Evidence for control of cerebral neurovascular function by circulating platelets in healthy older adults

Platelets play a vital role in preventing haemorrhage through haemostasis, but complications arise when platelets become overly reactive, leading to pathophysiology such as atherothrombosis. Elevated haemostatic markers are linked to dementia and predict its onset in long-term studies. Despite epidemiological evidence, the mechanism linking haemostasis with early brain pathophysiology remains unclear. Here, we aimed to determine whether a mechanistic association exists between platelet function and cerebral neurovascular function in 52 healthy mid- to older-age adults. To do this, we combined, for the first time, magnetic resonance imaging of cerebral neurovascular function, peripheral vascular physiology and in vitro platelet assaying. We show an association between platelet reactivity and cerebral neurovascular function that is both independent of vascular reactivity and mechanistically specific: Distinct platelet signalling mechanisms (ADP, collagen-related peptide, thrombin receptor activator peptide 6) were associated with different physiological components of the haemodynamic response to neuronal (visual) stimulation (full-width half-maximum, time to peak, area under the curve), an association that was not mediated by peripheral vascular effects. This finding challenges the previous belief that systemic vascular health determines the vascular component of cerebral neurovascular function, highlighting a specific link between circulating platelets and the neurovascular unit. Because altered cerebral neurovascular function marks the initial stages of neurodegenerative pathophysiology, understanding this novel association is now imperative, with the potential to lead to a significant advancement in our comprehension of early dementia pathophysiology. KEY POINTS: Haemostasis (platelet function) has been linked to the early stages of dementia, but the precise mechanisms are not well understood. This study considers whether a causal mechanism exists through atherothrombotic effects on the vasculature which can in turn affect brain health, or through platelet-specific interactions with brain physiology. Here, we show that elevated platelet reactivity is associated with blunted (delayed, shorter and smaller) cerebral blood flow responses to neuronal activation in healthy middle-aged and older adults. However, the association between platelet reactivity and cerebral neurovascular function was not mediated by systemic vascular reactivity. This finding challenges the previous belief that systemic vascular health determines the vascular component of cerebral neurovascular function, highlighting a specific link between circulating platelets and the neurovascular unit in early dementia pathophysiology.