Introduction
Dementia, an escalating health issue with the advancing age in industrialized countries, is a collective term for brain disorders associated with failure of cognitive functions including memory, mental speed, executive functions and speech [
1]. Previous studies have reported a possible association between high BP levels in midlife and development of dementia later in life [
2,
3]. In parallel, it has been demonstrated that both orthostatic hypotension (OH), a manifestation of autonomic failure, and symptoms of orthostatic intolerance in personal history such as light-headedness and dim vision may predict mild cognitive decline [
4]. However, OH is often asymptomatic i.e. without clinical signs indicating an underlying disorder, thus making the patient unaware of the problem. OH is a common condition among older individuals with a reported prevalence between 5 and 30% [
5]. In population-based prospective studies OH has been consistently linked with increased mortality and cardiovascular (CV) morbidity [
6,
7] but data on association between OH and dementia are very sparse. Impairment of orthostatic BP response is often associated with elevated BP and antihypertensive treatment [
7] while low habitual BP increases the risk of cerebral hypoperfusion in patients with OH, although cerebral autoregulation may effectively prevent symptoms [
8]. However, most studies regarding the association between impaired BP control and dementia are cross-sectional, describing the coexistence of these conditions at a specific point of time [
9]. Thus, there is a need for prospective studies investigating the role of BP changes, including OH, in developing dementia. To this end, we assessed the longitudinal relationship between resting BP, postural BP response and incident dementia in a large population-based cohort with a long-term follow-up.
Discussion
In this study, we have found that decrease in diastolic blood pressure on standing in the middle age, decline in blood pressure between middle-and advanced age, and lower blood pressure in the advanced age are all independent risk factors of developing dementia. The risk of dementia was highest in the extreme quartiles of assessed BP-related parameters: the most pronounced DBP fall on standing, lowest SBP and DBP at re-examination, and progression from higher to lower SBP and DBP between baseline and re-examination. Moreover, postural BP decrease indicated increased risk of dementia development in normotensive individuals only. Finally, higher BP at baseline was predictive of vascular dementia but not Alzheimer’s disease and mixed type.
In our cohort, the prevalence of OH according to consensus criteria was very low (≈2%), most likely due to the fact that patients with OH exceeded in mortality the rest of baseline population [
12] and, consequently, were not included in re-examination. Thus, apart from categorical OH, we decided to study postural i.e. orthostatic BP changes as a continuous variable. On the other hand, most of literature on dementia and orthostatic impairment report on categorical OH but longitudinal studies are very sparse [
13].
In order to understand a possible relationship between orthostatic BP fall and cognitive decline, cerebral perfusion and blood flow have been studied. Using electroencephalography it has been demonstrated that cerebral blood flow is reduced in OH, which may lead to cerebral damage and cognitive impairment [
14]. Additionally, single-photon emission computed tomography of the human brain has shown that during orthostatic stress the brain perfusion is reduced [
15]. The reduced cerebral blood flow seen in participants with orthostatic intolerance may result from dysfunction of the cerebral autoregulation, which plays an important role in order to maintain adequate cerebral blood flow and pressure [
16]. The cerebral perfusion pressure is preserved between ~60 and 160 mmHg of systemic SBP [
17]. Below 60 mmHg, the cerebral autoregulation collapses and the reduction of blood flow is compensated for by enhanced oxygen extraction [
18]. If the improved oxygen extraction fails to deliver enough amount of oxygen to cerebral tissues, cerebral hypoxia ensues which may result in irreversible tissue damage and development of dementia. Given that the prevalence of orthostatic and non-orthostatic hypotension reached 50% in clinically evaluated vascular dementia cases [
19], one possible explanation why OH individuals have higher burden of dementia might be BP fall below limits of autoregulation during orthostatic challenge. In addition, it has previously been indicated that patients with autonomic dysfunction have more severe neuropsychological deficits [
20]. This might be a consequence of cholinergic dysfunction, which may be a possible cause of autonomic failure in patients with dementia. Therefore, in further studies it will be important to examine how cholinesterase inhibitor therapy affects dementia patients with autonomic dysfunction.
The postural DBP decrease predicted dementia development in normotensive individuals only. A possible explanation is that these individuals already have lower BP and therefore are more sensitive to BP drop, which might significantly reduce cerebral perfusion if the critical level is reached. Orthostatic hypotension has been associated with arterial stiffness [
21] and earlier studies have implicated association between arterial stiffness and higher prevalence of cognitive dysfunction [
22]. Consequently, reduced arterial compliance might mediate the increased risk of dementia seen in participants with lower BP and postural DBP decline. Further, with advancing age the small resistance blood vessels undergo degenerative changes consisting of thickening and fibrosis of the media and intima, and patchy degeneration of smooth muscle cells producing luminal narrowing and increased vascular resistance. Although the resting cerebral blood flow is the same in normotensive and hypertensive individuals, these structural changes limit the capacity of the resistance vessels for maximal vasodilatation and impair tolerance of lower BP. When abrupt changes in BP occur, the cerebral autoregulation does not have the ability of BP adaptation, which may result in disruptions in neurovascular coupling and neurodegenerative changes [
23]. Reduction of both SBP and DBP has been associated with dementia risk in a number of previous studies [
24,
25]. So, while low BP has CVD-protective effects in healthy older individuals, it may constitute a risk factor for hemodynamic instability and cerebral hypoperfusion in the vulnerable older patient [
26]. Excessive SBP lowering may therefore be harmful for older patients with cognitive impairment, and BP monitoring can be useful to help avoid BP overtreatment in this population [
27].
We observed that study participants who developed dementia demonstrated a bimodal pattern of BP level, higher in the middle age and lower in later life. It supports the hypothesis that low pressure might be a consequence of incipient dementia or, alternatively, a predisposing factor for dementia development. This pattern of BP reduction within the years before clinical signs of dementia appear has been described earlier [
2,
28]. Several brain regions affected by dementia progress are involved in BP regulation. They include hypothalamus, amygdala, paraventricular cortex, insular cortex, anterior cingulated cortex, nucleus tractus solitarius, ambiguous nucleus, ventrolateral medulla and tracts in the spinal cord [
29]. A reversed causation has been suggested where brain lesions caused by dementia progress result in hypotension. Burke and colleagues reported a strong correlation between decrease in number of C1 neurones in the medulla oblongata and BP dysregulation in Alzheimer patients [
30]. High midlife BP has previously been described as an independent risk factor for dementia development [
31,
32]. A possible explanation is that hypertension contributes to stroke risk [
33] and progress of arteriosclerosis [
34], which may also lead to dementia. Neuroimaging and autopsy of participants in the Honolulu-Asia aging study has revealed that individuals with hypertension in midlife have higher incidence of hippocampal atrophy, neurofibrillary tangles and neuritic plaques, often seen in dementia [
35]. Our findings emphasises the importance of maintaining a sufficient BP level to preserve cerebral perfusion and thereby cognitive function.
Strengths and limitations
An important strength of the current study is the use of a well-characterized prospective cohort that has been followed longitudinally for decades. On the other hand, we missed subjects who participated in the MPP baseline exam but died during follow-up or did not participate in the re- examination for other reasons, which could lead to either over- or underestimation of the orthostatic BP change effect on dementia development. However, since OH-positive individuals demonstrated increased mortality compared with the rest of cohort, an underestimation of such associations is rather to be expected. Further, echocardiographic data and information on newly introduced antihypertensive treatment and incident diabetes between rescreening and end of follow up was not available, which might have influenced the results. Since primary care is not covered in the SNPR, an underestimation of dementia cases is possible. Finally, samples were comprised predominantly of individuals of European ancestry, and therefore, the results of this study may not be generalizable to other racial/ethnic groups.