Plasma proteomic profiling of mild cognitive impairment in two cohorts using the NULISAseq CNS Disease panel
Bibliographic record
Abstract
Abstract Background Recently, the development of ultra‐sensitive immunoassays has allowed for the detection, in blood, of proteins related to the pathophysiology of Alzheimer’s disease (AD), with phosphorylated tau (p‐tau) being the most promising. However, current methods are often limited by their ability to measure one analyte, lacking the potential for discovery and inclusion of additional biomarkers with supplemental value. In this pilot study, we explored proteomic changes using the novel NUcleic acid Linked Immuno‐Sandwich Assay (NULISA™) platform, focusing on patients with mild cognitive impairment (MCI). Method In this study, MCI patients with a confirmed Aβ status were recruited from two independent cohorts. A discovery cohort (mean[SD] age, 73.5 [5.5] years; 25 females [62.5%]) was classified by cerebrospinal fluid Aβ42/40 (Aβ+ =28; Aβ‐ =12). For the second cohort (mean[SD] age, 70.7 [7.31] years; 39 females[42.9%]; CDR 0.5), from the TRIAD study, amyloid positron emission tomography was utilized instead (Aβ+ =47; Aβ‐ =44). We performed the NULISAseq CNS Disease Panel measurements on the plasma samples (n=131) in two separate batch analyses. LIMMA models were used to evaluate differential expression of protein NPQ values between the two MCI (Aβ+ Vs. Aβ‐) patient groups, with a total of 121 proteins included in the analysis. Result In the discovery cohort (n=40), only p‐tau217 survived multiple comparison (Log2FC, 1.49; Padj <0.001). Further targets were present with a significant unadjusted p‐value (P <0.05) (Figure 1b). In the larger TRIAD cohort (n=91), p‐tau217 (Log2FC, 1.29; Padj <0.001), p‐tau231 (Log2FC, 0.76; Padj <0.05), p‐tau181 (Log2FC, 0.42; Padj <0.05) and GFAP (Log2FC, 0.78; Padj <0.05) remained significant after adjusting for multiple testing. Similarly to the discovery cohort, additional targets were identified as significantly changed with an unadjusted p‐value (P<0.05) (Figure 1A). This included PARK7, which was the only target present in both. Conclusion In this study, consisting of two independent groups of MCI patients characterized by Aβ burden, we utilized the NULISAseq CNS Disease Panel to identify dysregulated proteins of the prodromal stage of AD. This novel multiplex technology continues to demonstrate the importance of p‐tau217, p‐tau231, p‐tau181 and GFAP as indicators of cerebral amyloid deposition while offering additional markers that may increase their utility.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".