Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer's disease, and late-onset Alzheimer's disease

doi:10.1007/s00401-025-02844-z

Comparative Study

. 2025 Jan 18;149(1):9.

doi: 10.1007/s00401-025-02844-z.

Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer's disease, and late-onset Alzheimer's disease

Mitchell Martá-Ariza^{1

2

3}, Dominique F Leitner^{1

2

4}, Evgeny Kanshin^{5

6}, Jianina Suazo^{1

2}, Ana Giusti Pedrosa⁷, Manon Thierry^{1

2}, Edward B Lee⁸, Orrin Devinsky^{1

4}, Eleanor Drummond^{2

9}, Juan Fortea^{10

11

12}, Alberto Lleó^{10

11}, Beatrix Ueberheide^{1

5

6}, Thomas Wisniewski^{13

14

15

16}

Affiliations

¹ Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA.
² Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, USA.
³ Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.
⁴ Comprehensive Epilepsy Center, Department of Neurology, NYU Langone Health and Grossman School of Medicine, New York, NY, USA.
⁵ Proteomics Laboratory, Division of Advanced Research Technologies, NYU Grossman School of Medicine, New York, NY, USA.
⁶ Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA.
⁷ Center for Neural Science, New York University, New York, NY, USA.
⁸ Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁹ Brain and Mind Centre and School of Medical Sciences, University of Sydney, Camperdown, NSW, Australia.
¹⁰ Memory Unit, Department of Neurology, Institut de Recerca Sant Pau, Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
¹¹ Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
¹² Barcelona Down Medical Center, Fundació Catalana de Síndrome de Down, Barcelona, Spain.
¹³ Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA. Thomas.wisniewski@nyulangone.org.
¹⁴ Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, USA. Thomas.wisniewski@nyulangone.org.
¹⁵ Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA. Thomas.wisniewski@nyulangone.org.
¹⁶ Department of Psychiatry, NYU Grossman School of Medicine, New York, NY, USA. Thomas.wisniewski@nyulangone.org.

PMID: 39825890
PMCID: PMC11742868
DOI: 10.1007/s00401-025-02844-z

Comparative Study

Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer's disease, and late-onset Alzheimer's disease

Mitchell Martá-Ariza et al. Acta Neuropathol. 2025.

. 2025 Jan 18;149(1):9.

doi: 10.1007/s00401-025-02844-z.

Authors

Affiliations

¹ Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA.
² Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, USA.
³ Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.
⁴ Comprehensive Epilepsy Center, Department of Neurology, NYU Langone Health and Grossman School of Medicine, New York, NY, USA.
⁵ Proteomics Laboratory, Division of Advanced Research Technologies, NYU Grossman School of Medicine, New York, NY, USA.
⁶ Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA.
⁷ Center for Neural Science, New York University, New York, NY, USA.
⁸ Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁹ Brain and Mind Centre and School of Medical Sciences, University of Sydney, Camperdown, NSW, Australia.
¹⁰ Memory Unit, Department of Neurology, Institut de Recerca Sant Pau, Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
¹¹ Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
¹² Barcelona Down Medical Center, Fundació Catalana de Síndrome de Down, Barcelona, Spain.
¹³ Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA. Thomas.wisniewski@nyulangone.org.
¹⁴ Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, USA. Thomas.wisniewski@nyulangone.org.
¹⁵ Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA. Thomas.wisniewski@nyulangone.org.
¹⁶ Department of Psychiatry, NYU Grossman School of Medicine, New York, NY, USA. Thomas.wisniewski@nyulangone.org.

PMID: 39825890
PMCID: PMC11742868
DOI: 10.1007/s00401-025-02844-z

Abstract

Down syndrome (DS) is strongly associated with Alzheimer's disease (AD) due to APP overexpression, exhibiting Amyloid-β (Aβ) and Tau pathology similar to early-onset (EOAD) and late-onset AD (LOAD). We evaluated the Aβ plaque proteome of DS, EOAD, and LOAD using unbiased localized proteomics on post-mortem paraffin-embedded tissues from four cohorts (n = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 ± 4.07 y/o), LOAD (82.1 ± 6.37 y/o), and controls (66.4 ± 13.04). We identified differentially abundant proteins when comparing Aβ plaques and neighboring non-plaque tissue (FDR < 5%, fold-change > 1.5) in DS (n = 132), EOAD (n = 192), and LOAD (n = 128), with 43 plaque-associated proteins shared across all groups. Positive correlations were observed between plaque-associated proteins in DS and EOAD (R² = .77), DS and LOAD (R² = .73), and EOAD and LOAD (R² = .67). Top gene ontology biological processes (GOBP) included lysosomal transport (p = 1.29 × 10^-5) for DS, immune system regulation (p = 4.33 × 10^-5) for EOAD, and lysosome organization (p = 0.029) for LOAD. Protein networks revealed a plaque-associated protein signature involving APP metabolism, immune response, and lysosomal functions. In DS, EOAD, and LOAD non-plaque vs. control tissue, we identified 263, 269, and 301 differentially abundant proteins, with 65 altered proteins shared across all cohorts. Non-plaque proteins in DS showed modest correlations with EOAD (R² = .59) and LOAD (R² = .33) compared to the correlation between EOAD and LOAD (R² = .79). Top GOBP term for all groups was chromatin remodeling (p < 0.001), with additional terms for DS including extracellular matrix, and protein-DNA complexes and gene expression regulation for EOAD and LOAD. Our study reveals key functional characteristics of the amyloid plaque proteome in DS, compared to EOAD and LOAD, highlighting shared pathways in endo/lysosomal functions and immune responses. The non-plaque proteome revealed distinct alterations in ECM and chromatin structure, underscoring unique differences between DS and AD subtypes. Our findings enhance our understanding of AD pathogenesis and identify potential biomarkers and therapeutic targets.

Keywords: Alzheimer’s disease; Amyloid-β; Down syndrome; Neuropathology; Proteomics.

PubMed Disclaimer

Conflict of interest statement

Declarations. Conflict of interest: J.F. reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Fujirebio, Ionis, Laboratorios Carnot, Life Molecular Imaging, Lilly, Lundbeck, Novo Nordisk, Perha, Roche, Zambón and outside the submitted work. J.F. reports holding a patent for markers of synaptopathy in neurodegenerative disease (licensed to ADx, EPI8382175.0).

Figures

**Fig. 1**
Schematic of the localized proteomics protocol. a Laser-capture microdissection of 2 mm² total area of amyloid-β plaques from hippocampus and adjacent temporal cortex from FFPE autopsy brain tissue from control, DS, EOAD, and LOAD (n = 20 cases/experimental group). Amyloid plaque proteins were quantified by label-free mass spectrometry and posteriorly analyzed. **b–c** Microphotographs of a typical brain tissue section immunolabeled against Aβ illustrate the precise microdissection of amyloid plaques before (b) and after LCM (c). 2 mm (black bar, top) and 200 µm (white bar, bottom)

**Fig. 2**
Principal component analysis (PCA) and differential protein expression in Aβ plaques and non-plaque tissue. a PCA shows the distribution of the n = 20 cases per each experimental group, with minimal segregation. b Venn diagram of differentially abundant Aβ plaque proteins shows 43 common proteins for all the AD subtypes evaluated, 45 for DS, 97 for EOAD, and 51 for LOAD. c Venn diagram of differentially abundant non-plaque proteins depicts 138 proteins in DS, 76 proteins in EOAD, 148 proteins in LOAD, and 65 common proteins for all AD subtypes. **d–f** Volcano plots indicate differentially expressed proteins (enriched in red, decreased in blue) in Aβ plaques compared to non-plaque tissue in DS (132 proteins, d), EOAD (192 proteins, e) and LOAD (128 proteins, f). **g–i** Volcano plots depict differentially expressed proteins in DS non-plaque tissue compared to controls (263 proteins, g), EOAD non-plaques (269 proteins, h), and LOAD non-plaques (301 proteins, i). **j–l** Normalized protein expression obtained from the label-free quantitative mass spectrometry proteomics of Aβ peptide (j), APP protein (k), and COL25A1 (l). Significance was determined using a student’s two-tailed t test (FDR < 5%, fold-change > 1.5). P values are indicated based on the pairwise comparisons. *** p < 0.001, **** p < 0.0001. Error bars indicate standard error of the mean (SEM). Significant pairwise comparisons are indicated for those analyses that were performed, and controls are shown as reference

**Fig. 3**
Correlation analyses of differentially abundant proteins in Aβ plaques and non-plaque tissue. **a–c** Correlation analyses for significant proteins in Aβ plaques vs non-plaque tissue and **d–f** DS, EOAD and LOAD non-plaque vs control non-plaque tissue. Yellow dots represent proteins changing in the same direction (highly abundant or less abundant proteins in both groups evaluated) and that are significant for both groups compared. Magenta dots represent proteins changing in the same direction, but are significant only in one of the groups evaluated. Green dots represent proteins changing in opposite direction (i.e., abundant in one group and less abundant in the other group evaluated). Numbers are colored to match the dots. Proteins were selected for the correlation analysis if they were significant at least in one of the groups compared and its fold-change > 1.5. We observed a positive correlation between DS vs. EOAD a (p < 0.0001, R² = 0.77, b DS vs. LOAD (p < 0.0001, R² = 0.73) and c EOAD vs. LOAD (p < 0.0001, R² = 0.67). There is also a positive correlation when comparing non-plaque proteins in d DS vs. EOAD (p < 0.0001, R² = 0.59) and e DS vs. LOAD (p < 0.0001, R² = 0.33). h. Correlation between EOAD and LOAD non-plaque proteins (p < 0.0001, R² = 0.79)

**Fig. 4**
Mapping protein-coding genes to chromosome 21 (Hsa21). a Dashed box contains Venn diagram of proteins from genes in Hsa21 identified in the current study vs. Drummond et al. 2022, [31]. **a–c** The figure depicts fold-change (Log₂ FC) of the 22 Hsa21 genes whose corresponding protein products were found in Aβ plaques (circles) or neighboring non-plaque tissue (squares) in LOAD (a) EOAD (b) and DS (c). Paired two-tailed t tests (plaques vs. non-plaques) or unpaired two-tailed t tests (non-plaques vs. control) with permutation correction at a 5% FDR are indicated. Aβ peptide is shown as reference

**Fig. 5**
Gene ontology annotation and protein–protein interaction networks of significantly abundant proteins in Aβ plaques. a GO terms heatmap depicts top ten enriched BP and CC GO terms for significantly abundant Aβ plaque proteins in DS, EOAD, and LOAD. Color indicates the adjusted p value < 0.05 (− Log₁₀ [adj. p value]). **b–d** Protein networks (PPI Enrichment p = 1 × 10⁻¹⁶) show functional and physical amyloid plaques protein associations in DS (b), EOAD (c) and LOAD (d). Node color indicates fold-change (log₂ [FC]) and node size depicts adjusted p value (-log₁₀ [p value]) from the student’s two-tailed t test. Disconnected nodes are not shown in the network. Colored dotted lines highlight groups of proteins based on functions/pathways observed in the GO terms; blue: APP protein metabolic process, red: immune response and inflammation, green: lysosomal-related functions, and purple: intermediate filament proteins, glial cells. GO terms annotation was performed using R package *clusterProfiler* v 4.8.2. PPI networks were created in Cytoscape v 3.10.0 using STRING database v 11.5

**Fig. 6**
Enriched Aβ plaque proteins of interest in DS compared with EOAD and LOAD. (**a–f**) Normalized protein expression obtained from the label-free quantitative mass spectrometry proteomics of abundant Aβ plaque proteins of interest in DS. Proteins are shown by order of decreasing significance. Proteins of interest were defined as significant (FDR < 5%, fold-change > 1.5) only in DS and also have known or predicted roles in AD and DS. Pairwise comparisons p values are indicated. * p < 0.05, **** p < 0.0001. Error bars indicate standard error of the mean (SEM). Significant pairwise comparisons are indicated for those analyses that were performed, controls are shown as reference. Additional symbols on top of the control bar indicate that the given protein is not significantly abundant in non-plaque AD tissue compared to controls in # DS, † EOAD, and ‡ LOAD, respectively

**Fig. 7**
Comparison of protein changes with previous advanced AD proteomics studies. a Altered proteins identified in the current study were compared with proteins found altered in previous AD proteomics compiled in NeuroPro [4] (v1.12; https://neuropro.biomedical.hosting/). Pie charts show that 77.7% (234/301) of altered plaque proteins in the present study have been identified in previous AD plaque proteomics studies (gray). 13.6% (41/301) of the proteins have been seen only in bulk tissue proteomics studies (white), and 8.6% (26/301) of the altered proteins observed in the current study have not been described in previous AD proteomics (purple). In a similar fashion, 85.2% (478/561) proteins altered in AD non-plaque tissue have been observed in AD plaque proteomics, 10.9% (61/561) only in bulk tissue proteomics, and 3.9% (22/561) have not been described in previous AD proteomics studies. b Venn diagrams illustrate the altered proteins identified in Aβ plaques and AD non-plaque tissue for each AD subtype evaluated, in comparison to the 5104 altered proteins in advanced AD registered in NeuroPro database. c Heatmaps depicting the fold-change (Log₂ [FC]) of the plaque and AD non-plaque altered proteins identified in the present study that have not been described in previous AD proteomics. Numbers in the cells represent the significance (FDR < 0.05) values observed in the pairwise comparisons, n.s represent no significant differences regardless of the fold-change

**Fig. 8**
Comparison of protein changes between the DS plaques localized proteomics studies. a Venn diagram depicts differentially abundant proteins identified in the current study and the previous DS plaque proteomics study (Drummond et al. 2022, [31]). We identified 132 significantly altered proteins compared to 146 identified previously. From the 50 common proteins identified, 48 were enriched in Aβ plaques and 2 proteins were less abundant in both studies. b Correlation analysis between differentially abundant proteins in the current study and previous DS localized proteomics. Yellow dots represent significant proteins changing in the same direction (highly abundant or less abundant proteins in both groups evaluated) in both groups compared. Magenta dots represent proteins changing in the same direction, but are significant only in one of the groups evaluated. Green dots represent proteins changing in opposite direction (i.e., abundant in one group and less abundant in the other group evaluated). There was a significant positive correlation (p < 0.0001, R² = 0.60) between the two datasets

**Fig. 9**
Immunohistochemical validation of CLCN6 protein in human brain tissues. a Immunohistochemistry of Aβ and CLCN6 in control, DS, EOAD, and LOAD. Dotted line represents the plaque in CLCN6 panel. White arrowheads depict positive CLCN6 cells surrounding Aβ plaques. Merge panel shows intracellular colocalization of CLCN6 and Aβ. Scale bar 50 µm. b Bar graph showing normalized area occupied by CLCN6 and c normalized CLCN6 fluorescence, corresponding to plaque and non-plaque tissue. Paired two-tailed *t tests* indicate statistical differences between Plaque vs non-plaque tissue samples, whereas unpaired two-tailed *t tests* were performed to compare control non-plaque samples vs DS, EOAD, and LOAD non-plaque samples. For panels B and C, n = 6 cases. d Normalized protein expression of CLCN6 obtained from the label-free quantitative mass spectrometry proteomics. e Immunohistochemistry of neuronal protein MAP2 and CLCN6 in DS tissue away from plaques. Yellow arrowheads depict co-staining of MAP2 and CLCN6. White asterisks show small unidentified cells negative for MAP2 and positive for CLCN6. Scale bar 50 µm. Pairwise comparisons p values are indicated. * p < 0.05, ** p < 0.01, **** p < 0.0001. Error bars indicate standard error of the mean (SEM). Significant pairwise comparisons are indicated for those analyses that were performed, controls are shown as reference. Additional symbols on top of the control bar indicate that the given protein is not significantly abundant in non-plaque AD tissue compared to controls in # DS, † EOAD and ‡ LOAD, respectively

**Fig. 10**
Immunohistochemical validation of TPP1 protein in human brain tissues. a Immunohistochemistry of Aβ and TPP1 in control, DS, EOAD, and LOAD. Bottom panel, dotted lines highlight TPP1-positive immunolabeling embedded in Aβ plaques for DS, EOAD, and LOAD. Scale bar 200 µm and 20 µm for plaque zoom panels. b Normalized protein expression of TPP1 obtained from the label-free quantitative mass spectrometry proteomics. Pairwise comparisons p values are indicated. **** p < 0.0001. Significant pairwise comparisons are indicated for those analyses that were performed, controls are shown as reference. Additional symbols on top of the control bar indicate that the given protein is not significantly abundant in non-plaque AD tissue compared to controls in # DS, † EOAD, and ‡ LOAD, respectively. c Bar graph showing normalized TPP1 area, corresponding to plaque and non-plaque tissue. No statistical differences between plaque vs non-plaque tissue samples were found. For panels C, n = 6 cases. Error bars indicate standard error of the mean (SEM)

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Update of

Comparison of the Amyloid Plaque Proteome in Down Syndrome, Early-Onset Alzheimer's Disease and Late-Onset Alzheimer's Disease.
Martá-Ariza M, Leitner DF, Kanshin E, Suazo J, Pedrosa AG, Thierry M, Lee EB, Devinsky O, Drummond E, Fortea J, Lleó A, Ueberheide B, Wisniewski T. Martá-Ariza M, et al. Res Sq [Preprint]. 2024 Jul 15:rs.3.rs-4469045. doi: 10.21203/rs.3.rs-4469045/v1. Res Sq. 2024. Update in: Acta Neuropathol. 2025 Jan 18;149(1):9. doi: 10.1007/s00401-025-02844-z PMID: 39070643 Free PMC article. Updated. Preprint.

References

1. Aladeokin AC, Akiyama T, Kimura A, Kimura Y, Takahashi-Jitsuki A, Nakamura H et al (2019) Network-guided analysis of hippocampal proteome identifies novel proteins that colocalize with Abeta in a mice model of early-stage Alzheimer’s disease. Neurobiol Dis. 10.1016/j.nbd.2019.104603 - PubMed
1. Aldecoa I, Barroeta I, Carroll SL, Fortea J, Gilmore A, Ginsberg SD et al (2024) Down Syndrome biobank consortium: a perspective. Alzheimers Dement. 10.1002/alz.13692 - PMC - PubMed
1. Antonarakis SE, Skotko BG, Rafii MS, Strydom A, Pape SE, Bianchi DW et al (2020) Down syndrome. Nat Rev Dis Primers 6:9. 10.1038/s41572-019-0143-7 - PMC - PubMed
1. Askenazi M, Kavanagh T, Pires G, Ueberheide B, Wisniewski T, Drummond E (2023) Compilation of reported protein changes in the brain in Alzheimer’s disease. Nat Commun 14:4466. 10.1038/s41467-023-40208-x - PMC - PubMed
1. Balcomb K, Johnston C, Kavanagh T, Leitner D, Schneider J, Halliday G et al (2024) SMOC1 colocalizes with Alzheimer’s disease neuropathology and delays Abeta aggregation. Acta Neuropathol 148:72. 10.1007/s00401-024-02819-6 - PMC - PubMed

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[1] Aladeokin AC, Akiyama T, Kimura A, Kimura Y, Takahashi-Jitsuki A, Nakamura H et al (2019) Network-guided analysis of hippocampal proteome identifies novel proteins that colocalize with Abeta in a mice model of early-stage Alzheimer’s disease. Neurobiol Dis. 10.1016/j.nbd.2019.104603 - PubMed

[2] Aladeokin AC, Akiyama T, Kimura A, Kimura Y, Takahashi-Jitsuki A, Nakamura H et al (2019) Network-guided analysis of hippocampal proteome identifies novel proteins that colocalize with Abeta in a mice model of early-stage Alzheimer’s disease. Neurobiol Dis. 10.1016/j.nbd.2019.104603 - PubMed

[3] Aldecoa I, Barroeta I, Carroll SL, Fortea J, Gilmore A, Ginsberg SD et al (2024) Down Syndrome biobank consortium: a perspective. Alzheimers Dement. 10.1002/alz.13692 - PMC - PubMed

[4] Aldecoa I, Barroeta I, Carroll SL, Fortea J, Gilmore A, Ginsberg SD et al (2024) Down Syndrome biobank consortium: a perspective. Alzheimers Dement. 10.1002/alz.13692 - PMC - PubMed

[5] Antonarakis SE, Skotko BG, Rafii MS, Strydom A, Pape SE, Bianchi DW et al (2020) Down syndrome. Nat Rev Dis Primers 6:9. 10.1038/s41572-019-0143-7 - PMC - PubMed

[6] Antonarakis SE, Skotko BG, Rafii MS, Strydom A, Pape SE, Bianchi DW et al (2020) Down syndrome. Nat Rev Dis Primers 6:9. 10.1038/s41572-019-0143-7 - PMC - PubMed

[7] Askenazi M, Kavanagh T, Pires G, Ueberheide B, Wisniewski T, Drummond E (2023) Compilation of reported protein changes in the brain in Alzheimer’s disease. Nat Commun 14:4466. 10.1038/s41467-023-40208-x - PMC - PubMed

[8] Askenazi M, Kavanagh T, Pires G, Ueberheide B, Wisniewski T, Drummond E (2023) Compilation of reported protein changes in the brain in Alzheimer’s disease. Nat Commun 14:4466. 10.1038/s41467-023-40208-x - PMC - PubMed

[9] Balcomb K, Johnston C, Kavanagh T, Leitner D, Schneider J, Halliday G et al (2024) SMOC1 colocalizes with Alzheimer’s disease neuropathology and delays Abeta aggregation. Acta Neuropathol 148:72. 10.1007/s00401-024-02819-6 - PMC - PubMed

[10] Balcomb K, Johnston C, Kavanagh T, Leitner D, Schneider J, Halliday G et al (2024) SMOC1 colocalizes with Alzheimer’s disease neuropathology and delays Abeta aggregation. Acta Neuropathol 148:72. 10.1007/s00401-024-02819-6 - PMC - PubMed

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Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer's disease, and late-onset Alzheimer's disease

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Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer's disease, and late-onset Alzheimer's disease

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