Arterial stiffness and cognitive impairment

Journal of the Neurological Sciences 380 (2017) 1–10

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Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns

Review Article

Arterial stiffness and cognitive impairment Xiaoxuan Li a,b, Peiyuan Lyu a,b,⁎, Yanyan Ren a,b, Jin An c, Yanhong Dong a a b c

Department of Neurology, Hebei General Hospital, Shijiazhuang 050051, China Graduate School, HeBei Medical University, Shijiazhuang 050017, China Hebei North University, Zhangjiakou 075000, China

a r t i c l e

i n f o

Article history: Received 18 January 2017 Received in revised form 10 June 2017 Accepted 13 June 2017 Available online 27 June 2017 Keywords: Arterial stiffness Cognitive impairment Ankle-brachial index Pulse-wave velocity

a b s t r a c t Background: Arterial stiffness is one of the earliest indicators of changes in vascular wall structure and function and may be assessed using various indicators, such as pulse-wave velocity (PWV), the cardio-ankle vascular index (CAVI), the ankle-brachial index (ABI), pulse pressure (PP), the augmentation index (AI), flow-mediated dilation (FMD), carotid intima media thickness (IMT) and arterial stiffness index-β. Arterial stiffness is generally considered an independent predictor of cardiovascular and cerebrovascular diseases. To date, a significant number of studies have focused on the relationship between arterial stiffness and cognitive impairment. Objectives and methods: To investigate the relationships between specific arterial stiffness parameters and cognitive impairment, elucidate the pathophysiological mechanisms underlying the relationship between arterial stiffness and cognitive impairment and determine how to interfere with arterial stiffness to prevent cognitive impairment, we searched PUBMED for studies regarding the relationship between arterial stiffness and cognitive impairment that were published from 2000 to 2017. We used the following key words in our search: “arterial stiffness and cognitive impairment” and “arterial stiffness and cognitive impairment mechanism”. Studies involving human subjects older than 30 years were included in the review, while irrelevant studies (i.e., studies involving subjects with comorbid kidney disease, diabetes and cardiac disease) were excluded from the review. Results: We determined that arterial stiffness severity was positively correlated with cognitive impairment. Of the markers used to assess arterial stiffness, a higher PWV, CAVI, AI, IMT and index-β and a lower ABI and FMD were related to cognitive impairment. However, the relationship between PP and cognitive impairment remained controversial. The potential mechanisms linking arterial stiffness and cognitive impairment may be associated with arterial pulsatility, as greater arterial pulsatility damages the cerebral microcirculation, which causes various phenomena associated with cerebral small vessel diseases (CSVDs), such as white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), and lacunar infarctions (LIs). The mechanisms underlying the relationship between arterial stiffness and cognitive impairment may also be associated with reductions in white matter and gray matter integrity, medial temporal lobe atrophy and Aβ protein deposition. Engaging in more frequent physical exercise; increasing flavonoid and long-chain n-3 polyunsaturated fatty acid consumption; increasing tea, nitrite, dietary calcium and vitamin D intake; losing weight and taking medications intended to improve insulin sensitivity; quitting smoking; and using antihypertensive drugs and statins are early interventions and lifestyle changes that may be effective in preventing arterial stiffness and thus preventing cognitive impairment. Conclusion: Arterial stiffness is a sensitive predictor of cognitive impairment, and arterial stiffness severity has the potential to serve as an indicator used to facilitate treatments designed to prevent or delay the onset and progression of dementia in elderly individuals. Early treatment of arterial stiffness is beneficial and recommended. © 2016 Elsevier B.V. All rights reserved.

Contents 1.

The relationship between arterial stiffness and cognitive impairment 1.1. PWV . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. CAVI . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. ABI . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4. PP . . . . . . . . . . . . . . . . . . . . . . . . . . .

⁎ Corresponding author. E-mail addresses: [email protected], [email protected] (P. Lyu).

http://dx.doi.org/10.1016/j.jns.2017.06.018 0022-510X/© 2016 Elsevier B.V. All rights reserved.

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X. Li et al. / Journal of the Neurological Sciences 380 (2017) 1–10

1.5. AI . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6. FMD. . . . . . . . . . . . . . . . . . . . . . . . . . 1.7. IMT and arterial stiffness index-β . . . . . . . . . . . . 2. The mechanisms linking arterial stiffness and cognitive impairment 3. Prevention and treatment . . . . . . . . . . . . . . . . . . . 3.1. Physical exercise . . . . . . . . . . . . . . . . . . . . 3.2. Diet . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Living habits . . . . . . . . . . . . . . . . . . . . . . 3.4. Drugs . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusions and perspectives. . . . . . . . . . . . . . . . . . Funding sources . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. The relationship between arterial stiffness and cognitive impairment Atherosclerotic disease is an important global disease. As the incidence of atherosclerotic disease has increased, clinicians and researchers have focused increasing amounts of attention on subclinical atherosclerosis. Structural and functional changes in the vascular wall, which may be detected by clinicians, may occur during the early stage of vascular diseases. Arterial stiffness is characterized by decreases in arterial volume changes with pressure and is a consequence of the loss of vessel elasticity and arterial compliance. Arterial stiffness has become one of the earliest indicators of changes in vascular wall structure and function [1]. Cognitive impairment is defined as varying degrees of cognitive dysfunction attributable to deficits in a variety of domains, including learning, memory, language, executive function, orientation, attention, visuospatial reasoning and other domains. The symptoms of cognitive impairment are progressive and range from mild cognitive impairment (MCI) to dementia. Cognitive impairment may be caused by multiple diseases, such as Alzheimer's disease (AD), cerebral vascular disease-related cognitive dysfunction, lobar frontotemporal dementia, and hepatolenticular degeneration. AD and mixed dementia (AD combined with vascular disease-related cognitive dysfunction) are the two most common types of dementia. Arterial stiffness is generally considered an independent predictor of cardiovascular and cerebrovascular diseases, as well as other fatal diseases [2,3]. Numerous recent studies have demonstrated that an independent relationship exists between arterial stiffness and cognitive impairment [4]. Those studies assessed arterial stiffness using various parameters, such as pulse-wave velocity (PWV), the cardio-ankle vascular index (CAVI), the ankle-brachial index (ABI), pulse pressure (PP), the augmentation index (AI), flow-mediated dilation (FMD), intima media thickness (IMT) and arterial stiffness index-β. To investigate the relationships between each of the above arterial stiffness parameters and cognitive impairment, elucidate the pathophysiological mechanisms underlying the relationships and determine how to interfere with arterial stiffness to prevent cognitive impairment, we searched PUBMED for studies regarding the relationship between arterial stiffness and cognitive impairment that were published from 2000 to 2017. We used the following key words in our initial search: “arterial stiffness and cognitive impairment”. We subsequently performed a second search using the key words “pulse-wave velocity and cognitive impairment”, “cardiac-ankle vascular index and cognitive impairment”, “ankle-brachial index and cognitive impairment”, “pulse pressure and cognitive impairment”, “augmentation index and cognitive impairment”, “flow-mediated dilation and cognitive impairment”, “intima media thickness and cognitive impairment”, “arterial stiffness index-β and cognitive impairment”, “arterial stiffness and cognitive impairment mechanism”, and “arterial stiffness treatment”. We then

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reviewed the two sets of search results and screened them to identify relevant studies. Studies involving human research subjects older than 30 years were included in the study, while irrelevant studies (i.e., studies involving subjects with other comorbid diseases, such as kidney disease, diabetes and cardiac disease) were excluded from the review. We identified ninety-seven papers, including 41 papers (including 32 crosssectional studies, 10 longitudinal studies and 1 combined cross-sectional/longitudinal study) regarding the relationship between arterial stiffness and cognitive impairment (Table 1 summarizes the longitudinal studies, Table 2.1 summarizes the cross-sectional studies with positive results, and Table 2.2 summarizes the cross-sectional studies with neutral or negative results), 15 papers regarding the pathophysiological mechanisms underlying the relationship between arterial stiffness and cognitive impairment, and 41 papers regarding arterial stiffness prevention and treatment. 1.1. PWV PWV, a non-invasive measure of vascular wall elasticity, is defined as the propagation speed of pulse waves traveling between two points in an arterial system. A higher PWV is indicative of poor vessel wall elasticity and compliance, which contribute to increases in blood vessel stiffness [5]. PWV includes carotid-femoral pulsewave velocity (cfPWV) and brachial-ankle pulse-wave velocity (baPWV). cfPWV is defined as the propagation speed of pulse waves traveling from the carotid arteries to the femoral arteries, whereas baPWV is defined as the propagation speed of pulse waves traveling between the brachial and ankle arteries. cfPWV is currently considered the gold standard method for measuring arterial stiffness [6]. A previous review of twelve studies involving N 6000 individuals that was published in 2012 noted the existence of a significant association between increased arterial stiffness and cognitive impairment via multivariate analysis following adjustments for age, education level, and other factors that influence cognition. Moreover, the review determined that arterial stiffness is related to the longitudinal progression of cognitive decline and that a higher PWV is a significant predictor of subsequent cognitive decline [7]. We reviewed 11 clinical studies (6 cross-sectional studies, 4 longitudinal studies and 1 combined cross-sectional/longitudinal study) that were published from 2000 to the present day. Eight of these studies (3 cross-sectional studies, 4 longitudinal studies and 1 combined cross-sectional/longitudinal study) provided evidence supporting the idea that a higher PWV is linked to cognitive impairment and the longitudinal progression of cognitive decline [8–15]. In the indicated studies, a higher PWV was confirmed to be related to memory loss [8], poorer processing speeds [11] and declines in executive function [8,11,12]. Moreover, a higher continuous cfPWV was determined to predict an increased 10-year risk of MCI in dementia-free elderly Framingham individuals with a mean age of

X. Li et al. / Journal of the Neurological Sciences 380 (2017) 1–10

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Table 1 Relationship between arterial stiffness measurements and cognitive impairment - longitudinal studies. Study

Subject

N

Pase MP et al. Switzerland [13] Taniguchi Y et al. Japan [14] Zeki AHA et al. USA [15]

Dementia-free participants

Arterial stiffness measure

Study design

Findings

1101 69

PWV

Prospective study

*Higher continuous aortic stiffness predicted an increased 10-year risk of MCI

Cognitively intact Japanese participants

982

PWV

Community-dwelling individuals

2488 74

PWV

Longitudinal study with a 5-year follow-up period Prospective study with a 9-year follow-up period

Scuteri A et al. Italy [8]

Subjects with subjective complaints of memory loss and no previous stroke

280

78

PWV

Cross-sectional and longitudinal study

Yamamoto N et al. Japan [23] Espeland MA et al. USA [29]

Community-dwelling elderly individuals

229

75+

CAVI

Longitudinal study with 4-year follow-up period Randomized clinical trial with a 2-year follow-up period

*BaPWV was predictive of cognitive decline later in life *BaPWV was an independent risk factor for subsequent cognitive decline in a population of elderly Japanese *The odds of cognitive impairment after 9 years of follow-up was 40% greater for subjects with middle PWV and 59% greater for subjects with high PWV, compared with low PWV *High arterial stiffness was modestly associated with cognitive decline and impairment *Higher PWV and hypotension together with cerebral microvascular damage are significantly associated with poorer cognitive function and may identify older subjects with subjective complaints of memory loss at higher risk of cognitive decline *Elderly people with a high CAVI value are at a greater risk of cognitive decline

Wang Z et al. China [34]

71.7

Sedentary individuals, without 1601 78–89 ABI dementia and with functional limitations

Price JF et al. Older individuals Scotland [30] Tsao CW et al. Community-dwelling adults Boston [10] without stroke or dementia

Waldstein SR et al. USA [31]

Age

Nondemented, stroke-free persons

Patients with ischemic stroke/transient ischemic attack Moon JH et al. Non-demented individuals Korea [40]

717

55–74 ABI

Cohort study with a 10-year follow-up period Longitudinal study with a 6-year follow-up period

*In an older cohort sedentary individuals with dementia and with functional limitations, lower baseline ABI was independently correlated with cognitive function and associated with greater 2-year risk for progression to mild cognitive impairment or probable dementia *The ABI is predictive of poorer performance in nonverbal reasoning, verbal fluency, and information processing speed, ABI is also predictive of decline in information processing speed *Higher baseline cfPWV and central PP were associated with greater progression of neurocognitive decline *In middle-aged and older adults without evidence of clinical stroke or dementia, elevated arterial stiffness and PP were associated with the longitudinal progression of subclinical vascular brain injury and greater neurocognitive decline *Increases in PP were associated with declining performance on tests of verbal learning, nonverbal memory, working memory, and a cognitive screening measure *A higher baseline PWV was associated with declining performance on tests of verbal learning and delayed recall, nonverbal memory, and a cognitive screening measure *The relationship between PP and cognitive decline was U-shaped in the MMSE

1223 61

PP PWV

1749 60+

PP PWV

Longitudinal study with a 14-year follow-up period

406

75

PP

348

71

IMT

Longitudinal study with an 18-month follow-up period Prospective study with *Carotid IMT was associated with the progression of cognitive a 5-year follow-up dysfunction to MCI and dementia in elderly patients after a 5-year period follow-up period *A Greater baseline carotid IMT was independently associated with the risk of cognitive impairment, such as MCI and dementia in elderly subjects

Footnotes: Longitudinal studies regarding the relationship between arterial stiffness parameters and cognitive impairment. PWV-pulse wave velocity, cfPWV-carotid-femoral pulse wave velocity, baPWV-brachial-ankle pulse wave velocity, CAVI-cardio-ankle vascular index, ABI-ankle-brachial index, PP-pulse pressure, IMT-carotid intima media thickness, MCI-mild cognitive impairment.

69 years [13]. A higher baPWV was also found to be an independent predictor of cognitive decline within 5 years in cognitively normal Japanese individuals aged 65 years or older [14] and may thus be useful for predicting cognitive decline later in life (within at least 9 years) in community-dwelling elders aged 70–79 years [15]. In a meta-analysis consisting of 15 cross-sectional studies and 4 longitudinal studies, high cfPWVs and baPWVs were associated with cognitive impairment; however, the strengths of these associations were relatively weak [16]. Moreover there were also negative results. For example, a Swedish study and a Sydney study found that PWV was not associated with cognitive function in cognitively healthy elderly individuals [17,18], a higher PWV was related to declines in global cognition and memory only in males [18]. A Japanese study found that a high baPWV may not be an independent risk factor for cognitive impairment in community-dwelling elderly individuals older than 60 years [19]. Additional research is necessary to confirm the existence of a relationship between PWV and cognitive impairment in individuals of different genders, races and ages.

1.2. CAVI The CAVI is recorded and calculated using electrocardiography, heart sounds, brachial artery pulse waveforms and ankle pulse waveforms. The CAVI can overcome certain shortcomings of PWV. For example, the CAVI is not influenced by blood pressure changes during its measurement and may thus reflect vascular stiffness better than PWV [20]. An association between the CAVI and lower phonemic fluency was noted in a recent study involving community-dwelling elderly Japanese individuals with a mean age of 73 years. This association suggests that arterial stiffness is associated with poor executive function [21]. Similarly, another research study of community-dwelling elderly Japanese individuals noted that a high CAVI was associated with poor cognitive function following adjustments for age, height, weight and gender [22]. Notably, a higher CAVI has been linked not only to cognitive impairment but also to longitudinal progression of cognitive decline. A longitudinal study with a 4-year follow-up period showed that elderly individuals with higher CAVIs were at a greater risk for cognitive decline

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X. Li et al. / Journal of the Neurological Sciences 380 (2017) 1–10

Table 2.1 Relationship between arterial stiffness measurements and cognitive impairment-cross-sectional studies (positive results). Study

Subject

N

Pase MP et al. USA [11]

Individuals without symptoms of cognitive impairment

3207 46

PWV

Lim SL et al. Community-dwelling, non-demented Singapore [12] older Asians

463

63

Riba-Llena I et al. Spain [9]

Community-based population comprising individuals with who have MCI or normal cognitive function

699

50+

PWV AI Index β PWV PP

Scuteri A et al. Italy [8]

Subjects with subjective complaints of memory loss and no previous history of stroke

280

78

PWV

Sugimoto T et al. Community-dwelling elderly individuals 140 Japan [21]

73

CAVI

Yukutake T et al. Community-dwelling elderly subjects Japan [22] Wang A et al. Community-dwelling Chinese China [26] Weimar C et al. Community-dwelling elderly people Germany [24]

Ferreira NV et al. Individuals with a low or normal ABI Brazil [25] Hilal S et al. Chinese subjects Singapore [28] Laukka EJ et al. Non-demented elderly persons England [27]

Age

Arterial Study design stiffness measure

179

CAVI

3048 40+

ABI

4086 66

ABI

63

66

ABI

278

60+

ABI

918

87/73 ABI

Cross-sectional *Higher aortic stiffness was associated with poorer processing study speed and executive function, larger lateral ventricular volumes and a greater burden of WMHs *Aortic stiffness was associated with lateral ventricular volume in young adults (30–45 years old) *Aortic stiffness was associated with white-matter injury and cognition in midlife (45–65 years old) Cross-sectional *The study found inverse associations between MMSE and study β index; between executive function and cfPWV, β index; between verbal memory and AI Cross-sectional *CfPWV and PP at different periods were inversely cohort study correlated with several cognitive domains *All ambulatory PP measurements were related to MCI, which was independently associated with nocturnal PP and also related to the presence of WMHs Cross-sectional *Higher PWV and hypotension and cerebral microvascular and damage were significantly associated with poorer cognitive longitudinal function and may indicate that older subjects with subjective study complaints of memory loss are at higher risk for cognitive decline Cross-sectional *Higher CAVIs were independently associated with poorer study executive function *High CAVIs were associated with lower letter word fluency test scores Cross-sectional *Lower CAVIs were significantly correlated with higher MMSE scores study Cross-sectional *A low ABI was associated with cognitive impairment, especially in study non-hypertensive and diabetic patients Cross-sectional *A decreasing ABI was significantly associated with a higher MCI study prevalence A decreasing ABI was also significantly associated with non-amnestic MCI in fully adjusted models but not with amnestic MCI Cross-sectional *The group with a low ABI performed worse on tests of working study memory and semantic verbal fluency than the group with a normal ABI Cross-sectional A low ABI was associated with cognitive impairment independent of study MRI markers of CSVD or large artery atherosclerotic disease Cross-sectional *A higher ABI was associated with better general cognition and study processing speed in older subjects and better processing speed in younger subjects *A lower ABI was associated with worse cognitive performance in elderly individuals, especially in extremely elderly individuals (N85 years) Cross-sectional *Elevated PPs during the day and night were correlated with cognitive study impairment

Yaneva-Sirakova T et al. Bulgaria [33] Suleman R et al. Canada [35] Tachibana H et al. Japan [39]

Individuals suffer from hypertension

148

64

PP

Individuals with or without MCI

706

50+

Individuals with vascular dementia, individuals with Alzheimer's disease, or healthy individuals

207

70

PP AI FMD

Cross-sectional study Cross-sectional study

Vendemiale G et al. Italy [38]

Patients with MCI and normal individuals

71

60+

FMD

Cross-sectional study

Wang A et al. China [43]

Chinese individuals

3227 58

IMT

Cross-sectional study

Yue W et al. China [45] Suemoto CK et al. Brazil [44]

Patients with acute ischemic stroke

1826 63

IMT

Middle-aged subjects

8208 49

IMT

Cross-sectional study Cross-sectional study

Caucasian subjects

747

50+

IMT

Elderly subjects at high risk for cardiovascular disease

201

80

IMT index β

López-Olóriz J et al. Spain [41] Nagai M et al., Japan [42]

Findings

Cross-sectional study Cross-sectional study

*A significant relationship was observed between AI and abnormal clock-drawing and language, and between PP amplification and language *The FMD was significantly predicted by MMSE scores *The FMD was significantly lower in patients with AD or VaD than in healthy individuals *FMD may be more sensitive than other surrogate methods for detecting early-stage atherosclerosis and/or cognitive decline *Brachial FMD was significantly associated with MCI, and patients with MCI with amnestic multiple domain impairment showed the worst brachial FMD *Carotid IMT was significantly associated with cognitive function among middle-aged and older adults. The association was stronger in older adults and adults with low education levels *IMT was positively correlated with cognitive impairment in participants with acute ischemic stroke *Carotid IMT was inversely associated with memory function in middle-aged adults. Additionally, alcohol use strengthened the association between carotid IMT and poorer performance on a test of executive function *IMT was associated with poorer performance in almost all cognitive domains *Patients with a high IMT had significantly lower MMSE scores than patients with a low IMT *Stiffness index β was significantly associated with low MMSE scores

Footnotes: Cross-sectional studies with positive results regarding the relationships between arterial stiffness measurements and cognitive impairment. PWV-pulse-wave velocity, cfPWV-carotid-femoral pulse-wave velocity, CAVI-cardio-ankle vascular index, ABI-ankle-brachial index, PP-pulse pressure, AI-augmentation index, FMD-flowmediated dilation, IMT-carotid intima media thickness, MCI-mild cognitive impairment, index β-arterial stiffness index β, MCI-mild cognitive impairment, AD-Alzheimer's disease, VaDvascular dementia, CSVD-cerebral small vessel disease.

X. Li et al. / Journal of the Neurological Sciences 380 (2017) 1–10

than individuals with lower CAVIs, indicating the CAVI may have substantial potential as an early marker for dementia [23]. However, most of the current studies regarding the relationship between CAVI and cognitive impairment involve Asian populations, particularly Japanese populations; thus, studies involving individuals of different races are necessary. 1.3. ABI The ABI is the ratio of the highest ankle arterial systolic pressure to the highest brachial arterial systolic pressure. We reviewed 7 studies (5 cross-sectional studies and 2 longitudinal studies) involving Asian, European, South American and North American patients that investigated the relationship between the ABI and cognitive function. All 7 studies found that a low ABI was associated with cognitive impairment in elderly individuals [24–30]. These studies found that deficits in working memory, semantic verbal fluency [25], processing speed [27] and global cognitive function [26] were also related to a lower ABI. One study involving elderly individuals with MCI or its subtypes found that a lower ABI was significantly associated with higher prevalences of MCI and non-amnestic mild cognitive impairment (naMCI); however, a lower ABI was not associated with amnestic mild cognitive impairment (aMCI) [24]. A study of a Chinese population comprising individuals older than 60 years indicated that the association between a low ABI and cognitive impairment is independent of MRI markers of cerebral small vessel disease (CSVD) or large artery atherosclerotic disease [28]. Furthermore, a low baseline ABI may increase the risk of longitudinally progressing cognitive impairment in Americans aged 70–89 years [29]. Another study regarding Scottish individuals aged 55–74 years whose follow-up period lasted for 10 years reported that the ABI may be useful for identifying older individuals at higher risk for cognitive impairment [30]. 1.4. PP Many studies have examined the relationship between PP and cognitive impairment. Seven clinical studies (4 cross-sectional studies and 3 longitudinal studies) were reviewed. Six of these studies observed a relationship between a high PP and cognitive impairment. Specifically, these studies noted that a high PP was associated with impairments in global cognitive function and attention [9], verbal learning and cognitive screening performance [31], episodic secondary memory performance and memory retrieval speed [32], memory function [33] and language. Moreover, a Chinese study noted a U-type association

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between PP and cognitive function. That is, the study determined that both a high and a low PP may predict cognitive decline in patients with stroke/transient ischemic attack [34]. The link between PP and cognitive impairment has been noted in both cross-sectional studies and longitudinal studies. A high PP was associated with longitudinal progression of cognitive impairment and subclinical cerebrovascular injury in a study involving elderly individuals with a mean age of 61 years without clinical evidence of stroke or dementia [10]. A Spanish study in which 24-hour ambulatory PPs were recorded in a population of hypertensive patients aged 50– 70 years noted an association between higher 24-hour dynamic PPs and MCI. Moreover, that study determined that a higher awake PP was independently associated with attention deficits and that higher day and night ambulatory PPs were associated with poor cognitive outcomes [9]. However, another study found that PP could not predict declines in working memory, power of attention and continuity of attention in healthy middle-aged Australian individuals [32]. Thus, the relationship between PP and cognitive impairment remains controversial. Additional studies are needed to elucidate this relationship further.

1.5. AI Arterial stiffness is characterized by more rapid forward-wave transmission and earlier returns of reflected waves from the terminal aorta, phenomena that may be represented by the AI [5]. The authors of a study of community-dwelling, non-demented older Asians with a mean age of 63 years determined that the AI was negatively correlated with verbal memory, suggesting that individuals with a higher AI were more likely to suffer from cognitive impairment than individuals with a lower AI [12]. Another study involving Canadian patients older than 50 years noted significant relationships between the AI and poor executive function and language cognitive domain deficits [35]. In addition to investigating older individuals, some studies have also investigated middle-aged individuals. One such study noted an association between a higher AI and memory speed in healthy middle-aged Australian individuals aged 40–65 years, suggesting that the AI was an independent predictor of memory speed; however, the AI was not a predictor of working memory, power of attention and continuity of attention in the indicated study [32]. The relationship between the AI and different cognitive domains in different age groups and the effects of the AI on longitudinal progression of cognitive decline must be confirmed by future studies. In addition, the AI may be affected by heart rate, height and other factors. A slower heart rate and a shorter height may

Table 2.2 Relationships between arterial stiffness measurements and cognitive impairment-cross-sectional studies (neutral/negative results). Study

Subject

N

Gustavsson AM et al. Sweden [17]

Individuals without symptoms of cognitive impairment

208 72

Singer J et al. Australia [18]

Non-demented community-dwelling subjects Sugawara N et al. Community-dwelling older Japan [19] populations Pase MP et al., Australia [32].

Healthy individuals

Age

Arterial stiffness measure

Study design

PWV

Cross-sectional *Arterial stiffness was not associated with the presence of cognitive deficits or cohort study CMBs in cognitively healthy elderly subjects *Arterial stiffness was associated with the presence of WMHs, but the association was attenuated after multiple adjustments were made Cross-sectional *PWV was not associated with cognition after correction for multiple testing study *A higher PWV was associated with poorer global cognition and memory only in males Cross-sectional *A low ABI was an independent risk factor for cognitive impairment in study community-dwelling older populations, whereas a high baPWV may not have been Cross-sectional *A high pulse pressure was an independent predictor of both episodic study secondary memory performance and memory retrieval speed *AI was also an independent predictor of memory speed *Working memory, power of attention and continuity of attention were not predicted by PP or the AI

319 70–90 PWV

388 60+

92

PWV ABI

40–65 PP AI

Findings

Footnotes: Cross-sectional studies with neutral/negative results regarding the relationships between arterial stiffness parameters and cognitive impairment. PWV-pulse-wave velocity, cfPWV-carotid-femoral pulse-wave velocity, baPWV-brachial-ankle pulse wave velocity, ABI-ankle-brachial index, AI-augmentation index, WMHs-white matter hyperintensities, CMBs-cerebral microbleeds.

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contribute to increases in the AI [36]. Thus, the ability of the AI to predict cognitive impairment may be limited. 1.6. FMD Endothelial function, which is determined by vascular permeability, vascular tissue vasomotor tone, blood fluidity and inflammatory processes, is regulated by the distribution, activation and release of nitric oxide and other biologically active substances [37]. FMD, which is measured via a high-resolution ultrasonic tracking technique, may reflect vascular endothelial function and offers the advantages of being simple and non-invasive. A cross-sectional study from Italy indicated that patients with MCI who were older than 60 years had lower FMD values than healthy individuals and that lower FMD values were associated with lower MMSE scores. Patients with MCI with amnestic impairments in multiple domains exhibited the worst brachial FMD values [38]. In addition, a cross-sectional Japanese study showed that FMD was significantly lower in patients with AD or VaD than in healthy individuals. The same study determined that FMD values may be more sensitive indicators of early atherosclerosis and cognitive impairment than the ABI, the CAVI and IMT [39]. The results of current studies regarding the relationship between FMD and cognitive impairment are not sufficient for drawing conclusions regarding the relationship. The relationship between FMD and cognitive impairment has been reported in previous studies; however, whether a link exists between FMD and longitudinal progression of cognitive impairment remains to be determined by future studies. 1.7. IMT and arterial stiffness index-β The early stages of atherosclerosis are typically characterized by carotid artery intimal damage, which causes intimal vascular wall thickening. Carotid artery IMT is an alternative non-invasive means of detecting subclinical atherosclerosis [12]. We reviewed 6 clinical studies (5 crosssectional studies and 1 longitudinal study) regarding the relationship between IMT and cognitive impairment. All of the studies showed that higher IMT values were positively correlated with cognitive impairment [40–45]. Several studies noted that high carotid IMT values were associated with low MMSE scores and cognitive impairment [40–42]. Moreover, the association between IMT and cognitive impairment was particularly strong in a study involving Chinese individuals, particularly among older adults and adults with low education levels [43]. Alcohol use strengthened the association between higher carotid IMT values and worse executive function in healthy middle-aged (mean age of 49 years) Brazilian subjects [44], and a positive correlation between carotid IMT and cognitive impairment was noted in a cross-sectional study involving Chinese patients with acute ischemic stroke [45]. A longitudinal study from Korea with a five-year follow-up period noted that a greater baseline carotid IMT was independently associated with the risk of cognitive impairment progression in older Korean individuals with a mean age of 71 years [40]. A higher arterial stiffness index-β was associated with worse executive function and lower MMSE scores in community-dwelling, non-demented older Singaporean individuals [12] and elderly Japanese individuals at high risk for cardiovascular disease [42] in separate cross-sectional studies. 2. The mechanisms linking arterial stiffness and cognitive impairment Reduced white and gray matter integrity, medial temporal lobe atrophy, and endothelial injury have been identified as links between arterial stiffness and cognitive impairment in AD. In a study regarding healthy middle-aged (mean age of 46 years) adults, higher aortic stiffness was found to be related to reduced white matter and gray matter integrity in individuals with cognitive decline and AD [46]. Moreover,

PWV was significantly correlated with medial temporal lobe atrophy in patients with AD and patients with MCI in a recent study from France [47]. Additionally, another study showed that endothelial injury may play a role in the pathogenesis of AD [39]. Studies have also shown that PWV was associated with Aβ protein deposition in the brains of patients with AD, patients with MCI and individuals without dementia [48]. Increasing amounts of Aβ protein are gradually deposited in brain tissue with increasing age, and vascular stiffness progression may be associated with Aβ protein deposition over time [49]. The precise mechanism underlying the relationship between amyloid deposition and vascular stiffness is unclear; however, it has been suggested that amyloid cerebral vascular disease may be one of the mediators of the relationship between cognitive impairment and arterial stiffness [50]. In healthy young and middle-aged (30–59 years) Korean individuals, arterial stiffness, as measured by the CAVI, was significantly associated with CSVDs, including white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), and silent lacunar infarction (SLIs) [51]. One study consisting of 1820 Europeans showed that an elevated cfPWV was associated with a higher WMH volume and increased vascular resistance in elderly individuals, suggesting that the correlation between aortic stiffness and memory loss may be mediated by microvascular remodeling and microvascular damage [52]. WMH may also be related to other markers of arterial stiffness. In a study of hypertensive Spanish individuals aged 50–70 years, a higher nocturnal ambulatory PP was associated with MCI and WMHs [9]. WMHs were also shown to be related to the AI and IMT independent of blood pressure levels in elderly hypertensive patients, and WMH severity was shown to be independently associated with increased carotid IMT [53]. Additionally, PWV was shown to be associated with lacunar infarctions independent of other cerebrovascular disease risk factors [54]. In summary, greater arterial stiffness may cause greater arterial pulsatility, which damages the microcirculation. The brain microcirculation is vulnerable to insults as a result of its high-flow, low impedance characteristics [12]. CSVD is considered a major cause of vascular cognitive impairment and is the most common cause of VaD [55,56]. It may be associated with cognitive impairment through a mechanism similar to neurodegeneration referred to as microembolus formation [16]. Thus, the mechanism linking cognitive impairment and arterial stiffness may be related to CSVDs caused by endothelial dysfunction and cerebral blood flow abnormalities [51]. 3. Prevention and treatment Given that arterial stiffness may be a predictor of cognitive decline, arterial stiffness prevention and treatment, particularly early treatment, may effectively prevent cognitive decline. Reducing arterial stiffness severity may facilitate the prevention of dementia prior to its onset or slow its progression. Numerous studies have examined strategies for preventing and attenuating arterial stiffness. 3.1. Physical exercise Maintaining a high physical activity level may attenuate arterial stiffness in older adults. A study regarding middle-aged and elderly individuals from Spain indicated that the amounts of time spent engaged in moderate, vigorous and very vigorous physical activity were inversely associated with the central AI and that the amount of time spent engaged in sedentary activity was positively associated with the central AI [57]. Similarly, a longitudinal study of older individuals with a tenyear follow-up period found that engaging in at least 150 min of moderate-to-vigorous physical activity per week was associated with a lower baPWV [58]. In studies of obese men, dietary modification (adopting a well-balanced diet comprising 1680 kcal/day) and exercise training programs (walking, 40–60 min/day, 3 days/week) were found to reduce PWV and improve arterial function [59,60]. In addition to land-based

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exercise, swimming may also reduce the risk of arterial stiffness [61]. Regular physical activity has been shown to help maintain muscle mass and function and improve brain health and function, including executive function and memory. Moreover, aerobic exercise may reduce the risks of dementia and cognitive impairment by maintaining vascular elasticity [62,63]. However, sedentary behaviors, such as watching television, may result in a higher PWV [64].

3.2. Diet Diet may also have an effect on arterial stiffness and cognition. Different types of fatty acids have been shown to be related to arterial stiffness severity. A study regarding community-dwelling American individuals noted a positive association between higher plasma n-6 polyunsaturated fatty acid intake and arterial stiffness and a negative association between higher long-chain n-3 polyunsaturated fatty acid intake and arterial stiffness [65]. Increased flavonoid consumption has also been reported to be significantly associated with less severe arterial stiffness in Europeans [66]. A review article analyzed 2 cross-sectional and 16 intervention studies assessing the relationship between flavonoid intake and arterial stiffness. The authors of that article determined that isoflavones, anthocyanins and, to a lesser extent, cocoa flavan-3-ols appeared to be effective in improving vascular function [67]. Moreover, cocoa was shown to improve FMD and decrease PWV in a dose-dependent manner in an Italian study involving healthy white individuals [68]. Cocoa may have beneficial effects on arterial stiffness in healthy adults [69], postmenopausal women [70] and middle-aged, overweight women [71]. Tea consumption is also related to arterial stiffness. Habitual tea consumption was reported to have protective effects against arterial stiffness in two Chinese cross-sectional studies. One of those studies involved relatively healthy Chinese individuals and found that increased tea consumption (N450 mL/day for ≥ 1 year) was associated with a lower baPWV. However, moderate tea intake and low tea intake (≤150 mL/day) were not associated with a lower baPWV [72]. Another study showed that Chinese subjects who have habitually consumed N10 g of tea daily for N 6 years have a lower baPWV than subjects who have not [73]. In a clinical study in Italy, black tea ingestion improved FMD and decreased peripheral arterial stiffness in a dose-dependent manner in healthy volunteers [74]. In contrast, a cross-sectional study involving Japanese patients reported that baPWV was not associated with green tea consumption and was inversely associated with coffee consumption [75]. Moreover, a study from Greece showed that chronic coffee consumption (N 1 year) may have detrimental effects on aortic stiffness [76]. Thus, the effect of coffee on arterial stiffness remains unclear. The relationships between different types of tea and coffee and arterial stiffness must be investigated further. Nitrite may be effective in improving arterial stiffness in middleaged and older adults, according to the results of recent studies [77– 79]. In animal experiments, sodium nitrite treatment has been shown to reduce aortic PWV and arterial stiffness severity in older mice [80], and short-term nitrite therapy has been shown to attenuate age-related vascular endothelial dysfunction, large elastic artery stiffness, oxidative stress and inflammation [77]. Thus, sodium nitrite may be a novel therapy for arterial aging in humans. Additional studies involving humans are necessary to confirm that chronic nitrite or nitrate supplementation protects against arterial stiffness. Salt intake has been shown to have independent effects on arterial stiffness. In particular, a low-salt diet was recently reported to effectively preserve the health of arterioles in Asians [81]. Dietary calcium intake driven by dietary vitamin D intake was also shown to be related to improvements in arterial stiffness in middle-aged Japanese men, suggesting that adequate dietary calcium and vitamin D intake may protect against the development and progression of arterial stiffness [82].

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3.3. Living habits Lifestyle changes, such as losing weight and quitting smoking, and the adoption of positive living habits, have been reported to reduce the incidence of atherosclerosis. In a study involving healthy overweight and obese young Americans aged 20–45 years, 6 months of weight loss and improvements in insulin sensitivity were each effective in improving baPWV. Moreover, individuals who lost weight and improved their fasting insulin levels exhibited greater improvements in the baPWV than individuals who did not [83]. In addition, a previous study in Romania showed that controlling hypertriglyceridemia may prevent worsening of vessel stiffness [84]. Furthermore, studies involving Japanese patients demonstrated that an association exists between the number of cigarettes smoked per day and arterial stiffness, as measured by the CAVI, in Japanese males [85]. Continuous smoking is believed to accelerate age-related progression of vascular stiffening in middleaged Japanese individuals [86], and smoking cessation was found to be related to improved arterial stiffness in Chinese patients [87]. Moreover, avoiding secondhand smoke prevented arterial stiffening in Swiss patients [88]. 3.4. Drugs Long-term effective blood pressure control was reported to be effective in reducing cfPWV and improving arterial stiffness in a meta-analysis comprising 15 studies [89]. Antihypertensive drugs, such as beta blockers and calcium blockers, are effective in preserving vascular health [90]. Moreover, mineralocorticoid receptor blockers have been shown to improve endothelial function and reduce arterial stiffness [91]. For example, low-dose spironolactone, a type of mineralocorticoid receptor blocker, may be useful for attenuating vascular inflammation and preventing arterial stiffness progression [92]. A meta-analysis including 19 randomized trials and 11 studies analyzed the effects of antihypertensive treatments on cognition and showed that all types of antihypertensive treatment have beneficial effects on overall cognitive function. The results of the analysis indicated that angiotensin II receptor blockers were more effective than β-blockers, β-blockers had more benefits than diuretics, and diuretics were better than angiotensinconverting enzyme inhibitors in their effects [93]. Statins have been shown to have beneficial effects on arterial stiffness. A community-based longitudinal study involving elderly Chinese individuals with a mean age of 61 years who were followed up for 4.8 years showed that triglyceride levels were independently associated with cfPWV, suggesting that achieving low triglyceride levels may be a potential therapeutic consideration in arterial stiffness [94]. A metaanalysis including six randomized controlled studies regarding the use of statins for the treatment of arterial stiffness demonstrated that treatment with statins, including simvastatin, rosuvastatin, lovastatin, fluvastatin, and atorvastatin, has beneficial effects on aortic stiffness [95]. Additional studies are necessary to determine the effects of different doses of statins in individuals of different races, ages and genders. New drugs are being developed to prevent vascular dysfunction. Compound 21, a novel selective angiotensin II receptor agonist, has been determined to have promising effects on arterial stiffness [96]. Furthermore, an animal study in the United States showed that the combination of olmesartan and compound 21 may prevent hydroxyproline deposition and thus reduce arterial stiffness [97]. 4. Conclusions and perspectives Cognitive decline and age are closely related to blood vessel health. Arterial stiffness may increase the risks of subclinical cerebrovascular disease and cognitive impairment at an early age [46] and may also be useful for predicting cognitive injury. Arterial stiffness severity has the potential to serve as an indicator enabling clinicians to administer prompt treatments intended to prevent or delay the onset of dementia.

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Fig. 1. Pathophysiological mechanism of cognitive impairment related to arterial stiffness and its prevention and treatment approaches. Note: CSVDs-cerebral small vessel diseases, PWVpulse-wave velocity, CAVI-cardio-ankle vascular index, ABI-ankle-brachial index, PP-pulse pressure, AI-augmentation index, FMD-flow-mediated dilation, IMT-intima media thickness, index-β- arterial stiffness index-β.

Treating arterial stiffness early is beneficial and recommended (Fig. 1 summarizes the pathophysiological mechanisms underlying the development of cognitive impairments related to arterial stiffness, as well the methods for preventing and treating arterial stiffness). Funding sources This work was supported by the Science and Technology Pillar Program of Hebei Province of China (No. 14277787D) and the Science and Technology Plan Program of Hebei Province of China (No. 16397795D). Disclosure The authors report no conflicts of interest regarding the publication of this report. Acknowledgments We thank American Journal Experts for assisting us with the revision of the language and grammar of this manuscript. References [1] J.N. Cohn, D.A. Duprez, G.A. Grandits, Arterial elasticity as part of a comprehensive assessment of cardiovascular risk and drug treatment, Hypertension 46 (1) (2005) 217–220. [2] P. Boutouyrie, A.I. Tropeano, R. Asmar, et al., Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: a longitudinal study, Hypertension 39 (1) (2002) 10–15. [3] S. Laurent, P. Boutouyrie, R. Asmar, et al., Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients, Hypertension 37 (5) (2001) 1236–1241. [4] N. Saji, K. Toba, T. Sakurai, Cerebral small vessel disease and arterial stiffness: tsunami effect in the brain, Pulse 3 (3–4) (2016) 182–189. [5] S. Laurent, J. Cockcroft, L. Van Bortel, et al., Expert consensus document on arterial stiffness: methodological issues and clinical applications, Eur. Heart J. 27 (21) (2006) 2588–2605. [6] Y. Zhang, D. Agnoletti, Y. Xu, J.G. Wang, J. Blacher, M.E. Safar, Carotid-femoral pulse wave velocity in the elderly, J. Hypertens. 32 (8) (2014) 1572–1576 (discussion 1576). [7] S.W. Rabkin, Arterial stiffness: detection and consequences in cognitive impairment and dementia of the elderly, J. Alzheimers Dis. 32 (3) (2012) 541–549. [8] A. Scuteri, M. Tesauro, L. Guglini, D. Lauro, M. Fini, D.N. Di, Aortic stiffness and hypotension episodes are associated with impaired cognitive function in older subjects with subjective complaints of memory loss, Int. J. Cardiol. 169 (5) (2013) 371–377. [9] I. Riba-Llena, C. Nafría, J. Filomena, et al., High daytime and nighttime ambulatory pulse pressure predict poor cognitive function and mild cognitive impairment in hypertensive individuals, J. Cereb. Blood Flow Metab. 36 (1) (2016) 253–263.

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