Stroke Recovery Genetics.

Clinical outcomes after stroke are highly variable, and reasons for these variations are often unexplained. Recovery after ischemic or hemorrhagic stroke begins immediately after acute onset, and many different levels of biological responses are involved. These responses differ in time and between different areas of the affected brain. Recovery after a cerebrovascular event may, therefore, vary from being rapid, without detectable remaining neurological deficits, to prolonged improvement, if any, over months or years. Outcome prediction is consequently difficult and unreliable and often depends on factors with unclear and limited impact. Factors specific to pathophysiological subtypes of stroke add to the complexity of prediction. Stroke genetics research has shown that genome-wide association (GWA) results for stroke risk differ by subtype (for review on stroke genetics, see Lindgren). The same might be true for stroke recovery because lesion locations vary between stroke subtypes, and different recovery mechanisms may depend on whether cortical/subcortical structures and gray or white cerebral matter are affected. Further indication for differences in outcome between stroke subtypes is that ischemic stroke patients classified as having a cardioembolic mechanism have greater incidence of mortality and disability, whereas for large vessel disease strokes, the risk of new events within 30 days is high, >18%. However, it is also likely that some recovery pathways, for example, involved in cerebral ischemia are shared between stroke subtypes. In addition, biological factors, prevention of recurrent stroke, treatment of concomitant conditions, as well as social supports and amount of poststroke rehabilitation therapies are all relevant during recovery. But predictive models based on clinical factors remain limited by imprecision and difficulty with translation to the individual case. This may improve when mechanisms such as brain plasticity and brain stunning and factors that influence these concepts become better defined. Genetic factors also influence many different aspects of brain function and repair, as well as recurrent stroke risk and response to pharmacological interventions, and can, thereby, account for hitherto unexplained variation in stroke recovery. The majority of studies reviewed here used a candidate gene association design and investigated numerous gene variants’ associations with outcomes of mortality, further vascular event, poststroke depression, functional ability, or rehabilitation treatment (Table 1). We categorized 3 different clinical types of stroke outcomes in line with the International Classification of Function and Disability (ICF; Table 1) and also considered outcomes investigated by animal models and different surrogate/intermediate markers, such as biochemical and neuroimaging. The 3 ICF categories in this context are (1) neurological/physical deficit; (2) functional ability; and (3) social participation and illustrate different clinical aspects of stroke recovery. Notably, careful attention to timing is also essential in assessment of recovery because biological mechanisms are activated or deactivated at different time points (Table 2).