| 1. |
- 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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| 2. |
- Bergman, Lina, 1982, et al.
(författare)
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Cerebral biomarkers in neurologic complications of preeclampsia
- 2022
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Ingår i: American Journal of Obstetrics and Gynecology. - : Elsevier BV. - 0002-9378 .- 1097-6868. ; 227:2, s. 298.e1-298.e10
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is no tool to accurately predict who is at risk of developing neurologic complications of preeclampsia, and there is no objective method to determine disease severity. Objective: We assessed whether plasma concentrations of the cerebral biomarkers neurofilament light, tau, and glial fibrillary acidic protein could reflect disease severity in several phenotypes of preeclampsia. Furthermore, we compared the cerebral biomarkers with the angiogenic biomarkers soluble fms-like tyrosine kinase 1, placental growth factor, and soluble endoglin. Study Design: In this observational study, we included women from the South African Preeclampsia Obstetric Adverse Events biobank. Plasma samples taken at diagnosis (preeclampsia cases) or admission for delivery (normotensive controls) were analyzed for concentrations of neurofilament light, tau, glial fibrillary acidic protein, placental growth factor, soluble fms-like tyrosine kinase 1, and soluble endoglin. The cerebrospinal fluid concentrations of inflammatory markers and albumin were analyzed in a subgroup of 15 women. Analyses were adjusted for gestational age, time from seizures and delivery to sampling, maternal age, and parity. Results: Compared with 28 women with normotensive pregnancies, 146 women with preeclampsia demonstrated 2.18-fold higher plasma concentrations of neurofilament light (95% confidence interval, 1.64–2.88), 2.17-fold higher tau (95% confidence interval, 1.49–3.16), and 2.77-fold higher glial fibrillary acidic protein (95% confidence interval, 2.06–3.72). Overall, 72 women with neurologic complications (eclampsia, cortical blindness, and stroke) demonstrated increased plasma concentrations of tau (2.99-fold higher; 95% confidence interval, 1.92–4.65) and glial fibrillary acidic protein (3.22-fold higher; 95% confidence interval, 2.06–5.02) compared with women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications (n=31). Moreover, angiogenic markers were higher, but to a lesser extent. Women with hemolysis, elevated liver enzymes, and low platelet count (n=20) demonstrated increased plasma concentrations of neurofilament light (1.64-fold higher; 95% confidence interval, 1.06–2.55), tau (4.44-fold higher; 95% confidence interval, 1.85–10.66), and glial fibrillary acidic protein (1.82-fold higher; 95% confidence interval, 1.32–2.50) compared with women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications. There was no difference shown in the angiogenic biomarkers. There was no difference between 23 women with preeclampsia complicated by pulmonary edema and women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications for any of the biomarkers. Plasma concentrations of tau and glial fibrillary acidic protein were increased in women with several neurologic complications compared with women with eclampsia only. Conclusion: Plasma neurofilament light, glial fibrillary acidic, and tau were candidate biomarkers for the diagnosis and possibly prediction of cerebral complications of preeclampsia.
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| 3. |
- Daborg, Jonny, et al.
(författare)
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Association of the RAGE G82S polymorphism with Alzheimer's disease
- 2010
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Ingår i: Journal of Neural Transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 117:7, s. 861-867
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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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| 4. |
- Daborg, Jonny, et al.
(författare)
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Complement Gene Single Nucleotide Polymorphisms and Biomarker Endophenotypes of Alzheimer's Disease
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877. ; 35:1, s. 51-57
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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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| 5. |
- Davidsson, Johan, 1967, et al.
(författare)
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Analys av kollisioner vid hockeyspel med hjärnskakning som utfall
- 2020
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Detta projekt får anses utgöra en pilotstudie som visar på både möjligheter och svårigheter med att analysera hjärnskakningar hos hockeyspelare utifrån tillgängliga videofilmer, RTP och blodprovsdata. Att konstruera en modell som ger mer detaljerad information om orsaken till hjärnskakning och dess omfattning bedöms som möjlig men svårt. Med tillgång till fler kameravinklar och deras exakta positioner i förhållande till isen kan en bildanalys utföras mycket mer exakt. Man bör också ta i beaktning de relativt få spelare som analyserades. Data från fler spelare bedöms som en framkomlig väg även ifall insamlingsmetoderna och analysen förblir den samma som i den här studien. Ytterligare data skulle sannolikt medföra att analysen av korrelationer med RTP och HUC gav tydligare svar. Även om inte de planerade numeriska modellerna av spelarna gick att förverkliga gav kinematikanalysen användbara resultat; bland annat kollisionshastigheten. Försök att korrelera kollisionshastigheten med RTP gjordes men någon korrelation förelåg inte. Andra faktorer; som hur våldsam rotationen av huvudet var vid kollisionen har känd större inverkan på risken för hjärnskakning än ingångshastigheten. Noterbart är att de erhållna kollisionshastigheterna beror på manuell utplacering av referenspunkter som lagt grunden för koordinatsystemet. Utifrån detta koordinatsystem har sedan hastigheterna erhållits; små fel vid skapandet av koordinatsystemet påverka kollisionshastigheterna stort. Den utförda analysen är baserad på HUC. Den har utförts något annorlunda än på det sett som utvecklarna av HUC avsåg. Fyra bedömare har utfört analysen och det blev uppenbart att några faktorer var svårbedömda. Inför framtida studier där film från kollisioner karakteriseras med hjälp där HUC bör några av beskrivningarna av faktorerna kompletteras. Resultaten i korthet: I stort sätt alla analyserade kollisionerna uppstår i kontakt mellan två spelare. De vanligaste kontakterna var mellan huvud och opponentens axelskydd och mellan huvud och armbåge; 58% respektive 21% av de analyserade kollisionerna. Den drabbade träffades i 66% av kollisionerna i huvudet och 25% i överkroppen. Vanligast var träffar framifrån. Den resulterande huvudrörelsen var oftast komplex alternativt begränsad till sagittalplanet. Efter den första träffen följde det minst en andra huvudträff i 44% av kollisionerna. Hälften av dessa andra träffar var med isen och andra hälften med ringsargen. Kollisionerna skedde i alla zoner och på öppen is samt i närheten av sargen. Lika många av spelarna bedömdes varit medvetna om att en tackling väntade som de som var omedvetna. Straff utdelades som en följd i 34% av kollisionerna; trots att 75% av tacklingarna bedömdes planerade. Kollisionshastigheten varierade mellan 5,0 m/s och 11,6 m/s. RTP är inte en funktion av ålder, riktningen på huvudaccelerationen eller kollisionshastigheten. Resultaten indikerar att RTP var högre när den drabbade blev träffad av en axel relativt av en armbåge. RTP var högre för de spelare som bedömdes omedveten om den förstående tacklingen. RTP var mycket högre för planerade tacklingar i jämförelse med tacklagar som var en följd i en situation där tacklingen är en del i en oplanerad kollision. För varaktiga symptom, d.v.s. för de fyra spelare som inte återgick till spel på elitnivå efter kollisionen, var 75% träffade av motståndarens axel och lika stor andel träffade i huvudet. I alla fyra fallen ansågs den drabbade ej ha kunnat förutse tacklingen samt opponenten bedömdes ha planerat tacklingen. Medelkoncentrationen av blodmarkören NFL sjunker vid mätningarna vid 12 h och vid 36 h relativt 1 h men ökar något vid 144 h relativt 1 h. Medelvärdet av parade NFL-koncentrationerna förblir i stort sätt oförändrade över tiden förutom vid 144 h då det förekommer en icke statistiskt signifikant ökning. Det går att skönja en svag korrelation mellan RTP och förändringen av NFL vid 12 h, 36 h och 144 h i relation till värdena vid 1 h; högre RTP för högre NFL NFL-värden för gruppen RTP ≥ 9 dagar skiljer sig inte signifikant mot värden för gruppen RTP < 9 dagar vid 12h, 26 h eller vid 144 h efter kollisionen. NFL-värdena kan prediktera RTP men resultaten är inte signifikanta. Parade koncentrationer av blodmarkörerna NSE, S100B och tau sjunker signifikant vid 12 h i relation till nivåerna vid 1h efter trauma. Dessa förändringar var inte förväntade. Koncentrationsändringarna av NSE, S100B och tau för gruppen RTP ≥ 9 dagar skiljer sig inte signifikant mot värden för gruppen RTP < 9 dagar vid 12h, 26 h eller vid 144 h efter kollisionen.
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| 6. |
- Davidsson, Pia, 1962, et al.
(författare)
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Clinical mass spectrometry in neuroscience. Proteomics and peptidomics.
- 2003
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Ingår i: Cellular and molecular biology (Noisy-le-Grand, France). - 0145-5680 .- 1165-158X. ; 49:5, s. 681-8
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Forskningsöversikt (refereegranskat)abstract
- In this review we discuss the merits and drawbacks with the use of proteomic and peptidomic strategies for identification of proteins and peptides in their multidimensional interactions in complex biological processes. The progress in proteomics and peptidomics during the last years offer us new challenges to study changes in the protein and peptide synthesis. These strategies also offer new tools to follow post-translational modifications and other disturbed chemical processes that may be indicative of pathophysiological alteration(s). Furthermore these techniques can contribute to improvements in the diagnosis and therapy of neurodegenerative diseases, such as Alzheimer's disease, and psychiatric diseases, as depression and post traumatic stress disorders. We also consider different practical aspects of the applications of mass spectrometry in clinical neuroscience, illustrated by example from our laboratories. The new proteomic and peptidomic strategies will further enable the progress for clinical neuroscience research.
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| 7. |
- Dreos, Ambra, 1987, et al.
(författare)
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Investigating New Applications of a Photoswitchable Fluorescent Norbornadiene as a Multifunctional Probe for Delineation of Amyloid Plaque Polymorphism.
- 2023
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Ingår i: ACS sensors. - : American Chemical Society (ACS). - 2379-3694. ; 8:4, s. 1500-1509
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid beta (Aβ) plaques are a major pathological hallmark of Alzheimer's disease (AD) and constitute of structurally heterogenic entities (polymorphs) that have been implicated in the phenotypic heterogeneity of AD pathology and pathogenesis. Understanding amyloid aggregation has been a critical limiting factor to gain understanding of AD pathogenesis, ultimately reflected in that the underlying mechanism remains elusive. We identified a fluorescent probe in the form of a turn-off photoswitchable norbornadiene derivative (NBD1) with several microenvironment-sensitive properties that make it relevant for applications within advanced fluorescence imaging, for example, multifunctional imaging. We explored the application of NBD1 for in situ delineation of structurally heterogenic Aβ plaques in transgenic AD mouse models. NBD1 plaque imaging shows characteristic broader emission bands in the periphery and more narrow emission bands in the dense cores of mature cored plaques. Further, we demonstrate in situ photoisomerization of NBD1 to quadricyclane and thermal recovery in single plaques, which is relevant for applications within both functional and super-resolution imaging. This is the first time a norbornadiene photoswitch has been used as a probe for fluorescence imaging of Aβ plaque pathology in situ and that its spectroscopic and switching properties have been studied within the specific environment of senile Aβ plaques. These findings open the way toward new applications of NBD-based photoswitchable fluorescent probes for super-resolution or dual-color imaging and multifunctional microscopy of amyloid plaque heterogeneity. This could allow to visualize Aβ plaques with resolution beyond the diffraction limit, label different plaque types, and gain insights into their physicochemical composition.
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| 8. |
- Eckerström, Marie, 1981, et al.
(författare)
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Cognitive impairment without altered levels of cerebrospinal fluid biomarkers in patients with encephalitis caused by varicella-zoster virus: a pilot study.
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Varicella-zoster virus (VZV) is one of the most common agents causing viral infections of the central nervous system (CNS). VZV encephalitis is associated with severe neurological sequelae, despite antiviral treatment. Cognitive impairment has been reported and VZV has been associated with dementia. Our aim was to investigate the cognitive impairment and cerebrospinal fluid biomarkers in a follow-up study of patients with VZV encephalitis. Thirteen patients with VZV encephalitis, diagnosed by detection of VZV DNA in cerebrospinal fluid (CSF) by PCR and concomitant symptoms of encephalitis, were included. Neuropsychological assessment in parallel with a lumbar puncture to obtain CSF was performed 1.5-7years after acute disease. The CSF biomarkers neurofilament light chain (NFL), S100B, glial fibrillary acidic protein (GFAP), amyloid-β (Aβ) 40 and Aβ42, total tau (t-tau) and phosphorylated tau (p-tau) were analysed and compared to controls (n=24). Cognitive impairment was shown in the domains of executive functions and speed/attention and to a minor degree in the domains of learning/memory and language, indicated by a significantly poorer performance on seven neuropsychological test variables. No convincing evidence of alterations in concentrations of biomarkers in the CSF were shown. Our results indicate that patients with VZV encephalitis suffer from cognitive impairment long time after acute disease. Importantly, these impairments do not seem to be accompanied by biomarker evidence of ongoing neuronal or astrocytic injury/activation or induction of dementia-related brain pathologies by the infection.
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| 9. |
- Folkesson Hansson, Sara, 1976, et al.
(författare)
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Validation of a prefractionation method followed by two-dimensional electrophoresis - Applied to cerebrospinal fluid proteins from frontotemporal dementia patients.
- 2004
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Ingår i: Proteome science. - : Springer Science and Business Media LLC. - 1477-5956. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The aim of this study was firstly, to improve and validate a cerebrospinal fluid (CSF) prefractionation method followed by two-dimensional electrophoresis (2-DE) and secondly, using this strategy to investigate differences between the CSF proteome of frontotemporal dementia (FTD) patients and controls. From each subject three ml of CSF was prefractionated using liquid phase isoelectric focusing prior to 2-DE. RESULTS: With respect to protein recovery and purification potential, ethanol precipitation of the prefractionated CSF sample was found superior, after testing several sample preparation methods.The reproducibility of prefractionated CSF analyzed on 2-D gels was comparable to direct 2-DE analysis of CSF. The protein spots on the prefractionated 2-D gels had an increased intensity, indicating a higher protein concentration, compared to direct 2-D gels. Prefractionated 2-DE analysis of FTD and control CSF showed that 26 protein spots were changed at least two fold. Using mass spectrometry, 13 of these protein spots were identified, including retinol-binding protein, Zn-alpha-2-glycoprotein, proapolipoproteinA1, beta-2-microglobulin, transthyretin, albumin and alloalbumin. CONCLUSION: The results suggest that the prefractionated 2-DE method can be useful for enrichment of CSF proteins and may provide a new tool to investigate the pathology of neurodegenerative diseases. This study confirmed reduced levels of retinol-binding protein and revealed some new biomarker candidates for FTD.
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| 10. |
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