Multimodal evaluation of brain injury and cerebral iron deposition in thalassemia patients: A combined human-imaging and murine model study
Bibliographic record
Abstract
Abstract Introduction: Chronic anemia and iron overload in thalassemia (TM) may contribute to neurological injury, though this remains underexplored. We employed a multimodal strategy—integrating human imaging, neurocognitive assessment, and animal modeling—to investigate brain damage and iron deposition patterns in TM patients and the associated risk factors. Methods: We prospectively enrolled 88 TM patients (46 transfusion-dependent [TDT], 42 non-transfusion-dependent [NTDT]) and 79 healthy controls (HCs) between Sept 2022 and Sept 2024. Resting-state functional magnetic resonance imaging (rs-fMRI) was used to assess neural activity. Cognitive status was evaluated via Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). Brain iron content was quantified using quantitative susceptibility mapping (QSM), the magnetic susceptibility of regions of interest (ROI) and serum ferritin (SF), S100B protein, and neuron-specific enolase (NSE) levels were measured. A parallel mouse iron overload model was established with four groups (NC, L-IO, M-IO, H-IO), and brain tissues were analyzed at 8, 10, and 16 weeks using Prussian blue staining and iron quantification. Results: rs-fMRI revealed significant alterations in neural activity across cognition-, emotion-, motor-, and memory-related regions in both NTDT and TDT groups vs HCs (P<0.05). Cognitive testing confirmed impairments in attention, memory, and language domains in TM patients (P<0.05); SF negatively correlated with MMSE attention/calculation (r= –0.22) and recall (r= –0.23). QSM showed elevated magnetic susceptibility in the right subthalamic nucleus and left medial globus pallidus in TM patients (P<0.05). SF correlated positively with subthalamic nucleus iron (r=0.293, P<0.05), and cardiac T2* correlated negatively with pallidal iron (r=–0.376, P<0.01). In the murine model, iron accumulated in the choroid plexus at 8 weeks in M-IO and H-IO groups, with progressive deposition at weeks 10 and 16. Brain iron concentrations at week 16 differed significantly among groups (F=18.38, P<0.05), with the H-IO group showing significantly higher levels than others (P<0.01). S100B and NSE levels increased progressively from HC to NTDT to TDT groups, with significant elevations in the TDT group compared to HCs (P<0.05), indicating ongoing parenchymal brain injury. Conclusions: TM patients exhibit measurable cognitive impairment and functional brain alterations, likely associated with regional iron deposition. TDT patients may experience subclinical brain parenchymal injury. These findings underscore the value of integrated multimodal evaluation in identifying early neurological complications in thalassemia.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 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 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".