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Brain parenchymal fraction in healthy individuals and in clinical follow-up of multiple sclerosis
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.ORCID iD: 0000-0001-5125-7787
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background Multiple sclerosis (MS) is an autoimmune disease characterised by inflammatory damage to the central nervous system (CNS). Accumulated CNS injury can be quantified as brain atrophy, definable as a reduction in brain parenchymal fraction (BPF). BPF correlate with disability in MS and is used routinely as an endpoint in clinical trials. In 2009/2010, a new MS clinical care program, that includes follow-up of BPF, was introduced at Umeå University Hospital (NUS). Levels of neurofilament light polypetide (NFL) and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) are markers of axonal and astrocytic injury, respectively, and also potential surrogate biomarkers for BPF decline. The goals of this thesis were to establish age-adjusted values of BPF in healthy individuals and to relate these to the BPF values from individuals with MS as well as to the levels of NFL and GFAP in CSF. Another goal was to investigate if expanded disability status scale (EDSS)-worsening could be predicted in a clinical MS cohort and if BPF measurements could contribute to such predictions. Methods A group of 111 healthy individuals volunteered to participate in the studies. A total of 106 of these underwent MRI with BPF measurements, 53 underwent lumbar puncture (LP) with measurement of NFL and GFAP and 48 underwent both MRI and LP. Three different automatic and one manual method were utilised to determine BPF. A literature search on BPF in healthy individuals was performed for the purpose of a systematic review. For studying disability progression in MS, all individuals with MS followed at NUS and included in the Swedish MS registry were included if they had matched data on BPF, EDSS and lesion load as part of clinical follow-up (n=278). Results BPF as well as NFL and GFAP levels in CSF were all associated with age. NFL was associated with BPF and GFAP, but only the association with GFAP was retained when adjusting for age. Significant differences were found between different methods for BPF determination. In the MS population, BPF was associated with EDSS. Only progressive disease course could predict EDSS worsening. Conclusion The data on BPF and levels of NFL and GFAP in CSF of healthy individuals can aid in the interpretation of these variables in the setting of MS. Knowledge on differences in BPF data from different methods for BPF determination can be useful in comparing data across studies, but also highlights the need for a commonly accepted gold standard. The correlation between GFAP and NFL levels in CSF may indicate an association between glial and axonal turnover that is independent of the aging effect on the brain. However, the low number of volunteers for LP precluded clear conclusions. An association between BPF and EDSS was seen in the MS group. The ability to predict EDSS worsening in the clinical MS cohort was limited.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2016. , 80 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1867
Keyword [en]
Brain parenchymal fraction, Neurofilament light, Glial fibrillary acidic protein, Brain atrophy, Multiple Sclerosis, Clinical follow-up
National Category
Neurology
Identifiers
URN: urn:nbn:se:umu:diva-128697ISBN: 978-91-7601-621-3 (print)OAI: oai:DiVA.org:umu-128697DiVA: diva2:1055548
Public defence
2017-01-20, Sal A, Tandläkarhögskolan 9 trappor, byggnad 1D, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2016-12-16 Created: 2016-12-12 Last updated: 2016-12-20Bibliographically approved
List of papers
1. Levels and Age Dependency of Neurofilament Light and Glial Fibrillary Acidic Protein in Healthy Individuals and Their Relation to the Brain Parenchymal Fraction
Open this publication in new window or tab >>Levels and Age Dependency of Neurofilament Light and Glial Fibrillary Acidic Protein in Healthy Individuals and Their Relation to the Brain Parenchymal Fraction
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 8, e0135886Article in journal (Refereed) Published
Abstract [en]

Background Neurofilament light (NFL) and Glial Fibrillary Acidic Protein (GFAP) are integral parts of the axonal and astrocytal cytoskeletons respectively and are released into the cerebrospinal fluid (CSF) in cases of cellular damage. In order to interpret the levels of these biomarkers in disease states, knowledge on normal levels in the healthy is required. Another biomarker for neurodegeneration is brain atrophy, commonly measured as brain parenchymal fraction (BPF) using magnetic resonance imaging (MRI). Potential correlations between levels of NFL, GFAP and BPF in healthy individuals have not been investigated. Objectives To present levels of NFL and GFAP in healthy individuals stratified for age, and investigate the correlation between them as well as their correlation with BPF. Methods The CSF was analysed in 53 healthy volunteers aged 21 to 70 (1 sample missing for GFAP analysis) and 48 of the volunteers underwent determination of BPF using MRI. Results Mean (+/- SD) NFL was 355 ng/L (+/- 214), mean GFAP was 421 ng/L (+/- 129) and mean BPF was 0.867 (+/- 0.035). All three biomarkers correlated with age. NFL also correlated with both GFAP and BPF. When controlled for age, only the correlation between NFL and GFAP retained statistical significance. Conclusions This study presents data on age-stratified levels of NFL and GFAP in the CSF of healthy individuals. There is a correlation between levels of NFL and GFAP and both increase with age. A correlation between NFL and BPF was also found, but did not retain statistical significance if controlled for age.

Place, publisher, year, edition, pages
PLOS one, 2015
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-109378 (URN)10.1371/journal.pone.0135886 (DOI)000360299100048 ()26317831 (PubMedID)
Available from: 2015-09-29 Created: 2015-09-25 Last updated: 2016-12-14Bibliographically approved
2. Brain parenchymal fraction in an age-stratified healthy population: determined by MRI using manual segmentation and three automated segmentation methods
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, 384-391 p.Article 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.

Keyword
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)27720265 (PubMedID)2-s2.0-84995584817 (Scopus ID)
Available from: 2016-12-12 Created: 2016-12-12 Last updated: 2017-05-10Bibliographically approved
3. Brain parenchymal fraction in healthy adults: a systematic review of the literature
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, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 1, 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)
Available from: 2016-12-12 Created: 2016-12-12 Last updated: 2017-03-01Bibliographically approved
4. Prediction of disability increase in a real world multiple sclerosis cohort
Open this publication in new window or tab >>Prediction of disability increase in a real world multiple sclerosis cohort
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

BACKGROUND Multiple sclerosis (MS) is an autoimmune disease characterized by demyelinating CNS-lesions and neurodegeneration. Brain atrophy measurements have been demonstrated to provide prognostic information. Assessment of brain atrophy via magnetic resonance imaging (MRI) using the Brain Parenchymal Fraction (BPF) was added to the clinical follow-up of individuals with MS at Umeå University Hospital in 2009/2010.  

OBJECTIVE To investigate whether an increase in disability, measured by a short to medium term increase in EDSS, can be predicted using clinically available variables.  To assess if the previously described association between brain atrophy and disability could be detected in the setting of the clinical care program at Umeå University Hospital.

METHODS All adult MS patients with simultaneous data on BPF, lesion count and EDSS at least at one occasion (n=278) were included. Individuals with two (n=163) and three (n=68) time points with complete data were used for testing the ability to predict Expanded Disability Status Scale (EDSS) score longitudinally.

 RESULTS The EDSS was found to correlate with BPF (p<0.001). Progressive disease course and early EDSS-worsening (SPMS), but no other clinical variables, could predict subsequent EDSS-worsening over follow-up times of approximately 1 to 4 years.

CONCLUSION BPF was associated with concurrent EDSS, as previously described. Progressive disease course predicted risk for EDSS-increase but it was otherwise very difficult to predict increased disability in this treated MS-cohort. We discuss possible reasons for the lack of predictive value from clinically used variables in a treated MS cohort. 

National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-128696 (URN)
Available from: 2016-12-12 Created: 2016-12-12 Last updated: 2016-12-14

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