Frank’s Sign as a Dose-Dependent Marker of White Matter Burden in CADASIL: A Brain MRI Study

TL;DR

A diagonal earlobe crease, known as Frank’s sign, is linked to higher brain white matter damage in a genetic brain disease called CADASIL.

Contribution

This study introduces Frank’s sign as a dose-dependent biomarker for white matter burden in CADASIL using automated MRI-based detection.

Findings

Frank’s sign was more common in CADASIL patients than controls and correlated with greater white matter hyperintensity (WMH) volume.

Frank’s sign prevalence increased with higher WMH tertiles, showing a dose-response relationship.

CADASIL patients with Frank’s sign had lower cognitive scores but similar lacunes and microbleeds.

Abstract

Background/Objectives: Frank’s sign, a diagonal earlobe crease, may reflect systemic microvascular dysfunction. We investigated whether Frank’s sign serves as a clinical marker of white matter hyperintensity (WMH) burden in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a monogenic model of pure cerebral small vessel disease. Methods: We analyzed 81 genetically confirmed CADASIL patients (61.8 ± 12.6 years, 40.7% female) and 54 age/sex-matched controls (70.3 ± 6.6 years, 48.1% female). Frank’s sign was detected using deep learning from brain MRI-reconstructed 3D facial surfaces. WMH volumes were automatically quantified and adjusted for confounders using Random Forest regression residuals. We compared Frank’s sign prevalence between groups, assessed within-CADASIL associations, and evaluated dose–response relationships across WMH tertiles. Results: Frank’s sign prevalence was significantly higher in CADASIL versus controls (66.7% vs. 42.6%, p = 0.020), with strengthened association after multivariate adjustment (OR = 4.214, 95% CI: 1.128–15.733, p = 0.032). Within CADASIL, Frank’s sign-positive patients showed 72% greater WMH burden (51.5 ± 27.1 vs. 30.0 ± 26.1 mL, p < 0.001) and lower Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) total scores (57.7 ± 19.6 vs. 71.2 ± 22.8, p = 0.006), but similar lacunes, microbleeds, and hippocampal volumes. A robust dose–response relationship emerged across WMH tertiles, with Frank’s sign prevalence increasing from 37.0% (lowest) to 74.1% (highest tertile; adjusted OR = 3.571, 95% CI: 1.134–11.253, p = 0.030). Conclusions: Frank’s sign represents an accessible biomarker of WMH burden in CADASIL, demonstrating disease-specificity and dose–response characteristics independent of vascular risk factors. The automated MRI-based detection method of Frank’s sign enables retrospective analysis of existing neuroimaging databases, transforming a bedside observation into a quantifiable neuroimaging biomarker for genetic small vessel disease stratification.

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