Knockdown of PHOX2B in the retrotrapezoid nucleus reduces the central CO2 chemoreflex in rats.

PHOX2B is a transcription factor essential for the development of different classes of neurons in the central and peripheral nervous system. Heterozygous mutations in the PHOX2B coding region are responsible for the occurrence of Congenital Central Hypoventilation Syndrome (CCHS), a rare neurological disorder characterised by inadequate chemosensitivity and life-threatening sleep-related hypoventilation. Animal studies suggest that chemoreflex defects are caused in part by the improper development or function of PHOX2B expressing neurons in the retrotrapezoid nucleus (RTN), a central hub for CO2 chemosensitivity. Although the function of PHOX2B in rodents during development is well established, its role in the adult respiratory network remains unknown. In this study, we investigated whether reduction in PHOX2B expression in chemosensitive neuromedin-B (NMB) expressing neurons in the RTN altered respiratory function. Four weeks following local RTN injection of a lentiviral vector expressing the short hairpin RNA (shRNA) targeting Phox2b mRNA, a reduction of PHOX2B expression was observed in Nmb neurons compared to both naive rats and rats injected with the non-target shRNA. PHOX2B knockdown did not affect breathing in room air or under hypoxia, but ventilation was significantly impaired during hypercapnia. PHOX2B knockdown did not alter Nmb expression but it was associated with reduced expression of both Task2 and Gpr4, two CO2/pH sensors in the RTN. We conclude that PHOX2B in the adult brain has an important role in CO2 chemoreception and reduced PHOX2B expression in CCHS beyond the developmental period may contribute to the impaired central chemoreflex function.

Reperfusion therapies for ischemic stroke in dementia and cognitive impairment: A systematic review and meta-analysis.

BACKGROUND: Endovascular thrombectomy (EVT) and intravenous thrombolysis (IVT) have an unclear benefit in those with pre-stroke dementia or cognitive impairment, as these patients were often excluded from landmark stroke trials. We performed a systematic review and meta-analysis to assess the outcomes of IVT and EVT in these populations. AIMS: Our systematic review, conforming to the Meta-Analysis of Observational Studies in Epidemiology guidelines, investigated studies on acute ischemic stroke patients with pre-stroke dementia or cognitive impairment treated with IVT or EVT. Primary outcome was favorable 90-day outcome (mRS 0-2). Secondary outcomes included 90-day mortality, symptomatic intracranial hemorrhage (SICH), and radiographic intracranial hemorrhage (ICH). SUMMARY OF REVIEW: Nine articles were identified, with five observational studies of IVT use in patients with (n = 1078) and without dementia (n = 2805) being selected for the meta-analysis. There were no significant differences in favorable outcome (adjusted OR: 0.61, 95% CI 0.24-1.59), mortality (unadjusted OR: 1.19, 95% CI 0.86-1.64), ICH (unadjusted OR: 1.32, 95% CI 0.79-2.19), and symptomatic ICH (unadjusted OR: 0.94, 95% CI 0.70-1.25) for patients undergoing IVT with pre-stroke dementia versus those without. One EVT study (n = 615 with dementia vs n = 9600 without) found no significant differences in outcomes apart from an increased odds of ICH for those with pre-existing dementia (adjusted OR: 1.57, 95% CI 1.03-2.40). A pooled analysis of three IVT studies showed no significant association of cognitive impairment (n = 93 vs n = 211 without) with all assessed outcomes, whereas a study of EVT found that pre-stroke cognitive impairment was associated with poor 90-day outcomes (mRS 3-6). CONCLUSION: These results suggest no substantial safety issues in the use of IVT or EVT for patients with pre-existing dementia or cognitive impairment compared to those without. However, the efficacy of these therapies in this demographic remains uncertain. Further rigorous studies that include a more nuanced outcome measurement approach are warranted. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42021240499.

Iatrogenic Strokes and Covert Brain Infarcts After Percutaneous Cardiac Procedures: An Update.

Millions of cardiac procedures are performed worldwide each year, making the potential complication of periprocedural iatrogenic stroke an important concern. These strokes can occur intraoperatively or within 30 days of a procedure and can be categorised as either overt or covert, occurring without obvious acute neurologic symptoms. Understanding the prevalence, risk factors, and strategies for preventing overt and covert strokes associated with cardiac procedures is imperative for reducing periprocedural morbidity and mortality. In this narrative review, we focus on the impacts of perioperative ischemic strokes for several of the most common interventional cardiac procedures, their relevance from a neurologic standpoint, and future directions for the care and research on perioperative strokes. Depending on the percutaneous procedure, the rates of periprocedural overt strokes can range from as little as 0.01% to as high as 2.9%. Meanwhile, covert brain infarctions (CBIs) occur much more frequently, with rates for different procedures ranging from 10%-84%. Risk factors include previous stroke, atherosclerotic disease, carotid stenosis, female sex, and African race, as well as other patient- and procedure-level factors. While the impact of covert brain infarctions is still a developing field, overt strokes for cardiac procedures lead to longer stays in hospital and increased costs. Potential preventative measures include screening and vascular risk factor control, premedicating, and procedural considerations such as the use of cerebral embolic protection devices. In addition, emerging treatments from the neurologic field, including neuroprotective drugs and remote ischemic conditioning, present promising avenues for preventing these strokes and merit investigation in cardiac procedures.