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Background
Cognitive decline and dementia are major causes of morbidity and mortality worldwide and are substantially burdensome to the affected persons, their caregivers, and society in general. Despite extensive research over the past 20 years, there remain important and formidable challenges to conducting research, particularly into the area of prevention. A recent National Institutes of Health Consensus Development Conference concluded that large-scale population-based studies and randomised controlled trials are critically needed to investigate strategies to maintain cognitive function in individuals at risk or those experiencing cognitive decline. The Aspirin in Reducing Events in the Elderly (ASPREE) Study is one such large scale trial and this manuscript describes a neurovascular imaging sub-study (ENVIS-ion) that will explore the possible mechanisms through which aspirin may act to influence cognitive function.
Rationale for the ENVIS-ion Study
A decline in cognitive abilities is commonly held to be an inevitable consequence of aging with greater degrees of decline suggesting the superimposition of progressive neuropathology. Even in healthy older adults, a small but definite age-related decrease in performance on executive function, verbal fluency, verbal memory, and cognitive speed tasks is evident, but the mechanisms leading to decline are not completely understood. Similarly, reports of the effects of preventive interventions on the trajectories of changes of brain structure and cognitive performance with aging and early dementia are scarce. Nonetheless, it is clear that in adults over 70 years of age with declining cognitive performance, up to 15% per year will cross the threshold for the diagnosis of clinical dementia.
Ischaemia of brain white matter may cause cognitive decline in its own right, but it is also present in the majority of those with Alzheimer's (AD). Vascular risk factors have emerged as important contributors to the development of AD and to sub-clinical brain infarcts/ischaemia. This is the most common pathology found in community-based studies of older adults with cognitive decline. Therefore, vascular disease is an attractive target for primary preventive therapy.
The question of whether low-dose aspirin might be protective against cognitive decline, presumably via an effect on platelet aggregation, remains unanswered. Several community-based, prospective studies and a cross-sectional study have suggested an association of aspirin treatment with preservation of either episodic memory or global cognitive performance. Further studies have contradicted these results and found that long-term use of aspirin does not provide benefits for cognition among generally healthy women aged 65 years or over and may even increase the risk of development of AD.
However a number of studies have demonstrated the effective use of aspirin in the prevention of other conditions such as stroke, coronary heart disease events and diabetes. Aspirin has been shown to reduce the risk of serious vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death) by about one quarter, in high-risk patients.
Magnetic Resonance Imaging (MRI)
Brain MRI changes correlate with white matter ischaemia/infarction and MRI is commonly used to investigate the underlying mechanisms and predictors of dementia and cognitive decline. MRI can assess brain structure changes using volumetric tissue measurements, or intensity-based lesion identification to quantify structural changes such as hyper-intense white matter lesions (WMH) or infarcts. The association of greater WMH volume with poorer cognitive performance remains a focus of ongoing research. While some studies have found that WMH presence and volume rather than location determines the presence of executive dysfunction in those who are non-demented, others have specifically related periventricular WMH to such cognitive dysfunction. Silent brain infarcts (SBI) are frequently seen on MRI in healthy older adults and are associated with dementia incidence and cognitive decline as well as subsequent clinical stroke. The Rotterdam Stroke Study found that the presence of SBIs at baseline more than doubled the risk of dementia. In addition, the presence of SBIs at baseline was associated with poorer initial cognitive performance and a steeper decline in global cognition. Also, the incidence of SBI increased markedly with age and a prevalent SBI at baseline strongly predicted a new silent infarct on the second MRI. The authors concluded that the cardiovascular risk factors for SBI are similar to those for stroke.
The preventive effects of aspirin on MRI-detected SBI and WMH have previously been investigated. A study by Sato et al. found that in patients with non-valvular atrial fibrillation (NVAF), and perhaps also those in sinus rhythm, aspirin may reduce SBIs. Fujita et al. also reported a significant reduction in progression of WMH over 4 years with aspirin treatment for those with corrected platelet hyper-aggregability in a study of older, treated patients compared with age- and WMH-matched controls
Retinal Vascular Imaging
While brain MRI can potentially provide an efficient surrogate for cognitive decline and dementia, it is costly and not widely accessible, making it impracticable for population screening. Retinal vessels share many features with the cerebral vasculature. Hence, should changes in the two be highly correlated, retinal digital photography through non-dilated pupils would provide the opportunity to combine a relatively inexpensive, rapid, widely available tool with automated analysis to assess cerebrovascular pathology and inform selection of those likely to benefit most from further investigation and preventive therapies.
It is well known that clinically detectable changes in retinal blood vessels (retinal arteriolar narrowing, arteriovenous nicking, microaneurysms, retinal hemorrhages and cotton wool exudates) are markers of the effects of chronic hypertension and other vascular processes. Because the retinal circulation can be viewed non-invasively, it offers a unique insight into the cerebral microcirculation in vivo and may allow a greater understanding of cerebrovascular pathophysiology. Retinal and cerebral arteriolar histopathologies are highly correlated in those who have died of stroke, while retinal microvascular flow is reduced in persons with WMH and SBI on MRI.
Large population-based studies have shown that retinal vascular changes are associated with subclinical and clinical cerebrovascular disease, including cognitive impairment. Other studies have demonstrated that changes in RVI parameters have been associated with poorer cognitive performance in people with diabetes. In the Atherosclerosis Risk in Communities (ARIC) study, RVI changes on photomicrography were associated not only with incident stroke, but also with subclinical changes in MRI-defined parameters, including cerebral infarction, WMH (both sulcal and periventricular) and atrophy. Furthermore, the ARIC study demonstrated that in patients without a previous stroke, retinal vascular changes were associated with poorer cognitive function independent of traditional risk factors. However this study was unable to correlate changes in cognition with RVI changes over time. Similar studies have also examined the relationship between RVI changes and WMH volume. Retinal arterial pathology, especially retinal arterial sclerosis and narrowing, has also been shown to correlate with MRI signs of cerebral small-vessel disease in both hypertensive and normotensive subjects. In summary, there are few studies that have examined the effect of aspirin on MRI-detected SBI and WMH and RVI parameters and their relationship to cognition. Importantly, RVI may be a relatively inexpensive, more widely available imaging tool that could be used to screen and predict the onset and progression of subclinical cerebrovascular disease.
The ENVIS-ion trial
The ENVIS-ion trial is designed to determine whether;
a) low-dose aspirin reduces the development of WMH and SBI as assessed by MRI,
b) a reduction in changes in RVI parameters is observed with low-dose aspirin therapy,
c) changes in RVI parameters parallel changes in brain MRI,
d) baseline cognitive function correlates with baseline MRI and RVI parameters,
e) changes in cognitive function correlate with changes in brain MRI and RVI, and
f) factors such as age, gender, education or blood pressure influence the above associations.
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