Improved functional outcome after chronic stroke with delayed anti-Nogo-A therapy: A clinically relevant intention-to-treat analysis.

Many preclinical treatment strategies for stroke have failed when tested in human trials. Although the reasons for these translation failures are multifactorial, one potential concern is the statistical analysis of the preclinical data. One way to rigorously evaluate new therapies is to use an intention-to-treat analysis in preclinical studies. Therefore, in this study, we set out to evaluate the treatment efficacy of a potential clinically relevant therapeutic agent for stroke, i.e., anti-Nogo-A immunotherapy, using an intention-to-treat analysis. Adult rats were trained on the skilled forelimb reaching task and subsequently underwent an ischemic stroke. Nine weeks later, the rats either received intracerebroventricular anti-Nogo-A antibody, control antibody, or no treatment. Skilled reaching performance was assessed by a non-linear model using both an intention-to-treat and per-protocol analysis. Following testing, dendritic complexity was evaluated in the contralesional and perilesional sensorimotor cortex. Both intention-to-treat and per-protocol analysis showed that anti-Nogo-A immunotherapy resulted in statistically significant improved recovery on the skilled forelimb reaching task, although treatment effect was less (though statistically significant) in the intention-to-treat group. Improved functional performance was not shown to be associated with dendritic changes. In conclusion, this study provides evidence for the importance of using intention-to-treat paradigms in testing preclinical therapeutic strategies.

Factors Influencing the Management of Unruptured Intracranial Aneurysms.

Background Deciding how to manage an unruptured intracranial aneurysm can be difficult for patients and physicians due to controversies about management. The decision as to when and how to intervene may be variable depending on physicians' interpretation of available data regarding natural history and morbidity and mortality of interventions. Another significant factor in the decision process is the patients' conception of the risks of rupture and interventions and the psychological burden of harboring an unruptured intracranial aneurysm. Objective  To describe which factors are being considered when patients and their physicians decide how to manage unruptured intracranial aneurysms.  Materials & methods  In a retrospective chart review study, we identified patients seen for evaluation of an unruptured intracranial aneurysm. Data was collected regarding patient and aneurysm characteristics. The physician note pertaining to the management decision was reviewed for documented reasons for intervention. Results  Of 88 patients included, 36 (41%) decided to undergo open or endovascular surgery for at least one unruptured intracranial aneurysm. Multiple aneurysms were present in 14 (16%) patients. Younger patients and current smokers were more likely to undergo surgery, but gender and race did not affect management. Aneurysm size and location strongly influenced management. The most common documented reasons underlying the decision of whether to intervene were the risk of rupture, aneurysm size, and risks of the procedure. For 23 aneurysms (21%), there were no factors documented for the management decision.  Conclusion  The risk of rupture of unruptured intracranial aneurysms may be underestimated by currently available natural history data. Major factors weighed by physicians in management decisions include aneurysm size and location, the patient's age, and medical comorbidities along with the risk of procedural complications. Additional data is needed to define specific aneurysm characteristics and patient factors that influence rupture, in particular in small aneurysms. Physicians should carefully document their rationale along with the patient's perspective given the controversial nature of these management decisions.

Cerebral perfusion and oxygenation differences in Alzheimer's disease risk.

Functional MRI has demonstrated differences in response to memory performance based on risk for Alzheimer's disease (AD). The current study compared blood oxygen level dependent (BOLD) functional MRI response with arterial spin labeling (ASL) perfusion response during an associative encoding task and resting perfusion signal in different risk groups for AD. Thirteen individuals with a positive family history of AD and at least one copy of the apolipoprotien E epsilon4 (APOE4) gene (high risk) were compared to ten individuals without these risk factors (low risk). In the medial temporal lobes (MTLs) the high risk group had an elevated level of resting perfusion, and demonstrated decreased fractional BOLD and perfusion responses to the encoding task. However, there was no difference in the absolute cerebral blood flow during the task. These data demonstrate that individuals with increased risk for Alzheimer's disease have elevated MTL resting cerebral blood flow, which significantly influences apparent differences in BOLD activations. BOLD activations should be interpreted with caution, and do not necessarily reflect differences in neuronal activation.