PD Proteomics (continued)
| Source | Cohort | Findings | Right-margin tag |
|---|---|---|---|
| (Karayel, 2021 #2257) (Table S4) | mass spectrometry, 215 individuals from two independent cohorts, including 113 healthy controls (HC) and 102 PD. : 94 CSF samples from the Harvard Biomarkers Study and ? from LCC | Mc1-related work by PhReT | |
| 정재윤: AMP-PD, olink | 정재윤 AMP-PD, olink | ||
| AD/PD 2023: Pia Gutsmiedl, Mass spectrometry : in PD: ↑ IL-1-related pathway , ↓ (SAP, ZA2G, A1AG2, A1AG1), | N: PD 50, HC 44 | ||
| (Kaiser, 2023 #2243) (Kaiser 2023 #2561) | PPMI cohort , somascan |
the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed. Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest PD GWAS identified 68 potential causal proteins (Out of those proteins, GPNMB, FCGR2A and FCGR2B also had a strong colocalization signal (see Methods), indicating the same SNP is both associated with protein level and PD risk (Fig. 2). by Mendelian randomization. The top causal protein, GPNMB, was previously reported to be upregulated in the SN of PD patients. Proteome differences between GBA + patients and unaffected GBA + controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. In the LRRK2 + subcohort we found dysregulated lysosomal degradation, altered alpha-syn processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction/oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances. Finally, we used proteomic data to stratify idiopathic patients into "endotypes". [GBA-PD] (table 3) CALCA, CD2, DLK1, GCH1, IL17A, SEMG2 |
| HC | Endotype 1 | Endotype 2 (inflammatory) | |
|---|---|---|---|
| CSF p-tau≥11 pg/mL | CSF p-tau<11 pg/mL | ||
| updrs part I | ↑ | ↑ | |
| Endotype 2, however, showed 200 differentially expressed SOMAmers, 197 unique proteins (see Suppl Table 5). | |||
| Pathway analysis | ↑ proteins related to synaptic connectivity and signaling, axonal guidance, and neurotransmission (Supplementary Fig. 1).: eg. glial fibrillary acidic protein, asyn, microtubule associated protein tau, apolipoprotein E, 14-3-3 proteins (i.e., YWHAG, YWHAB, YWHAQ, YWHAZ) | ↑ inflammatory activity (proteins related to Th1, Th2, Th17 and macrophage activation pathways, as well as IL17 and other cytokines' signaling pathways) | |
| [HC vs endotype 1] five markers were significantly different compared to the control group (CNTFR, LPO, MMP10, RIPK2, and VEGFA). | |||
| CSF Aβ | ↓ | ||
| CSF p-tau | ↓ | ||
| CSF total tau | ↓ | ||
| CSF aSyn | ↓ |
| [HC vs PD all] (table 3) LPO (Lower LPO levels in idiopathic patients found here contrasts with previously reported elevated CSF LPO levelsss. dopamine and levodopa reduce LPO levelsss Given that the idiopathic patients recruited were drug-naïve early PD patients, dopamine levels in this subpopulation may have helped maintaining low levels of CSF LPO) , RIPK2 and VEGFA were also part of the differences between HC and the whole idiopathic group (see above) ...Among those proteins, AK1, CCL14, FRZB, GPI, HAMP, LPO, NETO1, PTPRR, RAB31, RELT, RIPK2, ROBO3, RSPO4, SHANK1, SPINK9, VEGFA, and VIP were dysregulated for the whole idiopathic group as compared to healthy controls. | |
| ngPD-ProS | ↑ 155 SOMAmers (i.e., 153 unique proteins; see Supplementary Table 5) were differentially expressed between endotypes. |
(Tsukita, 2022 #2371) (ngPD-ProS (non-genetic Parkinson’s Disease-associated Proteomic Score)
Supplementary Table 1 Details of 55 proteins included in the tuned model to calculate the ngPD-ProS
| SOMAmers ID | Target gene | Derivation cohort | Validation cohort | B coefficient | ||
|---|---|---|---|---|---|---|
| log2(FC) | OR (95%CI) | log2(FC) | OR (95%CI) | |||
| 11137-43_3 | CSF2RB | 0.05 | 1.49 (1.21–1.86) | 0.01 | 1.07 (0.58–2.15) | 1.13 |
| 9769-48_3 | DNER | 0.04 | 1.02 (0.84–1.24) | -0.09 | 0.76 (0.37–1.42) | 1.10 |
| 8356-88_3 | OXT | 0.09 | 1.38 (1.13–1.70) | 0.10 | 1.51 (0.80–3.07) | 0.83 |
| 2900-53_3 | CCL14 | 0.14 | 1.69 (1.36–2.11) | 0.13 | 1.35 (0.71–2.75) | 0.71 |
| 8071-114_3 | PCDHB7 | 0.05 | 1.41 (1.15–1.75) | 0.00 | 1.01 (0.54–1.92) | 0.71 |
| 3504-58_2 | HAMP | 0.22 | 1.74 (1.40–2.18) | 0.75 | 6.29 (2.46–22.1) | 0.64 |
| 9264-11_3 | CTSO | 0.08 | 1.22 (1.01–1.49) | -0.05 | 0.85 (0.44–1.56) | 0.53 |
| 13427-66_3 | MAN1C1 | 0.09 | 1.29 (1.06–1.58) | -0.07 | 0.78 (0.40–1.50) | 0.50 |
| 2813-11_2 | AGRP | 0.14 | 1.42 (1.15–1.76) | -0.24 | 0.60 (0.30–1.11) | 0.49 |
| 2711-6_2 | CNTFR | 0.06 | 1.01 (0.83–1.23) | -0.09 | 0.75 (0.37–1.42) | 0.49 |
| 12446-49_3 | GSTA1 | 0.10 | 1.55 (1.23–2.00) | 0.06 | 1.32 (0.71–2.73) | 0.38 |
| 3290-50_2 | CD109 | 0.09 | 1.27 (1.04–1.55) | 0.03 | 1.12 (0.56–2.24) | 0.38 |
| 9900-36_3 | NEFH | 0.12 | 1.72 (1.31–2.28) | -0.02 | 0.95 (0.47–2.05) | 0.35 |
| 11116-16_3 | C11orf87 | -0.04 | 0.72 (0.59–0.88) | -0.11 | 0.58 (0.29–1.09) | 0.34 |
| 2558-51_3 | POMC | 0.06 | 1.33 (1.09–1.64) | -0.04 | 0.84 (0.46–1.59) | 0.31 |
| 4272-46_2 | GPI | 0.13 | 1.21 (0.99–1.49) | 0.11 | 1.57 (0.70–3.80) | 0.24 |
| 7200-4_3 | LRFN2 | -0.09 | 0.66 (0.52–0.81) | -0.21 | 0.66 (0.32–1.24) | 0.20 |
| 5012-67_1 | AK1 | 0.09 | 1.15 (0.94–1.42) | 0.14 | 1.70 (0.84–3.94) | 0.17 |
| 8874-53_3 | CLN5 | 0.09 | 1.57 (1.25–1.99) | -0.09 | 0.71 (0.37–1.33) | 0.09 |
| 9986-14_3 | NPW | 0.17 | 1.47 (1.20–1.80) | 0.25 | 1.42 (0.77–2.71) | 0.06 |
| 8346-9_3 | DPP7 | 0.18 | 1.24 (1.03–1.50) | 0.04 | 1.06 (0.56–1.99) | 0.01 |
| 11516-7_3 | FABP1 | -0.12 | 0.98 (0.78–1.23) | -0.02 | 0.94 (0.48–1.89) | -0.02 |
| 4546-27_3 | ADGRE2 | -0.06 | 0.77 (0.63–0.93) | 0.03 | 1.18 (0.64–2.23) | -0.04 |
| 8819-3_3 | IGFBP2 | 0.06 | 1.50 (1.22–1.85) | 0.13 | 1.92 (0.99–4.06) | -0.05 |
| 6315-58_3 | PLBD1 | -0.17 | 0.86 (0.70–1.05) | -0.22 | 0.72 (0.35–1.35) | -0.10 |
| 5034-79_1 | PRSS2 | -0.12 | 0.92 (0.75–1.12) | 0.05 | 1.15 (0.60–2.29) | -0.12 |
| 3217-74_2 | SERPINE2 | -0.25 | 0.77 (0.63–0.94) | 0.00 | 1 (0.54–1.87) | -0.15 |
| 6973-111_4 | IGF2 | 0.06 | 1.51 (1.23–1.88) | 0.16 | 2.81 (1.31–7.16) | -0.23 |
| 3196-6_2 | HAPLN1 | -0.17 | 0.69 (0.57–0.84) | -0.23 | 0.69 (0.34–1.3) | -0.26 |
| 2962-50_2 | PTHLH | -0.12 | 0.75 (0.61–0.91) | -0.20 | 0.53 (0.25–1.01) | -0.28 |
| 3029-52_2 | CD209 | -0.06 | 0.73 (0.59–0.89) | -0.01 | 0.94 (0.49–1.78) | -0.29 |
| 9178-30_3 | NRG1 | -0.04 | 0.72 (0.57–0.88) | 0.03 | 1.29 (0.70–2.40) | -0.30 |
| 10974-20_3 | SPINK7 | -0.07 | 0.93 (0.75–1.15) | -0.12 | 0.55 (0.26–1.08) | -0.31 |
| 13114-50_3 | LUM | -0.05 | 0.83 (0.67–1.01) | -0.02 | 0.86 (0.44–1.68) | -0.32 |
| 4314-12_2 | DCTPP1 | -0.06 | 0.87 (0.71–1.07) | -0.17 | 0.48 (0.21–0.97) | -0.39 |
| 11656-110_3 | EVL | -0.04 | 0.75 (0.61–0.92) | -0.09 | 0.66 (0.32–1.26) | -0.40 |
| 6361-49_3 | PTPRR | -0.08 | 0.61 (0.48–0.76) | -0.16 | 0.61 (0.28–1.17) | -0.43 |
| 12702-13_3 | PELI2 | -0.05 | 0.74 (0.59–0.90) | -0.08 | 0.57 (0.26–1.08) | -0.46 |
| 14713-46_3 | AZU1 | -0.02 | 0.92 (0.76–1.12) | 0.01 | 1.18 (0.59–2.44) | -0.46 |
| 5400-52_3 | LEPR | -0.07 | 0.78 (0.63–0.95) | 0.00 | 1.01 (0.53–1.85) | -0.47 |
| 8479-4_3 | MMP10 | -0.09 | 0.76 (0.62–0.92) | -0.15 | 0.49 (0.22–0.94) | -0.48 |
| 10924-258_3 | CYB5D2 | -0.05 | 0.74 (0.60–0.91) | -0.12 | 0.57 (0.27–1.10) | -0.51 |
| 14090-23_3 | DEF6 | -0.08 | 0.78 (0.64–0.94) | 0.05 | 1.31 (0.66–3.20) | -0.52 |
| 3221-54_1 | SFRP1 | -0.17 | 0.66 (0.53–0.81) | -0.20 | 0.61 (0.29–1.16) | -0.63 |
| 8464-31_3 | RSPO4 | -0.08 | 0.65 (0.52–0.80) | -0.12 | 0.53 (0.26–1.01) | -0.65 |
| 3522-57_1 | VIP | -0.08 | 0.63 (0.51–0.78) | -0.13 | 0.67 (0.34–1.26) | -0.72 |
| 8285-64_3 | ADCYAP1 | -0.04 | 0.70 (0.57–0.85) | -0.03 | 0.71 (0.37–1.29) | -0.74 |
| 3495-15_2 | CXCL6 | -0.09 | 0.88 (0.72–1.07) | -0.03 | 0.91 (0.49–1.73) | -0.78 |
| 8783-216_3 | MAVS | -0.03 | 0.88 (0.72–1.06) | -0.01 | 0.95 (0.51–1.86) | -0.99 |
| 4542-24_2 | CLU | 0.05 | 1.42 (1.16–1.76) | 0.03 | 1.19 (0.63–2.32) | -1.06 |
| 8042-88_3 | SPINK9 | -0.06 | 0.78 (0.64–0.94) | -0.09 | 0.46 (0.18–1.04) | -1.10 |
| 4801-13_3 | LPO | -0.19 | 0.54 (0.42–0.68) | -0.30 | 0.30 (0.11–0.63) | -1.37 |
| 11616-9_3 | HSF1 | -0.04 | 0.72 (0.59–0.88) | -0.05 | 0.71 (0.35–1.37) | -1.83 |
| 6373-54_3 | SEMG2 | -0.10 | 0.68 (0.54–0.84) | -0.10 | 0.62 (0.32–1.14) | -2.01 |
| 8993-151_3 | RIPK2 | -0.08 | 0.53 (0.43–0.66) | -0.14 | 0.37 (0.16–0.74) | -2.42 |
Stastics
Power analysis
- select a threshold based on the minimum percentage of proteins to be quantified. In this context, the threshold is the statistical power expected for the majority of the proteins.
- Examples
- properly powered at a minimum of 80% (or 0.8), with a detectable fold change of 1.5 comparing two groups for all proteins, → the minimum sample size is 60 per group47. {Nakayasu, 2021 #2570}
- Reducing the power expectation to 75% of the proteins results in a minimum sample size of 35,
- Examples
Uncertain Spans
- “Stastics” — the in-document section heading is printed as “Stastics” (sic, missing ‘ti’); preserved as printed.
- “elevated CSF LPO levelsss” — source prints triple ‘s’ twice in this paragraph; preserved as printed (likely OCR-style typo carried over from the source PDF).
- “1 (0.54–1.87)” SERPINE2 validation OR — source prints the leading numeral as bare “1” without a decimal point; preserved as printed.
- “B coefficient” 8071-114_3 PCDHB7 — log2(FC) cell of derivation cohort is not visible separately in the row strip; transcribed as 0.05 from the OCR evidence row alignment.