Blood Pressure Control and Protection of the Aging Brain

Abstract

Hypertension and dementia are both common disorders whose prevalence increases with age. There are multiple mechanisms by which hypertension affects the brain and alters cognition. These include blood flow dynamics, development of large and small vessel pathology and diverse molecular mechanisms including formation of reactive oxygen species and transcriptional cascades. Blood pressure interacts with Alzheimer disease pathology in numerous and unpredictable ways, affecting both β-amyloid and tau deposition, while also interacting with AD genetic risk factors and other metabolic processes. Treatment of hypertension may prevent cognitive decline and dementia, but methodological issues have limited the ability of randomized clinical trials to show this conclusively. Recent studies have raised hope that hypertension treatment may protect the function and structure of the aging brain from advancing to mild cognitive impairment and dementia.

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Introduction

Blood pressure (BP) is a central regulatory process essential for homeostatic control of the living organism. BP is the force necessary to move blood forward so that glucose and oxygen delivery is adequate and waste products are eliminated via the venous system.

The aging brain is susceptible to many insults related to BP control. These can be roughly divided into direct effects and indirect effects, and acute versus chronic changes as well. Examples include acute hypertension or hypotension, blood vessel injury due to atherosclerotic disease related to chronic hypertension, or lack of nutrient delivery. Indirect effects include brain stressors such as oxidative stress or inflammation. In this article, we review the effects of hypertension and BP control on the aging brain, with special attention to dementia prevention through BP control.

Epidemiology of Hypertension

Worldwide, hypertension affects more than 1 billion people [1] and the majority of about 639 million live in the developing world [2]. Twenty-nine percent of American adults suffer from hypertension [3]. When this number is further broken down by gender and age, Americans over the age of 60 years make up the largest percentage of the hypertensive population [3]. The second largest cohort is persons age 40 years and older. Men have higher rates of hypertension until the age of 60 years after which more women suffer from hypertension [3], possibly due to differential survival bias. The prevalence of hypertension increased with age but the overall prevalence remained unchanged from 1999 to 2016 [3]. When the prevalence of hypertension is broken down by race, non-Hispanic blacks make up the largest group followed by non-Hispanic whites and Hispanics and with the lowest prevalence in non-Hispanic Asians [3].

About 48.3% of Americans who suffered from hypertension had pharmacologically treated blood pressure control in the year from 2015 to 2016. The prevalence of treated hypertension increased with age with the highest prevalence in Americans over age 60 years and lowest between ages18 to 39 years [3]. Non-Hispanic whites and women had higher rates of blood pressure control compared to men and non-Hispanic blacks [3]. Although the prevalence of pharmacological BP control increased from 1999 to 2010, no increase in the prevalence of BP control was noted from 2010 to 2016.

Basic Science Aspects

Several possible mechanisms have been postulated to explain the possible association between BP and cognition, including one hypothesis that chronic hypertension may cause oxidative stress, which leads to endothelial dysfunction, which in turn may result in dysfunction of the arteries and small vessels of the brain vasculature [4, 5].

Blood flow is the result of five major components: cardiac output, blood vessel compliance, intravascular volume, blood viscosity, and vessel length and diameter. These components are in turn regulated via multiple organ systems (kidney, heart, endocrine), neurohormonal control (anti-diuretic hormone), and fluid intake. One component that becomes more important with aging are the changes in the elastic properties of the blood vessels. Arterial wall stiffening, is functionally equivalent to reduced elasticity, and multiple studies have associated hypertension with increases in arterial wall stiffening with cognitive impairment [6–8]. As discussed below, older people in the intensive BP treatment arm of the SPRINT study showed an increase in the incidence of syncope possibly due to decreased vessel wall compliance [9]. Blood vessel length also affects both resistance and blood flow. During adulthood, the total body vessel length remains generally stable unless there is significant weight gain or loss [8, 10, 11].

Besides the abovementioned mechanism for BP control which can result in a hypertensive state, other systems have also been implicated in BP control such abnormal T-cell function, reactive oxygen species, and antioxidants for the development of hypertensive states [12–14]. Hypertensive disease usually develops over many years and is associated with increases in excess reactive oxygen species (ROS) throughout the body [14, 15]. Other causes of ROS production are hypoxic states in which tissue injury is mediated by a large number of activated transcription factors, regulators of signal transduction, and induction of defense genes [14]. ROS have been shown to affect the vascular tone, endothelial function, inflammation, and other important functions involved in end organ structures [13–15].

Definition of Vascular Cognitive Impairment

Cognitive impairment is variously defined and is recognized to be both heterogeneous in etiology, clinical presentation, and appearance on imaging. One limitation of clinical studies has been the variability on the definition of vascular dementia (VaD). The NINDS-AIREN criteria have been widely used in clinical studies. However, it includes large vessel infarcts, single strategically placed infarcts, multiple basal ganglia and subcortical lacunar infarcts, and “extensive” periventricular white matter lesions as causes of VaD. Hachinski and colleagues have introduced the concept of Vascular Cognitive Impairment (VCI) as an analog of mild cognitive impairment (MCI) [16, 17]. The relationship of VCI to the sub-classes of VaD etiology is not well defined, but seems most appropriate for subjects with extensive white matter lesions which present as VaD with insidious onset [16, 17].

Randomized Clinical Trials of BP Control and Preventing Cognitive Decline

The relationship between blood pressure control and improving cognition or more commonly, reducing the risk of cognitive decline is complex. Studies looking at this question have had conflicting results. Some studies such as ACCORD, which measured hypertension control in persons with diabetes, did not show a reduction in dementia risk but did show a reduction in slowing white matter lesion progression [18, 19], whereas other studies in which blood pressure was very tightly controlled at or below 120/80 mmHg noted a reduction in the risk of developing cognitive decline [9]. The role of hypertension is further muddled in cognitive decline when the age of the person is taken into account. In some studies, it is noted that in persons over the age of 90, hypertension is associated with reductions in cognitive decline [20–23].

Systolic Hypertension in Europe Study

The Systolic Hypertension in Europe (Syst-Eur) was one of the first double-blind studies followed by an open-label study that aimed at dementia prevention. The study was terminated early in 1997 because the primary outcome of stroke showed a significant reduction with BP control. Syst-Eur showed a reduction in the incidence of dementia by 50% from 7.7 to 3.8 cases/1000 subjects/year, but there were only 32 incident cases overall, limiting the result’s interpretation. In a follow-up study, the incidence of dementia cases was increased to 64 cases with 41 persons having Alzheimer’s disease (AD). The study concluded that for 1000 patients treated with nitrendipine, an additional 20 cases of dementia were prevented [24].

The limitation of the Syst-Eur study include the use of a single agent nitrendipine which is not available in the USA, and limited duration of the study. The absolute number of cases was small, especially in the relatively short double-blind phase, and it has been suggested that the practical benefits were therefore of limited value [24]. However, as proof of concept, Syst-Eur remains an important landmark, and some of the experiences from that study have been repeated in later studies, such as early termination of both HYVET and SPRINT.

Hypertension in the Very Elderly Trial (HYVET) Study

The HYVET study enrolled 4761 subjects throughout Europe, China, Tunisia, Southeast Asia, and Australia, over age 80 years. 3336 subjects of 3781 randomized had at least two visits and a mean follow-up of 2.2 years. The main study was again terminated early because interim analysis showed benefit, with reductions in mortality, stroke, and heart failure. The study itself did not show a significant dementia risk reduction based on 263 cases of incident dementia. The results were suggestive of an emerging effect, but the short follow-up precluded it from reaching statistical significance. However, when data were combined in a meta-analysis of other placebo-controlled studies, the combined risk ratio favored treatment over placebo (HR = 0.87, 95% CI 0.76–1.0 and p = 0.045) [25].

SPRINT and SPRINT-MIND

SPRINT was designed to compare the effectiveness of two different blood pressure targets, namely 120/80 mmHg (intensive treatment) versus 140/90 mmHg (standard treatment) [9, 26]. The study subjects were age 50 years and above and known to have increased Framingham cardiovascular risk scores, or subclinical risk with chronic kidney disease stage 3, defined as a glomerular filtration rate 40 to 60 mL/min/1.73 m². The study enrolled 9361 subjects and included an expanded cohort > 75 years in age. The main study was stopped prematurely in 2015 after positive results of analyses showed reductions in the composite endpoint of cardiovascular events and mortality favoring intensive BP control.

SPRINT-MIND occurred in several phases and the subjects were followed for a median of 3.3 years [26]. The primary pre-specified outcome was a reduction in incident all-cause dementia. Dementia occurred in 149 subjects, and was not statistically significant between groups. Analyzing mild cognitive impairment and dementia showed significant differences favoring intensive BP control (20.2 vs 24.1 cases per 1000 person years; hazard ratio 0.85; 95% confidence interval 0.74 to 0.97). The disparity between dementia and mild cognitive impairment was probably due to the low event rate because the main study was stopped earlier than originally planned, due to positive findings with regard to cardiovascular events, as has been seen in previous anti-hypertensive studies described above.

The MRI findings from SPRINT-MIND involved a subset of subjects given a brain MRI at baseline and the study conclusion [27]. The findings of the primary analyses have been published in abstract form. It showed a significantly smaller increase in total brain white matter lesion volume favoring intensive treatment. Changes in total brain volume were larger in the intensive treatment group [27]. The reasons for this were unclear, and the findings indicated a significant gender difference in total brain volume change, but not in total white matter lesion volume change. Brain volume changes in women favored intensive treatment, the opposite of what was found in males. The underlying etiology for these changes in brain volume and gender differences is also unknown.

The findings from SPRINT-MIND are notable for several reasons. This is the first large study to show the value of vascular risk factor reduction in preventing cognitive decline (functionally defined as mild cognitive impairment). Mild cognitive impairment is the prodrome for both vascular cognitive impairment due to extensive white matter disease, as well as primary degenerative dementias such as AD. It can only be surmised that had the study continued, the differences in incidence of mild cognitive impairment would translate into lowered dementia risk with intensive BP control. The clinical findings also found a structural correlate in the volume of white matter lesions with smaller increases over several years in the intensive BP control group. As discussed below, the relationship of small vessel disease, the main underlying pathology of white matter disease to cognition is complex, but all of the findings seem concordant with the popular mantra that “What is good for the Heart is also good for the brain” [28].

Specific Anti-hypertensives and the Aging Brain

A frequently asked question is whether specific anti-hypertensives confer special protection on the aging brain? The ability to answer this question is difficult, partly because available data is mostly derived from clinical trials, which have not always matched specific classes of pharmaceuticals against each other. These clinical trails have limitations in their own right, as shown in the previous section.

Sink et al. (2009) reported results from the Cardiovascular Health Study-cognition sub-study [29]. Compared to other anti-hypertensives, there was no association of ACE inhibitors and incident dementia risk, difference in 3MSE scores, or odds of developing disability in instrumental activities of daily living (IADL). Even in the same study, however, centrally active ACE inhibitors were associated with 65% less decline in 3MSE scores, whereas peripherally acting ACE inhibitors were associated with greater risk of incident dementia. In the Ginkgo Evaluation of Memory study, 3069 non-demented subjects over age 75 were studied. About 35% had a history of hypertension and spread between diuretics, ACE inhibitors, and angiotensin-2 receptor blockers. Potassium-sparing diuretic use was associated with better verbal learning and memory function, whereas the other two classes showed no difference from those subjects not taking anti-hypertensives [30].

In a review of human studies, Hughes et al. [31] noted a linked between midlife hypertension and cognitive decline later in life. However, the link between elevated BP in older persons and subsequent cognitive decline was inconsistent; the link between elevated BP and cognitive decline become more apparent in older persons when systolic BP (SBP) was elevated above 180 mmHg. In observational studies, Hughes et al. noted a linear association between midlife elevated SBP and cognitive decline, and the association was stronger for Caucasian populations compared to African-Americans [31]. Persons with elevated SBP were noted to have reduced total brain size with a reduction in volume in dementia-associated regions such as the hippocampus [31]. The reduced brain size was evident even if the subjects were treated with antihypertensives [32]. Another interesting finding in Hughes et al. review was that in older persons, lowered BP was associated with reductions in brain size, and lower diastolic BP was associated with cortical thinning [31]. The exactly etiology for these findings is unknown but caution should be taken in concluding that aggressive BP control in the older persons only produces negative effects on the brain.

Structural Changes in the Brain in Hypertension Studies

The development of new imaging modalities in recent years has added a new dimension to our understanding of hypertension effects on the brain. In the PROGRESS study, hypertensive persons had increased white matter intensities on MRI, and when BP was controlled there was a reduction in the number of white matter intensities on the Magnetic Resonance Imaging (MRI) [32]. In this study hypertensive persons also showed increased frequency of vascular amyloid deposition [32].

Small Vessel Disease and the Aging Brain

Small vessel disease (SVD), a heterogonous group of disorders, is a known risk factor for cognitive impairment and a cause of dementia [33]. Small vessel disease is best defined pathologically, although this includes a variety of microscopic findings including reduced vessel caliber, reduced vessel number, lipohyalinosis, and small cerebral infarcts. Vessel caliber is itself non-specific and may be related to lipohyalinosis, amyloid angiopathy, thrombosis leading to ischemia and infarction, and other causes [34–36].

Adding to the confusion around the meaning, causes, and manifestations of SVD is the non-specific nature of leukoariaosis (sometimes spelled leukoariosis) seen commonly on MRIs especially in middle-aged and older individuals. Evidence of small vessel disease found on MRI may relate to various findings: small lacunar infarcts, primary demyelinating lesions caused by many inflammatory diseases of the CNS, and periventricular or deep white matter lesions, with or without brainstem lesions. The most common locations for small vessel disease lesions include the frontal lobe, basal ganglia, and thalamo-cortical areas of the brain [34]. SVD may also be related to changes in specific white matter tracts such as are commonly seen early in degenerative disorders, affecting the inferior fronto-occipital fasciculus and causing white matter changes adjacent to the cerebral ventricles [37].

SVD can either be clinically silent or clinically significant depending on the location, etiology, and volume of the lesion. The changes noted in SVD may occur with normal aging in 40 to 50% of brain MRIs in midlife or older adults [38, 39]. The hyperintensities are much more diverse in normal aging than those seen with pathological conditions such as lacunar stroke presenting as SVD on MRI [38–40]. These lesions can be found as early as midlife and in association with multiple etiologies: aging, hypertension, diabetes, migraine, stroke, and barotrauma [40]. Other SVD risk factors include metabolic abnormalities, renal disease, tobacco smoking, elevated homocysteine levels, and alcohol use [40–42].

Symptomatic SVD can manifest itself in multiple ways such as micro-hemorrhage or lacunar infarcts. Over time, there is an accumulative effect from the collection of lesions leading to multiple neurological symptoms and ultimately contributing to vascular dementia [42–45]. Although SVD in itself can lead to dementia, it can also contribute as a significant co-morbidity to other neurodegenerative processes (e.g., AD), and leading to multifactorial mixed dementia, which is particularly common in older persons [43, 45].

SVD can present on MRI either as white matter hyperintensities on T2-weighted and FLAIR sequences, or circular hypointensities on gradient echo/susceptibility weighted images known as microbleeds [46]. Microbleeds are usually 5 mm or less in diameter with a variable relationship to cognitive impairment. Thus, they range from a single asymptomatic lesion to dozens or even hundreds of lesions, especially in persons with advanced cerebral amyloid angiopathy (CAA). CAA is often considered as a pathological form of small vessel disease, but is beyond the resolution of MRI, and often diagnosed indirectly based on microbleeds or symptomatic cerebral hemorrhage in older individuals occurring in locations not considered typical for hypertension-related cerebral hemorrhage [34, 46]. The presence of > 4 microbleeds has been associated with amyloid-related imaging abnormalities (edema or hemorrhage), and may be symptomatic in the setting of amyloid-lowering drugs, and occurs especially in those with an APO E e4 allele [47].

The pathological features of SVD at the microscopic level are variable, and besides amyloid angiopathy, these changes often include gliosis, enlarged perivascular spaces, myelin pallor, and changes to the ependymal lining [42–44]. These processes are associated with axonal demyelination and rarefaction of axons in the cerebral white matter. As the SVD burden increases over long periods of time, there is a correlation with increased cortical and hippocampal neuronal loss leading to global atrophy. MRI cannot detect neuronal loss which is the hallmark of atrophy, but is very sensitive to reductions in parenchymal volume, and FLAIR sequences are very sensitive to changes in white matter, albeit nonspecific as to etiology [34, 43, 44, 48, 49].

Genetic Forms of Small Vessel Disease

There are a number of genetic disorders, presenting as apparent vascular dementia with SVD. Most notable among them is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL presents with a constellation of symptoms, including long-standing migraines with aura, motor symptoms, and ultimately vascular dementia due to strokes with early onset of cognitive symptoms in the late 40s to 50s. Neuroimaging of CADASIL shows extensive small vessel disease with a high burden of white matter hyperintensities and subcortical infarcts [50]. Histological findings of CADASIL include thickening of the small vessels. Genetic testing reveals mutations in the Notch3 gene with inheritance in an autosomal dominant pattern. Rare cases of an autosomal recessive disorder known as CARASIL have also been reported [50, 51]. Another genetic form of small vessel disease is Fabry disease, an X-linked disorder which belongs to the class of disorders collectively knowns as lysosomal storage disorders. Fabry disease (also known as Anderson-Fabry disease) is caused by a deficiency in alpha-galactosidase, which is required to break down sphingolipids. As sphingolipids accumulate, they deposit in the blood vessel wall affecting multiple organ systems. In the brain, the disorder manifests itself as multiple infarcts in both small and large blood vessels alongside diffuse white matter changes [51, 52].

Life Style Modification

Besides direct control of hypertension through pharmacological interventions, another area that may reduce the risk of dementia/cognitive decline and the development of hypertension are collectively called lifestyle modifications [53]. These lifestyle modifications include a balanced heart-healthy diet, physical and cognitive exercises, weight loss, social engagement, improving sleep quality, and absence of tobacco and limited alcohol use [53, 54]. One might believe that cognitive exercises such as games requiring attention and memory or reading would have clear benefits, but unfortunately, the benefits from such activities remain elusive [54–58].

Physical activity especially cardio-type exercises have been shown to improve cognitive functions [59, 60]. Physical exercise may improve BP control and has been shown to increase neuroplasticity, improve blood flow, increase hemoglobin oxygen saturation, reduce inflammation, reduce the incidence of depression, and promote weight control [61, 62]. Physical exercise also decreases abdominal fat deposits, which have been linked to small vessel disease and brain ischemia [62]. Physical activity is often tied to weight loss, which has also been shown to improve cognitive functions [61, 62]. Chen et al. [63] noted that walking improves cognition in people diagnosed with AD. In their study, just 40 min of daily physical activity over a 12-week period improved blood flow to the brain and increase neurogenesis in the hippocampal dentate gyrus [63].

In animal models, it has shown that exercise helps reduce the toxic effects of oxidative stress, which is associated with improvements in insulin resistance, reduced cholesterol, increased autonomic nervous system reactivity, and increased neurogenesis, all of which may affect cognitive abilities albeit in a non-specific manner [64–69].

Primary Degenerative Dementia, Hypertension and the Aging Brain

Dementia, an umbrella symptom, is often the end product of multiple neurodegenerative processes. The most common form of dementia, Alzheimer’s disease, accounts for about 60 to 70% case of dementia [70, 71]. AD has been divided in multiple ways, but a common classification is further division into familial versus sporadic Alzheimer’s disease, early onset Alzheimer’s disease (diagnosis before age of 65), and late onset Alzheimer’s disease diagnosed after age 65 [71]. AD evolves over many years, and is preceded by a prodromal state that is now recognized as mild cognitive impairment (MCI); MCI is itself heterogeneous, and not all cases of MCI impairment progress into Alzheimer disease [72, 73]. People diagnosed with MCI have about a incident risk of 10 to 15% per year progressing to Alzheimer’s disease [72].

Amyloid and Blood Pressure

The full relationship between hypertension and β-amyloid burden and other variables such as clinical diagnosis of Alzheimer’s disease and APOE status are quite complex [74, 75]; this field is also being revisited because advances in neuroimaging such as amyloid PET and now tau PET are enabling greater precision of diagnosis across clinical populations in line with new staging framework for AD [76, 77].

At a simple level of resolution, it is known that hypertension doubles the risk of Alzheimer’s disease [78]. The complexity of these overlapping relationships is highlighted by the findings from a clinical study of 259 normal controls and 79 clinical patients with AD conducted by Jeon et al. [75]. In one of their analyses of ApoE e4 carriers versus ApoE e4 non-carriers, hypertensive ApoE e4 carriers had an increased frequency of β-amyloid deposition and cortical thinning, common structural findings in AD [75]. The same findings were not noted in hypertensive ApoE e4 non-carriers. Clark et al. showed that persons with a combination of hypertension and increased β-amyloid burden had an accelerated cognitive decline when compared to either of the risk factors alone [79]. Yun et al. showed that persons with obstructive sleep apnea (a known risk factor for elevated BP) with increased β-amyloid deposition have an accelerated progressive cognitive decline course when compared to controls [80]. Gottesman et al. showed that midlife vascular risk factors including smoking, obesity, and hypertension were significantly associated with increased β-amyloid burden later in life [78].

An interesting finding in Gottesman et al. study was that vascular risk factors in older persons were not associated with increased β-amyloid burden [78]. Faraco and colleagues showed that hypertension increased the β secretase activity resulting in increased β-amyloid 1 to 42 and increased β-amyloid 42/40 ratio [74]. Ashby et al. were able to demonstrate postmortem that hypertensive persons had greater β-amyloid burden compared to normotensive subjects [81]. Another interesting finding is that treated hypertensive persons may have increased β-amyloid burden compared to untreated hypertensives [82].

The relationship between hypertension and amyloid deposition may also be reciprocal. Hypertension is a risk factor for AD, and hypertension has been noted with increased β-amyloid burden, which in turn is associated with the development of AD. β-amyloid often accumulates in the perivascular spaces leading to the disruption in the blood-brain barrier causing a dysregulation of brain homeostasis [82, 83] The damaged blood-brain barrier may affect cholinergic neurons whose terminals directly interact with foot processes of the astrocytes, which are an essential part of the blood-brain barrier. Parrotta et al. also noted that β-amyloid deposition led to neurotoxicity and neuronal death and that hypertension accelerates the deposition of microvascular β-amyloid [82].

Mixed Dementia

Mixed dementia is caused by the coexisting of multiple dementing pathologies (Alzheimer’s, cerebrovascular disease, Lewy body disease, TDP 43 and others) in the same patient [84]. Although Zekry et al. noted controversy regarding the term mixed dementia, the Nun study showed subjects who meet the criteria for pathological Alzheimer’s disease and also suffered cerebrovascular disease were more impaired [85, 86]. As people age, those ages 85 years or older are frequently cognitively impaired, but the link between isolated AD pathology and cognitive decline become more clouded. The oldest Americans age 90 years and older showed higher prevalence of mixed pathology compared to their younger cohort ages 65 to 89 years [84].

Hypertension and Tau

The relationship between intracellular tau tangles and hypertension is also unclear. Kester et al. [87] showed that hypertension in the setting of homozygous ApoE e4 individuals was associated with higher CSF phospho tau 181 (p-tau181) and tau levels when compared to hypertensive people who either ApoE e4 non-carriers or heterozygous for ApoE e4 [87]. They concluded that hypertension has a detrimental effect on AD dementia pathology.

Glodzik et al. reviewed the impact effect of blood pressure in cognitively intact elderly people with and without hypertension. They noted that only people with hypertension who had an overall reduction in mean arterial pressure (MAP) showed decreased memory and increased CSF p-tau181 levels. In the entire study group (N = 77 followed for approximately 2 years) they noted an elevation in CSF p-tau181 and reduction in hippocampal volume [88]. Their overall conclusion was that the hypertensive group may be sensitive to blood pressure reductions.

Petrovitch et al. looked at the relation between midlife hypertension and pathologies associated with dementia in the Honolulu-Asia aging study [89]. They found that systolic blood pressure over > 160 mmHg was associated with increased neuritic plaques and neurofibrillary plaques deposition throughout the cortices and hippocampus and lower total brain volume. In that study Diastolic blood pressure > greater 95 mmHg was associated with increased deposition of neurofibrillary tangles in the hippocampus [89]. The findings in that study were limited because of the lack of female participants.

Moonga et al. [90] reviewed AD patients with and without hypertension. They found that persons with AD and hypertension when compared to AD person without hypertension were more cognitively impaired, had greater burden of neuropsychiatric symptoms, and had greater hypometabolism in the hippocampus bilaterally. Interestingly, in their findings, they noted that hypertension did not affect the numbers of neuritic plaques and neurofibrillary tangles [90].

New Blood Pressure Guidelines and Implementation

Hypertension is ubiquitous in our society, and its effects on multiple organ systems and treatment remain a challenge. The 2017 guidelines introduced by the American College of Cardiology and American Heart Association Task force changed the parameters for hypertensive disease. The new criteria for diagnosis of stage 1 hypertension changed from 140 to 149/80 to 89 mmHg to 130 to 193/80 to 89 mmHg and for stage II from150 to 159/90 to 99 mmHg to 140 to 149/90 to 99 mmHg [91].

The reasoning for the change to new parameters was the linear relationship between elevated BP and strokes and heart disease [91]. Lamprea-Montelalegre et al. noted that with the new guidelines, more people would be diagnosed with hypertension leading to increased usage of antihypertensive medications and overall decrease in cardiovascular disease [92]. Smith et al. noted a decrease in cardiovascular disease and stroke in patients who were diagnosed with resistant hypertension and treated to the lower BP < 130/80 mmHg goal [93]. Sakima et al. also noted that intense BP control resulted in a significant reduction in stroke, heart attacks, and cardiovascular disease, and concluded that the BP target of < 130/80 mmHg is optimal [94]. Hajjar et al. looked at the effects of the new BP guidelines on the cognitive function of African-Americans and noted that BP targets < 130/80 mmHg may result in improved outcomes regarding cognition in African-Americans [95].

Bakris et al. addressed some of the controversy regarding newer guidelines including that new stage 1 hypertensive patients might get pharmacological intervention without taking into account the 10-year risk of cardiovascular disease for these people [96]. They also noted that the new recommendations for BP control were the same for the young and elderly population, which could lead to adverse events in people with poor vascular compliance [9, 96]. Those with poor vascular compliance had increases in dizziness and mentation when systolic BP was closer to 140 mmHg, a similar finding in the SPRINT study [9, 96]. However, the latter study concluded that the new parameters will better benefit individuals that are at high risk for cardiovascular disease [96].

Kristnaswami et al. found that older adults with elevated pulse pressure whose BP was aggressively controlled resulted in more adverse events when compared to control in the SPRINT study [97].

Guidelines by themselves do not improve health and compliance with treatment. Ideally, BP control over long periods could be measured by summing the area under the BP curve as an integrative measure. Hypertensive disease does not have easily defined daily symptoms which makes it difficult for the hypertensive individual to appreciate the full impact of the disease on a regular basis. As a corollary to this situation, because the adverse effects of elevated BP do not manifest until much later (years to decades), outcome criteria of studies should not be the sole determinant of success in BP control over a short-term observation period.

Technological advances offer some hope for more sophisticated interventions. With the advent of smartphones, wearable or even implanted tech, and other similar devices, increasing treatment compliance and improvement in BP control might be considered feasible. Morawski et al. in their evaluation of healthcare mobile app showed an average decrease of 10 mmHg in an intervention group versus control [98]. Ciemins et al. in a trial of home monitoring of BP combined smartphone technology and education, leading to improvement in mean BP control from 42 to 67% in the intervention group when compared to controls who showed improvement of mean BP control from 59 to 67% [99]. Milani et al. had a similar results, showing an increase in compliance and better BP control when technology was combined with education [100]. They noted that in traditional office-based care, the involvement by the patient is limited compared to technology-driven care in which there is an increased engagement or “treatment ownership” by the patient in their care [100]. Lu et al. looked at the role of telemedicine combined with nurse case management and found an average of 22.1 mmHg reduction in systolic BP in linear regression analysis at 1 year [101]. Hedegaard et al. took a different approach to increase adherence by using a multifaceted pharmacist-driven program combined with motivational interviewing; they noted improvement in medication adherence in the intervention group versus control [102]. Green et al. looked at multiple combinations of technology and education compared to care as usual [103]. However, in their study, when they looked at home BP monitoring with web training only, they did not have a significant change in BP control compared to care as usual (36% vs 31% respectively) [103]. But adding a web-based pharmacist to the home BP monitoring and web training group produced a significant change in BP control from 36 to 56% versus care as usual at 31% [102]. Technology helps people become more engaged in their care, but current technology alone does not appear sufficient to improve compliance and long-term outcome data is not yet available. As noted by both Green et al. and Hedegaard et al., education combined with healthcare providers are an integral part in the process of improving medication adherence and BP control [102]. The hope is that technology will help deliver and monitor care more closely allowing for a more immediate, personal, and direct care to the individual, although retaining goals such as improving overall health, morbidity, and mortality.

Dementia prevalence is also a growing public health problem in many societies, and the interactions of these two common disorders reveal new and complex relationships at the molecular, brain structure, individual, and population levels. Current and future studies are exploring the benefits of vascular risk factor reduction, which hold the promise of dementia prevention through well-established pharmacological and non-pharmacological interventions.

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