The Effect of Midlife to Late-life Hypertension on Cognitive Outcomes  

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Pallavi Malladi 

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ABSTRACT

Hypertension, or high blood pressure (BP), is a modifiable cardiovascular risk factor that has shown mixed associations with dementia, or cognitive decline. This review aims to present evidence to solidify the relationship between hypertension and cognition. The studies discussed in the review have utilized cross-sectional and longitudinal cohorts between the midlife to late-life ages. Hypertension exerts neuropathological damage to the brain's protein metabolism, blood flow, and white matter intensity. On one hand, researchers have identified systolic BP as a component of hypertension that affects cognitive outcomes. On the other hand, diastolic BP has not yielded conclusive associations with cognition. Studies have explored whether treating patients with antihypertensive medications would reduce the risk of dementia onset. Some studies found a significant decrease in dementia risk with the use of antihypertensives, while other studies found no such associations. However, there was no detriment to cognition from taking antihypertensive medications. The discrepancies between findings highlight the need to continue comprehensive longitudinal studies to resolve contended findings.

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INTRODUCTION

As of 2019, the World Health Organization has reported over 50 million cases of dementia, or cognitive decline [1]. Studies have shown that addressing cardiovascular risk factors, including body mass index (BMI), total cholesterol, glucose levels, diet, physical activity, smoking, and hypertension, lower the risk of age-related cognitive decline [2]. Hypertension, defined as high blood pressure (BP) over 140/90 mmHg, globally affects over 33% of adults and 67% of adults over 65 years old [3]. To reduce the onset of 10 million new dementia cases each year [1], researchers are investigating whether there is an association between midlife to late-life hypertension and dementia. This review focuses on three aspects of hypertension and cognition: 1) neuropathology (the study of degenerative changes in the brain); 2) the associations between systolic and diastolic BP and dementia; and 3) the effect of antihypertensive medications on reducing dementia risk.

 

The articles used in this literature review have been published within the past five years and represent much of the current literature surrounding hypertension and cognition associations. The articles were found through a PubMed search using the keywords “hypertension,” “blood pressure,” “Alzheimer’s Disease,” and “cognition.”

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NEUROPATHOLOGY OF HYPERTENSION

Compared to normotensive (normal BP) individuals, hypertensive individuals experience more neurological changes [3]. This section will focus on neurofibrillary tangles, reduced cerebral blood flow, and white matter disruptions caused by hypertension [3].

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Neurofibrillary tangles, or tau protein buildup, are commonly found in Alzheimer's patients. Hyperphosphorylation of tau protein results in protein aggregation, leading to the formation of tangles [3]. Wharton et al. looked at the Rush Alzheimer's Disease Core Center (Rush ADCC) cohort of postmortem patients with mild cognitive impairment. The patients had taken antihypertensives that reduced the amount of abnormal hyperphosphorylation of tau [4]. Lower severity of hypertension influenced the amount of tau protein buildup in patients with dementia [3]. Wharton et al. found lower levels of neurofibrillary tangles in patients who had taken these antihypertensives [4], suggesting that hypertension was correlated with neuropathology progression. The postmortem patients were over 80 years old, indicating that the study results could extend to late-life hypertensive individuals. Perhaps these studies can guide physicians to closely monitor hypertension progression in midlife to late-life individuals as it may indicate the development of dementia neuropathology.

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Patients with hypertension have also shown reduced cerebral blood flow (CBF) in comparison to normotensive individuals [3]. Reduced CBF disrupts oxygen and glucose transport. Impacted transport affects the ability to efficiently eliminate toxins, which may contribute to neuronal impairment [3]. A study by Glodzik et al. looked at blood flow within 630 adults and elderly participants without dementia. Their results confirmed that patients in a longitudinal cohort with higher systolic BP had lower CBF within the cortex and hippocampus [5]. Parts of the cortex are associated with higher thinking, such as executive functioning and information processing, and the hippocampus is associated with memory consolidation [3]. If damaged by hypertension and/or reduced CBF, these affected areas could worsen cognition. The Glodzik et al. study, along with the previously mentioned literature [3], suggested that hypertension and reduced blood flow lead to worse cognitive outcomes.

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Along with oxygen and glucose deficiencies, hypertension also affects the brain's white matter. The cerebral white matter is more susceptible to hypertension and hypoxia (low oxygen) damage, causing macrostructural lesions and reducing microstructural integrity [6].  White matter susceptibility may be due to hypertension promoting arteriosclerosis in smaller arterioles that supply the subcortical white matter structures [3]. Luo et al. listed 74 white matter bundles, 14 of which were damaged in hypertensive patients [6].  Researchers investigated the effect of these 14 white matter bundles that mediate cognitive impairments induced by hypertension. The study utilized 66 cognitively healthy older adults, with 41 out of the 66 being hypertensive. The researchers calculated mean generalized fractional anisotropy (mGFA) scores, which averages the degree of diffusion within white matter tracts and indicates cognitive health. The mGFA scores were used to compare white matter microstructural integrity between the tracts [6].

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5 out of 14 studied bundles showed lower mGFA values, which indicates lower microstructural integrity in these areas. These five bundles, located around the frontal and posterior regions, showed adverse relationships between hypertension and some cognitive outcomes when tested separately. The cognitive outcomes included processing speed, executive function, memory encoding, and memory retention [6]. Since white matter is susceptible to hypertension damage, physicians could monitor hypertensive patients using the Mini-Mental State Exam and other forms of cognitive screening. If there is suspicion of mild cognitive impairment, it is essential to monitor changes in the five white matter bundles as they may precede dementia.

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While Luo et al. consisted of a relatively small cohort [6], a longitudinal study by Aljondi et al. confirmed the results by looking specifically at white matter hyperintensity amongst 135 women [7]. White matter hyperintensity (WMH) lesions are a risk factor for dementia and stroke in late-life [7]. WMH lesions were characterized by "demyelination, axonal loss, and mild gliosis," which can all contribute to cognitive decline [7]. Aljondi et al. noted differences in white matter integrity in women with and without hypertension for over 20 years. Patients with greater midlife systolic BP showed significantly higher amounts of WMH lesions after 20 years (during late-life) [7].

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INDIVIDUAL HYPERTENSION COMPONENTS (SYSTOLIC AND DIASTOLIC BP)

Studies examined the effects of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on cognition. While some DBP studies have yielded inconclusive findings, the literature shows strong support for the negative relationship between SBP and cognitive outcomes [8].

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The Maastricht study sought to solidify associations between BP and memory in a cohort of 3,451 participants aged 45 to 75-year-olds [8]. Composite BP variability (BPV) measurements were recorded at three different times: “within visit, 24-hour, and 7-day” visits. Each visit recorded BP at different times of the day to reduce “biological variability” in each recording [8]. Along with the BPV measurements, participants were also assessed with a neuropsychological test battery. The study looked specifically at short-to-mid-term periods since previous studies have suggested greater BPV and poorer cognition associations in long-term cohorts [8]. The researchers found that higher SBP variability in a short to mid-term period led to poorer memory [8]. A longitudinal study from the Atherosclerosis Risk in Communities (ARIC) cohort looked at 11,408 participants over 15 years to understand how midlife BPV can affect late-life cognition. Here, the researchers conducted four clinic visits to collect BP measurements. Mean BP and average levels of variability were calculated throughout the study. The results, similar to the Maastricht cohort, showed that higher SBP variability was associated with worse cognitive performance [9]. Finally, Glodzik et al. looked at cerebral blood flow in hypertensive adults and elders without dementia [5]. Impacted cerebral blood flow can influence executive functioning, information processing speed, and memory. The researchers found that SBP had a more significant effect on blood flow compared to DBP [5]. The results from the three studies highlight the physiological impact of SBP in hypertensive patients. Future research can test whether lowering SBP yields better cognitive outcomes in hypertensive patients.

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There is no established association between DBP and cognition. Two studies showed positive associations, whereas another study showed no associations. The Maastricht study showed that greater DBP caused more impaired cognitive outcomes than greater SBP [8]. Another study by Tsang et al. focused on 94 cognitively normal African Americans over 60 years old to find correlations between SBP and DBP variability with cognitive outcomes. Using the Mini-Mental State Examination and Computer Assessment of Mild Cognitive Impairment, Tsang et al. collected cognitive results and BP measurements taken from the three most recent primary care visits. Results also showed that greater DBP was negatively associated with verbal and incidental memory scores [10]. While the Maastricht and Tsang et al. study yielded negative associations between DBP and cognition, other longitudinal studies produced different results. The ARIC cohort reported that lower DBP contributed to worse cognitive performance [9]. However, the researchers noted that varied results (lower DBP) might be due to arterial stiffening, which shows associations with cognitive decline. Arterial stiffening may decrease cognitive function through several mechanisms, including excessive pulsatile forces on the brain structure, inflammation and oxidative stress, impaired β amyloid clearance, and τ‐mediated neurodegeneration [9]. Furthermore, Tsang et al. conducted their study to find associations explicitly within African Americans while the ARIC cohort had 21% blacks and 79% whites. The uneven distribution of races within the studies could explain the discrepant findings. Though the study by Tsang et al. lasted 9 years and the ARIC cohort study lasted for 15 years, it is difficult to establish the cognitive effects of DBP since there is no clear evidence. Further research on longitudinal cohorts regarding DBP associations with cognition should continue to solidify findings.

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ANTIHYPERTENSIVE MEDICATIONS AND THEIR EFFECT ON COGNITION 

Antihypertensive medications (AHM) studies on cognitive performance could indicate if they effectively reduce or even prevent cognitive decline. While some studies reported significant findings of AHM improving cognition, others did not find any associations.

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A prospective study on 1,236 African Americans in the Indianapolis Ibadan Dementia Project (IIDP) looked at the impact of controlling BP on dementia outcomes [11]. Here, Murray et al. divided the participants into two groups. One group took prescribed AHM while the other modified their diet, exercise, and lifestyle factors. Researchers found that participants taking AHM had a 43% lower risk of dementia. Interestingly, loop diuretics, a specific category of AHM, showed more significant protective effects against dementia compared to the other medications. The researchers decided that loop diuretics had better results since it increased sodium excretion through urine to reduce hypertension more effectively [11]. Overall, the study suggests that adherence to controlling BP via AHM is vital in controlling dementia outcomes. The Rush ADCC study also found similar results. The researchers investigated postmortem patients who had taken renin-angiotensin system (RAS) acting medications. RAS acting AHM is a subcategory of AHM that prevents hyperphosphorylation of tau proteins, thereby reducing neurofibrillary tangles [4]. The study divided the hypertensive patients into five categories of AHM: angiotensin-converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (A2RB), beta blockers, calcium channel blockers, and diuretics. Patients who took ACE-I, A2RB, or both were categorized as taking RAS acting AHM. After four years, patients taking RAS acting AHM showed a decrease in the transition from mild cognitive impairment to Alzheimer's Disease compared to non-RAS AHM participants [4]. The mechanism behind the RAS acting AHM was not solidified in this study.4 Though they did not specify which AHM were studied in their statistical analyses, Luo et al. also reported differences in white matter bundle mGFA values between patients who did and did not take AHM [6]. Patients taking AHM to control their BP experienced fewer WMH lesions than those not taking the medications. These studies indicate that control of BP could be a protective factor against cognitive decline.

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On the other hand, multiple studies showed insignificant associations between AHM and cognitive outcomes. A longitudinal study on 9,361 hypertensive participants investigated whether intensive BP control could lower the incidence of mild cognitive impairment (MCI) [12]. The study results showed no significant decrease in dementia risk amongst hypertensive adults.12 In addition, longitudinal AHM effects on cognition were not significant [5]. Furthermore, Tsang et al. reanalyzed data from the African American cohort to see if the use of AHM impacted their initial findings (regarding DBP and cognition associations) [10]. The reanalyzed data with unspecified AHM showed no difference in results. The cohort was already cognitively healthy at baseline, which can explain why there were no correlations between AHM and cognitive performance. Furthermore, Murray et al. and the Rush ADCC studies specified which AHM participants took, whereas Luo et al. and Tsang et al. did not specify AHM categories. The study of general, rather than specific, categories of AHM in the latter two studies may have failed to include relevant AHM that showed positive cognitive outcomes.

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As AHM studies have not yielded conclusive findings, more research needs to be conducted to confirm any associations. Future studies should look more closely at MCI development in pre-hypertensive patients who may progress to hypertensive. Seeing whether pre-hypertensive patients have signs of MCI before hypertension diagnosis may provide more information on preventative measures and treatments.

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CONCLUSION

The high rate of dementia and hypertension in the global population and the associated comorbidities of hypertension, such as stroke and cardiovascular disease [3], have raised questions about the relationship between the two. Though numerous studies solidified associations regarding hypertension components and cognitive outcomes, other areas still require more research. Hypertension leads to increased tau bundles, reduced cerebral blood flow, and greater WMH lesions in the brain. While higher SBP negatively affected cognitive status, studies on DBP had disparate findings. Given the more substantial impact of SBP on cognitive outcomes, targeting this component would be more efficient. Antihypertensive medications did not show any conclusive evidence of reducing dementia risk. However, none of the presented studies showed a worsening effect of AHM on cognition. While there is no definitive link between hypertension and dementia, it is worth acknowledging that hypertension causes other comorbidities and is thus a reason to continue giving hypertensive patients AHM. Future studies within AHM prescription should look at cognitive status within pre-hypertensive subjects to investigate if preventing hypertension progression could yield better cognitive outcomes.

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Conflicts of Interest: The author of this review has no conflicts of interest to disclose. 

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References: 

1. Dementia. World Health Organization. 2019 Sep 19 [accessed 2020 Jun 8]. https://www.who.int/news-room/fact-sheets/detail/dementia

2. Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, Ballard C, Banerjee S, Burns A, Cohen-Mansfield J, et al. Dementia prevention, intervention, and care. The Lancet. 2017;390(10113):2673–2734. doi:10.1016/s0140-6736(17)31363-6

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4. Wharton, W., Zhao, L., Steenland, K., Goldstein, F. C., Schneider, J. A., Barnes, L. L., … Yasar, S. (2019). Neurofibrillary Tangles and Conversion to Mild Cognitive Impairment with Certain Antihypertensives. Journal of Alzheimers Disease, 70(1), 153–161. doi: 10.3233/jad-190011

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6. Luo, D.-H., Tseng, W.-Y. I., & Chang, Y.-L. (2019). White matter microstructure disruptions mediate the adverse relationships between hypertension and multiple cognitive functions in cognitively intact older adults. NeuroImage, 197, 109–119. doi: 10.1016/j.neuroimage.2019.04.063

7. Aljondi, R., Szoeke, C., Steward, C., Gorelik, A., & Desmond, P. (2018). The effect of midlife cardiovascular risk factors on white matter hyperintensity volume and cognition two decades later in normal ageing women. Brain Imaging and Behavior, 14(1), 51–61. doi: 10.1007/s11682-018-9970-5

8. Zhou, T. L., Kroon, A. A., Sloten, T. T. V., Boxtel, M. P. V., Verhey, F. R., Schram, M. T., … Henry, R. M. (2019). Greater Blood Pressure Variability Is Associated With Lower Cognitive Performance. Hypertension, 73(4), 803–811. doi: 10.1161/hypertensionaha.118.12305

9. Yano, Y., Griswold, M., Wang, W., Greenland, P., Lloyd‐Jones, D. M., Heiss, G., … Mosley, T. H. (2018). Long‐Term Blood Pressure Level and Variability From Midlife to Later Life and Subsequent Cognitive Change: The ARIC Neurocognitive Study. Journal of the American Heart Association, 7(15). doi: 10.1161/jaha.118.009578

10. Tsang, S., Sperling, S. A., Park, M. H., Helenius, I. M., Williams, I. C., & Manning, C. (2017). Blood Pressure Variability and Cognitive Function Among Older African Americans. Cognitive And Behavioral Neurology, 30(3), 90–97. doi: 10.1097/wnn.0000000000000128

11. Murray, M. D., Hendrie, H. C., Lane, K. A., Zheng, M., Ambuehl, R., Li, S., … Gao, S. (2018). Antihypertensive Medication and Dementia Risk in Older Adult African Americans with Hypertension: A Prospective Cohort Study. Journal of General Internal Medicine, 33(4), 455–462. doi: 10.1007/s11606-017-4281-x

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