The altered aggregation of proteins in non-native conformation is associated 
with endoplasmic reticulum derangements, mitochondrial dysfunction and excessive 
production of reactive oxygen species. Cerebral autosomal dominant arteriopathy 
with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary 
systemic vasculopathy, caused by NOTCH3 mutations within the receptor 
extracellular domain, that lead to abnormal accumulation of the mutated protein 
in the vascular wall. NOTCH3 misfolding could cause free radicals increase also 
in CADASIL. Aim of the study was to verify whether CADASIL patients have 
increased oxidative stress compared to unrelated healthy controls. We enrolled 
15 CADASIL patients and 16 gender- and age-matched healthy controls with 
comparable cardiovascular risk factor. Blood and plasma reduced and total 
aminothiols (homocysteine, cysteine, glutathione, cysteinylglycine) were 
measured by HPLC and plasma 3-nitrotyrosine by ELISA. Only plasma reduced 
cysteine (Pr-Cys) and blood reduced glutathione (Br-GSH) concentrations differed 
between groups: in CADASIL patients Br-GSH levels were higher (p = 0.019) and 
Pr-Cys lower (p = 0.010) than in controls. No correlation was found between 
Br-GSH and Pr-Cys either in CADASIL patients (rho 0.25, P = 0.36) or in controls 
(rho -0.15, P = 0.44). Conversely, 3-nitrotyrosine values were similar in 
CADASIL and healthy subjects (p = 0.82). The high levels of antioxidant 
molecules and low levels of oxidant mediators found in our CADASIL population 
might either be expression of an effective protective action against free 
radical formation at an early stage of clinical symptoms or they could suggest 
that oxidative stress is not directly involved in the pathogenesis of CADASIL.