—The possibility of reopening an occluded cerebral artery by means of thrombolysis has renewed interest in a number of the several mechanisms that are active during acute cerebral ischemia. Over recent years, it has become apparent that leukocytes play a central role not only during the healing stage of brain infarction but also during the early phases of cerebral ischemia, when it is postulated that these cells produce harmful effects, particularly in the presence of reperfusion. This review is based on the critical analysis of more than 150 publications dealing with the role of leukocytes and some inflammatory mediators (cytokines, chemokines, and adhesion molecules) in cerebral ischemia. Animal studies indicate that leukocyte involvement is promoted by a variety of inflammatory molecules produced immediately after the onset of cerebral ischemia. Considerable experimental evidence suggests that these mediators play a key role in the progression from ischemia to irreversible injury (ie, cellular death and necrosis). However, the precise role of each molecule alone remains to be further elucidated as well as in relation to the complex network existing among different mediators. Progress in our understanding of the inflammatory mechanisms operating in cerebral ischemia has enabled the testing of new compounds with promising results in animals; in contrast, one recent controlled trial of an anti-leukocyte molecule in acute stroke patients showed negative results. This discrepancy may derive in part from our incomplete understanding of the complexity of the inflammatory mechanisms involved in cerebral ischemia. Our analysis suggests that until sufficient knowledge of the underlying disease mechanisms is acquired, more care should be taken when testing new and potentially efficacious drugs in stroke patients.

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.

Background and Purpose— A full appreciation of the presence of cerebral vascular lesions in cognitively impaired patients can be ultimately reached at the neuropathological level. However, there are no detailed guidelines regarding what neuropathologists should look for at autopsy in cases of suspected vascular dementia or vascular cognitive impairment. We aimed at surveying the postmortem neuropathological procedures used in different centers in examining brain lesions of presumable or possible vascular origin in cognitively impaired patients. Methods— Thirteen laboratories participated in the survey by filling in a semistructured questionnaire. We reviewed sampling and histology procedures in use and the neuropathological definitions of some of these lesions. Neuropathological criteria for the definition of a vascular origin of the dementing process were also surveyed. Results— A large variability across centers was observed in the procedures used for the neuropathological examination and the histology techniques. Heterogeneity existed also in the definition of commonly found lesions (eg, white matter alterations, small vessel disease), interpretation of whether or not the lesions were reputed to be of vascular origin, and consequently in the interpretation of the cause of cognitive decline. Conclusions— The appreciation of the presence of neuropathologically verified vascular lesions in cognitively impaired cases may be heavily influenced by the laboratory tools used and also by the heterogeneity of the criteria applied in different centers. Harmonization of neuropathological procedures is badly needed in the field of vascular dementia and vascular cognitive impairment to better understand the association between various vascular lesions and clinical symptoms such as cognitive impairment.