Cerebral small vessel disease (SVD) is characterized by changes in the pial and parenchymal microcirculations. SVD produces reductions in cerebral blood flow and impaired blood-brain barrier function, which are leading contributors to age-related reductions in brain health. End-organ effects are diverse, resulting in both cognitive and noncognitive deficits. Underlying phenotypes and mechanisms are multifactorial, with no specific treatments at this time. Despite consequences that are already considerable, the impact of SVD is predicted to increase substantially with the growing aging population. In the face of this health challenge, the basic biology, pathogenesis, and determinants of SVD are poorly defined. This review summarizes recent progress and concepts in this area, highlighting key findings and some major unanswered questions. We focus on phenotypes and mechanisms that underlie microvascular aging, the greatest risk factor for cerebrovascular disease and its subsequent effects.

The cellular lipidome is comprised of thousands of unique lipid species. This complexity underpins the many roles of lipids in cellular biology. How lipidome composition varies between cell types and how such differences contribute to cell-specific functionality is poorly understood. Here, using mass spectrometry-based targeted lipidomics, we have characterised the cellular lipid landscape of the human and mouse immune systems (www.cellularlipidatlas.com). We find that myeloid and lymphoid cell lineages have unique lipid compositions, notably in the usage of ester and ether bonds within glycerophospholipids (PLs) and PL acyl chain composition. To determine if immune cell-specific lipid phenotypes promote cell-specific functional properties we focused on differences in poly-unsaturated fatty acid (PUFA)-containing PL, the levels of which are markedly higher in lymphoid cells relative to myeloid cells. We firstly show that differences in PUFA-PL content provides a mechanistic basis for previously described differences in immune cell susceptibility to ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, and secondly, that the low PUFA-PL content of neutrophils restrains NADPH oxidase-driven ferroptosis. In summary, we show that the lipid landscape is a defining feature of immune cell identity and that cell-specific lipid phenotypes underpin aspects of immune cell physiology.

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Obesity is a major global health concern, with prevalence rates rapidly rising due to increased availability of highly processed foods rich in fats and/or sugars and technological advances promoting more sedentary behaviour. There is increasing evidence to suggest that obesity predisposes individuals to developing cognitive impairment and dementia. However, the relationship between the brain and the peripheral metabolic state is complex, and many of the underlying mechanisms of cognitive impairment in obesity are yet to be fully elucidated. To better understand the links between obesity and dementia, further work is required to determine pathological changes occurring in the brain during obesity. In this mini-review, we discuss the role of two pathological features of obesity (the gut-brain axis and systemic inflammation) and their potential contribution to dementia.