Comment on “Age-inappropriate white matter injury reveals hidden cerebral small vessel disease burden and mortality risk”

Highlights

• •Age-adjusted WMH deviation may reflect cumulative vascular risk burden.
• •Incremental value beyond absolute WMH burden requires validation.
• •Mortality associations should be assessed for clinical utility.
• •Risk prediction metrics are needed to support implementation.
• •Network-level analyses may strengthen biological interpretation.
• •Vascular and neurodegenerative mechanisms require further differentiation.
• •Normative WMH grading shows promise for personalized CSVD assessment.

Dear Editor,

We read with great interest the study by Lee et al., who proposed an age- and sex-referenced normative framework for interpreting white matter hyperintensity (WMH) burden in covert cerebral small vessel disease (CSVD) [1]. By demonstrating associations between age-inappropriate WMH accumulation, cognitive dysfunction, gray matter atrophy, and mortality, the authors advance an important precision-medicine approach that seeks to contextualize lesion burden beyond chronological aging. The work is innovative and clinically relevant; however, several methodological considerations may influence the interpretation and translational applicability of the findings.

A central concern relates to the biological specificity of the proposed WMH deviation metric. The normative model was constructed using age, sex, and imaging-site effects, whereas other determinants of WMH accumulation, including hypertension, diabetes, obesity, and metabolic dysfunction, were deliberately excluded from the reference framework. Consequently, the derived deviation score may represent a composite measure of vascular risk exposure rather than a pure indicator of accelerated cerebral microvascular injury. This distinction is clinically important because individuals classified as having “age-inappropriate” WMH burden may simply reflect long-standing cardiometabolic disease trajectories [2]. Incorporating vascular-risk-adjusted normative models or comparing predictive performance between age-only and multivariable reference frameworks could clarify whether the deviation metric captures unique biological information beyond established vascular risk factors.

The interpretation of prognostic utility also warrants further scrutiny. Although the high-deviation group demonstrated a statistically significant increase in all-cause mortality, only 120 deaths occurred during follow-up, and the reported confidence interval remained relatively wide. More importantly, the study did not evaluate whether WMH deviation improves risk prediction beyond conventional measures such as absolute WMH volume, hypertension status, diabetes, or established cerebrovascular risk scores. Demonstrating independent association is not equivalent to demonstrating incremental prognostic value. Metrics such as changes in concordance statistics, net reclassification improvement, calibration performance, or decision-curve analysis would provide stronger evidence that normative grading meaningfully enhances clinical risk stratification [3]. Without such analyses, it remains uncertain whether the proposed framework offers practical advantages over simpler and more readily interpretable imaging measures.

Another issue concerns the neuroanatomical interpretation of the observed gray matter associations. The study focused on global gray matter volume and predefined hippocampal and thalamic regions, reporting significant volume reductions with increasing WMH deviation. However, CSVD is increasingly recognized as a network disorder involving distributed disruptions of structural and functional connectivity rather than isolated regional injury. Restricting analyses to selected subcortical structures may underestimate the extent of cortical vulnerability associated with disproportionate WMH accumulation. Whole-brain morphometric mapping, network-based analyses, or assessments of cortical thickness could determine whether the proposed deviation metric identifies broader neurodegenerative signatures [4]. Such information would strengthen mechanistic understanding and help distinguish whether WMH deviation primarily reflects vascular injury, neurodegeneration, or the interaction between both processes.

Despite these considerations, Lee et al. provide an important contribution by reframing WMH interpretation through individualized normative expectations rather than absolute lesion burden alone. Establishing whether WMH deviation offers incremental prognostic information, greater biological specificity, and broader network-level correlates may further enhance its role as a clinically actionable biomarker for covert CSVD and age-related brain vulnerability.

Statements and declarations

• •Declaration of funding: No funding was received for this study.
• •Ethical approval: Not required.
• •Clinical trial registration details/number: Not applicable, as this study does not report a clinical trial.
• •Research registry number: Not applicable.
• •Human ethics and consent to participate declarations: Not applicable, as no patient data were collected or analyzed in this study.
• •Declaration of generative AI and AI-assisted technologies in the writing process: During the preparation of this work the authors used Grammarly and ChatGPT in order to refine language, grammar, and style. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.
• •Data availability statement: Not applicable, as no data were generated or analyzed in this study.

CRediT authorship contribution statement

Madhuri Tribhuvan: Project administration, Supervision, Validation, Writing – original draft, Writing – review & editing. Shashikant N. Phatke: Conceptualization, Methodology, Writing – original draft, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.