| 31. |
- Simrén, Joel, 1996, et al.
(författare)
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The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer's disease
- 2021
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 17:7, s. 1145-1156
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: This study investigated the diagnostic and disease-monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals. Methods: Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants. Results: Phosphorylated-tau181 (P-tau181), neurofilament light, amyloid-β (Aβ42/40), Total-tau and Glial fibrillary acidic protein were altered in AD dementia but P-tau181 significantly outperformed all biomarkers in differentiating AD dementia from CU (area under the curve [AUC] = 0.91). P-tau181 was increased in MCI converters compared to non-converters. Higher P-tau181 was associated with steeper cognitive decline and gray matter loss in temporal regions. Longitudinal change of P-tau181 was strongly associated with gray matter loss in the full sample and with Aβ measures in CU individuals. Discussion: P-tau181 detected AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss. These findings highlight the potential value of plasma P-tau181 as a non-invasive and cost-effective diagnostic and prognostic biomarker in AD.
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| 32. |
- Smith, Rebecca G., et al.
(författare)
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Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study
- 2024
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Ingår i: Alzheimer's & Dementia. - : John Wiley & Sons. - 1552-5260 .- 1552-5279.
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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.
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| 33. |
- Stamate, Daniel, et al.
(författare)
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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
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Ingår i: Alzheimer’s & Dementia. - : John Wiley & Sons. - 2352-8737. ; 5:C, s. 933-938
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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.
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| 34. |
- van Maurik, Ingrid S., et al.
(författare)
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Biomarker-based prognosis for people with mild cognitive impairment (ABIDE) : a modelling study
- 2019
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Ingår i: Lancet Neurology. - : The Lancet Publishing Group. - 1474-4422 .- 1474-4465. ; 18:11, s. 1034-1044
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Biomarker-based risk predictions of dementia in people with mild cognitive impairment are highly relevant for care planning and to select patients for treatment when disease-modifying drugs become available. We aimed to establish robust prediction models of disease progression in people at risk of dementia.METHODS: In this modelling study, we included people with mild cognitive impairment (MCI) from single-centre and multicentre cohorts in Europe and North America: the European Medical Information Framework for Alzheimer's Disease (EMIF-AD; n=883), Alzheimer's Disease Neuroimaging Initiative (ADNI; n=829), Amsterdam Dementia Cohort (ADC; n=666), and the Swedish BioFINDER study (n=233). Inclusion criteria were a baseline diagnosis of MCI, at least 6 months of follow-up, and availability of a baseline Mini-Mental State Examination (MMSE) and MRI or CSF biomarker assessment. The primary endpoint was clinical progression to any type of dementia. We evaluated performance of previously developed risk prediction models-a demographics model, a hippocampal volume model, and a CSF biomarkers model-by evaluating them across cohorts, incorporating different biomarker measurement methods, and determining prognostic performance with Harrell's C statistic. We then updated the models by re-estimating parameters with and without centre-specific effects and evaluated model calibration by comparing observed and expected survival. Finally, we constructed a model combining markers for amyloid deposition, tauopathy, and neurodegeneration (ATN), in accordance with the National Institute on Aging and Alzheimer's Association research framework.FINDINGS: We included all 2611 individuals with MCI in the four cohorts, 1007 (39%) of whom progressed to dementia. The validated demographics model (Harrell's C 0·62, 95% CI 0·59-0·65), validated hippocampal volume model (0·67, 0·62-0·72), and updated CSF biomarkers model (0·72, 0·68-0·74) had adequate prognostic performance across cohorts and were well calibrated. The newly constructed ATN model had the highest performance (0·74, 0·71-0·76).INTERPRETATION: We generated risk models that are robust across cohorts, which adds to their potential clinical applicability. The models could aid clinicians in the interpretation of CSF biomarker and hippocampal volume results in individuals with MCI, and help research and clinical settings to prepare for a future of precision medicine in Alzheimer's disease. Future research should focus on the clinical utility of the models, particularly if their use affects participants' understanding, emotional wellbeing, and behaviour.
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| 35. |
- Visser, Pieter Jelle, et al.
(författare)
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Cerebrospinal fluid total tau levels indicate aberrant neuronal plasticity in Alzheimer's disease.
- 2020
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory.
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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.
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| 36. |
- Vos, Stephanie J. B., et al.
(författare)
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Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage
- 2015
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Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 138:5, s. 1327-1338
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Tidskriftsartikel (refereegranskat)abstract
- Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimer's disease at the mild cognitive impairment stage and progression to Alzheimer's disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimer's disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimer's disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimer's disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimer's disease likelihood group. The 3-year progression rate to Alzheimer's disease-type dementia was 59% in the high Alzheimer's disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimer's disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimer's disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimer's disease likelihood group or the International Working Group-2 prodromal Alzheimer's disease group could be considered.
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| 37. |
- Wesenhagen, Kirsten E. J., et al.
(författare)
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Effects of age, amyloid, sex, and APOE ε4 on the CSF proteome in normal cognition
- 2022
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Ingår i: Alzheimer's & dementia (Amsterdam, Netherlands). - : John Wiley & Sons. - 2352-8729. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: It is important to understand which biological processes change with aging, and how such changes are associated with increased Alzheimer's disease (AD) risk. We studied how cerebrospinal fluid (CSF) proteomics changed with age and tested if associations depended on amyloid status, sex, and apolipoprotein E Ɛ4 genotype.Methods: We included 277 cognitively intact individuals aged 46 to 89 years from Alzheimer's Disease Neuroimaging Initiative, European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery, and Metabolic Syndrome in Men. In total, 1149 proteins were measured with liquid chromatography mass spectrometry with multiple reaction monitoring/Rules-Based Medicine, tandem mass tag mass spectrometry, and SOMAscan. We tested associations between age and protein levels in linear models and tested enrichment for Reactome pathways.Results: Levels of 252 proteins increased with age independently of amyloid status. These proteins were associated with immune and signaling processes. Levels of 21 proteins decreased with older age exclusively in amyloid abnormal participants and these were enriched for extracellular matrix organization.Discussion: We found amyloid-independent and -dependent CSF proteome changes with older age, perhaps representing physiological aging and early AD pathology.
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| 38. |
- Westwood, Sarah, et al.
(författare)
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The influence of insulin resistance on cerebrospinal fluid and plasma biomarkers of Alzheimer's pathology.
- 2017
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Ingår i: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Insulin resistance (IR) has previously been associated with an increased risk of developing Alzheimer's disease (AD), although the relationship between IR and AD is not yet clear. Here, we examined the influence of IR on AD using plasma and cerebrospinal fluid (CSF) biomarkers related to IR and AD in cognitively healthy men. We also aimedto characterise the shared protein signatures between IR and AD.Fifty-eight cognitively healthy men, 28 IR and 30 non-IR (age and APOE ε4 matched), were drawn from the Metabolic Syndrome in Men study in Kuopio, Finland. CSF AD biomarkers (amyloid β-peptide (Aβ), total tau and tau phosphorylated at the Thr181 epitope) were examined with respect to IR. Targeted proteomics using ELISA and Luminex xMAP assays were performed to assess the influence of IR on previously identified CSF and plasma protein biomarker candidates of AD pathology. Furthermore, CSF and plasma SOMAscan was performed to discover proteins that associate with IR and CSF AD biomarkers.CSF AD biomarkers did not differ between IR and non-IR groups, although plasma insulin correlated with CSF Aβ/tau across the whole cohort. In total, 200 CSF and 487 plasma proteins were differentially expressed between IR and non-IR subjects, and significantly enriched pathways, many of which have been previously implicated in AD, were identified. CSF and plasma proteins significantly associated with CSF AD biomarkers were also discovered, and those sensitive to both IR and AD were identified.These data indicate that IR is not directly related to the level of CSF AD pathology in cognitively healthy men. Proteins that associated with both AD and IR are potential markers indicative of shared pathology.
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| 39. |
- Westwood, Sarah, et al.
(författare)
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Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort
- 2020
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 74:1, s. 213-225
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Tidskriftsartikel (refereegranskat)abstract
- We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.
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| 40. |
- Xu, Jin, et al.
(författare)
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Sex-Specific Metabolic Pathways Were Associated with Alzheimer's Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort
- 2021
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: physiological differences between males and females could contribute to the development of Alzheimer's Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives.METHODS: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites' discriminatory performance in AD.RESULTS: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046).CONCLUSIONS: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment.
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