Sex and gender differences in cognitive resilience to aging and Alzheimer's disease.

Sex and gender-biological and social constructs-significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex- and gender-specific drivers of resilience, including a sex/gender-oriented review of risk factors, genetics, AD and non-AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender-aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender-specific resilience throughout disease stages. HIGHLIGHTS: Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex-specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex-specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular.

Clozapine induces astrocyte-dependent FDG-PET hypometabolism.

PURPOSE: Advances in functional imaging allowed us to visualize brain glucose metabolism in vivo and non-invasively with [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) imaging. In the past decades, FDG-PET has been instrumental in the understanding of brain function in health and disease. The source of the FDG-PET signal has been attributed to neuronal uptake, with hypometabolism being considered as a direct index of neuronal dysfunction or death. However, other brain cells are also metabolically active, including astrocytes. Based on the astrocyte-neuron lactate shuttle hypothesis, the activation of the glutamate transporter 1 (GLT-1) acts as a trigger for glucose uptake by astrocytes. With this in mind, we investigated glucose utilization changes after pharmacologically downregulating GLT-1 with clozapine (CLO), an anti-psychotic drug. METHODS: Adult male Wistar rats (control, n = 14; CLO, n = 12) received CLO (25/35 mg kg-1) for 6 weeks. CLO effects were evaluated in vivo with FDG-PET and cortical tissue was used to evaluate glutamate uptake and GLT-1 and GLAST levels. CLO treatment effects were also assessed in cortical astrocyte cultures (glucose and glutamate uptake, GLT-1 and GLAST levels) and in cortical neuronal cultures (glucose uptake). RESULTS: CLO markedly reduced in vivo brain glucose metabolism in several brain areas, especially in the cortex. Ex vivo analyses demonstrated decreased cortical glutamate transport along with GLT-1 mRNA and protein downregulation. In astrocyte cultures, CLO decreased GLT-1 density as well as glutamate and glucose uptake. By contrast, in cortical neuronal cultures, CLO did not affect glucose uptake. CONCLUSION: This work provides in vivo demonstration that GLT-1 downregulation induces astrocyte-dependent cortical FDG-PET hypometabolism-mimicking the hypometabolic signature seen in people developing dementia-and adds further evidence that astrocytes are key contributors of the FDG-PET signal.

Comparison Between Brain and Cerebellar Autoradiography Using [18F]Flortaucipir, [18F]MK6240, and [18F]PI2620 in Postmortem Human Brain Tissue.

Our objective was to evaluate the in vitro binding properties of [18F]flortaucipir, 6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([18F]MK6240), and 2-(2-([18F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5c']dipyridine ([18F]PI2620) head-to-head in postmortem human brain tissue. Methods: Autoradiography was used to assess uptake of [18F]flortaucipir, [18F]MK6240, and [18F]PI2620 in control and Alzheimer disease (AD) autopsy-confirmed brain tissues. The study focused on the analysis of the prefrontal cortex, hippocampus, and cerebellum sections in 12 controls and 12 AD cases, as well as whole-brain hemisphere in 1 control and 1 AD sample, for each radiotracer. The binding values of [18F]flortaucipir, [18F]MK6240, and [18F]PI2620 were calculated from regions of interest manually drawn in the prefrontal, hippocampal, and cerebellar cortices. Results: For all 3 radioligands investigated, we observed significant tracer binding differences between control and AD tissues in the whole-brain hemisphere, prefrontal cortex, and hippocampus but not in the cerebellar cortex. [18F]MK6240 and [18F]PI2620 had higher effect sizes to differentiate control and AD cases than did [18F]flortaucipir. Bland-Altman analyses revealed strong correlations between [18F]MK6240, [18F]PI2620, and [18F]flortaucipir, with the highest agreement found for [18F]MK6240 versus [18F]PI2620. Conclusion: The 3 radioligands showed comparable diagnostic properties to assess tau aggregates in vitro. Binding to AD brain tissues was higher for [18F]MK6240 and [18F]PI2620 than for [18F]flortaucipir. Additionally, [18F]MK6240 and [18F]PI2620 had greater selectivity, displaying decreased uptake in control brain tissue compared with [18F]flortaucipir. These results might provide insights on ongoing initiatives to create a universal scale for tau imaging studies.