Convergent observations of MK-801-induced impairment in rat 5C-CPT performance across laboratories: reversal with a D1 but not nicotinic agonist.

INTRODUCTION: Cognitive function is closely linked to functional outcomes in psychiatric disorders such as schizophrenia, however developing effective treatments for cognitive dysfunction have proven elusive. Potential reasons for this may include the complexity of diseases, the absence of appropriate and translatable animal tests of cognitive dysfunction, and the reproducibility of findings. Attention is a key component of cognitive function traditionally assessed in the clinic using a variant of the continuous performance test (CPT). The 5-choice (5C)-CPT was developed as a translational cross-species version of this task. Given the association between glutamatergic abnormalities and cognitive dysfunction in schizophrenia, we hypothesized that the NMDA receptor antagonist MK-801 would impair 5C-CPT in rats across different laboratories, and determined whether the dopamine D1 receptor agonist SKF38393 or the nonspecific nicotinic agonist nicotine would remediate such deficits. METHOD: Rats were trained in the 5C-CPT at Beacon Discovery and UCSD. These rats were then treated with MK-801, agonist treatment, and combinations of the two. RESULTS: MK-801 produced 5C-CPT deficits in the same domains of rats across sites at similar doses. Neither nicotine nor SKF38393 treatment alone improved performance. Importantly, SKF38393, but not nicotine, remediated the MK-801-induced deficits. CONCLUSION: Convergent observation of MK-801-induced deficits in 5C-CPT was seen across laboratories, resulting in deficits consistent with those seen in people with schizophrenia. Treatment with SKF38393 but not nicotine reversed these deficits. More work is needed, but the 5C-CPT is a reliable method for detecting NMDA receptor disruption-induced deficits in attention.

Radiomics-based assessment of ultra-widefield leakage patterns and vessel network architecture in the PERMEATE study: insights into treatment durability.

AIM: To evaluate the potential of radiomics-based ultra-widefield fluorescein angiography (UWFA)-derived imaging biomarkers in retinal vascular disease for predicting therapeutic durability of intravitreal aflibercept injection (IAI). METHODS: The Peripheral and Macular Retinal Vascular Perfusion and Leakage Dynamics in Diabetic Macular Edema and Retinal Venous Occlusions During Intravitreal Aflibercept Injection (IAI) Treatment for Retinal Edema (PERMEATE) study prospectively evaluated quantitative UWFA dynamics in diabetic macular oedema or macular oedema secondary to retinal vascular occlusion. 27 treatment-naïve eyes were treated with 2 mg IAI q4 weeks for the first 6 months, and then administered q8 weeks. Morphological and graph-based attributes were used to model the spatial distribution of leakage areas, while tortuosity measures were used to model the vessel network disorder. Eyes were grouped based on functional tolerance of the first 8-week treatment interval challenge. 'Non-rebounders' (N=15) maintained/improved best-corrected visual acuity (BCVA) following the 8-week challenge. 'Rebounders' (N=12) exhibited worsened BVCA. The image biomarkers were used with a machine learning classifier to preliminarily evaluate their ability to predict BCVA stability. RESULTS: Two new UWFA image-derived biomarkers were identified and extracted. The cross-validated area under the receiver operating characteristic curve (AUC) was 0.77±0.14 using baseline leakage distribution features and 0.73±0.10 for the UWFA baseline tortuosity measures. Additionally, the change in vascular tortuosity between month 4 and baseline yielded an AUC of 0.73±0.08. Three baseline clinical features of letter score, macular volume and central subfield thickness yielded a corresponding AUC of 0.42±0.09. CONCLUSIONS: Two computer-extracted UWFA radiomics-based descriptors were identified as potential biomarkers for predicting treatment durability and tolerance of longer treatment intervals. Conventional treatment parameters were not significantly different between these same groups.