Molecular and imaging biomarker responses to brain mutant HTT lowering in a mouse model of Huntington disease
Bibliographic record
Abstract
Therapies targeting mutant huntingtin (mHTT) reduction in the brain hold promise as disease-modifying treatments for Huntington disease (HD), necessitating biomarkers that accurately reflect treatment response. We evaluated candidate molecular and imaging biomarkers after mHTT reduction in YAC128 HD mice, with equal numbers of males and females per group. At 6 months of age, YAC128 mice received unilateral intracerebroventricular injections of saline or mHTT-lowering antisense oligonucleotide (HTT ASO). Plasma neurofilament light chain (NEFL) and glial fibrillary acidic protein (GFAP) were measured longitudinally from 6 to 12 months. Structural MRI was performed at 6, 9, and 12 months. At study endpoint, we quantified mHTT target engagement in the brain and performed striatal RNA sequencing. Treatment with HTT ASO produced a sustained reduction of mHTT levels throughout the brain for up to 6 months, significantly slowed plasma NEFL increases, and moderately attenuated GFAP elevation. Although mHTT levels inversely correlated with gray and white matter volumes, treatment did not significantly stabilize regional brain atrophy, highlighting an association between mHTT load and neuroanatomical integrity. HTT ASO also partially reversed striatal transcriptome dysregulation and restored oligodendrocyte-specific gene expression. Plasma NEFL, but not brain imaging, emerges as a sensitive and dynamic response biomarker for mHTT-lowering therapies.
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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) | 0.000 | 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".