The Association of UCHL5 Levels with AT(N) Biomarkers
Bibliographic record
Abstract
BACKGROUND: Alzheimer's disease (AD) is a proteinopathy characterized by the accumulation of amyloid-β (Aβ) and hyperphosphorylated tau, leading to the formation of amyloid plaques and neurofibrillary tangles. Dysfunction of the ubiquitin-proteasome system has been implicated in these pathological processes. Ubiquitin C-terminal hydrolase L5 (UCHL5), a deubiquitinase that regulates proteasomal activity, plays a crucial role in degrading damaged proteins. However, its role in AD progression remains poorly understood. This study aims to investigate the association between UCHL5 levels in cerebrospinal fluid (CSF) and AD biomarkers. METHOD: We assessed 168 cognitively unimpaired (CU) and 540 cognitively impaired (CI) individuals from ADNI (Table 1), with available baseline FDG-PET, Aβ-PET, cognitive assessments, CSF and plasma biomarkers. The association between CSF UCHL5 levels and CSF Aβ42, total tau, p-Tau181, plasma GFAP, hippocampal volume, Mini-Mental State Exam (MMSE), Aβ-, and FDG-PET were analyzed using generalized linear mixed models adjusted for age and sex. Additionally, voxel-wise analyses explored the association of UCHL5 levels with FDG- and Aβ-PET. RESULT: Our analysis revealed higher UCHL5 CSF levels in CU compared to CI individuals (Figure 1). In CU, UCHL5 CSF levels were positively associated with p-Tau181 and total tau levels (Figures. 2A, 2B). Additionally, CI individuals showed positive correlations between UCHL5 CSF levels and CSF Aβ42 ratio, plasma GFAP, MMSE scores, and hippocampal volume (Figures. 2C, 2D, 2E and 2F). Notably, UCHL5 CSF levels were negatively associated with AV45 SUVR rates of Aβ burden, in occipital, temporal and predominantly in parietal and frontal cortices (Figure 2G). On the other hand, a positive correlation was observed between UCHL5 CSF levels and FDG SUVR values, further supported by FDG-PET voxel-wise analyses, highlighting prefrontal cortex, temporal gyrus and parietal lobe (Figure 2H). CONCLUSION: These findings reveal intriguing correlations between AT(N) biomarkers and CSF UCHL5 levels, suggesting a potential role for this protein across different stages of Alzheimer's disease. However, further analyses are needed to clarify UCHL5's involvement in early tau accumulation, clinical conversion, and the degradation of misfolded proteins associated with AD proteinopathies, as well as its impact on neurodegeneration.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".