The term cerebral small vessel disease (SVD) refers to a group of pathologic processes with various etiologies that affect small arteries, arterioles, venules, and capillaries of the brain. Magnetic resonance imaging (MRI) correlates of SVD are lacunes, recent small subcortical infarcts, white-matter hyperintensities, enlarged perivascular spaces, microbleeds, and brain atrophy. Endothelial dysfunction is thought to have a role in the mechanisms leading to SVD-related brain changes, and the study of endothelial dysfunction has been proposed as an important step for a better comprehension of cerebral SVD. Among available methods to assess endothelial function in vivo, measurement of molecules of endothelial origin in peripheral blood is currently receiving selective attention. These molecules include products of endothelial cells that change when the endothelium is activated, as well as molecules that reflect endothelial damage and repair. This review examines the main molecular factors involved in both endothelial function and dysfunction, and the evidence linking endothelial dysfunction with cerebral SVD, and gives an overview of clinical studies that have investigated the possible association between endothelial circulating biomarkers and SVD-related brain changes.

Background and Purpose—: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) phenotype is highly variable, and, although the full clinical–neuroimaging picture may be suggestive of the disease, no characteristic is pathognomonic. Thus, a genetic test remains the diagnostic gold standard, but because it is costly and time-consuming, a pregenetic screening appears desirable. We aimed at developing the CADASIL scale, a screening tool to be applied in the clinical setting. Methods—: A preliminary scale was created assigning weighted scores to common disease features based on their frequencies obtained in a pooled analysis of selected international CADASIL series. The accuracy of the scale versus the genetic diagnosis was tested with receiver operating characteristic analysis after the application of this scale to 61 CADASIL and 54 NOTCH3 -negative patients (no pathogenic mutation on exons 2–23 of the NOTCH3 gene). To improve the scale accuracy, we then developed an ad hoc optimization algorithm to detect the definitive scale. A third group of 39 patients affected by sporadic small-vessel disease was finally included in the algorithm to evaluate the stability of the scale. Results—: The cutoff score of the definitive CADASIL scale had a sensitivity of 96.7% and a specificity of 74.2%. This scale was robust to contamination of patients with sporadic small-vessel disease. Conclusions—: The CADASIL scale is a simple and sufficiently accurate screening tool to select patients with a high probability to be affected by the disease and therefore to be subjected to the genetic testing.

Objective: To report the characteristics of patients suspected to have cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) but in whom no NOTCH3 gene pathogenic mutation was found. Methods: Between 2002 and 2008, we performed NOTCH3 gene analysis (exons 2–23) in 81 probands because CADASIL was clinically suspected. A retrospective analysis and comparison of clinical, familial, and neuroimaging features of patients with and without pathogenic mutations was performed. Results: CADASIL was diagnosed in 16/81 (20%) probands by finding a mutation leading to a cysteine substitution within the epidermal growth factor (EGF)–like repeats of the NOTCH3 receptor. In the remaining 65 patients, no pathogenic mutation was found. Some features were significantly (Fisher exact test p < 0.05) more frequent in CADASIL than in NOTCH3-negative patients: history of migraine (73 vs 39%), stroke before the age of 60 among relatives (71 vs 32%), severe leukoencephalopathy (94 vs 62%), white matter changes extended to the anterior temporal lobes (93 vs 45%), external capsule involvement (100 vs 50%), and presence of lacunar infarcts (100 vs 65%). The frequency of vascular risk factors was balanced between the 2 groups. No feature was peculiar to either group. Conclusions: Although certain clinical and neuroimaging features are more frequent in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) than in NOTCH3-negative patients, none is pathognomonic. Clinicians should be aware that when diagnosing CADASIL, a number of patients with a cerebral disease phenotypically similar to CADASIL emerge. The genetic profile of these diseases and the full phenotypic difference with CADASIL remain to be further defined.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease, clinically characterized by a variable combination of migraine, recurrent transient ischemic attack (TIA) or lacunar strokes, cognitive decline, and mood disturbances. However, the assessment of psychiatric disturbances in this disease has never been carried out systematically. This paper presents a brief review of the literature regarding the occurrence of psychiatric disorders in CADASIL patients. The prevalence of psychiatric disorders in CADASIL patients is reported to range from 20% to 41%. The psychiatric disturbances reported with the highest frequency are mood disturbances (9-41%). Pooling together the studies and considering a total of 454 CADASIL patients reported in the literature, 106 of these were affected by mood disturbances (24%). The majority of studies however did not use any defined criteria to assess the presence of psychiatric disorders and diagnoses were mainly based on history or review of clinical records. The review of CADASIL literature suggests the need for a more structured approach to the investigation of these disturbances that are highly prevalent and may greatly impact quality of life in these patients.