Serum unsaturated phosphatidylcholines predict longitudinal basal forebrain degeneration in Alzheimer’s disease
Bibliographic record
Abstract
Abstract Basal forebrain cholinergic neurons are among the first cell types affected by Alzheimer’s disease pathology, but the cause of their early vulnerability is unknown. The lipid phosphatidylcholine is an essential component of the cell membrane, and phosphatidylcholine levels have been shown to be abnormal in the blood and brain of Alzheimer’s disease patients. We hypothesized that disease-related changes in phosphatidylcholine metabolism may disproportionately affect basal forebrain cholinergic neurons due to their extremely large size, plasticity in adulthood and unique reliance on phosphatidylcholine for acetylcholine synthesis. To test this hypothesis, we examined whether serum phosphatidylcholine levels predicted longitudinal basal forebrain degeneration in Alzheimer’s disease. All data were collected by the Alzheimer’s Disease Neuroimaging Initiative. Participants were divided into a normal CSF group (controls; n = 77) and an abnormal CSF group (preclinical and clinical Alzheimer’s disease; n = 236) based on their CSF ratios of phosphorylated tau and amyloid beta at baseline. Groups were age-matched (t = 0.89, P > 0.1). Serum lipidomics data collected at baseline were clustered by chemical similarity, and enrichment analyses were used to determine whether serum levels of any lipid clusters differed between the normal and abnormal CSF groups. In a subset of patients with longitudinal structural MRI (normal CSF n = 62, abnormal CSF n = 161), two timepoints of MRI data were used to calculate grey matter annual percent change for each participant. Multivariate partial least squares analyses tested for relationships between neuroimaging and lipidomics data which are moderated by CSF pathology. Our clustering analyses produced 23 serum lipid clusters. Of these clusters, six were altered in the abnormal CSF group, including a cluster of unsaturated phosphatidylcholines. In the subset of participants with longitudinal structural MRI data, a priori nucleus basalis of Meynert partial least squares analyses detected a relationship between unsaturated phosphatidylcholines and degeneration in the nucleus basalis which is moderated by Alzheimer’s disease CSF pathology (P = 0.0008). Whole-brain grey matter partial least squares analyses of all 23 lipid clusters revealed that only unsaturated phosphatidylcholines and unsaturated acylcarnitines exhibited an Alzheimer’s disease-dependent relationship with longitudinal degeneration (P = 0.0022 and P = 0.0018, respectively). Only the unsaturated phosphatidylcholines predicted basal forebrain degeneration in the whole-brain analyses. Overall, this study provides in vivo evidence for a selective relationship between phosphatidylcholine and basal forebrain degeneration in human Alzheimer’s disease, highlighting the importance of phosphatidylcholine to basal forebrain grey matter integrity.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".