| 1. |
- Böttiger, Anna, 1977-
(author)
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Genetic variation in the folate receptor-alpha and methylenetetrahydrofolate reductase genes as determinants of plasma homocysteine concentrations
- 2008
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Doctoral thesis (other academic/artistic)abstract
- Elevated total plasma homocysteine (tHcy) is a risk factor for cardiovascular disease and neurocognitive disease such as dementia. The B vitamins folate and B12 are the main de terminants of tHcy. tHcy concentration can also be affected by mutations in genes coding for receptors, enzymes and transporters important in the metabolism of Hcy. This thesis focuses on mutations in the genes for folate receptor-alpha and methylenetetrahydrofolate reductase (MTHFR) and the effect they have on tHcy concentrations. Six novel mutations in the gene for folate receptor-alpha were described in Paper I. Taken together they exist in a population with a prevalence of approximately 1% and thus are not unusual. There may be an association of –69dupA and –18C>T to tHcy but for the 25-bp deletion, –856C>T, –921T>C and –1043G>A there is probably no association to tHcy. Mutation screening was continued and four additional mutations, 1314G>A, 1816delC, 1841G>A and 1928C>T, were described in Paper II. The prevalences for the heterozygotes were between 0.5% and 13% in an elderly population. There was no significant difference in prevalence between the elderly subjects and patients with dementia. The 1816(–)-allele and the 1841A-allele were in complete linkage and the haplotype 1816(–)-1841A may possibly have a tHcy raising effect. The 1314G>A and 1928C>T mutations had no association to tHcy. The genotype prevalences and haplotype frequencies of the MTHFR 677C>T, 1298A>C and 1793G>A polymorphisms were determined in a population sample of Swedish children and adolescents (Paper III). The MTHFR 677T-allele was associated with increased tHcy concentrations in both children and adolescents. A small elevating effect of the 1298C-allele and a small lowering effect of the 1793A-allele could be shown. In an epidemiological sample of adults from the Canary Islands, Spain, data for serum folate and vitamin B12 were used for a broader study of the nutrigenetic impact on tHcy (Paper IV). The 677T-allele had a significant tHcy increasing effect in men but not in women. The 1298C-allele had a minor elevating effect on tHcy in men with the 677CT genotype. It was not possible to document any effect of the 1793A-allele on tHcy due to its low prevalence. A slightly superior explanatory power for the genetic impact was obtained using the MTHFR haplotypes in the analysis compared to the MTHFR 677C>T genotype-based approach in both the Swedish children and adolescents and in the Spanish adults. Therefore MTHFR haplotypes should be considered when analysing the impact of the MTHFR 677C>T, 1298A>C and 1793G>A polymorphisms on tHcy. Notwithstanding the large geographical distance between our study populations the haplotype composition is quite similar. The MTHFR 677T-allele is slightly more prevalent in Spain compared to Sweden but it has only an effect on tHcy in the Spanish men. Age, gender and factors linked to the ethnicity of the studied subjects, seem to be able to override the nutrigenetic impact of tHcy-raising genotypes or haplotypes in particular settings, such as in the Spanish women in our study. Gene-nutrient interactions on plasma tHcy levels thus may or may not exist in a certain population. The transferability of nutrigenetic findings may therefore be limited, and must be re-evaluated for each particular setting of age-gender-ethnicity.
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| 2. |
- Benedict, Christian, Docent, 1976-, et al.
(author)
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Effects of acute sleep loss on diurnal plasma dynamics of CNS health biomarkers in young men
- 2020
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In: Neurology. - : LIPPINCOTT WILLIAMS & WILKINS. - 0028-3878 .- 1526-632X. ; 94:11, s. E1181-E1189
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Journal article (peer-reviewed)abstract
- Objective: Disrupted sleep increases CSF levels of tau and beta -amyloid (A beta) and is associated with an increased risk of Alzheimer disease (AD). Our aim was to determine whether acute sleep loss alters diurnal profiles of plasma-based AD-associated biomarkers.Methods: In a 2-condition crossover study, 15 healthy young men participated in 2 standardized sedentary in-laboratory conditions in randomized order: normal sleep vs overnight sleep loss. Plasma levels of total tau (t-tau), A beta 40, A beta 42, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were assessed using ultrasensitive single molecule array assays or ELISAs, in the fasted state in the evening prior to, and in the morning after, each intervention.Results: In response to sleep loss (+17.2%), compared with normal sleep (+1.8%), the evening to morning ratio was increased for t-tau (p = 0.035). No changes between the sleep conditions were seen for levels of A beta 40, A beta 42, NfL, or GFAP (all p > 0.10). The AD risk genotype rs4420638 did not significantly interact with sleep loss-related diurnal changes in plasma levels of A beta 40 or A beta 42 (p > 0.10). Plasma levels of A beta 42 (-17.1%) and GFAP (-12.1%) exhibited an evening to morning decrease across conditions (p < 0.05).Conclusions: Our exploratory study suggests that acute sleep loss results in increased blood levels of t-tau. These changes provide further evidence that sleep loss may have detrimental effects on brain health even in younger individuals. Larger cohorts are warranted to delineate sleep vs circadian mechanisms, implications for long-term recurrent conditions (e.g., in shift workers), as well as interactions with other lifestyle and genetic factors.
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| 3. |
- Herman, Stephanie, et al.
(author)
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Integration of magnetic resonance imaging and protein and metabolite CSF measurements to enable early diagnosis of secondary progressive multiple sclerosis
- 2018
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In: Theranostics. - : Ivyspring International Publisher. - 1838-7640. ; 8:16, s. 4477-4490
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Journal article (peer-reviewed)abstract
- Molecular networks in neurological diseases are complex. Despite this fact, contemporary biomarkers are in most cases interpreted in isolation, leading to a significant loss of information and power. We present an analytical approach to scrutinize and combine information from biomarkers originating from multiple sources with the aim of discovering a condensed set of biomarkers that in combination could distinguish the progressive degenerative phenotype of multiple sclerosis (SPMS) from the relapsing-remitting phenotype (RRMS). Methods: Clinical and magnetic resonance imaging (MRI) data were integrated with data from protein and metabolite measurements of cerebrospinal fluid, and a method was developed to sift through all the variables to establish a small set of highly informative measurements. This prospective study included 16 SPMS patients, 30 RRMS patients and 10 controls. Protein concentrations were quantitated with multiplexed fluorescent bead-based immunoassays and ELISA. The metabolome was recorded using liquid chromatography-mass spectrometry. Clinical follow-up data of the SPMS patients were used to assess disease progression and development of disability. Results: Eleven variables were in combination able to distinguish SPMS from RRMS patients with high confidence superior to any single measurement. The identified variables consisted of three MRI variables: the size of the spinal cord and the third ventricle and the total number of T1 hypointense lesions; six proteins: galectin-9, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor alpha (TGF-alpha), tumor necrosis factor alpha (TNF-alpha), soluble CD40L (sCD40L) and platelet-derived growth factor AA (PDGF-AA); and two metabolites: 20 beta-dihydrocortisol (20 beta-DHF) and indolepyruvate. The proteins myelin basic protein (MBP) and macrophage-derived chemokine (MDC), as well as the metabolites 20 beta-DHF and 5,6-dihydroxyprostaglandin F1a (5,6-DH-PGF1), were identified as potential biomarkers of disability progression. Conclusion: Our study demonstrates, in a limited but well-defined and data-rich cohort, the importance and value of combining multiple biomarkers to aid diagnostics and track disease progression.
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| 4. |
- Josefsson, Henrik
(author)
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Good Ecological Status : Advancing the Ecology of Law
- 2015
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Doctoral thesis (other academic/artistic)abstract
- For a meaningful discussion of the effectiveness of ecological objectives and ecological quality standards, their terms and purposes must be examined and clarified. This study explores the terms and content of ecological quality objectives and ecological quality standards, based on the Water Framework Directive’s legal conceptualization of ‘ecological status’. This exploration is accomplished by analysing and describing the Water Framework Directive’s ‘ecological status’ aspect from a legal-ecological perspective. The analysis of ‘ecological status’ and its main constructs forms the basis for a possible alternative form of regulation, which addresses the shortcomings identified in the analysis.
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| 5. |
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| 6. |
- van Egmond, L. T., et al.
(author)
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Acute sleep loss increases CNS health biomarkers and compromises the ability to stay awake in a sex-and weight-specific manner
- 2022
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In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 12:1
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Journal article (peer-reviewed)abstract
- Night shift work impairs vigilance performance, reduces the ability to stay awake, and compromises brain health. To investigate if the magnitude of these adverse night shift work effects differs between sexes and weight groups, 47 men and women with either normal weight or obesity participated in one night of sleep and one night of total sleep loss. During the night of sleep loss, participants' subjective sleepiness, vigilance performance, and ability to stay awake during 2-min quiet wake with eyes closed were repeatedly assessed. In addition, blood was collected in the morning after sleep loss and sleep to measure central nervous system (CNS) health biomarkers. Our analysis showed that women were sleepier during the night of sleep loss (P < 0.05) and spent more time in microsleep during quiet wake testing (P < 0.05). Finally, higher blood levels of neurofilament light chain, a biomarker of axonal damage, were found among women in the morning after sleep loss (P < 0.002). Compared with normal-weight subjects, those with obesity were more prone to fall asleep during quiet wake (P < 0.05) and exhibited higher blood levels of the CNS health biomarker pTau181 following sleep loss (P = 0.001). Finally, no differences in vigilance performance were noted between the sex and weight groups. Our findings suggest that the ability to stay awake during and the CNS health biomarker response to night shift work may differ between sexes and weight groups. Follow-up studies must confirm our findings under more long-term night shift work conditions.
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| 7. |
- Zhang, Zefan, et al.
(author)
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Melatonin : A potential nighttime guardian against Alzheimer's.
- 2024
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In: Molecular Psychiatry. - 1359-4184 .- 1476-5578.
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Journal article (peer-reviewed)abstract
- In the context of the escalating global health challenge posed by Alzheimer's disease (AD), this comprehensive review considers the potential of melatonin in both preventive and therapeutic capacities. As a naturally occurring hormone and robust antioxidant, accumulating evidence suggests melatonin is a compelling candidate to consider in the context of AD-related pathologies. The review considers several mechanisms, including potential effects on amyloid-beta and pathologic tau burden, antioxidant defense, immune modulation, and regulation of circadian rhythms. Despite its promise, several gaps need to be addressed prior to clinical translation. These include conducting additional randomized clinical trials in patients with or at risk for AD dementia, determining optimal dosage and timing, and further determining potential side effects, particularly of long-term use. This review consolidates existing knowledge, identifies gaps, and suggests directions for future research to better understand the potential of melatonin for neuroprotection and disease mitigation within the landscape of AD.
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