Toward precision diagnosis and treatment of radiation-induced brain injury

Radiation-induced brain injury (RIBI) is a serious and often delayed complication of cranial radiotherapy, which remains a cornerstone in the treatment of brain tumors such as gliomas, metastases, and lymphomas. While modern radiotherapy techniques have improved survival rates, they have also led to an increased incidence of RIBI, adversely affecting patients' neurological function and quality of life. This review synthesizes recent advances in multimodal imaging and emerging therapeutic strategies for RIBI, highlighting the shift from conventional symptomatic management to mechanism-driven, precision interventions.

Pathophysiological mechanisms of RIBI

RIBI is a multifactorial process involving vascular, inflammatory, and cellular damage. Key mechanisms include:

• Blood-brain barrier (BBB) disruption: Ionizing radiation damages cerebral microvascular endothelial cells, increasing BBB permeability and allowing inflammatory mediators to infiltrate the brain.

• Neuroinflammation: Activation of microglia and astrocytes, along with elevated pro-inflammatory cytokines (e.g., IL-6, IL-1β), contributes to neuronal apoptosis and cognitive decline.

• Oxidative stress and DNA damage: Reactive oxygen species (ROS) generation leads to direct and indirect cellular injury, including DNA strand breaks and impaired protein synthesis.

• White matter injury: Demyelination and axonal loss disrupt neural signaling, leading to cognitive impairment.

• Genetic susceptibility: Polymorphisms in genes such as CEP128 have been linked to individual differences in RIBI risk.

Clinical manifestations

RIBI progresses through three clinical phases:

1. Acute phase (hours to weeks): Symptoms include headache, nausea, and somnolence due to cerebral edema.

2. Subacute phase (1–6 months): Transient cognitive impairment and memory deficits may occur, often with reversible white matter changes.

3. Late-delayed phase (beyond 6 months): Progressive cognitive decline, executive dysfunction, seizures, and irreversible brain necrosis may develop.

Advances in multimodal imaging

Conventional MRI alone is often insufficient for early detection or differentiation of RIBI from tumor recurrence. Multimodal imaging integrates structural, functional, metabolic, and AI-driven analyses to improve diagnostic accuracy:

• Structural MRI (T1/T2/FLAIR): Sensitive to white matter lesions and necrosis.

• Diffusion imaging (DWI/DTI): Helps differentiate hypercellular tumors (low ADC) from necrosis (high ADC). DTI parameters (e.g., fractional anisotropy) detect microstructural white matter damage.

• Perfusion imaging (PWI/ASL/DSC/DCE): Distinguishes hypoperfused radiation necrosis from hyperperfused tumor recurrence.

• MRS and PET/CT: Quantify metabolic changes (e.g., choline/NAA ratios) and glucose metabolism to identify necrosis versus recurrence.

• Radiomics and AI: Machine learning models extract quantitative imaging features to support non-invasive diagnosis with high accuracy.

Therapeutic strategies

Current RIBI management is evolving from glucocorticoid-based symptomatic care to targeted and multimodal interventions:

• Pharmacotherapy: Bevacizumab (anti-VEGF) is the only treatment validated by randomized trials for radiation necrosis. Corticosteroids reduce edema but have long-term side effects. Sildenafil and simvastatin show neuroprotective potential via anti-inflammatory and antioxidant pathways.

• Hyperbaric oxygen (HBO): Promotes angiogenesis and repair, though large-scale trials are lacking.

• Stem cell therapy: Mesenchymal and endothelial progenitor cells may support vascular and neural repair, but clinical translation remains experimental.

• Neuromodulation: Techniques such as transcranial magnetic stimulation and fMRI neurofeedback offer non-pharmacological options for cognitive rehabilitation.

• Gut-brain axis interventions: Probiotics and fecal microbiota transplantation modulate neuroinflammation and cognitive function in preclinical models, representing a novel therapeutic frontier.

Challenges and future directions

Despite progress, several challenges persist:

• Lack of standardized diagnostic criteria and early biomarkers.

• Limited mechanism-driven treatments and high-level evidence for emerging therapies.

• Insufficient integration of multimodal imaging into clinical workflows.

• Need for interdisciplinary collaboration and large-scale multicenter studies.

Future efforts should focus on:

• Establishing consensus diagnostic and grading standards.

• Developing predictive models using clinical, imaging, and genetic data.

• Advancing targeted therapies against neuroinflammation, oxidative stress, and vascular injury.

• Promoting collaborative research to translate preclinical findings into clinical practice.

Conclusion

RIBI remains a significant and complex complication of cranial radiotherapy. Multimodal imaging has enhanced early detection and differential diagnosis, while therapeutic approaches are increasingly targeting underlying pathological mechanisms. However, most treatments are still palliative, and future research must prioritize biomarker discovery, standardized imaging protocols, and rigorous clinical trials to achieve precision management of RIBI.