# DTI Histogram and Texture Features as Early Predictors of Post-Radiotherapy Cognitive Decline
## 4 Discussion  
This study investigated radiotherapy-induced microstructural WM changes and their relationship with cognitive function using DTI histogram and texture analysis. The findings revealed significant associations between the \(\Delta\) of DTI features and cognitive performance, primarily semantic fluency. It is noteworthy that only the relationship between \(\Delta\mathrm{AD}_{\mathrm{mean}}\) and semantic fluency remained statistically significant after FDR correction for multiple comparisons, highlighting its robust and reliable association. The observed DTI changes likely reflect early, transient radiation-induced microstructural alterations in whole-brain WM rather than permanent damage. Our analysis revealed that \(\Delta\mathrm{AD}_{\mathrm{mean}}\) was predominantly negative, indicating a decrease in AD following radiotherapy. This reduction in AD aligns with acute-phase reactions to radiation, potentially reflecting transient axonal swelling from inflammatory responses, cytotoxic edema, temporary disruption of axonal transport mechanisms, and early metabolic changes--all stemming from radiation effects on neurons and glial cells [32,33]. Since imaging was performed immediately after treatment completion, these changes likely represent acute radiation reactions rather than chronic degeneration. These early alterations may resolve, persist, or evolve into more permanent changes, such as demyelination over time [34]. \(\Delta\mathrm{AD}_{\mathrm{skewness}}\) reflects alterations in the distribution pattern of AD values following radiotherapy. This suggests radiation effects on WM are not uniformly distributed, with some regions potentially showing differential vulnerability to radiation [33]. This heterogeneity in response patterns may explain why certain cognitive networks show greater functional changes despite similar radiation exposure [35]. Similarly, \(\Delta\mathrm{RD}_{\mathrm{kurtosis}}\) indicates alterations in the peakedness of the RD distribution, potentially affecting functions requiring coordination among multiple brain regions [34]. Furthermore, pathological studies on laboratory animals have provided concrete evidence of these microstructural changes occurring within hours to days post-radiotherapy. Acute responses observed in preclinical models have demonstrated early axonal swelling, microglial activation, and initial demyelination as immediate reactions to radiation exposure [32,36]. Notably, these alterations in WM integrity can begin within hours after exposure, as indicated by early-phase DTI changes in high-dose regions [37]. Different cognitive domains exhibited varying sensitivity to WM changes. Semantic fluency demonstrated the strongest associations with all three \(\Delta\mathrm{DTI}\) features (\(\Delta\mathrm{AD}_{\mathrm{mean}}\), \(\Delta\mathrm{AD}_{\mathrm{skewness}}\), \(\Delta\mathrm{RD}_{\mathrm{kurtosis}}\)), possibly because it relies on distributed neural networks and long-range WM connections [16,38]. This aligns with prior studies showing that semantic fluency tasks engage frontotemporal and interhemispheric pathways, which are particularly vulnerable to radiotherapy-related WM injury [39]. In contrast, MMSE showed limited associations, emphasizing the importance of domain-specific assessments when evaluating radiation-induced cognitive changes. Compared to \(\Delta\mathrm{AD}_{\mathrm{mean}}\), which showed robust associations across multiple cognitive domains, the weak correlation between \(\Delta\mathrm{AD}_{\mathrm{skewness}}\) and semantic fluency (r = 0.073) warrants caution. Although this association reached statistical significance in the regression model, the minimal correlation coefficient value suggests limited practical and likely clinical relevance. The findings of this study have important clinical applications. DTI histogram and texture features may serve as early biomarkers of radiation-induced cognitive vulnerability, potentially identifying high-risk patients before symptom onset [36].