| 31. |
- Reijs, Babette L R, et al.
(författare)
-
Association Between Later Life Lifestyle Factors and Alzheimer's Disease Biomarkers in Non-Demented Individuals : A Longitudinal Descriptive Cohort Study
- 2017
-
Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 60:4, s. 1387-1395
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Lifestyle factors have been associated with the risk of dementia, but the association with Alzheimer's disease (AD) remains unclear.OBJECTIVE: To examine the association between later life lifestyle factors and AD biomarkers (i.e., amyloid-β 1-42 (Aβ42) and tau in cerebrospinal fluid (CSF), and hippocampal volume) in individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). In addition, to examine the effect of later life lifestyle factors on developing AD-type dementia in individuals with MCI.METHODS: We selected individuals with SCD (n = 111) and MCI (n = 353) from the DESCRIPA and Kuopio Longitudinal MCI studies. CSF Aβ42 and tau concentrations were assessed with ELISA assay and hippocampal volume with multi-atlas segmentation. Lifestyle was assessed by clinical interview at baseline for: social activity, physical activity, cognitive activity, smoking, alcohol consumption, and sleep. We performed logistic and Cox regression analyses adjusted for study site, age, gender, education, and diagnosis. Prediction for AD-type dementia was performed in individuals with MCI only.RESULTS: Later life lifestyle factors were not associated with AD biomarkers or with conversion to AD-type dementia. AD biomarkers were strongly associated with conversion to AD-type dementia, but these relations were not modulated by lifestyle factors. Apolipoprotein E (APOE) genotype did not influence the results.CONCLUSIONS: Later life lifestyle factors had no impact on key AD biomarkers in individuals with SCD and MCI or on conversion to AD-type dementia in MCI.
|
|
| 32. |
- Shi, Liu, et al.
(författare)
-
Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology.
- 2020
-
Ingår i: Journal of Alzheimer's disease : JAD. - : IOS Press. - 1875-8908 .- 1387-2877. ; 77:3, s. 1353-1368
-
Tidskriftsartikel (refereegranskat)abstract
- Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown.We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes.We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677).We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts.Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.
|
|
| 33. |
- Shi, Liu, et al.
(författare)
-
Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay.
- 2019
-
Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279 .- 1552-5260. ; 15:11, s. 1478-1488
-
Tidskriftsartikel (refereegranskat)abstract
- Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins.4001 plasma proteins were measured in two groups of participants (discovery group=516, replication group=365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid.A panel of proteins (n=44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve=0.78) and the replication group (area under the curve=0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization.The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.
|
|
| 34. |
- Shi, Liu, et al.
(författare)
-
Replication study of plasma proteins relating to Alzheimer's pathology.
- 2021
-
Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279 .- 1552-5260. ; 17:9, s. 1452-1464
-
Tidskriftsartikel (refereegranskat)abstract
- This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis.Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively.Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis.Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.
|
|
| 35. |
- Smith, Rebecca G., et al.
(författare)
-
Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study
- 2024
-
Ingår i: Alzheimer's & Dementia. - : John Wiley & Sons. - 1552-5260 .- 1552-5279.
-
Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: We investigated blood DNA methylation patterns associated with 15 well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration.METHODS: We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF-AD) study using the EPIC array.RESULTS: We identified Bonferroni-significant differential methylation associated with CSF YKL-40 (five loci) and neurofilament light chain (NfL; seven loci) levels, with two of the loci associated with CSF YKL-40 levels correlating with plasma YKL-40 levels. A co-localization analysis showed shared genetic variants underlying YKL-40 DNA methylation and CSF protein levels, with evidence that DNA methylation mediates the association between genotype and protein levels. Weighted gene correlation network analysis identified two modules of co-methylated loci correlated with several amyloid measures and enriched in pathways associated with lipoproteins and development.DISCUSSION: We conducted the most comprehensive epigenome-wide association study (EWAS) of AD-relevant CSF biomarkers to date. Future work should explore the relationship between YKL-40 genotype, DNA methylation, and protein levels in the brain.HIGHLIGHTS: Blood DNA methylation was assessed in the EMIF-AD MBD study. Epigenome-wide association studies (EWASs) were performed for 15 Alzheimer's disease (AD)-relevant cerebrospinal fluid (CSF) biomarker measures. Five Bonferroni-significant loci were associated with YKL-40 levels and seven with neurofilament light chain (NfL). DNA methylation in YKL-40 co-localized with previously reported genetic variation. DNA methylation potentially mediates the effect of single-nucleotide polymorphisms (SNPs) in YKL-40 on CSF protein levels.
|
|
| 36. |
- Stamate, Daniel, et al.
(författare)
-
A metabolite-based machine learning approach to diagnose Alzheimer-type dementia in blood : Results from the European Medical Information Framework for Alzheimer disease biomarker discovery cohort
- 2019
-
Ingår i: Alzheimer’s & Dementia. - : John Wiley & Sons. - 2352-8737. ; 5:C, s. 933-938
-
Tidskriftsartikel (refereegranskat)abstract
- IntroductionMachine learning (ML) may harbor the potential to capture the metabolic complexity in Alzheimer Disease (AD). Here we set out to test the performance of metabolites in blood to categorize AD when compared to CSF biomarkers.MethodsThis study analyzed samples from 242 cognitively normal (CN) people and 115 with AD‐type dementia utilizing plasma metabolites (n = 883). Deep Learning (DL), Extreme Gradient Boosting (XGBoost) and Random Forest (RF) were used to differentiate AD from CN. These models were internally validated using Nested Cross Validation (NCV).ResultsOn the test data, DL produced the AUC of 0.85 (0.80–0.89), XGBoost produced 0.88 (0.86–0.89) and RF produced 0.85 (0.83–0.87). By comparison, CSF measures of amyloid, p‐tau and t‐tau (together with age and gender) produced with XGBoost the AUC values of 0.78, 0.83 and 0.87, respectively.DiscussionThis study showed that plasma metabolites have the potential to match the AUC of well‐established AD CSF biomarkers in a relatively small cohort. Further studies in independent cohorts are needed to validate whether this specific panel of blood metabolites can separate AD from controls, and how specific it is for AD as compared with other neurodegenerative disorders.
|
|
| 37. |
- Stanaway, Jeffrey D., et al.
(författare)
-
Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017
- 2018
-
Ingår i: The Lancet. - 1474-547X .- 0140-6736. ; 392:10159, s. 1923-1994
-
Tidskriftsartikel (refereegranskat)abstract
- Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk- outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017.
|
|
| 38. |
- van Rossum, Ineke A, et al.
(författare)
-
Injury markers predict time to dementia in subjects with MCI and amyloid pathology.
- 2012
-
Ingår i: Neurology. - 1526-632X. ; 79:17, s. 1809-16
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer disease (AD) can now be diagnosed in subjects with mild cognitive impairment (MCI) using biomarkers. However, little is known about the rate of decline in those subjects. In this cohort study, we aimed to assess the conversion rate to dementia and identify prognostic markers in subjects with MCI and evidence of amyloid pathology.
|
|
| 39. |
- Van Steenkiste, Christophe, et al.
(författare)
-
Inhibition of Placental Growth Factor Activity Reduces the Severity of Fibrosis, Inflammation, and Portal Hypertension in Cirrhotic Mice
- 2011
-
Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 0270-9139 .- 1527-3350. ; 53:5, s. 1629-1640
-
Tidskriftsartikel (refereegranskat)abstract
- Placental growth factor (PlGF) is associated selectively with pathological angiogenesis, and PlGF blockade does not affect the healthy vasculature. Anti-PlGF is therefore currently being clinically evaluated for the treatment of cancer patients. In cirrhosis, hepatic fibrogenesis is accompanied by extensive angiogenesis. In this paper, we evaluated the pathophysiological role of PlGF and the therapeutic potential of anti-PlGF in liver cirrhosis. PlGF was significantly up-regulated in the CCl4-induced rodent model of liver cirrhosis as well as in cirrhotic patients. Compared with wild-type animals, cirrhotic PlGF(-/-) mice showed a significant reduction in angiogenesis, arteriogenesis, inflammation, fibrosis, and portal hypertension. Importantly, pharmacological inhibition with anti-PlGF antibodies yielded similar results as genetic loss of PlGF. Notably, PlGF treatment of activated hepatic stellate cells induced sustained extracellular signal-regulated kinase 1/2 phosphorylation, as well as chemotaxis and proliferation, indicating a previously unrecognized profibrogenic role of PlGF. Conclusion: PlGF is a disease-candidate gene in liver cirrhosis, and inhibition of PlGF offers a therapeutic alternative with an attractive safety profile.
|
|
| 40. |
- Visser, Pieter Jelle, et al.
(författare)
-
Cerebrospinal fluid total tau levels indicate aberrant neuronal plasticity in Alzheimer's disease.
- 2020
-
Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory.
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer's disease (AD) is characterised by abnormal amyloid beta and tau processing. Previous studies reported that cerebrospinal fluid (CSF) total tau (t-tau) levels vary between patients. Here we show that CSF t-tau variability is associated with distinct impairments in neuronal plasticity mediated by gene repression factors SUZ12 and REST. AD individuals with abnormal t-tau levels have increased CSF concentrations of plasticity proteins regulated by SUZ12 and REST. AD individuals with normal t-tau, on the contrary, have decreased concentrations of these plasticity proteins and increased concentrations in proteins associated with blood-brain and blood CSF-barrier dysfunction. Genomic analyses suggested that t-tau levels in part depend on genes involved in gene expression. The distinct plasticity abnormalities in AD as signaled by t-tau urge the need for personalised treatment.
|
|
