Objective: It is unknown if impaired cerebral vasoreactivity recovers after ischemic stroke, and whether it compromises perfusion in regions surrounding infarct and other vascular territories. We investigated the regional differences in CO2 vasoreactivity (CO2VR) and their relationships to peri-infarct T2 hyperintensities (PIHs), chronic infarct volumes, and clinical outcomes. Methods: We studied 39 subjects with chronic large middle cerebral artery territory infarcts and 48 matched controls. Anatomic and three-dimensional continuous arterial spin labeling imaging at 3-Tesla MRI were used to measure regional cerebral blood flow (CBF) and CO2VR during normocapnia, hypercapnia, and hypocapnia in main arteries distributions. Results: Stroke patients showed a significantly lower augmentation of blood flow at increased CO2 but greater reduction of blood flow with decreased CO2 than the control group. This altered vasoregulatory response was observed both ipsilateral and contralateral to the stroke. Lower CO2VR on the stroke side was associated with PIHs, greater infarct volume, and worse outcomes. The cases with PIHs (n = 27) had lower CBF during all conditions bilaterally (p < 0.0001) compared to cases with infarct only. Conclusions: Perfusion augmentation is inadequate in multiple vascular territories in patients with large artery ischemic infarcts, but vasoconstriction is preserved. Peri-infarct T2 hyperintensities are associated with lower blood flow. Strategies aimed to preserve vasoreactivity after an ischemic stroke should be tested for their effect on long-term outcomes.
"Intranasal drug administration is an effective method that has shown promise for delivering drugs directly to the brain. This approach is associated with many challenges, and efficacy in bypassing blood-brain barrier (BBB) is debated. This review describes the pathways of nose-to-brain drug delivery, physicochemical drug properties that influence drug uptake through the nasal epithelium, physiological barriers, methods to enhance nose-to-brain absorption, drug bioavailability and biodistribution, and intranasal devices for nose-to-brain drug delivery. The mechanism of each device is described and supporting evidence from clinical trials is presented. This paper summarizes strategies involved in nose-to-brain drug delivery and provides evidence of potential efficacy of nose-braindelivery from clinical trials."
Balance impairment is common following cerebral infarction. However, the effects of lesion hemisphere on postural control are largely unknown. We examined dependence upon vision and noninfarcted regional brain tissue volumes for postural control in individuals with right and left hemisphere middle cerebral artery (MCA) infarcts.Subjects with right MCA infarct (n = 17, age = 65 +/- 8 years, 7 +/- 6 years poststroke), left MCA infarct (n = 20, age = 65 +/- 8 years, 7 +/- 6 years poststroke), and controls (n = 55, age = 65 +/- 8 years) were studied. Postural control was defined by average velocity and the range and variability of mediolateral (ML) and anteroposterior (AP) sway during eyes-open and eyes-closed standing. Regional brain volumes were quantified using anatomic MRI at 3 Tesla.Right and left hemisphere stroke groups had similar infarct volumes and outcomes. Subjects with right hemisphere infarcts demonstrated greater sway velocity, ML range, and ML variability with eyes closed compared to eyes open. In this group, smaller occipital lobe volumes were associated with greater eyes-open sway velocity (R = -0.64, p = 0.012) and ML range (R = -0.82, p = 0.001). Smaller cerebellar volumes were associated with greater eyes-closed sway velocity (R = -0.60, p = 0.015), ML range (R = -0.70, p = 0.007), and ML variability (R = -0.85, p < 0.001). These associations were not observed in left hemisphere infarct subjects or controls. AP sway was unaffected by infarct hemisphere or visual condition and did not correlate with regional brain volumes.Right hemisphere middle cerebral artery infarcts are associated with increased dependence on vision and noninfarcted brain regions (i.e., occipital lobes, cerebellum) to control postural sway. Strategies emphasizing postural tasks under reduced visual conditions may enhance functional recovery in these individuals.
Acute ischemic stroke (AIS) is a leading cause of death and long-term disability in the USA and worldwide. Significant advances in the last two decades have resulted in the introduction of intravenous tissue plasminogen activator and more recently catheter based endovascular interventions in selected patients (Berkhemer et al., 2015; Goyal et al., 2015). These interventions are applicable to a limited number of patients fulfilling specific criteria; therefore neuroprotection has attracted significant attention. Neuroprotection refers to strategies and interventions aiming to limit the extent of AIS-related injury and facilitate the naturally occurring regenerative mechanisms. Acute ischemic injury triggers a series of events in a cellular and molecular level, resulting in energy failure and ultimately neuronal death: Inflammation, excitotoxicity, apoptosis, reactive oxygen and nitrogen species formation, mitochondrial failure have been implicated in the ischemic cascade (Lioutas et al., 2015). In contrast to many other neuroprotective agents used in past clinical trials targeting specific single steps along the process, insulin's effects are pleiotropic: It suppresses pro-inflammatory transcription factors and might limit the detrimental effect of the inflammatory response (Garg et al., 2006). It produces an antithrombotic effect by decreasing the tissue factor and plasminogen activator inhibitor-1 levels and a vasodilatory effect by promoting activation of endothelial nitric oxide synthase; both actions could facilitate recruitment of collateral vessels and enhance the effect of thrombolysis, ultimately reducing the final infarct volume and improving long-term functional outcome (Huang et al., 2014). Insulin also favorably regulates cerebral energy homeostasis. In addition to the acute phase, insulin's effects extend to the subacute and chronic phase, exerting a potent antiapoptotic effect and promoting myelin and neurite regeneration, neurotransmission and functional connectivity of the brain (Duarte et al., 2012). The putative neuroprotective mechanisms of insulin in the ischemic cascade are summarized in Figure 1.Figure 1: Mechanisms implicated in the ischemic cascade and potential targets for insulin in response to acute ischemia. "Stop" signs indicate the steps of the ischemic cascade where insulin can intervene to limit the extent of ischemic damage.Image reprinted with permission from Springer, License No. 3670991012466, issued July 16, 2015.The intranasal route presents significant advantages: The absorption occurs mostly through paracellular transport and endocytosis, following the course of olfactory and trigeminal neurons that are present in the nasal cavity. This offers the significant advantage of bypassing the blood-brain barrier and achieving rapid, widespread central nervous system (CNS) penetration (detected in the CNS within 1 hour from administration). In animal experiments intranasal administration resulted in 100-fold higher CNS concentration compared to intravenous administration of equal insulin dose (Thorne et al., 2004). Although there is a predilection for higher concentrations in areas related to the trigeminal and olfactory pathways and there is a rostral-caudal transmission vector, there is evidence of more diffuse spread in various cerebral regions (Lochhead and Thorne, 2012). Intranasal insulin has been used in healthy adult human subjects, diabetics and non-diabetics, patients with mild cognitive impairment (MCI) and Alzheimer's disease, focusing on safety, feasibility tolerability, neurologic and cognitive improvement. Intranasal insulin administration resulted in significant improvement in visuospatial memory, immediate and delayed recall, attention and verbal learning acutely and in the chronic phase, without any concerning side effects (Craft et al., 2012). In addition to clinical performance metrics, functional MRI and PET scan studies provided robust evidence suggesting improved vasoreactivity and cerebral perfusion in the gray and white matter, improved connectivity, slowing of cerebral hypometabolism. It is important to highlight that the effects were not limited to diabetics or MCI/Alzheimer's disease patients only, healthy adults benefitted in a similar way, indicating an overall positive effect of intranasal administered insulin in the cerebral function (Reger et al., 2008). Intranasal administration of insulin has significant practical advantages: It is simple, fast, feasible, painless, uncomplicated and well-tolerated by patients. Therefore, it would not interfere with the rest of time-sensitive interventions during acute stroke, such as IV thrombolysis. If approved for treatment in acute stroke its simplicity will allow for rapid administration in the emergency department or even by the paramedical staff. The major safety concern would be the risk of hypoglycemia, which can be detrimental to human brain. However, this has not shown to be a problem in several human studies involving healthy and diabetic adults (Craft et al., 2012), as intranasal administration results in minimal systemic absorption and first-pass metabolism of insulin. Insulin actions on the CNS in fact favor energy homeostasis, as already described. Neuroprotection has attracted significant interest and numerous agents have been tested in large scale human trials. Despite robust theoretical background and promising in vivo (animal) experimental data, none of these trials resulted in unequivocal success and there is no neuroprotectant approved for use in acute stroke. N-methyl-D-aspartate (NMDA) receptor antagonists, free radical scavengers, cellular membrane stabilizers, monoclonal antibodies all had neutral or, at times negative effects (Lioutas et al., 2015). The reasons for the series of translational failures have concerned academic trialists and the pharmaceutical industry likewise and resulted in a series of recommendations on how to optimize the process of developing an agent with neuroprotective properties and minimizing premature advancement to futile, resource-demanding trials (Albers et al., 2011). Specific qualities that a neuroprotective agent should ideally possess include: • A pleiotropic mechanism of action. It has been felt that the failure of many of the above mentioned agents to provide a functional benefit was at least in part due to their very specific target. However, the ischemic cascade includes a series of different events and it is unlikely that blocking on step along the process would significantly limit the damage. In a conceptual level, hypothermia is considered an ideal paradigm of a plurifunctional agent, although it should be noted that its benefit in cerebral ischemia has not been proven. Insulin's actions in the CNS indeed are not limited to a singular mechanism; in the contrary it has an overarching effect, blocking multiple detrimental processes in the acute and subacute phase and augmenting neuroplasticity mechanisms. • Rapid, preferably pre-hospital, administration. Recent large scale acute stroke trials have showed that "in the field" treatment is feasible for the appropriate agents. Intranasal insulin delivery is very simple, straightforward and easily applicable without the need for sophisticated equipment or special personnel training. Some if insulin's properties, namely its vasodilatory and antithrombotic effect might prove particularly beneficial in penumbral salvage and extending the time window upon which reperfusion therapies will prove beneficial. Moreover, its safety profile across several age groups, underlying neurologic and other comorbid conditions is reassuring, not necessitating narrow screening or specific pre-administration laboratory or imaging testing. This will need to be confirmed in a stroke population. • Selective cerebral delivery. Intranasal administration has the benefit of bypassing the blood brain barrier and enter the CNS rapidly and achieving significantly higher (up to 100-fold in animals) CNS concentrations compared to intravenous administration. Besides the significant practical and theoretical advantages, there are areas of uncertainty that merit clarification before advancing to a large scale trial: Additional data from animal stroke models, following randomized, blinded, high-quality experiments. Current information on animal stroke models is limited and the available data, although encouraging could be enhanced by replication from independent groups, improved blinding and randomization of animals, and ideally replication in different animal species. Additionally, in the case that the pre-hospital administration is investigated in a clinical trial setting, this should be preceded by demonstration of safety in hemorrhagic animal models: Ischemic and hemorrhagic stroke are essentially clinically indistinguishable without ancillary imaging testing (CT brain scan) which is not readily available in the prehospital setting, with rare, remarkable exceptions of studies that are in a pilot phase and are unlikely to become a widespread standard of care. Therefore if pre-hospital administration is to be considered, the safety in intracerebral hemorrhage should be very robustly demonstrated. The optimal timing and duration of treatment following acute stroke have not been clarified at the moment. Although there is an acute effect, more prolonged administration has yielded robustly positive results in subjects with cognitive impairment (Craft et al., 2012) and insulin's antiapoptotic and neurotrophic effect makes it biologically plausible that it might be beneficial in the subacute and early chronic phase of ischemic stroke during which neuroplasticity mechanisms are crucial. This raises the question whether intranasal insulin administration should not be limited to the acute phase. Proper dosing is also not clearly defined for stroke yet. Animal studies suggest a dose-dependent beneficial effect (Liu et al., 2001) and human data do not raise safety concerns with higher doses. Both of these critical questions could be assessed with early Phase 1 or 2a duration and dose-response studies in acute stroke subjects that. In summary, intranasally administered insulin possesses many of the ideal properties for acute stroke neuroprotection, due to its plurifunctional mechanism of action, wide applicability, safety and simplicity of CNS distribution. Well-designed animal and phase I human studies are necessary to improve our understanding of its neuroprotective potential in acute stroke. Dr VN has received grants from the NIH-National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (5R21-DK-084463-02 and 1R01 DK103902-01A1) and National Institute on Aging (NIA) (1R01-AG-0287601-A2) and National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK103902-01A1) related to this study, and VN received salaries from these grants. The authors wish to thank Katharina Dormanns, Ph.D. candidate Brains Trust Research Group, BlueFern Supercomputing Unit (University of Canterbury, NZ), for her contribution in the design of the figure presented in the paper.
Introduction: Glycemic variability (GV) has been associated with worse prognosis in critically ill patients. We sought to evaluate the potential association between GV indices and clinical outcomes in acute stroke patients. Methods: Consecutive diabetic and nondiabetic, acute ischemic or hemorrhagic stroke patients underwent regular, standard-of-care finger-prick measurements and continuous glucose monitoring (CGM) for up to 96 h. Thirteen GV indices were obtained from CGM data. Clinical outcomes during hospitalization and follow-up period (90 days) were recorded. Hypoglycemic episodes disclosed by CGM but missed by finger-prick measurements were also documented. Results: A total of 62 acute stroke patients [48 ischemic and 14 hemorrhagic, median NIHSS score: 9 (IQR: 3–16) points, mean age: 65 ± 10 years, women: 47%, nondiabetic: 79%] were enrolled. GV expressed by higher mean absolute glucose (MAG) values was associated with a lower likelihood of neurological improvement during hospitalization before and after adjusting for potential confounders (OR: 0.135, 95% CI: 0.024–0.751, p = 0.022). There was no association of GV indices with 3-month clinical outcomes. During CGM recording, 32 hypoglycemic episodes were detected in 17 nondiabetic patients. None of these episodes were identified by the periodic blood glucose measurements and therefore they were not treated. Conclusions: Greater GV of acute stroke patients may be related to lower odds of neurological improvement during hospitalization. No association was disclosed between GV indices and 3-month clinical outcomes.
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