| 11. |
- Slemmon, J Randall, et al.
(författare)
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Impact of cerebrospinal fluid matrix on the detection of Alzheimer's disease with Aβ42 and influence of disease on the total-Aβ42/Aβ40 ratio.
- 2015
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Ingår i: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 135:5
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Tidskriftsartikel (refereegranskat)abstract
- The 42 amino acid fragment of amyloid β (Aβ1-42) in cerebrospinal fluid (CSF) has continued to be important for detecting cerebral β-amyloidosis in Alzheimer's disease (AD). However, there are impediments to our ability to fully understand this measurement, including matrix interference and changes linked to APOE ε4 genotype. The current study investigated matrix interference as a contributing factor for detecting AD in APOE ε4-negative patients by comparing total extractable Aβ1-42 to free Aβ1-42. It also examined the ratio of total Aβ1-42 to Aβ1-40, since changes relative to other Aβ peptides may provide a measurement of cerebral β-amyloidosis that is neutral to changes in APP metabolism. Total Aβ1-42 lost diagnostic power for detecting AD, confirming a role for matrix in the diagnostic. However, when total Aβ1-42/Aβ1-40 was examined, the separation between groups was reestablished. This result was confirmed in a second sample set of unknown APOE status. These results confirmed that matrix interference in some CSF samples appears to contribute to identifying AD patients and this can be compensated by using a total extracted Aβ1-42/Aβ1-40 ratio when matrix interference is small. It may be preferable to employ a total Aβ1-42/Aβ1-40 measurement, since this could minimize variability due to matrix and compensate for across patient differences. This article is protected by copyright. All rights reserved.
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| 12. |
- Smith, Ruben, et al.
(författare)
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The α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases
- 2023
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Ingår i: Nature Communications. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- A positron emission tomography (PET) tracer detecting α-synuclein pathology will improve the diagnosis, and ultimately the treatment of α-synuclein-related diseases. Here we show that the PET ligand, [18F]ACI-12589, displays good in vitro affinity and specificity for pathological α-synuclein in tissues from patients with different α-synuclein-related disorders including Parkinson’s disease (PD) and Multiple-System Atrophy (MSA) using autoradiography and radiobinding techniques. In the initial clinical evaluation we include 23 participants with α-synuclein related disorders, 11 with other neurodegenerative disorders and eight controls. In vivo [18F]ACI-12589 demonstrates clear binding in the cerebellar white matter and middle cerebellar peduncles of MSA patients, regions known to be highly affected by α-synuclein pathology, but shows limited binding in PD. The binding statistically separates MSA patients from healthy controls and subjects with other neurodegenerative disorders, including other synucleinopathies. Our results indicate that α-synuclein pathology in MSA can be identified using [18F]ACI-12589 PET imaging, potentially improving the diagnostic work-up of MSA and allowing for detection of drug target engagement in vivo of novel α-synuclein targeting therapies.
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| 13. |
- 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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| 14. |
- Timmers, Maarten, et al.
(författare)
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Relevance of the interplay between amyloid and tau for cognitive impairment in early Alzheimer's disease.
- 2019
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Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 79, s. 131-141
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid β (Aβ) and tau are key hallmark features of Alzheimer's disease (AD) neuropathology. The interplay of Aβ and tau for cognitive impairment in early AD was examined with cross-sectional analysis, measured by cerebrospinal fluid biomarkers (Aβ1-42, total tau [t-tau], and phosphorylated tau [p-tau181P]), and on cognitive performance by the repeatable battery for assessment of neuropsychological status (RBANS). Participants (n = 246) included cognitively normal (Aβ-), mild cognitively impaired (Aβ-), preclinical AD (Aβ+), and prodromal AD (Aβ+). Overall, cognitive scores (RBANS total scale score) had a moderate negative correlation to t-tau (n = 246; r = -0.434; p < 0.001) and p-tau181P (r = -0.389; p < 0.001). When classified by Aβ status, this correlation to t-tau was applicable only in Aβ+ participants (n = 139; r = -0.451, p < 0.001) but not Aβ- participants (n = 107; r = 0.137, p = 0.16), with identical findings for p-tau. Both tau (p < 0.0001) and interaction of Aβ1-42 with tau (p = 0.006) affected RBANS, but not Aβ1-42 alone. Cognitive/memory performance correlated well with cerebrospinal fluid tau levels across early stages of AD, although the correlation is Aβ dependent.
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| 15. |
- 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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| 16. |
- 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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| 17. |
- 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 aimed to 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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| 18. |
- 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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| 19. |
- 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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