# DTI Histogram and Texture Features as Early Predictors of Post-Radiotherapy Cognitive Decline
## 4 Discussion
The differential sensitivity of cognitive domains suggests that targeted assessments focusing on semantic fluency and list learning may better detect early radiation effects than global measures like MMSE [16]. This is corroborated by findings that adding a brief semantic fluency test dramatically improves mild cognitive impairment detection over MMSE alone [40]. Understanding regional damage patterns could inform treatment planning strategies aimed at preserving critical cognitive networks. This study presents several advances in understanding radiation-induced WM injury. First, it characterizes the immediate post-treatment microstructural alterations, revealing predominantly negative \(\Delta\)AD\({}_{\text{mean}}\), which suggests an acute-phase response different from later-stage changes. Second, the histogram and texture analysis approach demonstrates that damage distribution patterns--not merely extent--largely impact cognitive outcomes. Third, this study identifies semantic fluency as particularly sensitive to early WM changes, potentially serving as a valuable early indicator of radiation-induced cognitive vulnerability. Finally, the \(\Delta\) feature approach isolates treatment-specific effects by controlling for individual baseline differences. Pathological studies on laboratory animals further contextualize our findings. Animal models have demonstrated microstructural WM changes beginning within days to weeks post-radiotherapy, with early axonal swelling and initial myelin alterations [41]. These models reveal both acute changes and potential progression over time, with our observations of increased \(\Delta\)AD\({}_{\text{mean}}\) potentially capturing early axonal responses to radiation [42]. Histological analyses confirmed the differential vulnerability of brain regions to radiation, with oligodendrocyte precursor cells critical for myelin maintenance and repair showing particular sensitivity [43], consistent with the observation of increased \(\Delta\)AD\({}_{\text{skewness}}\). Their early disruption may contribute to the heterogeneous injury patterns detected in our DTI analysis. Additionally, acute inflammatory responses and microglial activation occur soon after radiation exposure, potentially explaining the early microstructural changes, likely explaining early microstructural changes, and suggesting mechanisms for longer-term effects beyond our study timeframe [44]. Human longitudinal studies also provide an important context for interpreting our early post-treatment findings. These suggest that WM changes observed immediately after radiotherapy may represent the initial phase of a dynamic process that evolves over time [45]. Research examining DTI changes at multiple time points--from 6 months to 5 years post-radiotherapy--indicates that frontal and temporal regions often show continued microstructural alterations, particularly in high-dose areas [46; 47]. There is compelling evidence of reversible changes in some patients, especially during the early-delayed phase (1-6 months post-treatment), when physiological adaptations can occur without permanent structural damage [48; 49; 50]. The eventual outcome appears influenced by multiple factors, including radiation parameters (dose, volume, fractionation), patient characteristics (age, vascular risk factors), and concurrent treatments. Our findings capture an early snapshot in this continuum--a critical window where both recovery and progression remain possible pathways. This temporal perspective emphasizes the potential of early DTI markers in identifying individuals who are vulnerable to long-term neurocognitive effects. Additionally, these markers can help guide timely interventions that may lead to better outcomes and improved quality of life for patients undergoing radiotherapy. Several limitations should be considered. First, our relatively small sample size limited statistical power, which may explain the modest number of significant associations observed.