Abstract Body: Background: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common genetic cerebral small vessel disease and is caused by mutations in the NOTCH3 gene. Although characterized by progressive neurologic decline, NOTCH3 mutant protein accumulates in the vascular media of small arteries throughout the body, suggesting a widespread systemic arteriopathy with documented extracerebral involvement in ocular, dermatologic, psychiatric, and cardiovascular systems. This broader disease involvement is associated with functional decline affecting cognitive, motor, emotional, and behavioral outcomes with significant implications for quality of life (QOL).
Hypothesis: We assessed the hypothesis that a large comprehensive CADASIL literature search and database, and its systematic analysis, would reveal significant research gaps in the representation of patient demographics and QOL measures.
Methods: We conducted a systematic literature review spanning 45 years (1980–2025) across PubMed, CINAHL, EBSCO, Embase, and ClinicalTrials.gov that yielded 520 unique records. CADA-PRO (CADASIL Patient-Reported Outcome) is a relatively new validated instrument for measuring four outcomes related to QOL: cognitive, motor, emotional, and behavioral. We retrospectively applied a checklist to map association of the CADA-PRO outcomes impacting QOL.
Results: Analysis of our database found 298 records in-scope for this study. CADASIL was reported worldwide and the literature focused predominantly on middle-aged adults, Figure 1 and Figure 2. Overall, 840 associations to CADA-PRO outcomes were mapped. The emotional QOL outcome was less frequently associated than behavioral, cognitive or motor (p<0.001), Figure 3. The most frequently observed number of CADA-PRO outcomes mapped was 3 per article (113/298, 38%) and mix of outcomes was behavioral|cognitive|motor (87/298, 29%).
Conclusions: CADASIL is a progressive cerebrovascular disease with global reach and meaningful impact on QOL. Despite the lifelong nature of CADASIL, our analysis reveals a paucity of literature on pediatric, adolescent, and young adult populations. These research gaps need further investigation to better characterize functional disease burden. In conclusion, future studies should incorporate QOL assessment, develop patient-centered endpoints, and expand research to younger patients.