Defining patient-reported outcomes and priorities for clinical trials in CADASIL through an international survey

Background: A major challenge faced by clinical trials for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the heterogeneity of symptoms and variable progression pace, while treatments should attenuate symptoms that bother patients most. To this end, we set to describe the symptomatic landscape for CADASIL with the ultimate goal of developing Patient Reported Outcomes (PRO) for clinical trials. Methods: A survey was compiled through iterative consensus meetings between patients, family members, CADASIL clinicians, and patient advocacy group members (cureCADASIL). The final questionnaire included demographic information, subjective symptom severity ratings, medication use and lifestyle factors. Data were collected over a period of 16 months from 11/2023 to 3/2025 and analyzed through descriptive and quantitative methods. Results: We collected 226 responses from 25 countries. The average age of responders was 52 (SD 12) years, and 158 (69.9 %) identified as women. Out of all symptoms, fatigue was reported as the most frequent (86.3 %), and most bothersome (14.2 %). Symptom severity differed across age groups only for headaches, with younger participants reporting higher scores (Kruskal–Wallis χ² = 8.64, p = 0.03). All symptoms were intercorrelated, with strongest clustering among congruent categories such as slowed thinking, cognitive fog, and memory complaints (Spearman’s ρ ≥ 0.70, adjusted p < 0.001). Medication use was widespread: 156 participants (69 %) reported prescription medications, 116 (51.3 %) over-the-counter drugs, and 128 (56.6 %) supplements. Conclusions: By identifying symptom domains most salient to patients, our study provides a foundation for the development of PRO tools in CADASIL.