| 1. |
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| 2. |
- Abramsson, Alexandra, 1973, et al.
(författare)
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No Association of LOXL1 Gene Polymorphisms with Alzheimer's Disease
- 2011
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Ingår i: NeuroMolecular Medicine. - : Springer Science and Business Media LLC. - 1535-1084 .- 1559-1174. ; 13:2, s. 160-166
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Tidskriftsartikel (refereegranskat)abstract
- Aggregation of amyloid-beta is one of the major characteristics in brains of patients with Alzheimer's disease (AD). Although several mechanisms behind the formation of such aggregates have been suggested the regulatory factors are still unknown. The present study aimed at investigating the association of lysyl oxidase-like 1 (LOXL1) polymorphisms with AD diagnosis and cerebrospinal fluid biomarkers (CSF) for the disease. Proteins of the lysyl oxidase (LOX) family are involved in cross-linking extracellular matrix proteins to insoluble fibers and have been associated with neurodegenerative diseases including AD. Genetic polymorphisms in LOXL1 (rs1048661, rs3825942, and rs2165241) have been linked to exfoliation syndrome and exfoliation glaucoma, conditions that have shown association with AD. The polymorphisms were genotyped by Taqman allelic discrimination in a study sample including AD patients (n = 318) and controls (n = 575). In a subgroup of the population, the polymorphisms were analyzed in relation to APOE epsilon 4 genotype and to CSF (T-tau, P-tau, and A beta(1-42)). No evidence for associations of these polymorphisms with risk for AD or any of the studied CSF biomarkers measured was found. These results do not support LOXL1 as being a major risk gene for AD.
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| 3. |
- Andersson, Carl-Henrik, et al.
(författare)
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A Genetic Variant of the Sortilin 1 Gene isAssociated with Reduced Risk ofAlzheimer's Disease
- 2016
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 53:4, s. 1353-1363
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is a neurodegenerative disorder represented by the accumulation of intracellular tau protein and extracellular deposits of amyloid-β (Aβ) in the brain. The gene sortilin 1 (SORT1) has previously been associated with cardiovascular disease in gene association studies. It has also been proposed to be involved in AD pathogenesis through facilitating Aβ clearance by binding apoE/Aβ complexes prior to cellular uptake. However, the neuropathological role of SORT1 in AD is not fully understood. To evaluate the associations between gene variants of SORT1 and risk of AD, we performed genetic analyses in a Swedish case-control cohort. Ten single nucleotide polymorphisms (SNPs), covering the whole SORT1 gene, were selected and genotyped in 620 AD patients and 1107 controls. The SNP rs17646665, located in a non-coding region of the SORT1 gene, remained significantly associated with decreased risk of AD after multiple testing (pc=0.0061). In addition, other SNPs were found to be nominally associated with risk of AD, as well as altered cognitive function and the CSF biomarker Aβ42, but these associations did not survive correction for multiple testing. The fact that SORT1 has been strongly associated with risk of cardiovascular disease is intriguing as cardiovascular disease is also regarded as a risk factor for AD. Finally, increased knowledge about SORT1 function has a potential to increase our understanding of APOE, the strongest risk factor for AD.
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| 4. |
- Andersson, Jeanette, et al.
(författare)
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Results from the Swedish National Screening programme 2005. Sub report 1 Antibiotics, Anti-inflammatory substances and Hormones
- 2006
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Measurements of pharmaceuticals were performed in 179 samples of water, sludge, manure, sediment and biota at background sites, municipal STPs, landfills, hospital effluents and recipient water from STPs. Bioassays of hormone activity were performed for a selected number of water samples. The NSAIDs were the most frequently detected pharmaceuticals and occurred in the highest concentrations. There were large differences in concentrations both between substances and between sampling sites. A regional trend in the STP effluent water could be observed for the NSAIDs and for some antibiotics with increased concentrations in samples originating from the north. No pattern could be seen for the hormones. Estrogenic effects were detected in STP outlets to the aquatic environment while values obtained for androgenicity were in most samples close to or below the detection limit. Based on the risk asessment (MEC/PNEC) risk quotients >1 was obtained for estradiol, estriol, ethinylestradiol and ibuprofen.
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| 5. |
- Andersson, Maria A, et al.
(författare)
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The cognitive profile and CSF biomarkers in dementia with Lewy bodies and Parkinson's disease dementia.
- 2011
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Ingår i: International journal of geriatric psychiatry. - : Wiley. - 1099-1166 .- 0885-6230. ; 26:1, s. 100-5
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Tidskriftsartikel (refereegranskat)abstract
- Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) may be viewed as different points on a continuum reflecting the regional burden and distribution of pathology. An important clinical consideration is overlapping Alzheimer's disease (AD) pathology, since it has been reported that associated AD pathology in DLB shortens survival and leads to a more rapid cognitive decline. We aimed to investigate cerebrospinal fluid (CSF) biomarkers and the associated cognitive profile in DLB and PDD.
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| 6. |
- Andersson, Malin E, 1978, et al.
(författare)
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Kinesin gene variability may affect tau phosphorylation in early Alzheimer's disease.
- 2007
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Ingår i: International journal of molecular medicine. - 1107-3756 .- 1791-244X. ; 20:2, s. 233-9
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Tidskriftsartikel (refereegranskat)abstract
- Kinesin is a microtubule-associated motor protein that transports Alzheimer-associated amyloid precursor protein (APP) in neurons. In animal models, impaired kinesin-mediated APP transport seems to enhance formation of the neurotoxic 42 amino acid fragment of beta-amyloid (A beta 42). In man, one study suggests that a polymorphism (rs8702, 56,836G>C) in the kinesin light chain 1 gene (KNS2) may affect the risk of Alzheimer's disease (AD). To further assess KNS2 as a susceptibility gene for AD we analyzed 802 patients with sporadic AD and 286 controls, 134 longitudinally followed patients with mild cognitive impairment (MCI) and 39 cognitively stable controls for the rs8702 polymorphism. The rs8702 polymorphism did not influence risk of AD (p=0.46). However, rs8702 interacted with APOE epsilon 4 carrier status in AD (p=0.006) and influenced cerebrospinal fluid levels of hyperphosphorylated tau in MCI patients who converted to AD during follow-up (p=0.018). These findings support earlier indications that genetic variability in the KNS2 gene may play a role during early stages of AD pathogenesis.
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| 7. |
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| 8. |
- Bignert, Anders, et al.
(författare)
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Comments Concerning the National Swedish Contaminant Monitoring Programme in Marine Biota, 2015
- 2015
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The environmental toxicants examined in this report can be classified into five groups – heavy metals, chlorinated compounds, brominated flame retardants, polyaromatic hydrocarbons and perfluorinated compounds. Each of these contaminants have been examined from various sites for up to six different fish species, in blue mussels, and in guillemot eggs, for varying lengths of time. The following summary examines overall trends, spatial and temporal, for the five groups.Condition and Fat ContentCondition and fat content in different species tended to follow the same pattern at the same sites, with a few exceptions. Most of the fish species generally displayed a decreasing trend in both condition and fat content at most sites examined. Exceptions to this were increases in condition factor seen in cod liver at Fladen, perch muscle at Kvädöfjärden, and for herring at Ängskärsklubb in spring. Also, an increase in fat content was seen during the most recent ten years for herring at Ängskärsklubb in spring. There were also some sites where no log linear trends were seen.Heavy MetalsDue to a change in methods for metal analysis (not mercury) in 2004, values between 2003 and 2007 should be interpreted with care. From 2009 metals are analyzed at ACES, Stockholm University.Generally, higher mercury concentrations are found in the Bothnian Bay, but also from one station in the Northern parts of Baltic Proper, compared to other parts of the Swedish coastline. The time series show varying concentrations over the study period. The longer time series in guillemot egg and spring-caught herring from the southern Bothnian Sea and southern Baltic Proper show significant decreases of mercury. On the other hand, increasing concentrations are seen in e.g., cod muscle, but the concentrations are fairly low compared to measured concentrations in perch from fresh water and coastal sites. In most cases, the mercury concentrations are above the EQSbiota of 20 ng/g wet weight.Lead is generally decreasing over the study period (in time series of sufficient length), supposedly due to the elimination of lead in gasoline. The highest concentrations are seen in the southern part of the Baltic Sea. Elevated lead concentrations between 2003 and 2007 (e.g. Harufjärden) should be viewed with caution (see above regarding change in analysis methods). Lead concentrations are below the suggested target level at all stations.Cadmium concentrations show varying non-linear trends over the monitored period. It is worth noting that despite several measures taken to reduce discharges of cadmium, generally the most recent concentrations are similar to concentrations measured 30 yearsago in the longer time series. Cadmium concentrations in herring and perch are all below the suggested target level of 160 μg/kg wet weight.The reported nickel concentrations show no consistent decreasing trends. Some series begin with two elevated values that exert a strong leverage effect on the regression line and may give a false impression of decreasing trends. Chromium generally shows decreasing concentrations, possibly explained by a shift in analytical method. The essential trace metals, copper and zinc, show no consistent trends during the monitored period.Generally higher concentrations of arsenic and silver are found along the west coast compared to other parts of the Sweadish coast line. However for silver a few stations in the Bothnian Sea and Bothnian Bay show comparable concentrations to the west coast stations.Chlorinated CompoundsGenerally, a decreasing concentrations were observed for all compounds (DDT’s, PCB’s, HCH’s, HCB) in all species examined, with a few exceptions, such as no change in TCDD-equivalents being seen in herring muscle (except at Änskärsklubb where very high concentrations at the beginning of the sampling period were seen and also at the west coast station Fladen). The longer time-series in guillemot also show a marked decrease in TCDD-equivalents from the start in the late 1960s until about 1985 from where no change occurred for many years, however, during the most recent ten years a decrease in the concentration is seen. Concentrations of DDE and CB-118 are for some species and sites still above their respective target levels.The chlorinated compounds generally show higher concentrations in the Bothnian Sea and/or Baltic Proper when compared to the Bothnian Bay and the Swedish west coast.Brominated Flame RetardantsElevated levels of HBCDD are seen in sites from the Baltic Proper, while the investigated PBDEs show higher concentrations in the Bothnian Bay. In addition, lower concentrations of all investigated PBDEs and HBCDD are seen on the Swedish west coast compared to the east coast. Temporally, significant increases in BDE-47, -99 and -100 have been seen in guillemot eggs since the late 1960s until the early 1990s, where concentrations then began to show decreases. Also, the concentration of HBCDD in guillemot eggs shows a decrease during the most recent ten years. For fish and blue mussels, BDE-47, -99, and -153 decreased at some sites and showed no trend at other sites. The concentration of HBCDD in fish and blue mussels showed inconsistent trends. The concentration of HBCDD is below the EQSbiota of 167 μg/kg wet weight for all fish species from all areas, while the concentration of BDE-47 alone is above the EQSbiota for sumPBDE of 0.0085 ng/g wet weight.PAHsOnly blue mussels have been examined for spatial differences in PAH concentrations. Concentration of ΣPAH was found to be higher from Kvädöfjärden in the Baltic Proper compared to stations at the West coast, but individual PAHs showed varying spatial patterns. Over time, acenaphthalene was rarely found above the detection limit. Significant decreasing trends were observed for ΣPAH, chrysene, fluoranthene and pyrene at Fjällbacka; for naphthalene at Kvädöfjärden; and for pyrene at Fladen.All time series where concentrations of various PAHs were compared with the target value based on OSPAR Ecological Assessment Criteria, or EC Environmental Quality Standards were below the target value.PFASsPFHxS and PFOS show a similar spatial pattern, but PFOS concentrations were approximately 25 times higher than PFHxS levels. The distribution of PFOS is quite homogenous along the Swedish coast but with somewhat higher concentrations in the Baltic Proper. PFOS concentrations in guillemot eggs are about 100-200 times higher than in herring liver. An overall increasing concentration of PFOS in guillemot eggs has been observed throughout the whole time period, however, during the most recent ten years, a change of direction is detected. The longer herring time series from Harufjärden, Landsort, and Utlängan show increasing concentrations for PFOS and most carboxylates. For FOSA, on the other hand, decreasing concentrations are seen during the most recent ten years.Organotin compoundsThe majority of the analysed tinorganic compounds showed concentrations below LOQ. However TBT and DPhT showed concentrations above LOQ at all stations with highest reported concentrations in fish from Örefjärden in the northern part of Bothnian Sea.
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| 9. |
- Bjerke, Maria, 1977, et al.
(författare)
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Confounding factors influencing amyloid Beta concentration in cerebrospinal fluid.
- 2010
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Ingår i: International journal of Alzheimer's disease. - : Hindawi Limited. - 2090-0252. ; 2010
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Tidskriftsartikel (refereegranskat)abstract
- Background. Patients afflicted with Alzheimer's disease (AD) exhibit a decrease in the cerebrospinal fluid (CSF) concentration of the 42 amino acid form of beta-amyloid (Abeta(42)). However, a high discrepancy between different centers in measured Abeta(42) levels reduces the utility of this biomarker as a diagnostic tool and in monitoring the effect of disease modifying drugs. Preanalytical and analytical confounding factors were examined with respect to their effect on the measured Abeta(42) level. Methods. Aliquots of CSF samples were either treated differently prior to Abeta(42) measurement or analyzed using different commercially available xMAP or ELISA assays. Results. Confounding factors affecting CSF Abeta(42) levels were storage in different types of test tubes, dilution with detergent-containing buffer, plasma contamination, heat treatment, and the origin of the immunoassays used for quantification. Conclusion. In order to conduct multicenter studies, a standardized protocol to minimize preanalytical and analytical confounding factors is warranted.
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| 10. |
- Blennow, Kaj, 1958, et al.
(författare)
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Evolution of Abeta42 and Abeta40 Levels and Abeta42/Abeta40 Ratio in Plasma during Progression of Alzheimer's Disease: A Multicenter Assessment.
- 2009
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Ingår i: The journal of nutrition, health & aging. - 1279-7707. ; 13:3, s. 205-8
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To better understand the seemingly contradictory plasma beta-amyloid (Abeta) results in Alzheimer's disease (AD) patients by using a newly developed plasma Abeta assay, the INNO-BIA plasma Abeta forms, in a multicenter study. Methods: A combined retrospective analysis of plasma Abeta isoforms on mild cognitive impairment (MCI) from three large cross-sectional studies involving 643 samples from the participating German and Swedish centers. Results: Detection modules based on two different amino (N)-terminal specific Abeta monoclonal antibodies demonstrated that Abeta in plasma could be reliable quantified using a sandwich immunoassay technology with high precision, even for low Abeta42 plasma concentrations. Abeta40 and Abeta42 concentrations varied consistently with the ApoE genotype, while the Abeta42/Abeta40 ratio did not. Irrespective of the decrease of the Abeta42/Abeta40 ratio with age and MMSE, this parameter was strongly associated with AD, as defined in this study by elevated hyperphosphorylated (P-tau181P) levels in cerebrospinal fluid (CSF). Conclusion: A highly robust assay for repeatedly measuring Abeta forms in plasma such as INNO-BIA plasma Abeta forms might be a useful tool in a future risk assessment of AD.
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| 11. |
- Blennow, Kaj, 1958, et al.
(författare)
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Longitudinal stability of CSF biomarkers in Alzheimer's disease
- 2007
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 419:1, s. 18-22
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Tidskriftsartikel (refereegranskat)abstract
- Biomarker levels in cerebrospinal fluid (CSF) may serve as surrogate markers for treatment efficacy in clinical trials of disease-modifying drugs against Alzheimer's disease (AD). A prerequisite, however, is that the marker is sufficiently stable over time in individual patients. Here, we tested the stability of the three established CSF biomarkers for AD, total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181) and the 42 amino acid isoform of β-amyloid (Aβ42), over 6 months in a cohort of AD patients on stable treatment with acetylcholinesterase (AChE) inhibitors. Fifty-three patients completed the study, 29 men and 24 women, mean age (±S.D.) 76.1 ± 7.9 years. Mean levels of CSF biomarkers were very stable between baseline and endpoint, with coefficients of variation (CVs) of 4.4–6.1%. Intra-individual biomarker levels at baseline and endpoint were also highly correlated with Pearson r-values above 0.95 (p < 0.0001), for all three markers. We conclude that T-tau, P-tau and Aβ42 concentrations in CSF are remarkably stable over a 6-month period in individual AD patients. This suggest that these biomarkers may have a potential to identify and monitor very minor biochemical changes induced by treatment, and thus support their possible usefulness as surrogate markers in clinical trials with drug candidates with disease-modifying potential, such as secretase inhibitors, Aβ immunotherapy and tau phosphorylation inhibitors.
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| 12. |
- Blennow, Kaj, 1958, et al.
(författare)
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No association between the alpha2-macroglobulin (A2M) deletion and Alzheimer's disease, and no change in A2M mRNA, protein, or protein expression.
- 2000
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Ingår i: Journal of neural transmission (Vienna, Austria : 1996). - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 107:8-9, s. 1065-79
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Tidskriftsartikel (refereegranskat)abstract
- A polymorphism consisting of a deletion near the 5' splice site of exon 18 on the alpha2-macroglobulin (A2M) gene (A2M-2) has been suggested to be associated with Alzheimer's disease (AD) in family-based studies. We studied the A2M-2 allele together with the ApoE alleles in a large series on patients with AD (n = 449) and age-matched controls (n = 349). Neuropathologically confirmed diagnoses were available in 199 cases (94 AD and 107 control cases). We found no increase in A2M-2 genotype or allele frequencies in AD (27.5% and 14.6%) versus controls (26.4% and 14.9%). In contrast, a marked increase (p < 0.0001) in ApoE epsilon4 genotype or allele frequencies was found in AD (66.6% and 41.2%) as compared with controls (29.8% and 16.5%), suggesting sufficient statistical power in our sample. No relation was found between the A2M-2 and the ApoE epsilon4 allele. No change in A2M exon 17-18 mRNA size or sequence or A2M protein size was found in cases carrying the A2M-2 deletion, suggesting that there is no biological consequences of the A2M intronic deletion. No change in A2M protein level in cerebrospinal fluid was found in AD, suggesting that the A2M-2 allele does not effect the A2M protein expression in the brain. The lack of an association between the A2M-2 allele and AD in the present study, and the lack of abnormalities in the A2M mRNA or protein suggest that the A2M-2 allele is not associated with AD.
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| 13. |
- Blennow, Kaj, et al.
(författare)
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Starka belägg för att proffsboxning leder till kroniska hjärnskador. Ju fler slag mot huvudet under en boxares karriär, desto större är risken
- 2005
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Ingår i: Läkartidningen. - 0023-7205. ; 102:36, s. 2468-2475
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Tidskriftsartikel (refereegranskat)abstract
- The clinical symptomatology and pathogenic mechanisms of chronic traumatic brain injury associated with boxing (CTBI-B) is reviewed. This syndrome is also known as punch drunk syndrome or dementia pugilistica. Since even milder forms of CTBI-B are rare among amateur boxers, we make a distinction between amateur and professional boxing throughout the review. Focus is also set on the interesting similarities in neurochemical changes and pathogenic mechanisms between CTBI-B, acute traumatic brain injury (e.g. road traffic accidents) and Alzheimer's disease.
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| 14. |
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| 15. |
- Boström, Fredrik, et al.
(författare)
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Cerebrospinal fluid total tau is associated with shorter survival in dementia with Lewy bodies.
- 2009
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Ingår i: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 28:4, s. 314-9
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Tidskriftsartikel (refereegranskat)abstract
- A pathology typical of dementia with Lewy bodies (DLB) has been demonstrated to increase mortality to a greater extent than the pathology of Alzheimer's disease (AD). However, mortality in DLB has also been shown to increase with concomitant AD pathology. Furthermore, in a recent publication, we showed that there is a robust and specific increase in CSF calcium and magnesium in DLB patients compared to both AD patients and controls. Thus, in order to explore the influence of CSF AD markers and trace element concentrations on mortality in DLB, we undertook a longitudinal prospective study of 47 clinically diagnosed DLB patients and 157 AD patients as well as 49 healthy volunteers. Both AD and DLB patients showed an increased mortality compared to the healthy controls (relative risk: 10 and 8, respectively; p < 0.001). Increased levels of CSF total tau were associated with increased mortality among the DLB patients (p < 0.05), but not among the AD patients or controls. Gender, age, MMSE score, Abeta42 concentration and phosphorylated tau, and CSF trace element concentrations did not influence survival in the obtained models.
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| 16. |
- Brinkmalm, Gunnar, et al.
(författare)
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Soluble amyloid precursor protein alpha and beta in CSF in Alzheimer's disease
- 2013
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Ingår i: Brain Research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 1513, s. 117-126
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Cerebral accumulation of amyloid beta (A beta) is a pathological hallmark of Alzheimer's disease (AD). Proteolytic processing of amyloid precursor protein (APP) by alpha- or beta-secretase results in two soluble metabolites, sAPP alpha and sAPP beta, respectively. However, previous data have shown that both alpha- and beta-secretase have multiple cleavage sites. The aim of this study was to characterize the C-termini of sAPP alpha and sAPP beta in cerebrospinal fluid (CSF) by mass spectrometry (MS) and to evaluate whether different combinations of these fragments better separate between AD patients and controls by comparing two different sAPP immunoassays. Methods: Using immunoprecipitation and high resolution MS, the APP species present in CSF were investigated. CSF levels of sAPP alpha and sAPP beta from patients with AD (n=43) and from non-demented controls (n=44) were measured using AlphaLISA and MSD immunoassays that employ different antibodies for C-terminal recognition of sAPP alpha. Results: Four different C-terminal forms of sAPP were identified, sAPP beta-M671, sAPP beta-Y681, sAPP alpha-Q686, and 5APP alpha-K687 (APP770 numbering). Neither immunoassay for the sAPP species could separate the two patient groups. The correlation (R-2) between the two immunoassays was 0.41 for sAPP alpha and 0.45 for sAPP beta. Conclusion: Using high resolution MS, we show here for the first time that sAPP alpha in CSF ends at Q686 and K687. The findings also support the conclusion from several previous studies that sAPP alpha and sAPP beta levels are unaltered in AD. (C) 2013 Elsevier B.V. All rights reserved.
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| 17. |
- Brinkmalm, Gunnar, et al.
(författare)
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Soluble amyloid precursor protein α and β in CSF in Alzheimer's disease.
- 2013
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Ingår i: Brain research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 1513, s. 117-26
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral accumulation of amyloid β (Aβ) is a pathological hallmark of Alzheimer's disease (AD). Proteolytic processing of amyloid precursor protein (APP) by α- or β-secretase results in two soluble metabolites, sAPPα and sAPPβ, respectively. However, previous data have shown that both α- and β-secretase have multiple cleavage sites. The aim of this study was to characterize the C-termini of sAPPα and sAPPβ in cerebrospinal fluid (CSF) by mass spectrometry (MS) and to evaluate whether different combinations of these fragments better separate between AD patients and controls by comparing two different sAPP immunoassays. Methods: Using immunoprecipitation and high resolution MS, the APP species present in CSF were investigated. CSF levels of sAPPα and sAPPβ from patients with AD (n=43) and from non-demented controls (n=44) were measured using AlphaLISA and MSD immunoassays that employ different antibodies for C-terminal recognition of sAPPα. Results: Four different C-terminal forms of sAPP were identified, sAPPβ-M671, sAPPβ-Y681, sAPPα-Q686, and sAPPα-K687 (APP770 numbering). Neither immunoassay for the sAPP species could separate the two patient groups. The correlation (R(2)) between the two immunoassays was 0.41 for sAPPα and 0.45 for sAPPβ. Conclusion: Using high resolution MS, we show here for the first time that sAPPα in CSF ends at Q686 and K687. The findings also support the conclusion from several previous studies that sAPPα and sAPPβ levels are unaltered in AD.
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| 18. |
- Brinkmalm-Westman, Ann, 1966, et al.
(författare)
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SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer's disease
- 2014
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Synaptic degeneration is an early pathogenic event in Alzheimer's disease, associated with cognitive impairment and disease progression. Cerebrospinal fluid biomarkers reflecting synaptic integrity would be highly valuable tools to monitor synaptic degeneration directly in patients. We previously showed that synaptic proteins such as synaptotagmin and synaptosomal-associated protein 25 (SNAP-25) could be detected in pooled samples of cerebrospinal fluid, however these assays were not sensitive enough for individual samples. Results: We report a new strategy to study synaptic pathology by using affinity purification and mass spectrometry to measure the levels of the presynaptic protein SNAP-25 in cerebrospinal fluid. By applying this novel affinity mass spectrometry strategy on three separate cohorts of patients, the value of SNAP-25 as a cerebrospinal fluid biomarker for synaptic integrity in Alzheimer's disease was assessed for the first time. We found significantly higher levels of cerebrospinal fluid SNAP-25 fragments in Alzheimer's disease, even in the very early stages, in three separate cohorts. Cerebrospinal fluid SNAP-25 differentiated Alzheimer's disease from controls with area under the curve of 0.901 (P < 0.0001). Conclusions: We developed a sensitive method to analyze SNAP-25 levels in individual CSF samples that to our knowledge was not possible previously. Our results support the notion that synaptic biomarkers may be important tools for early diagnosis, assessment of disease progression, and to monitor drug effects in treatment trials.
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| 19. |
- Brorström-Lundén, Eva, et al.
(författare)
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Measurements of Sucralose in the Swedish Screening Program 2007 : PART I; Sucralose in surface waters and STP samples
- 2008
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- IVL har på uppdrag av Naturvårdsverket genomfört en screening av sötningsmedlet sukralos. Sukralos är en disackarid, som modifierats i tre positioner med klor. Ämnet är ca 600 gånger sötare än sackaros och används efter tillstånd i USA och Europaunionen, m.fl. länder som tillsats i livsmedel. Ämnet är lättlösligt i vatten och vid intag utsöndras minst 95 % i oförändrad form. Ingen ackumulering i organismen är känd och nedbrytning eller omvandling har endast påvisats i vattenmiljö under inverkan av mikroorganismer. Tre primära klorinnehållande omvandlingspordukter har påvisats. De studier i djurförsök som legat till grund för tillståndsgivningen har visat mycket små effekter. Det huvudsakliga syftet med denna översiktliga kartläggning var att bestämma koncentrationer av sukralos i några olika matriser i miljön, framförallt för att belysa viktiga transportvägar i vattenmiljön i Sverige. Totalt bestämdes sukralos i 57 prover. Studien visar att; • Sucralose detekteras i vattenrecipienter i Sverige som tar emot utgående vatten ifrån reningsverk. • Inkommande vatten till svenska avloppsreningsverk (2 ARV) innehåller 3 500-7 900 ng sukralos/l. • Reningsgraden m a p. sukralos är låg i reningsverk, maximalt uppmättes 10 % reningsgrad i de parade prover som analyserats (inkommande/utgående). • Sukralos detekterades i alla de 29 utgående reningsverksvattenproverna ifrån 25 olika reningsverk i landet; 1 800-10 800 ng/l, median 4 900 ng/l. • Det sker ingen ackumulation av sukralos i slam. Denna rapport utgör den första delen av en fördjupad screening av sukralos i den svenska miljön. I en fortsättande, kommande rapport kommer resultat ifrån undersökningar av sukralosupptag i akvatiska biotaprover att redovisas.
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| 20. |
- Brorström-Lundén, Eva, et al.
(författare)
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Measurements of Sucralose in the Swedish Screening Program 2007 -PART I; Sucralose in surface waters and STP samples.
- 2008
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- IVL has performed a 'screening study' of sucralose on commission from the Swedish EPA. Sucralose is a chlorine containing derivative of sucrose, manufactured by selectively substituting three hydroxyls with chlorine. The substance is used as a sweetener in food products; on a weight basis it tastes ca. 600 times sweeter than the parent compound. The objectives of the study were to determine the concentrations of sucralose in media in the Swedish environment related to wastewater effluents and to highlight important transport pathways. In total 57 samples were analysed representing wastewater and sludge from sewage treatment plants as well as surface waters.
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| 21. |
- Brorström-Lundén, Eva, et al.
(författare)
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Measurements of Sucralose in the Swedish Screening program 2007. PART II; Sucralose in Biota samples and regional STP samples
- 2008
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- IVL has performed a 'screening study' of sucralose on commission from the Swedish EPA, reported in two consecutive parts. Sucralose is a chlorine containing derivative of sucrose, manufactured by selectively substituting three hydroxyls with chlorine. The substance is used as a sweetener in food products; on a weight basis it tastes ca. 600 times sweeter than the parent compound. The objectives of the study were to determine the concentrations of sucralose in media in the Swedish environment such as biota, wastewater effluents and to highlight important transport pathways. In total 84 samples were analysed. This report constitutes part 2 of the study.
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| 22. |
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| 23. |
- Brorström-Lundén, Eva, et al.
(författare)
-
Results from the Swedish National Screening Programme 2008. Screening of unintentionally produced organic contaminants
- 2010
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This report considers the screening of unintentionally produced substances. Substance groups included in the screening program were oxygenated and nitrated forms of polycyclic aromatic hydrocarbons (PAHs) as well as nitrogen, sulphur and oxygen containing heterocyclic compounds. Polybrominated dibenzodioxins (PBDD) and furans (PBDF), polychlorinated dibenzothiophenes (PCDT) and dibenzotianthrenes (PCDTA) were also included in the study. PAHs and polychlorinated biphenyls (PCBs) were included as reference substances. The results of the screening showed that oxidized and nitrated forms of PAHs as well as heterocyclic analogues of PAHs were frequently found in background and urban areas and in most of the environmental matrices included in the study. PCDTs were found in most abiotic samples while PCDTA generally was below the limit-of-detection. The concentrations of PBDDs were generally below the limit-of-detection but were found in deposition, urban sediment, background sediment, and fish from Kvädöfjärden. The PBDF concentrations in air varied widely in time and space. OBDF occurred in similar concentrations as PCBs in air, deposition, sediment and soil.
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| 24. |
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| 25. |
- Brorström-Lundén, Eva, et al.
(författare)
-
Screening of benzothiazoles, benzenediamines, dicyclohexylamine and benzotriazoles 2009
- 2012
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- En screeningundersökning av bensotiazoler, bensendiaminer, dicyclohexylamin och bensotriazoler har genomförts inom ramen för Naturvårdsvekets screeningprogram. Avsikten med en screeningundersökning är att bestämma koncentrationer av de utvalda substanserna i olika delar av den svenska miljön och därigenom belysa viktiga emissions- och transportvägar. Denna undersökning har genomförts i sammarbete med forskningsprogrammet ChEmiTecs “Organic Chemicals Emitted from Technosphere Articles" (www.chemitecs.se) finansierat av Naturvårdsverket. Målet med Chemitecs är att öka kunskapen om emissioner av organiska ämnen från varor. Resultaten ska stödja utvecklingen av svenska och europeiska handlingsprogram som ska minska riskerna med särskilt farliga ämnen. Bensotiazolerna MBT, CBS, DBS och DBD fanns i en eller flera av de undersökta provtyperna. Detektionsfrekvenserna varierade både mellan substanserna och provtyperna. Fördelningsmönstret påverkades troligen både av föreningarnas egenskaper, såsom kemisk stabilitet och tendens att fördelas mellan olika faser, och av användningen. MBT hade högst detektionsfrekvens medan de andra bensotiazolerna hittades mera sporadiskt. En viktig spridningsväg till miljön för MBT är via reningsverk vilket pekar på diffusa emissioner från konsumentprodukter. Förekomst i dagvatten indikerar trafik-relaterade emissioner. MBT och övriga bensotiazoler förekom främst i vattenmiljön medan lufttransport verkar vara av mindre betydelse. Bensendiaminen DPP hittades i vissa fall i till exempel ytvatten, dagvatten och reningsverksslam.DCHA var vanligt förekommande i alla provtyper utom i gröda. Att DCHA återfinns i luft och deposition indikerar att substansen emitteras till luft och att lufttransport är en viktig spridningsväg. Förekomsten i dagvatten och i jord visar att trafikrelaterade emissioner är viktiga. DCHA hittades emellertid inte i gröda insamlad i närheten av trafikerade vägar. En annan viktig spridningsväg för DCHA är via reningsverk vilket antyder diffusa emissioner från till exempel konsumentprodukter Bensotriazoler är vanligt förekommande i miljön både i bakgrundsmiljö och i urbana områden. Substanserna förekom i alla analyserade matriser: luft, deposition, ytvatten, sediment, jord och biota. Resultaten visade också att diffus spridning via reningsverk, deponier och dagvatten kan vara viktigt för förekomsten i miljön. Detta indikerar emissioner via användning av produkter. UVP är den bensotriazol som används mest följd av UV 328 och UV 327. Dessa substanser hittades också i högst koncentrationer.I en enkel riskbedömning för vattenmiljöns pelagiska ekosystem identifierades inga större risker, dvs halterna var generellt lägre än PNEC i ytvatten och i avloppsvatten med hänsyn till förväntad utspädning. DPP förekom dock i koncentrationer över PNEC i Viskan. Koncentrationen av DPP och DCHA i outspätt avloppsvatten överskred vid några tillfällen PNEC. Inga toxicitets eller ekotoxicitetsdata har hittats för någon av benzotriazolerna i tillgänglig litteratur. Några riskbedömningar för dessa har därför inte utförts.
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| 26. |
- Brunnström, Hans, et al.
(författare)
-
Cerebrospinal fluid biomarker results in relation to neuropathological dementia diagnoses.
- 2010
-
Ingår i: Alzheimer's & dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 6:2, s. 104-109
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Clinical dementia diagnoses are not always consistent with neuropathological findings. As correct diagnosis is important for treatment and care, new diagnostic possibilities for dementia are in demand. Cerebrospinal fluid biomarkers should ideally be able to identify ongoing processes in the brain, but need to be further compared with neuropathological findings for evaluation of their diagnostic validity. METHODS: This study included 43 patients with a clinical dementia disorder. All patients were neuropathologically examined at the University Hospital in Lund, Sweden, during the years 2001-2008, and all had a lumbar puncture carried out as part of the clinical investigation during the time of cognitive impairment. RESULTS: Of eight patients, five with Alzheimer's disease had elevated total tau protein (T-tau) and decreased amyloid beta 1-42 protein (Abeta42), while both values for the other three patients were normal. Slightly elevated T-tau and/or decreased Abeta42 were also seen in several patients with other dementia diagnoses such as Lewy body disease, frontotemporal lobar degeneration and vascular dementia. Furthermore, T-tau levels did not differ markedly between patients with morphologically tau-positive and tau-negative frontotemporal lobar degeneration. Also, seven of nine patients with Creutzfeldt-Jacob disease exhibited pronounced elevation in T-tau concentration. CONCLUSION: From this rather limited study, being the first of its kind in Sweden, we may conclude that there is no perfect concordance between cerebrospinal fluid biomarker levels and pathological findings, which should be taken into account in the clinical diagnostic setting.
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| 27. |
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| 28. |
- Buchhave, Peder, et al.
(författare)
-
Cube copying test in combination with rCBF or CSF A beta(42) predicts development of Alzheimer's disease
- 2008
-
Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 25:6, s. 544-552
-
Tidskriftsartikel (refereegranskat)abstract
- <i>Background/Aim: </i>The aim was to identify subjects with incipient Alzheimer’s disease (AD) among patients with mild cognitive impairment (MCI) using brief cognitive tests. <i>Methods: </i>A total of 147 MCI patients were followed for 4–6 years and the incidence of AD was 11.6%/year. At baseline, the cube copying test, clock drawing test, MMSE and measurements of regional cerebral blood flow (rCBF) and cerebrospinal fluid (CSF) β-amyloid<sub>1–42</sub> (Aβ<sub>42</sub>) were performed. <i>Results: </i>The cube copying test, but not the clock drawing test, could predict AD among MCI patients with an area under the receiver operating characteristic curve of 0.64 (p < 0.01). The relative risk for future AD was increased in MCI subjects with impaired cube copying test (sex- and age-adjusted hazard ratio = 1.8, p < 0.05) and the incidence of AD was 18.2% in this subgroup. Combining the cube copying test with either rCBF or CSF Aβ<sub>42</sub> had additive effects on the risk assessment for future development of AD. MCI patients achieving high scores on both MMSE and cube copying test had a very low risk of developing AD (incidence of AD = 1.6%). <i>Conclusion: </i>In conclusion, combinations of the cube copying test with MMSE, rCBF and CSF Aβ<sub>42</sub> measurements can identify subgroups of MCI subjects with either substantially reduced or increased risk for future development of AD.
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| 29. |
- Buchhave, Peder, et al.
(författare)
-
Elevated plasma levels of soluble CD40 in incipient Alzheimer's disease.
- 2009
-
Ingår i: Neuroscience letters. - : Elsevier BV. - 0304-3940. ; 450:1, s. 56-9
-
Tidskriftsartikel (refereegranskat)abstract
- CD40 is a member of the tumor necrosis factor receptor super-family and has been suggested to play a role in the metabolism of beta-amyloid (Abeta) in Alzheimer's disease (AD). However, the role of CD40-signalling in incipient AD has not yet been studied. We investigated the plasma levels of soluble CD40 (sCD40) and the soluble CD40 ligand (sCD40L) at baseline in 136 subjects with mild cognitive impairment (MCI) and 30 age-matched controls. Sixty of the 136 MCI cases converted to AD (MCI-AD) during a clinical follow-up period of 4-7 years. The baseline levels of sCD40, but not sCD40L, were elevated in MCI-AD cases when compared to age-matched controls (Mann-Whitney U-test, p=0.02). However, MCI patients who were cognitively stable or developed vascular dementia during follow-up did not have significantly increased levels of sCD40 or sCD40L when compared to controls. The levels of sCD40 correlated to decreased baseline performance on mini-mental state examination (MMSE) in both controls (r(s)=-0.37, p<0.05) and MCI-AD cases (r(s)=-0.29, p<0.05). Finally, the plasma levels of sCD40 correlated with the levels of soluble amyloid precursor protein-alpha (sAPP-alpha) (r(s)=0.28, p<0.01) and sAPP-beta (r(s)=0.23, p<0.05) in cerebrospinal fluid. In conclusion, CD40-signalling might play a role in the pathogenesis of early AD.
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| 30. |
- Buchhave, Peder, et al.
(författare)
-
Longitudinal study of CSF biomarkers in patients with Alzheimer's disease.
- 2009
-
Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 16:Suppl 3, s. 337-337
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The CSF biomarkers tau and Abeta42 can identify patients with AD, even during the preclinical stages. However, previous studies on longitudinal changes of tau and Abeta42 in individual patients with AD and elderly controls report somewhat inconsistent results. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the levels of tau and Abeta42 at baseline and after 1 year in 100 patients with AD. In a second cohort of 45 AD patients we measured the CSF biomarkers at baseline and after 2 years. Moreover, in 34 healthy elderly controls the CSF biomarkers were followed for 4 years. The baseline levels of tau were increased with >60% in AD patients compared to controls (p<0.001), while baseline Abeta42 levels were decreased with >50% (p<0.001). In the AD group followed for 2 years, tau increased with 16% compared to the baseline levels (p<0.05). However, the levels of tau were stable over 4 years in the controls. The levels of Abeta42 did not change significantly over time in any of the groups. In the patients with AD, tau was moderately associated with worse cognitive performance already at baseline (p<0.05). CONCLUSIONS/SIGNIFICANCE: Tau and Abeta42 in CSF seem to reflect the underlying disease state in both early and late stages of AD. The slight increase in tau over time observed in the patients with AD is modest when compared to the relatively large difference in absolute tau levels between AD patients and controls. Therefore, these markers maintain their usefulness as state markers over time and might serve as surrogate markers for treatment efficacy in clinical trials.
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| 31. |
- Buchhave, Peder, et al.
(författare)
-
Soluble TNF receptors are associated with Abeta metabolism and conversion to dementia in subjects with mild cognitive impairment.
- 2010
-
Ingår i: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 31:11, s. 1877-1884
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: There is evidence supporting that tumor necrosis factor receptor (TNFR)-signaling can induce production of beta-amyloid (Abeta) in the brain. Moreover, amyloid-induced toxicity has been shown to be dependent on TNFR-signaling. However, it is still unclear whether TNFRs are involved in the early stages of dementia. METHODS: We analyzed soluble TNFR1 and TNFR2 levels in plasma and cerebrospinal fluid (CSF) at baseline in 137 patients with mild cognitive impairment (MCI) and 30 age-matched controls. The MCI patients were followed for 4-6 years with an incidence of Alzheimer's disease (AD) or vascular dementia (VaD) of 15% per year. RESULTS: The patients with MCI who subsequently developed these forms of dementias had higher levels of sTNFR1 and sTNFR2 in both CSF and plasma already at baseline when compared to age-matched controls (p<0.05). In the CSF of MCI subjects and controls the levels of both sTNFR1 and sTNFR2 correlated strongly with beta-site APP-cleaving enzyme 1 (BACE1) activity (r(s)=0.53-0.68, p<0.01) and Abeta 40 levels (r(s)=0.59-0.71, p<0.001). Similarly, both sTNFRs were associated with Abeta 40 (r(s)=0.39-0.46, p<0.05) in plasma. Finally, the levels of both sTNFRs correlated with the axonal damage marker tau in the CSF of MCI subjects and controls (r(s)=0.57-0.83, p<0.001). CONCLUSION: TNFR-signaling might be involved in the early pathogenesis of AD and VaD, and could be associated with beta-amyloid metabolism.
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| 32. |
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| 33. |
- Buerger, Katharina, et al.
(författare)
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Prediction of Alzheimer's disease using midregional proadrenomedullin and midregional proatrial natriuretic peptide: a retrospective analysis of 134 patients with mild cognitive impairment.
- 2011
-
Ingår i: The Journal of clinical psychiatry. - 1555-2101 .- 0160-6689. ; 72:4, s. 556-63
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Development of biomarkers for early detection of Alzheimer's disease (AD) is a major clinical research goal. On the basis of the hypothesis that cardiovascular risk factors contribute to the pathogenesis of AD, we investigated whether the cardiovascular risk markers midregional proadrenomedullin (MR-proADM) and midregional proatrial natriuretic peptide (MR-proANP) predict a major clinical milestone, ie, conversion from predementia mild cognitive impairment (MCI) to manifest AD. METHOD: A group of 134 MCI patients, among 137 originally prospectively recruited at the memory disorder clinic at Malmö University Hospital, Malmö, Sweden, between July 1998 and June 2001, was clinically followed for 4-6 years. We determined whether plasma concentrations of MR-proADM and MR-proANP at baseline predicted time to conversion from MCI to clinically diagnosed AD (DSM-III-R). MCI was diagnosed according to Petersen criteria. RESULTS: During follow-up, 41.8% of MCI patients remained cognitively stable, 42.5% converted to possible and probable AD, and 15.7% converted to other forms of dementia (MCI-other). MCI converters and MCI-other patients showed increased concentrations of MR-proANP and MR-proADM compared to the stable MCI patients (P = .0001). At a cutoff of 87 pmol/L, MR-proANP yielded a sensitivity of 73.7% and a specificity of 64.3% for predicting conversion to AD. The survival analysis showed that higher values of MR-proANP and MR-proADM were associated with progression to AD. In a multivariate Cox regression model including known risk factors, MR-proANP and MR-proADM remained independent risk factors for conversion to AD for patients below the age of 72 years. CONCLUSIONS: Our study shows that plasma concentrations of MR-proANP and MR-proADM have predictive value in the progression from predementia MCI to clinical AD. Sensitivity was particularly high, which may recommend this test for first-stage screening in patients at risk for AD.
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| 34. |
- Chapuis, Julien, et al.
(författare)
-
Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism
- 2017
-
Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 133:6, s. 955-966
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer’s disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the “post-GWAS” era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a β3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aβ peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aβ peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aβ peptide production.
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| 35. |
- Daborg, Jonny, et al.
(författare)
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Association of the RAGE G82S polymorphism with Alzheimer's disease
- 2010
-
Ingår i: Journal of Neural Transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 117:7, s. 861-867
-
Tidskriftsartikel (refereegranskat)abstract
- The receptor for advanced glycation end-products (RAGE) has been implicated in several pathophysiological processes relevant to Alzheimer's disease (AD), including transport and synaptotoxicity of AD-associated amyloid beta (A beta) peptides. A recent Chinese study (Li et al. in J Neural Transm 117:97-104, 2010) suggested an association between the 82S allele of the functional single nucleotide polymorphism (SNP) G82S (rs2070600) in the RAGE-encoding gene AGER and risk of AD. The present study aimed to investigate associations between AGER, AD diagnosis, cognitive scores and cerebrospinal fluid AD biomarkers in a European cohort of 316 neurochemically verified AD cases and 579 controls. Aside from G82S, three additional tag SNPs were analyzed to cover the common genetic variation in AGER. The 82S allele was associated with increased risk of AD (P (c) = 0.04, OR = 2.0, 95% CI 1.2-3.4). There was no genetic interaction between AGER 82S and APOE epsilon 4 in producing increased risk of AD (P = 0.4), and none of the AGER SNPs showed association with A beta(42), T-tau, P-tau(181) or mini-mental state examination scores. The data speak for a weak, but significant effect of AGER on risk of AD.
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| 36. |
- Daborg, Jonny, et al.
(författare)
-
Cerebrospinal fluid levels of complement proteins C3, C4 and CR1 in Alzheimer's disease.
- 2012
-
Ingår i: Journal of neural transmission (Vienna, Austria : 1996). - : Springer Science and Business Media LLC. - 1435-1463 .- 0300-9564. ; 119:7, s. 789-97
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is strongly associated with loss of synapses. The complement system has been shown to be involved in synaptic elimination. Several studies point to an association between AD and the complement system. The purpose of this study was to examine the association of cerebrospinal fluid (CSF) levels of complement components 3 and 4 (C3 and C4, respectively), and complement receptor 1 (CR1) with AD in 43 patients with AD plus dementia, 42 patients with mild cognitive impairment (MCI) who progressed to AD during follow-up (MCI-AD), 42 patients with stable MCI and 44 controls. Complement levels were also applied in a multivariate model to determine if they provided any added value to the core AD biomarkers Aβ42, T-tau and P-tau. We found elevated CSF levels of C3 and C4 in AD compared with MCI without progression to AD, and elevated CSF levels of CR1 in MCI-AD and AD when these groups were merged. These results provide support for aberrant complement regulation as a part in the AD process, but the changes are not diagnostically useful.
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| 37. |
- Daborg, Jonny, et al.
(författare)
-
Complement Gene Single Nucleotide Polymorphisms and Biomarker Endophenotypes of Alzheimer's Disease
- 2013
-
Ingår i: Journal of Alzheimer's Disease. - 1387-2877. ; 35:1, s. 51-57
-
Tidskriftsartikel (refereegranskat)abstract
- The complement system has been implicated in both physiological synapse elimination and Alzheimer's disease (AD). Here, we investigated associations between four single nucleotide polymorphisms (SNPs) in complement genes and cerebrospinal fluid (CSF) biomarkers for AD in 452 neurochemically or neuropathologically verified AD cases and 678 cognitively normal controls. None of the SNPs associated with risk of AD but there were potential associations of rs9332739 in the C2 gene and rs4151667 in the complement factor B gene with CSF tau levels (p = 0.023) and Mini-Mental State Examination scores (p = 0.012), both of which may be considered markers of disease intensity/severity.
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| 38. |
- De Meyer, Geert, et al.
(författare)
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Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people.
- 2010
-
Ingår i: Archives of neurology. - : American Medical Association (AMA). - 1538-3687 .- 0003-9942. ; 67:8, s. 949-56
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To identify biomarker patterns typical for Alzheimer disease (AD) in an independent, unsupervised way, without using information on the clinical diagnosis. DESIGN: Mixture modeling approach. SETTING: Alzheimer's Disease Neuroimaging Initiative database. Patients or Other PARTICIPANTS: Cognitively normal persons, patients with AD, and individuals with mild cognitive impairment. MAIN OUTCOME MEASURES: Cerebrospinal fluid-derived beta-amyloid protein 1-42, total tau protein, and phosphorylated tau(181P) protein concentrations were used as biomarkers on a clinically well-characterized data set. The outcome of the qualification analysis was validated on 2 additional data sets, 1 of which was autopsy confirmed. RESULTS: Using the US Alzheimer's Disease Neuroimaging Initiative data set, a cerebrospinal fluid beta-amyloid protein 1-42/phosphorylated tau(181P) biomarker mixture model identified 1 feature linked to AD, while the other matched the "healthy" status. The AD signature was found in 90%, 72%, and 36% of patients in the AD, mild cognitive impairment, and cognitively normal groups, respectively. The cognitively normal group with the AD signature was enriched in apolipoprotein E epsilon4 allele carriers. Results were validated on 2 other data sets. In 1 study consisting of 68 autopsy-confirmed AD cases, 64 of 68 patients (94% sensitivity) were correctly classified with the AD feature. In another data set with patients (n = 57) with mild cognitive impairment followed up for 5 years, the model showed a sensitivity of 100% in patients progressing to AD. CONCLUSIONS: The mixture modeling approach, totally independent of clinical AD diagnosis, correctly classified patients with AD. The unexpected presence of the AD signature in more than one-third of cognitively normal subjects suggests that AD pathology is active and detectable earlier than has heretofore been envisioned.
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| 39. |
- De Meyer, Geert, et al.
(författare)
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Diagnosis-Independent Alzheimer Disease Biomarker Signature in Cognitively Normal Elderly People
- 2010
-
Ingår i: Archives of Neurology. - 0003-9942. ; 67:8, s. 949-956
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To identify biomarker patterns typical for Alzheimer disease (AD) in an independent, unsupervised way, without using information on the clinical diagnosis. Design: Mixture modeling approach. Setting: Alzheimer's Disease Neuroimaging Initiative database. Patients or Other Participants: Cognitively normal persons, patients with AD, and individuals with mild cognitive impairment. Main Outcome Measures: Cerebrospinal fluid derived p-amyloid protein 1-42, total tau protein, and phosphorylated tau(181p) protein concentrations were used as biomarkers on a clinically well-characterized data set. The outcome of the qualification analysis was validated on 2 additional data sets, 1 of which was autopsy confirmed. Results: Using the US Alzheimer's Disease Neuroimaging Initiative data set, a cerebrospinal fluid beta-amyloid protein 1-42/phosphorylated tau(181P) biomarker mixture model identified 1 feature linked to AD, while the other matched the "healthy" status. The AD signature was found in 90%, 72%, and 36% of patients in the AD, mild cognitive impairment, and cognitively normal groups, respectively. The cognitively normal group with the AD signature was enriched in apolipoprotein E 64 allele carriers. Results were validated on 2 other data sets. In 1 study consisting of 68 autopsy-confirmed AD cases, 64 of 68 patients (94% sensitivity) were correctly classified with the AD feature. In another. data set with patients (n=57) with mild cognitive impairment followed up for 5 years, the model showed a sensitivity of 100% in patients progressing to AD. Conclusions: The mixture modeling approach, totally independent of clinical AD diagnosis, correctly classified patients with AD. The unexpected presence of the AD signature in more than one-third of cognitively normal subjects suggests that AD pathology is active and detectable earlier than has heretofore been envisioned.
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| 40. |
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| 41. |
- Deming, Yuetiva, et al.
(författare)
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Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers
- 2017
-
Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 133:5, s. 839-856
-
Tidskriftsartikel (refereegranskat)abstract
- More than 20 genetic loci have been associated with risk for Alzheimer’s disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case–control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ42 near GLIS1 on 1p32.3 (β = −0.059, P = 2.08 × 10−8) and within SERPINB1 on 6p25 (β = −0.025, P = 1.72 × 10−8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10−2), disease progression (GLIS1: β = 0.277, P = 1.92 × 10−2), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10−3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.
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| 42. |
- Deming, Yuetiva, et al.
(författare)
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Sex-specific genetic predictors of Alzheimer’s disease biomarkers
- 2018
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 136:6, s. 857-872
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer’s disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = − 0.03, p = 4.25 × 10−8; β = 0.03, p = 3.97 × 10−8) than males (β = − 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10−10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD’s genetic architecture.
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| 43. |
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| 44. |
- Duits, Flora H., et al.
(författare)
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The cerebrospinal fluid "Alzheimer profile": Easily said, but what does it mean?
- 2014
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Ingår i: Alzheimer's & Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 10:6, s. 713-723
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Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to identify the most useful definition of the "cerebrospinal fluid Alzheimer profile," based on amyloid-beta(1-42) (A beta(42)), total tau, and phosphorylated tau (p-tau), for diagnosis and prognosis of Alzheimers disease (AD). Methods: We constructed eight Alzheimer profiles with previously published combinations, including regression formulas and simple ratios. We compared their diagnostic accuracy and ability to predict dementia due to AD in 1385 patients from the Amsterdam Dementia Cohort. Results were validated in an independent cohort (n = 1442). Results: Combinations outperformed individual biomarkers. Based on the sensitivity of the best performing regression formulas, cutoffs were chosen at 0.52 for the tau/A beta(42) ratio and 0.08 for the p-tau/A beta(42) ratio. Ratios performed similar to formulas (sensitivity, 91%-93%; specificity, 81%-84%). The same combinations best predicted cognitive decline in mild cognitive impairment patients. Validation confirmed these results, especially regarding the tau/A beta(42) ratio. Conclusions: A tau/A beta(42) ratio of greater than0.52 constitutes a robust cerebrospinal fluid Alzheimer profile. We recommend using this ratio to combine biomarkers.
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| 45. |
- Enell, Magnus, et al.
(författare)
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Organiskt bunden klor (AOX) i Västerdalälven 1988
- 1989
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Dalälvsdelegationen har finansierat en undersökning för att klarlägga orsakerna till de höga AOX-koncentrationerna (adsorberbar organiskt bunden halogen) i Västerdalälven. Vid provtagningstillfället i september 1988 var AOX-koncentrationerna i Västerdalälven och i dess tillflöden mellan 11,9 och 63,5 µg/l, med undantag för Njupeån, vars halt var 5,8 µg/l. I de torvrika områdena i trakterna kring Sälen var arealkoefficienterna mycket höga, mellan 61 och 91 kg AOX/km2*år. Vid sammanflödet med Österdalälven var koefficienten betydligt lägre, 20 kg AOX/km2*år. Vid jämförelse mellan vattnets organiska innehåll och AOX-koncentration föreligger ett starkt samband, såväl mellan AOX och TOC (totalt organiskt kol) (r=0,92) som mellan AOX och absorbanserna vid 254 och 400 nm (r=0,94). Sambandet mellan AOX och vattnets humusinnehåll tyder på att de uppmätta klororganiska föreningarna är av naturligt ursprung. Humusmaterialet tillförs från torv- och skogsmarker. Nederbördens tillskott av AOX till Västerdalälvens avrinningsområde uppgår till 40 ton/år. Denna kvantitet bör jämföras med Västerdalälvens årstransport av AOX, som uppgår till 120 ton /år.
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| 46. |
- Enell, Magnus, et al.
(författare)
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Storskalig spridning av organiskt bunden klor AOX. Förekomst i svenska vattendrag och i nederbörd. Koncentrationer och belastningar på omgivande havsområden. Oktober 1987 - september 1988.
- 1990
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Genom samarbete med SNVs PMK-provtagare har vattenprov för AOX analys tagits 6-12 gånger per år vid 47 provpunkter i 33 vattendrag, från Torne älv i norr till Örekilsälven på Sveriges norra västkust. Provtagningarna startade i oktober 1987 och avslutades i september 1988. Koncentrationen av AOX (adsorberbar organiskt bunden halogen) varierade mycket mellan de olika vattendragen. De lägsta halterna uppmättes i de vattendrag som mynnar i Bottenviken och Bottenhavet, medelvärdena för de olika vattendragen var upp till ca 20 ug/l. I vattendragen som mynnar i egentliga Östersjön var halterna mellan 20 och 60 ug/l. De högsta halterna uppmättes i Örekilsälven (98ug/l), vilka mynnar i Kattegatt och Skagerack. Transporterna av AOX för den aktuella perioden till Sveriges omgivande hav, uppgick till 5 200 ton. Den största AOX-mängden transporterades med de vattendrag som mynnar i Bottenviken och Bottenhavet. Parallellt med provtagningarna i vattendragen togs nederbördsprov. I oktober 1987 startade nederbördsprovtagningen på fem platser i landet: Abisko, Umeå, Grimsö, Aneboda och Stenungsund. I juli 1988 utökades nederbördsprovtagningen med ytterligare elva stationer. Provtagningen avslutades i juni 1989. Medelvärdet för AOX-koncentrationen i nederbörden för hela landet var 15 µg/l. Tillsammans med medelnederbörden i Sverige ger detta en årlig deposition av AOX över Sverige på 5 100 ton.
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| 47. |
- Enell, Magnus, et al.
(författare)
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Storskalig spridning av organiskt bunden klor. AOX. Halvårsrapport. Oktober 1987 - mars 1988.
- 1988
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Genom samarbete med SNV's PMK-provtagare har vattenprov för AOX-analys tagits 6-12 gånger/år vid 47 provpunkter, från Torne älv i norr till Örekilsälven på Sveriges norra västkust. Provtagningarna började i oktober 1987 och skall avslutas i september 1988. AOX-halterna i de vattendrag som mynnar i Bottenviken och Bottenhavet är låga, omkring 20 ug/l. Halterna i vattendragen som mynnar i Egentliga Östersjön är betydligt högre, mellan 40 och 70 ug/l. De högsta halterna finner man i Nissan (93 ug/l) och i Örekilsälven (90 ug/l), vilka mynnar i Kattegatt och Skagerack. Trots att AOX-halterna i de norrländska älvarna är låga så transporteras relativt stora mängder AOX. Ca 50% av all AOX-transport ut till Sveriges omgivande kusthav, sker med de älvar som mynnar i Bottenviken och Bottenhavet. Årligen transporteras ca 3.700 ton AOX till våra omgivande kusthav. Denna mängd är preliminärt beräknad och baserad på vattenflöden för perioden 1931-1960. Höga AOX-halter förekommer även i vissa vattendragssystem helt utan skogsindustriella anläggningar.
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| 48. |
- Ewers, Michael, et al.
(författare)
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Body mass index is associated with biological CSF markers of core brain pathology of Alzheimer's disease
- 2012
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 33:8, s. 1599-1608
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Tidskriftsartikel (refereegranskat)abstract
- Weight changes are common in aging and Alzheimer's disease (AD) and postmortem findings suggest a relation between lower body mass index (BMI) and increased AD brain pathology. In the current multicenter study, we tested whether lower BMI is associated with higher core AD brain pathology as assessed by cerebrospinal fluid (CSF)-based biological markers of AD in 751 living subjects: 308 patients with AD, 296 subjects with amnestic mild cognitive impairment (MCI), and 147 elderly healthy controls (HC). Based upon a priori cutoff values on CSF concentration of total tau and beta-amyloid (A beta(1-42)), subjects were binarized into a group with abnormal CSF biomarker signature (CSF+) and those without (CSF-). Results showed that BMI was significantly lower in the CSF+ when compared with the CSF- group (F = 27.7, df = 746, p < 0.001). There was no interaction between CSF signature and diagnosis or apolipoprotein E (ApoE) genotype. In conclusion, lower BMI is indicative of AD pathology as assessed with CSF-based biomarkers in demented and nondemented elderly subjects. Published by Elsevier Inc.
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| 49. |
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| 50. |
- Fatima, Tahzeeb, et al.
(författare)
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Association between serum urate and CSF markers of Alzheimer's disease pathology in a population-based sample of 70-year-olds
- 2021
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Ingår i: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. - : Wiley. - 2352-8729. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The relationship between urate and biomarkers for Alzheimer's disease (AD) pathophysiology has not been investigated. Methods: We examined whether serum concentration of urate was associated with cerebrospinal fluid biomarkers, amyloid beta (A beta)(42), A beta(40), phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), and A beta(42)/A beta(40) ratio, in cognitively unimpaired 70-year-old individuals from Gothenburg, Sweden. We also evaluated whether possible associations were modulated by the apolipoprotein E (APOE) epsilon 4 allele. Results: Serum urate was positively associated with A beta(42) in males (beta = 0.55 pg/mL, P = .04). There was a positive urate-APOE epsilon 4 interaction (1.24 pg/mL, P-interaction = .02) in relation to A beta(42) association. The positive urate and A beta(42) association strengthened in male APOE epsilon 4 carriers (beta = 1.28 pg/mL, P = .01). Discussion: The positive association between urate and A beta(42) in cognitively healthy men may suggest a protective effect of urate against deposition of amyloid protein in the brain parenchyma, and in the longer term, maybe against AD dementia.
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