This project represents a continuation of ongoing investigations that focus on the two major neurological complications of sickle cell disease: namely, stroke and chronic encephalopathy. Stroke represents a focal brain insult whereas chronic encephalopathy represents a diffuse brain disturbance involving cognition and memory. The predisposition to stroke and the potential for dementia are increasingly apparent from our studies and the work of other investigators. The ontogeny of these two processes requires further study before the mechanisms can be clearly articulated; and a coordinate assessment of cerebrovascular perfusion is needed to decipher the relationship between focal perfusion deficits and occlusion of large and small cerebral vessels. These investigative needs represent the basis for the subsequent study design and testable hypotheses. We propose to test three hypotheses: (1) clinically-silent cranial MRI abnormalities represent the minimal expression of the neurovascular diathesis, and are the harbingers of clinically-overt strokes (study A); (2) sickle cell disease patients who develop cerebral infarctions have a predisposing risk factor(s) that contributes to this neurological complication (study B); and (3) sickle cell disease patients develop a chronic encephalopathy and dementia that is independent of the neurovascular diathesis (study C). 150 subjects will be enrolled in these studies. This population will include 100 patients with SCD and 50 controls without SCD. 100 subjects (50 patients and 50 siblings or nearest relative controls) will participate in studies A, B and C; and 50 subjects (25 SCD patients - stroke victims, and 25 SCD patients - clinically free of strokes) will participate in study B. The patients and controls in studies A, B, and C will range in age from 6 to 12 years. The patients in the retrospective portion of study B will be young adults. Study A is a prospective evaluation of 50 SCD children aged 6 to 12 years attempting to identify a subgroup of patients at risk for the development of a clinically-apparent stroke. These patients will be evaluated clinically, and will undergo MRI scan, magnetic resonance angiography (MRA), and single photon emission computerized tomography (SPECT). Study B represents two studies designed to analyze risk factors for stroke. The first study is a retrospective case-control analysis of 25 young adults who suffered one or more strokes. These patients will be age-matched to an SCD control group who have been clinically free of strokes and will have MRI, MRA, and SPECT studies. The second study represents a prospective case-control analysis of children who are being followed in study A. Study C represents a prospective study of 50 SCD children, and 50 age-matched siblings or closest available relatives. Annual neurological examinations and neuropsychological evaluations will be performed searching for evidence of chronic encephalopathy and dementia. The longitudinal study design is necessary to dissect out the subtle variables that contribute to the cognitive deficits. Improved understanding of the mechanisms underlying these two devastating neurological complications of SCD should result in prevention or effective treatment.