BPF between methods. This study contributes to increased knowledge on BPF in healthy individuals, which may assist in the interpretation of BPF in the setting of disease. We highlight the differences between post-processing methods and the need for a consensus gold standard. 

National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-128695 (URN)10.1371/journal.pone.0170018 (DOI)000392372300051 ()28095463 (PubMedID)2-s2.0-85009853921 (Scopus ID)
Available from: 2016-12-12 Created: 2016-12-12 Last updated: 2023-03-24Bibliographically approved
de Flon, P., Laurell, K., Söderström, L., Gunnarsson, M. & Svenningsson, A. (2017). Improved treatment satisfaction after switching therapy to rituximab in relapsing-remitting MS. Multiple Sclerosis Journal, 23(9), 1249-1257
Open this publication in new window or tab >>Improved treatment satisfaction after switching therapy to rituximab in relapsing-remitting MS
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2017 (English)In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 23, no 9, p. 1249-1257Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: New disease-modifying treatment strategies in multiple sclerosis offer possibilities for individualised treatment. In this study, we evaluated patient-reported outcome measures before and after a switch in therapy from first-line injectable treatments to rituximab.

METHOD: A total of 75 patients with clinically stable relapsing-remitting multiple sclerosis (RRMS) receiving ongoing first-line injectable treatment at three Swedish centres had their treatment switched to rituximab in this open-label phase II multicentre study. Assessment of treatment satisfaction, patient-perceived impact of the disease on daily life, fatigue, cognitive symptoms and disease progression was performed 3 months before and at the time of the treatment shift and then for a subsequent 2-year period.

RESULTS: The overall treatment satisfaction rating improved significantly from a mean of 4.8 (scale range: 1-7), while on injectable therapies, to a mean of 6.3 after 1 year of rituximab treatment ( p < 0.001). This improvement was sustained after 2 years. There was no significant change in scores for patient-perceived impact of disease, fatigue or disease progression.

CONCLUSION: A shift in therapy from first-line injectables to rituximab in a cohort of clinically stable RRMS patients was followed by improved treatment satisfaction. This is clinically relevant as it may influence long-term adherence to immunomodulating therapy.

Keywords
B-cell depletion therapy, Multiple sclerosis, clinical trial, patient-reported outcome measures, rituximab, treatment satisfaction
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-134988 (URN)10.1177/1352458516676643 (DOI)000406386600013 ()27780912 (PubMedID)2-s2.0-85040373443 (Scopus ID)
Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2023-03-24Bibliographically approved
Vågberg, M., Ambarki, K., Lindqvist, T., Birgander, R. & Svenningsson, A. (2016). Brain parenchymal fraction in an age-stratified healthy population: determined by MRI using manual segmentation and three automated segmentation methods. Journal of neuroradiology, 43(6), 384-391
Open this publication in new window or tab >>Brain parenchymal fraction in an age-stratified healthy population: determined by MRI using manual segmentation and three automated segmentation methods
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2016 (English)In: Journal of neuroradiology, ISSN 0150-9861, E-ISSN 1773-0406, Vol. 43, no 6, p. 384-391Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND PURPOSE: Brain atrophy is a prominent feature in many neurodegenerative diseases, such as multiple sclerosis, but age-related decrease of brain volume occurs regardless of pathological neurodegeneration. Changes in brain volume can be described by use of the brain parenchymal fraction (BPF), most often defined as the ratio of total brain parenchyma to total intracranial space. The BPF is of interest both in research and in clinical practice. To be able to properly interpret this variable, the normal range of BPF must be known. The objective of this study is to present normal values for BPF, stratified by age, and compare manual BPF measurement to three automated methods. MATERIALS AND METHODS: The BPFs of 106 healthy individuals aged 21 to 85 years were determined by the automated segmentation methods SyMap, VBM8 and SPM12. In a subgroup of 54 randomly selected individuals, the BPF was also determined by manual segmentation. RESULTS: The median (IQR) BPFs of the whole study population were 0.857 (0.064), 0.819 (0.028) and 0.784 (0.073) determined by SyMap, VBM8 and SPM12, respectively. The BPF decreased with increasing age. The correlation coefficients between manual segmentation and SyMap, VBM8 and SPM12 were 0.93 (P<0.001), 0.77 (P<0.001) and 0.56 (P<0.001), respectively. CONCLUSIONS: There was a clear relationship between increasing age and decreasing BPF. Knowledge of the range of normal BPF in relation to age group will help in the interpretation of BPF data. The automated segmentation methods displayed varying degrees of similarity to the manual reference, with SyMap being the most similar.

Place, publisher, year, edition, pages
Masson Editeur, 2016
Keywords
BPF, Brain atrophy, SPM, SyMap, VBM
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-128693 (URN)10.1016/j.neurad.2016.08.002 (DOI)000391158900004 ()27720265 (PubMedID)2-s2.0-84995584817 (Scopus ID)
Available from: 2016-12-12 Created: 2016-12-12 Last updated: 2023-03-24Bibliographically approved
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