Does Atrial Septal Anatomy Still Matter in the Etiological Evaluation of Ischemic Stroke Beyond the Age of 60?

BACKGROUND: Patent foramen ovale (PFO) is causally associated with stroke in some patients younger than 60 years, especially when it is large or associated with an atrial septal aneurysm (ASA). After 60 years of age, this association is less well understood. We assessed the relationships between detailed atrial septal anatomy and the cryptogenic nature of stroke in this population. METHODS AND RESULTS: We reviewed all patients aged 60 to 80 years admitted to our stroke center for ischemic stroke who underwent contrast echocardiography between 2016 and 2021. The atherosclerosis, small-vessel disease, cardiac pathology, other causes, and dissection (ASCOD) classification was used to reevaluate the etiological workup. Associations between cryptogenic stroke and (1) PFO presence or (2) categories of PFO anatomy (nonlarge PFO without ASA, nonlarge PFO with ASA, large PFO without ASA, and large PFO with ASA) were assessed using logistic regression. Among 533 patients (median National Institutes of Health Stroke Scale score=1), PFO was present in 152 (prevalence, 28.5% [95% CI, 24.9-32.5]). Compared with noncryptogenic stroke, cryptogenic stroke (n=218) was associated with PFO presence (44.5% versus 17.5%; P<0.0001). Among patients with a PFO, septal anatomy categories were associated with cryptogenic stroke (P=0.02), with a strong association for patients with both large PFO and ASA (38.1% versus 14.5%, P=0.002). CONCLUSIONS: PFO presence remains strongly associated with cryptogenic stroke between 60 and 80 years of age. Large PFO, ASA, and their association were strongly associated with cryptogenic stroke in this age group. Our results support performing contrast echocardiography even after 60 years of age, although the optimal secondary prevention therapy in this population remains to be determined in randomized trials.

The immunoglobulin-like superfamily member IGSF3 is a developmentally regulated protein that controls neuronal morphogenesis.

The establishment of a functional brain depends on the fine regulation and coordination of many processes, including neurogenesis, differentiation, dendritogenesis, axonogenesis, and synaptogenesis. Proteins of the immunoglobulin-like superfamily (IGSF) are major regulators during this sequence of events. Different members of this class of proteins play nonoverlapping functions at specific developmental time-points, as shown in particular by studies of the cerebellum. We have identified a member of the little studied EWI subfamily of IGSF, the protein IGSF3, as a membrane protein expressed in a neuron specific- and time-dependent manner during brain development. In the cerebellum, it is transiently found in membranes of differentiating granule cells, and is particularly concentrated at axon terminals. There it co-localizes with other IGSF proteins with well-known functions in cerebellar development: TAG-1 and L1. Functional analysis shows that IGSF3 controls the differentiation of granule cells, more precisely axonal growth and branching. Biochemical experiments demonstrate that, in the developing brain, IGSF3 is in a complex with the tetraspanin TSPAN7, a membrane protein mutated in several forms of X-linked intellectual disabilities. In cerebellar granule cells, TSPAN7 promotes axonal branching and the size of TSPAN7 clusters is increased by downregulation of IGSF3. Thus IGSF3 is a novel regulator of neuronal morphogenesis that might function through interactions with multiple partners including the tetraspanin TSPAN7. This developmentally regulated protein might thus be at the center of a new signaling pathway controlling brain development. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 75-92, 2017.