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- Visser, P. J., et al.
(författare)
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Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease
- 2022
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer's disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels. Methods We performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer's Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study. Results We found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood-brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC, associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins. Conclusions CSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood-brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles.
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| 4. |
- Tijms, B. M., et al.
(författare)
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Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics
- 2020
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143, s. 3776-3792
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease is biologically heterogeneous, and detailed understanding of the processes involved in patients is critical for development of treatments. CSF contains hundreds of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. We studied whether Alzheimer's disease biological subtypes can be detected in CSF proteomics using the dual clustering technique non-negative matrix factorization. In two independent cohorts (EMIF-AD MBD and ADNI) we found that 705 (77% of 911 tested) proteins differed between Alzheimer's disease (defined as having abnormal amyloid, n=425) and controls (defined as having normal CSF amyloid and tau and normal cognition, n=127). Using these proteins for data-driven clustering, we identified three robust pathophysiological Alzheimer's disease subtypes within each cohort showing (i) hyperplasticity and increased BACE1 levels; (ii) innate immune activation; and (iii) blood-brain barrier dysfunction with low BACE1 levels. In both cohorts, the majority of individuals were labelled as having subtype 1 (80, 36% in EMIF-AD MBD; 117, 59% in ADNI), 71 (32%) in EMIF-AD MBD and 41 (21%) in ADNI were labelled as subtype 2, and 72 (32%) in EMIF-AD MBD and 39 (20%) individuals in ADNI were labelled as subtype 3. Genetic analyses showed that all subtypes had an excess of genetic risk for Alzheimer's disease (all P>0.01). Additional pathological comparisons that were available for a subset in ADNI suggested that subtypes showed similar severity of Alzheimer's disease pathology, and did not differ in the frequencies of co-pathologies, providing further support that found subtypes truly reflect Alzheimer's disease heterogeneity. Compared to controls, all non-demented Alzheimer's disease individuals had increased risk of showing clinical progression (all P<0.01). Compared to subtype 1, subtype 2 showed faster clinical progression after correcting for age, sex, level of education and tau levels (hazard ratio = 2.5; 95% confidence interval = 1.2, 5.1; P=0.01), and subtype 3 at trend level (hazard ratio = 2.1; 95% confidence interval = 1.0, 4.4; P=0.06). Together, these results demonstrate the value of CSF proteomics in studying the biological heterogeneity in Alzheimer's disease patients, and suggest that subtypes may require tailored therapy.
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- Chumakov, A., et al.
(författare)
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Sprayed Nanometer-Thick Hard-Magnetic Coatings with Strong Perpendicular Anisotropy for Data Storage Applications
- 2022
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Ingår i: ACS Applied Nano Materials. - : American Chemical Society (ACS). - 2574-0970. ; 5:7, s. 8741-8754
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Tidskriftsartikel (refereegranskat)abstract
- The rapid growth of digital information in the world necessitates a big leap in improving the existing technologies for magnetic recording. For the best modern perpendicular recording, the highest coercivity materials with minimal volume are required. We present a study of a facile technology for establishing mono- and multilayer surfaces from various single-domain flat magnetic nanoparticles that exhibit a strong perpendicular-oriented magnetic moment on solid and flexible substrates. Surfactant-free, hard ferromagnetic, and single-domain anisotropic strontium hexaferrite SrFe12O19nanoparticles with a perpendicular magnetic moment orientation and two different aspect ratios are self-ordered into magnetic thin nanofilms, exploiting the templating effect of cellulose nanofibrils and magnetic fields. Uniform magnetic coatings obtained by the scalable layer-by-layer spray deposition from a monolayer coverage up to thicknesses of a few tens of nanometers show a preferred in-plane orientation of the hard-magnetic nanoparticles. High coercivities of the films of up to 5 kOe and a high perpendicular anisotropy of Mr⊥/Ms> 80% are found. The application of the magnetic field during film deposition ensures additional improvement in perpendicular magnetic anisotropy and the appearance of residual magnetization in the film of up to 0.6Ms. For low-aspect-ratio nanoparticles stacked in periodic planar structures, the signs of the photonic band gap are revealed. The ability to create scalable, thin magnetic structures based on nanosized particles/building blocks opens great opportunities for their application in a wide variety of optoelectronic and magnetic storage devices.
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| 9. |
- Delvenne, A., et al.
(författare)
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Cerebrospinal fluid proteomic profiling of individuals with mild cognitive impairment and suspected non-Alzheimer's disease pathophysiology
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:3, s. 807-820
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Tidskriftsartikel (refereegranskat)abstract
- Background Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker concept that encompasses individuals with neuronal injury but without amyloidosis. We aim to investigate the pathophysiology of SNAP, defined as abnormal tau without amyloidosis, in individuals with mild cognitive impairment (MCI) by cerebrospinal fluid (CSF) proteomics. Methods Individuals were classified based on CSF amyloid beta (A beta)1-42 (A) and phosphorylated tau (T), as cognitively normal A-T- (CN), MCI A-T+ (MCI-SNAP), and MCI A+T+ (MCI-AD). Proteomics analyses, Gene Ontology (GO), brain cell expression, and gene expression analyses in brain regions of interest were performed. Results A total of 96 proteins were decreased in MCI-SNAP compared to CN and MCI-AD. These proteins were enriched for extracellular matrix (ECM), hemostasis, immune system, protein processing/degradation, lipids, and synapse. Fifty-one percent were enriched for expression in the choroid plexus. Conclusion The pathophysiology of MCI-SNAP (A-T+) is distinct from that of MCI-AD. Our findings highlight the need for a different treatment in MCI-SNAP compared to MCI-AD.
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- Reus, L. M., et al.
(författare)
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Alzheimer's disease genetic risk variants show brain cell type-specific associations with protein levels in cerebrospinal fluid
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Neuronal dysfunction is central to the clinical manifestation of Alzheimer's disease (AD). However, genome-wide studies also suggest important roles for non-neuronal brain cell-types such as microglia and astrocytes. Our objective was to study whether brain cell type-specific polygenic risk scores (PGRS) for AD, including single nucleotide polymorphisms (SNPs) of genes expressed in one brain cell type, showed relationships with levels of cerebrospinal fluid (CSF) AD markers in individuals across the clinical spectrum of AD. METHOD: We selected 1,535 subjects (552 controls/709 mild cognitive impairment/274 AD-dementia, age 71±8 years, 48%female) from the ADNI (N=617) and EMIF-AD MBD (N=918) study, who had genetic data available. We labelled AD risk genes as specific for neurons, astrocytes, microglia, oligodendrocytes or endothelial cells when more than 50% of the gene expression was produced by one cell type (otherwise as 'non-specific') according to the BRAIN RNASeq database (Zhang et al., 2014). We calculated cell type-specific-PGRS with cell type-corresponding SNPs (P<5e-8 ) using weights from De Rojas et al., (2020) AD case-control summary statistics. Associations between cell type-specific-PGRS and CSF biomarkers (amyloid-beta, total tau (t-tau), phosphorylated tau (p-tau), neurofilament light, neurogranin and YKL-40) were examined using linear regressions, adjusted for population structure, study, age and sex. RESULT: Of 40 AD risk genes, 26 had detectable RNA levels in at least one brain cell type. Of these, sixteen were cell type-specific: 11 were microglia-specific, 4 astrocyte-specific (including APOE) and 1 neuron-specific (Figure 1). Astrocyte-PGRS (P=1.4e-6 , Pwithout_APOE =.1) and microglia-PGRS (P=6.3e-3 ) were increased in AD-type dementia compared to controls, whereas other PGRS were not (Figure 2). Astrocyte-PGRS (including APOE) were most strongly associated with CSF amyloid-beta (P=1.4e-31 ), t-tau (P=6.3e-10 ), p-tau (P=4.9e-9 ), and neurogranin (P=0.01). Astrocyte-specific (excluding APOE) and microglia-specific PGRS-AD also associated with CSF amyloid-beta (P<0.05), and with p-tau at trend-level (Figure 2). Apart from the tentative association between neuron-PGRS and CSF YKL-40, no other associations were observed. CONCLUSION: Findings indicate that AD risk variants have cell type-specific associations with amyloid and tau pathology, which seems mostly expressed by astrocytes (also without APOE) and microglia, suggesting that these cell types play a role in amyloid pathogenesis. © 2021 the Alzheimer's Association.
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