We here demonstrate that changes in blood pressure profile and cardiovascular response to cardiac stress might precede the appearance of cognitive decline. In this retrospective analysis of the CST performed on 7224 patients with no cognitive complaints, we found that 186 individuals had developed cognitive impairment, including MCI, dementia or subjective cognitive decline cognitive after a follow-up period of 6 years. Interestingly, these groups of patients differed in basal blood pressure and, after exercise, significant differences were also found in maximal HR and increases in both systolic and diastolic blood pressure (p<0.05). Patients who developed cognitive impairment had lower systolic, diastolic and mean blood pressure at rest than the control group (p<0.05), and these differences are not explained by anti-hypertensive drugs or the presence of vascular risk factors, as patients and controls were matched for vascular risk factors, including antihypertensive drug use and presence of hypertension itself.
At peak exercise, patients who subsequently developed cognitive dysfunction also had a lower basal blood pressure and after exercise there were no differences in maximum systolic or diastolic blood pressure. A greater increase in HR and in systolic and diastolic blood pressure were observed, indicating that the baroreflex is intact in this group. Hence, the cardiovascular response to exercise is characterized by a greater increase in systolic and diastolic blood pressure from basal values and a larger increase in maximum HR. That is, we found that differences in cardiovascular profile are already present years before the diagnosis of dementia is established.
It is widely accepted that cerebral hypoperfusion leads to functional oligoaemia, hypoxia, oxidative stress, a decrease in ATP synthesis, synaptic dysfunction, and neuroinflammation. All these events cause disruption of the blood-brain barrier and provoke biochemical changes such as pericyte damage, microvascular degeneration, increased deposition of basement membrane proteins and perivascular amyloid, accumulation of thrombin and fibrin and secretion of multiple neurotoxic and inflammatory factors such as interleukin 1-6, tumour necrosis factor-alpha, and hypoxia-inducible factor 1, resulting in beta-amyloid deposits27. Interestingly, all these changes have also been reported in damaged myocardium28. The damage provoked by vascular changes may cause microangiopathy, macroangiopathy, cerebral hypoperfusion and consequently cognitive deficits including promoting or accelerating neurodegeneration27. This hypothesis is supported by single photon emission computed tomography and magnetic resonance imaging studies that have shown changes in brain perfusion in the amygdala, insular cortex, anterior cingulated cortex and hippocampus29.
We here hypothesize that the blood pressure profile may be a risk factor itself for neurodegeneration. In this work, we investigated whether cardiovascular changes are present before the appearance of cognitive impairment, seeking to identify potentially modifiable risk factors and explain how cardiovascular response to exercise affect cognitive performance. Changes in cardiovascular function are linked to age, vascular rigidity, smoking and other vascular risk factors but also to a secondary response to other risk factors such as hypertension. As a matter of fact, high blood pressure is a risk factor for cognitive impairment in midlife, whereas it becomes protective in late life, when low diastolic pressure is associated with cognitive impairment, due to brain hypoperfusion. Our results are consistent with previous reports that patients with cognitive impairment have lower systolic and diastolic blood pressure than controls before they develop clinical cognitive symptoms10,18 and the decline in blood pressure takes place around 3 years before the dementia is clinically evident18. Low blood pressure may reflect insufficient sympathetic response, due to the damage of the peripheral sympathetic nervous system, which mainly controls blood flow and arterial pressure, whereas the sympathetic cardiac innervation, involved in the control of the HR, is unaffected. In line with this hypothesis, orthostatic intolerance and hypotension have been also linked to dementia, through reductions in cerebral blood flow30, cerebral hypoperfusion10 and higher levels of white matter hyperintensities on neuroimaging. The underlying mechanism in this scenario is related to orthostatic intolerance and hypotension, without a compensatory increase in HR16, causing reductions in cerebral blood flow.
Impaired cerebral autoregulation in ageing contributes to this phenomenon, characterized by hypotension in late life8 that may be present in patients with cognitive dysfunction. Blood pressure changes and lack of cerebrovascular and cardiovascular regulation lead to brain hypoperfusion and hypoxia resulting in brain damage, manifested clinically as cognitive decline. Therefore, chronic cerebral hypoperfusion and small vessel disease may contribute to cognitive impairment31, and some of these changes may be present years earlier, and not necessarily associated with autonomic dysfunction.
We observed lower BP, at least, a few years before cognitive decline, but with preserved capacity of the heart to increase the HR (intact baroreflex) during exercise. This is an interesting point, as compared with other neurodegenerative disorders such as Parkinson Disease (PD), we describe that there is still a compensatory response with the ability to increase the frequency, while in PD there is chronotropic insufficiency32.
In patients with cognitive impairment, the vasomotor tone fails, and there is a dysfunction in the peripheral regulation of the sympathetic arteries, causing brain hypoperfusion. The process starts some years before memory loss is present, causing over the years cerebral hypoperfusion and ischemic lesions that may contribute to cognitive disturbances. On the other hand, in patients with vascular risk factors, hypertension may be present during midlife, causing continuous vascular damage and vessel rigidity, leading to ischemic lesions. We therefore recommend treating vascular risk factors including high blood pressure, optimising antihypertensive treatment seeking to avoid hypotension.
Longitudinal studies with longer observational periods and 24-hour monitoring of diurnal and nocturnal changes in blood pressure and HRV would be interesting in order to explore the changes in cardiac response with age and how to adjust therapy to prevent brain damage. There is a need for prospective studies investigating the role of blood pressure changes, including orthostatic hypotension, in cognitive dysfunction.