Genetic animal models of cerebral vasculopathies.
ABSTRACT Cerebral amyloid angiopathy (CAA) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are genetic cerebrovasculopathies associated with neurodegeneration and vascular cognitive impairment. Linked to autosomal dominant mutations in diverse genes that encode cell-surface receptors (i.e., amyloid precursor protein in CAA and NOTCH3 in CADASIL), both diseases are associated with accumulation of abnormal material around cerebral vessels, such as amyloid in CAA or granular osmiophilic material in CADASIL. Both CAA and CADASIL share clinical features of white matter degeneration and infarcts, and vascular dementia in the human adult; microbleeds occur in both CADASIL and CAA, but large intracerebral hemorrhages are more characteristic for the latter. While the mechanisms are poorly understood, wall thickening, luminal narrowing, and eventual loss of vascular smooth muscle cells are overlapping pathologies involving leptomeningeal, and pial or penetrating small arteries and arterioles in CAA and CADASIL. Dysregulation of cerebral blood flow and eventual hypoperfusion are believed to be the key pathophysiological steps in neurodegeneration and cognitive impairment. Although animal models expressing CAA or CADASIL mutations have partially reproduced the human pathology, there has been marked heterogeneity in the phenotypic spectrum, possibly due to genetic background differences among mouse models, and obvious species differences between mouse and man. Here, we provide an overview of animal models of CAA and CADASIL and the insight on molecular and physiological mechanisms of disease gained from these models.
Article: Translating basic science research to clinical application: models and strategies for intracerebral hemorrhage.[show abstract] [hide abstract]
ABSTRACT: Preclinical stroke models provide insights into mechanisms of cellular injury and potential therapeutic targets. Renewed efforts to standardize preclinical practices and adopt more rigorous approaches reflect the assumption that a better class of compounds will translate into clinical efficacy. While the need for novel therapeutics is clear, it is also critical that diagnostics be improved to allow for more rapid treatment upon hospital admission. Advances in imaging techniques have aided in the diagnosis of stroke, yet current limitations and expenses demonstrate the need for new and complementary approaches. Intracerebral hemorrhage (ICH) exhibits the highest mortality rate, displays unique pathology and requires specialized treatment strategies relative to other forms of stroke. The aggressive nature and severe consequences of ICH underscore the need for novel therapeutic approaches as well as accurate and expeditious diagnostic tools. The use of experimental models will continue to aid in addressing these important issues as the field attempts to translate basic science findings into the clinical setting. Several preclinical models of ICH have been developed and are widely used to recapitulate human pathology. Because each model has limitations, the burden lies with the investigator to clearly define the question being asked and select the model system that is most relevant to that question. It may also be necessary to optimize and refine pre-existing paradigms, or generate new paradigms, as the future success of translational research is dependent upon the ability to mimic human sequelae and assess clinically relevant outcome measures as means to evaluate therapeutic efficacy.Frontiers in neurology. 01/2012; 3:85.