Postoperative cognitive dysfunction (POCD) has been reported with widely varying frequency but appears to be strongly associated with aging. Outside of the surgical arena, chronic and acute cerebral hypoxia may exist as a result of respiratory, cardiovascular, or anemic conditions. Hypoxia has been extensively implicated in cognitive impairment. Furthermore, disease states associated with hypoxia both accompany and progress with aging. Perioperative cerebral hypoxia is likely underdiagnosed, and its contribution to POCD is underappreciated. Herein, we discuss the various disease processes and forms in which hypoxia may contribute to POCD. Furthermore, we outline hypoxia-related mechanisms, such as hypoxia-inducible factor activation, cerebral ischemia, cerebrovascular reserve, excitotoxicity, and neuroinflammation, which may contribute to cognitive impairment and how these mechanisms interact with aging. Finally, we discuss opportunities to prevent and manage POCD related to hypoxia.

Women show disproportionate burden of Alzheimer’s disease (AD) pathology and higher AD dementia prevalences compared to men, yet the mechanisms driving these vulnerabilities are unknown. There is sexual dimorphism in immunologic functioning, and neuroimmune processes are implicated in AD genesis. Using neuropathology indicators from human brain tissue, we examined the mediational role of microglial activation on the relationship between amyloid and tau and how it differs by sex. 187 decedents (64% female; 89 mean age at death; 62% non-demented) from the Rush Memory and Aging Project completed neuropathological evaluations with brain tissue quantified for microglial activation, amyloid-β, and tau. Proportion of morphologically activated microglia was determined via immunohistochemistry (HLA-DP-DQ-DR) and morphological staging (stage I, II, or III). Amyloid-β and tau burden were quantified via immunohistochemistry (M00872 or AT8, respectively). Using causal counterfactual modeling, we estimated the mediational effect of microglial activation on the amyloid-β to tau relationship in the whole sample and stratified by sex (amyloid-β → microglial activation→ tau). Alternative models tested the role of microglia activation as the precipitating event (microglial activation→ amyloid-β → tau). Microglial activation significantly mediated 33% (95%CI 10-67) of the relationship between amyloid-β and tau in the whole sample; stratified analyses suggested this effect was stronger and only statistically significant in women. 57% (95%CI 22-100) of the effect of amyloid-β on tau was mediated through microglial activation in women, compared to 19% (95%CI 0-64) in men. Regional analyses suggested that mediational effects were driven by greater cortical versus subcortical microglial activation. Relationships were independent of cerebrovascular disease indices. Alternative models suggested that in women, microglial activation was a significant exposure both preceding the amyloid-β to tau relationship (mediational effect: 50%, 95%CI 23-90) and directly related to tau burden (microglia direct effect: 50%, 95%CI 10-77). In contrast, in men, only the direct effect of microglial activation to tau reached significance (74%, 95%CI 32-100) (mediational effect: 26%, 95%CI 0-68). Our models suggest a reciprocal, bidirectional relationship between amyloid-β and microglial activation that significantly accounts for tau burden in women. In contrast, in men, direct independent (non-mediational) relationships between microglial activation or amyloid-β with tau were observed. Microglial activation may be disproportionately important for AD pathogenesis in women. Determining sex-specific vulnerabilities to AD development both inform fundamental pathophysiology and support precision health approaches for this heterogeneous disease.

Objective: This review describes the relatively small body of neuropsychological and cognitive research conducted over the past 100 years focused on theoretical models explaining the neurocognitive processes that support everyday functioning and the breakdown of functional abilities in the face of neurological damage or disease. Method: The historical roots of the theories of everyday activities based on direct observation of behavior in neurology and diary reports of everyday errors in cognitive psychology are presented, followed by a review of the empirical findings and resulting theoretical conceptualizations from case studies and group studies of various clinical populations in neuropsychology. Results: We conclude with a new framework (the goal-control model) that integrates the most recent empirical findings in neuropsychology with mechanisms proposed by cognitive models. Conclusions: The goal-control model offers empirically supported solutions to understanding and predicting functioning in the real world. This new model generates testable predictions for future research and provides guidance for clinical assessment and interventions.

Virtual Reality Cognitive Function Assessment feasible approach for function assessment even with older adults who might have very limited computer experience, no prior VR exposure, average educational experiences, and mild cognitive difficulties. Because of inherent limitations of single case reports (e.g., unknown generalizability, potential practice effects, etc.), group studies are needed to establish the full psychometric properties of the Virtual Reality Action Test.

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