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      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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          Abstract

          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.

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          Most cited references18

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          Normative estimates of cross-sectional and longitudinal brain volume decline in aging and AD.

          To test the hypotheses 1) that whole-brain volume decline begins in early adulthood, 2) that cross-sectional and longitudinal atrophy estimates agree in older, nondemented individuals, and 3) that longitudinal atrophy accelerates in the earliest stages of Alzheimer disease (AD). High-resolution, high-contrast structural MRIs were obtained from 370 adults (age 18 to 97). Participants over 65 (n = 192) were characterized using the Clinical Dementia Rating (CDR) as either nondemented (CDR 0, n = 94) or with very mild to mild dementia of the Alzheimer type (DAT, CDR 0.5 and 1, n = 98). Of these older participants, 79 belonged to a longitudinal cohort and were imaged again a mean 1.8 years after baseline. Estimates of gray matter (nGM), white matter (nWM), and whole-brain volume (nWBV) normalized for head sizes were generated based on atlas registration and image segmentation. Hierarchical regression of nWBV estimates from nondemented individuals across the adult lifespan revealed a strong linear, moderate quadratic pattern of decline beginning in early adulthood, with later onset of nWM than nGM loss. Whole-brain volume differences were detected by age 30. The cross-sectional atrophy model overlapped with the rates measured longitudinally in older, nondemented individuals (mean decline of -0.45% per year). In those individuals with very mild DAT, atrophy rate more than doubled (-0.98% per year). Nondemented individuals exhibit a slow rate of whole-brain atrophy from early in adulthood with white-matter loss beginning in middle age; in older adults, the onset of dementia of the Alzheimer type is associated with a markedly accelerated atrophy rate.
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            CSF neurofilament light differs in neurodegenerative diseases and predicts severity and survival.

            We hypothesized that CSF neurofilament light (NFL) levels would be elevated in dementias with subcortical involvement, including vascular dementia (VaD), but less elevated in dementias primarily affecting gray matter structures, such as Alzheimer disease (AD), and that elevated CSF NFL would correlate with disease severity and shorter survival time irrespective of clinical diagnosis. We included 3,356 individuals with dementia who had CSF NFL analyzed in our laboratory between 2005 and 2012. Clinical diagnoses and Mini-Mental State Examination (MMSE) scores were obtained from the Swedish Dementia Registry, and in selected cases (n = 478), date of death from the Swedish Mortality Registry. CSF NFL differed among clinical diagnoses, with the highest levels seen in frontotemporal dementia, VaD, and mixed AD and VaD. Early-onset AD (younger than 65 years) had the lowest levels. High CSF NFL correlated with low MMSE score and short survival time irrespective of diagnosis, and was also particularly evident in AD. CSF NFL differs among different neurodegenerative diseases and is especially high in dementias engaging subcortical brain regions, such as VaD and mixed AD and VaD, but also in frontotemporal dementia. The association of high CSF NFL levels with disease severity and short survival supports the notion that high CSF NFL levels indicate more aggressive disease processes. © 2014 American Academy of Neurology.
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              Neuronal intermediate filaments.

              Neurofilaments (NFs) are the most abundant structural components in large-diameter myelinated axons. Assembled as obligate heteropolymers requiring NF-L and substoichiometric amounts of NF-M and/or NF-H, NF investment into axons is essential for establishment of axonal caliber, itself a key determinant of conduction velocity. Use of transgenic mice to increase axonal accumulation of NFs or to express mutant NFs subunits has proven that aberrant organization or assembly of NFs is sufficient to cause disease arising from selective dysfunction and degeneration of motor neurons. Because aberrant accumulation of NFs is a common pathology in a series of motor neuron diseases-including amyotrophic lateral sclerosis-NF misaccumulation, and the resultant disruption in axonal transport, is probably a key intermediate in the pathogenesis of these diseases.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                28 August 2015
                2015
                : 10
                : 8
                : e0135886
                Affiliations
                [1 ]Department of Pharmacology and Clinical Neuroscience, Section of Neuroscience, Umeå University, Umeå, Sweden
                [2 ]UmanDiagnostics AB, Umeå, Sweden
                [3 ]Department of Radiation Sciences, Section of Diagnostic Radiology, Umeå University, Umeå, Sweden
                [4 ]Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
                [5 ]UCL Institute of Neurology, Queen Square, London, United Kingdom
                Medical University of Innsbruck, AUSTRIA
                Author notes

                Competing Interests: The study was partially funded by an unrestricted research grant from BiogenIdec. UmanDiagnostics AB supplied NFL-kits for the study, provided lab-space for NFL analysis and is the employer of Niklas Norgren. Mattias Vågberg has received unconditional research grants from BiogenIdec AB and Neuro Sweden. He received lecture honoraria from BiogenIdec AB, and received travel grants from BiogenIdec AB, Novartis and Baxter Medical AB. Ann Dring reports nothing to disclose. Thomas Lindqvist reports nothing to disclose. Richard Birgander has received lecture honoraria from BiogenIdec. Henrik Zetterberg reports nothing to disclose. Anders Svenningsson has served on the advisory board for Sanofi-Genzyme and has received travel funding and/or speaker honoraria from BiogenIdec AB, Sanofi/Genzyme, Novartis and Baxter Medical, and has received an unconditional research grant from BiogenIdec AB. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

                Conceived and designed the experiments: MV AS NN TL RB. Performed the experiments: MV TL RB NN AD HZ. Analyzed the data: MV AS NN. Contributed reagents/materials/analysis tools: NN AD HZ TL RB. Wrote the paper: MV NN AD TL RB HZ AS. Investigated MRI scans for signs of pathology: TL RB. Acquiring funding: MV AS.

                Article
                PONE-D-15-16675
                10.1371/journal.pone.0135886
                4552591
                26317831
                0cca1265-bedc-42d0-8eea-c5fc4d126b41
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 21 April 2015
                : 27 July 2015
                Page count
                Figures: 2, Tables: 2, Pages: 8
                Funding
                The study was partially funded by unrestricted research grants from BiogenIdec AB and Neuro Sweden. Financial support was further provided through a regional agreement between Umeå University and Västerbotten County Council (ALF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. UmanDiagnostics AB provided support in the form of salaries for author NN, supplied NFL-kits for the study and provided lab-space for NFL analysis, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of all authors are articulated in the ‘author contributions’ section.
                Categories
                Research Article
                Custom metadata
                The complete data set can not be made publicly available for ethical reasons. Data are available after decision from the Regional Ethical Review Board of Umeå University for researchers who meet the criteria for access to confidential data.

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                Uncategorized

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