Differential synaptic marker involvement in the different genetic forms of frontotemporal dementia
Bibliographic record
Abstract
Abstract Background Approximately a third of frontotemporal dementia (FTD) is genetic with mutations in three genes accounting for the majority of the inheritance: C9orf72, GRN and MAPT . Synaptic dysfunction is a common mechanism in all of them and the use of fluid biomarkers could be helpful to improve the diagnostic accuracy and useful as a readout of cellular dysfunction within therapeutic trials. Method A total of 193 cerebrospinal fluid samples from the GENetic FTD Initiative including 77 presymptomatic (31 C9orf72 , 23 GRN , 23 MAPT ), 55 symptomatic mutation carriers (26 C9orf72 , 17 GRN , 12 MAPT ) and 61 mutation‐negative controls were measured using a microflow LC PRM‐MS set‐up targeting 15 synaptic proteins: 14‐3‐3 proteins (eta, zeta/delta and epsilon), AP‐2 complex subunit beta, beta‐synuclein, gamma‐synuclein, complexin‐2, neurogranin, neuronal pentraxin receptor (NPTXR), neuronal pentraxin 1 (NPTX1), neuronal pentraxin 2 (NPTX2), phosphatidylethanolamine‐binding protein 1 (PEBP‐1), rab GDP dissociation inhibitor α (rab GDIα), syntaxin‐1B and syntaxin‐7. Mutation carrier groups were compared to each other and to controls using a bootstrapped linear regression model, adjusting for age and sex. Result Eight proteins were increased only in symptomatic MAPT mutation carriers (compared with controls) and not in symptomatic C9orf72 or GRN mutation carriers: 14‐3‐3‐eta, beta‐synuclein, gamma‐synuclein, neurogranin, PEBP‐1, rab GDIα, syntaxin‐1B and syntaxin‐7. In contrast, NPTX1 and NPTX2 were affected in all three genetic groups (decreased compared to controls), with NPTXR being affected in C9orf72 and GRN mutation carriers only (decreased compared to controls). No changes were seen in presymptomatic mutation carriers in these proteins. Figure 1 contains p‐values for all significant changes. Conclusion Differential involvement of synaptic markers is seen in the genetic forms of FTD, with impairment particularly in those with MAPT mutations, with only the neuronal pentraxins affected in GRN and C9orf72 mutation carriers. Further work is needed to explore correlations with clinical and imaging biomarkers, whether there are changes in the late presymptomatic period, and how these markers change over time.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| 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 teacher head, 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".