**4. Cognitive impairment after atherosclerosis**

Aging is a major risk factor for neurodegenerative disease associated with atherosclerosis [65]. Previous studies have demonstrated a strong association between aging and vascular diseases. Recent clinical investigations have focused on the relationship between levels of circulating adhesion factors in peripheral blood and cerebrovascular diseases [66]. Platelets and leukocytes play a major role in atherothrombosis, aggregates of which result in the formation of atherosclerotic plaques [67]. Although other factors associated with vascular disease can influence the cognitive state, few studies have utilized flow cytometry to investigate platelet and leukocyte markers in older adults with cognitive decline. Research has demonstrated a correlation between circulating adhesion molecules in patients with atherosclerosis and atherosclerosis factors such as intima-media thickness (IMT) and the number of plaques, which may assist in determining the presence and/or extent of cognitive decline [68]. To determine the potential usefulness of this correlation for determining diagnoses/prognoses, blood factor analysis is required. Based on the pathophysiological mechanism underlying dementia, most relevant studies have aimed to identify molecular markers based on drug responses [69]. As such, little is known regarding the potential role of circulating adhesion molecules in patients with vascular diseases during the early and later stages of cognitive dysfunction.

Many definitions have been proposed for the transition point when healthy aging with a slight cognitive decline progresses to dementia [70]. Mild cognitive impairment (MCI), which was first proposed by a group of investigators from the Mayo Clinic in the late 1990s [70], was defined to be based on a memory problem. This section provides our results about assessing the relationship between changes in blood factors and ultrasound findings in patients with MCI and dementia who were also exhibiting signs of atherosclerosis.

#### **4.1. Atherosclerosis and dementia**

chaperone shuttling protein aggregates from cytosol to autophagosomes, is combined to protein aggregates and degraded, increased level of p62/SQSTM1 indicate defective in autophagic flux autophagy [62]. Correspondingly, deficient autophagy of macrophage can facilitate atherosclerotic plaque progression. *Atg*5 knock-out mice with ApoE-null background showed that western diet for 2 months increased the level of p62/SQSTM1 in the vessel with similar level of control mice whereas atherosclerotic lesion was bigger than control both in aortic root and whole aorta [62]. Using animals with experimental atherosclerosis, ApoE-null mice, recent study proposed that plaque formation expands when macrophagic autophagy is completely disrupted and not partially disrupted. Partially disrupted autophagic condition induces rather macrophagy inflammation and excess IL-1beta, because cholesterol crystal of atherosclerotic

Cholesterol efflux is induced to balance the level of macrophage storing lipid by transferring increased cholesterol from peripheral tissues to the liver. The primary cholesterol efflux mechanism has been thought that cholesterols are hydrolyzed cholesteryl esters cytosolic hydrolases; free cholesterols are moved to the plasma membrane; finally free cholesterols are delivered to the periphery by ATP-binding cassette transporters (ABCA1 or ABCG1) [63]. Autophagic malfunction of macrophages abrogates this cholesterol efflux when macrophages are faced to hinder autophage by chemically (chloroquine) or genetically (*Atg*5 deficiency). Furthermore, inhibitors of lysosomal acid lipase also diminish cholesterol efflux. These showed that cholesterol hydrolysis as well as autophagic delivery is a critical step in atherosclerotic plaque progression and regression. Although lipid-laden macrophages induce lipophagy and also trigger a counter regulatory mechanism are unclear, it is clear that lipophagy-mediated efflux plays an important role in cholesterol transport in vivo [7]. Therefore, efficient cholesterol metabolism and efflux considered athero-protective mechanisms against

Aging is a major risk factor for neurodegenerative disease associated with atherosclerosis [65]. Previous studies have demonstrated a strong association between aging and vascular diseases. Recent clinical investigations have focused on the relationship between levels of circulating adhesion factors in peripheral blood and cerebrovascular diseases [66]. Platelets and leukocytes play a major role in atherothrombosis, aggregates of which result in the formation of atherosclerotic plaques [67]. Although other factors associated with vascular disease can influence the cognitive state, few studies have utilized flow cytometry to investigate platelet and leukocyte markers in older adults with cognitive decline. Research has demonstrated a correlation between circulating adhesion molecules in patients with atherosclerosis and atherosclerosis factors such as intima-media thickness (IMT) and the number of plaques, which may assist in determining the presence and/or extent of cognitive decline [68]. To determine the potential usefulness of this correlation for determining diagnoses/prognoses, blood factor analysis is required. Based on the pathophysiological mechanism underlying dementia, most relevant studies have aimed to identify molecular markers based on drug responses [69]. As

plaques is potent stimuli to activate inflammasome [62].

104 Atherosclerosis - Yesterday, Today and Tomorrow

accumulated lipid-laden atherogenic condition [64].

**4. Cognitive impairment after atherosclerosis**

Carotid atherosclerosis severity is assessed by considering the plaque number, proportions, and location as well as the presence of carotid stenosis that is caused by plaques. Additionally, the severity of carotid stenosis is determined according to the blood flow velocities, residual rumen diameter, and carotid artery flow velocities ratio to internal carotid artery versus the common carotid artery [71]. For AD, it is generally accepted that vascular risk factors have an epidemiological effect on dementia [72]. It has been reported that a narrowed carotid lumen is a risk factor for cognitive impairment in steno-occlusive carotid artery disease patients [72]. Revascularization procedures may have some benefit in the alleviation of dementia, but not for all of these patients [72]. In cases of mild AD with severe asymptomatic intra-carotid artery (ICA) stenosis, cognitive decline progressed even though they have not experienced cerebral ischemia [72]. One possible explanation of this relationship is that insufficient cerebrovascular flow causes cerebral atrophy. Another one is vascular factors that are promoting the degenerative changes of AD [72].

The available studies have identified factors associated with aging and vascular dysfunction that exhibit a cross-sectional relationship with mental status based on the Mini-Mental State Examination (MMSE) score. Recent studies have reported that carotid artery atherosclerosis is associated with a subsequent risk of new or recurrent cerebrovascular diseases, such as stroke, post-stroke vascular dementia, and MCI [66, 73, 74]. Furthermore, chronic hypoperfusion caused by carotid stenosis has been reported to play a role in cognitive decline [75]. Dementia represents a major public health concern [68], as accumulating evidence has demonstrated that the incidence and prevalence of dementia increases rapidly with advancing age. Although it has been difficult to investigate changes in the incidence and prevalence of dementia due to variations in diagnostic criteria and methods, a recent epidemiological study indicated that the dementia prevalence and incidence have decreased in some countries. Moreover, the number of patients with dementia has remained stable in the aging population of these countries [76]. Some evidence has suggested that vascular risk factors are associated with the onset and progression of AD [77]. There are increasing concerns that microvascular disease and tau deposition are found concomitantly and it is thought that treating vascular risk factors is as important as preventing cognitive decline [66]. Although the association between anterior cerebral artery (ACA) plaques and dementia has not been fully determined for the number and the location of plaques, it can be used as a better indicator of disease progression and severity.

In addition, increased cerebrovascular risk has been associated with more severe dementia and a higher MCI incidence [78]. Considering the role of vascular blood factors in patients with MCI, such factors may also influence the progression of cognitive decline [79]. However, there are currently no markers for the prediction of prognosis or the risk of conversion from MCI to dementia. Therefore, it is necessary to develop noninvasive diagnostic methods for the assessment of vascular status [80]. This aspect is discussed in more detail in the next subsection with my results.

plaques are associated with dementia even after controlling for vascular risk factors [66]. Other researchers have suggested that atherosclerosis plays a role in cognitive impairment, particularly in older adults [83]. Such research has further demonstrated a converging relationship between degenerative vascular dysfunction and cognitive dysfunction. In our study, most patients with MCI exhibit atherosclerotic vessel abnormalities, such as increased IMT and plaque numbers, increasing the risk for progression to dementia. An estimated 15–42% of people over the age of 65 years exhibit some form of MCI, and approximately 5–15% of patients with MCI go on to develop dementia [70]. Recent evidence has revealed that vessel dysfunction contributes to AD as well as vascular dementia [84]. In this previous study, the authors reported an IMT cutoff value of 0.805 for the prediction of MCI development (baseline: 0.825 mm) [84]. Diagnosis of dementia in such patients is required in order to ensure the

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Our results indicated that intima thickness and plaque number are associated with higher levels of p-selectin, supporting the evidence that platelets are engaged in the formation of PLAs [85]. In the dementia group of the present study, which included individuals with dementia, plaque numbers corresponded strongly with levels of PSGL-positive platelets. Control of plaque numbers with appropriate therapy such as statin treatment may thus delay or prevent the progression of cognitive decline to dementia. Our findings also indicated that carotid atherosclerosis correlates with MCI as well as increased numbers of PSGL-expressing platelets. Analysis of blood factors using ultrasonography may aid clinicians in determining the most appropriate treatment strategy for patients with cognitive decline with vessel disease. Our simple assessment of vascular risk factors does not seem to be a fully satisfactory approach for adequately counteracting the risk of developing dementia, when compared to other largescale studies [86]. Nevertheless, we suggest that analysis of circulating adhesion factors may aid in predicting the risk of progressive cognitive impairment. Additionally, aggressive treatments for vascular disease should be considered for individuals with a predisposition toward dementia. Despite these limitations, our findings provide a basis for a future study regarding

In conclusion, our findings demonstrate that circulating adhesion molecule levels and interaction between factors present significant differences in patient with MCI or dementia. Alterations in IMT and plaque number are associated with an increased risk of cognitive decline as well as conversion from MCI to dementia. These results suggest that ultrasound findings may aid in identifying older individuals at increased risk for the progression of cognitive decline when there is cerebrovascular damage. Moreover, our findings suggest that the presence of atherosclerotic changes and changes in blood factors such as p-selectin, PSGL,

The World Alzheimer Report 2015 announced the estimate that 46.8 million people worldwide have dementia, and this number is expected to increase to 74.7 million by 2030 and 131.5 million by 2050 [76]. Accordingly, due to concerns about the increasing incidence of dementia, dementia is predicted to be 'epidemic' and a consequent economic burden. The G8 dementia

appropriate therapeutic guidelines and treatments are utilized [76].

biomarkers of both cerebrovascular disease and cognitive dysfunction.

PLA, and PMA can be used to predict the progression of MCI and dementia.

**4.3. Prevalence and incidence of MCI and dementia in atherosclerosis**

#### **4.2. Neurosonological findings of atherosclerosis and dementia**

In our recent study, we demonstrated that alterations in IMT and plaque number are associated with an increased risk of cognitive decline as well as a risk of dementia. Our results suggest that ultrasound findings may aid in identifying older individuals at increased risk for the progression of cognitive decline when morphological impairment of cerebrovascular structures has been identified. Moreover, our findings suggest that the presence of atherosclerotic changes and changes in blood factors such as p-selectin glycoprotein ligand (PSGL, CD162), platelet-leukocyte aggregation (PLA), and platelet-monocyte aggregation (PMA) can be used to predict MCI and dementia.

Our study showed that levels of p-selectin in circulating platelets, PSGL, and circulating platelet-monocyte aggregates were significantly increased in patients with MCI relative to controls. The changes in circulating blood factors have been reported to relate with vascular diseases such as ischemic stroke or atherosclerosis [81]. Based on this association, several noninvasive measures for evaluating subclinical atherosclerosis have received intense attention in clinical and research settings for the predictive diagnosis of cerebrovascular diseases. Researchers have suggested a relationship between atherosclerotic severity and circulating adhesion blood factors and atherosclerotic severity and cognitive decline in the above-mentioned reports. With one step further linked between them, our findings provide insight into the use of blood factor analysis (using FACS) as well as ultrasonographic evaluation of vessel status in both clinical and research settings. Changes in platelet activation and monocyte distribution are observed in the early stages of atherosclerosis. Such changes are strongly associated with stroke onset, as demonstrated by various studies [82]. The monocyte receptor CD14 and leukocyte antigen CD45 are best known for their crucial role in immunity. In addition, CD14 and CD16 are well-known biomarkers for atherosclerotic disease progression [67]. Research has also suggested that PSGL is a pro-atherogenic marker of vascular disease progression [67].

The present study shows that increased IMT was more frequently observed in patients with MCI, whereas increased numbers of carotid plaques were more frequently observed in patients with dementia. The patients with MCI in our study comprise 32% of all patients with atherosclerosis, and all patients of the MCI group in the present study had been diagnosed with carotid vascular stenosis or atherosclerosis. These findings suppose that vessel damage is followed by MCI. A lot of findings in previous studies suggest that greater degrees of carotid atherosclerosis are associated with the progression from MCI to dementia [66, 68, 78]. A recent study reported that up to 50% of patients develop vascular stenosis, and that ACA plaques are associated with dementia even after controlling for vascular risk factors [66]. Other researchers have suggested that atherosclerosis plays a role in cognitive impairment, particularly in older adults [83]. Such research has further demonstrated a converging relationship between degenerative vascular dysfunction and cognitive dysfunction. In our study, most patients with MCI exhibit atherosclerotic vessel abnormalities, such as increased IMT and plaque numbers, increasing the risk for progression to dementia. An estimated 15–42% of people over the age of 65 years exhibit some form of MCI, and approximately 5–15% of patients with MCI go on to develop dementia [70]. Recent evidence has revealed that vessel dysfunction contributes to AD as well as vascular dementia [84]. In this previous study, the authors reported an IMT cutoff value of 0.805 for the prediction of MCI development (baseline: 0.825 mm) [84]. Diagnosis of dementia in such patients is required in order to ensure the appropriate therapeutic guidelines and treatments are utilized [76].

In addition, increased cerebrovascular risk has been associated with more severe dementia and a higher MCI incidence [78]. Considering the role of vascular blood factors in patients with MCI, such factors may also influence the progression of cognitive decline [79]. However, there are currently no markers for the prediction of prognosis or the risk of conversion from MCI to dementia. Therefore, it is necessary to develop noninvasive diagnostic methods for the assessment of vascular status [80]. This aspect is discussed in more detail in the next sub-

In our recent study, we demonstrated that alterations in IMT and plaque number are associated with an increased risk of cognitive decline as well as a risk of dementia. Our results suggest that ultrasound findings may aid in identifying older individuals at increased risk for the progression of cognitive decline when morphological impairment of cerebrovascular structures has been identified. Moreover, our findings suggest that the presence of atherosclerotic changes and changes in blood factors such as p-selectin glycoprotein ligand (PSGL, CD162), platelet-leukocyte aggregation (PLA), and platelet-monocyte aggregation (PMA) can be used

Our study showed that levels of p-selectin in circulating platelets, PSGL, and circulating platelet-monocyte aggregates were significantly increased in patients with MCI relative to controls. The changes in circulating blood factors have been reported to relate with vascular diseases such as ischemic stroke or atherosclerosis [81]. Based on this association, several noninvasive measures for evaluating subclinical atherosclerosis have received intense attention in clinical and research settings for the predictive diagnosis of cerebrovascular diseases. Researchers have suggested a relationship between atherosclerotic severity and circulating adhesion blood factors and atherosclerotic severity and cognitive decline in the above-mentioned reports. With one step further linked between them, our findings provide insight into the use of blood factor analysis (using FACS) as well as ultrasonographic evaluation of vessel status in both clinical and research settings. Changes in platelet activation and monocyte distribution are observed in the early stages of atherosclerosis. Such changes are strongly associated with stroke onset, as demonstrated by various studies [82]. The monocyte receptor CD14 and leukocyte antigen CD45 are best known for their crucial role in immunity. In addition, CD14 and CD16 are well-known biomarkers for atherosclerotic disease progression [67]. Research has also suggested that PSGL is a pro-atherogenic marker of vascular disease

The present study shows that increased IMT was more frequently observed in patients with MCI, whereas increased numbers of carotid plaques were more frequently observed in patients with dementia. The patients with MCI in our study comprise 32% of all patients with atherosclerosis, and all patients of the MCI group in the present study had been diagnosed with carotid vascular stenosis or atherosclerosis. These findings suppose that vessel damage is followed by MCI. A lot of findings in previous studies suggest that greater degrees of carotid atherosclerosis are associated with the progression from MCI to dementia [66, 68, 78]. A recent study reported that up to 50% of patients develop vascular stenosis, and that ACA

**4.2. Neurosonological findings of atherosclerosis and dementia**

section with my results.

106 Atherosclerosis - Yesterday, Today and Tomorrow

to predict MCI and dementia.

progression [67].

Our results indicated that intima thickness and plaque number are associated with higher levels of p-selectin, supporting the evidence that platelets are engaged in the formation of PLAs [85]. In the dementia group of the present study, which included individuals with dementia, plaque numbers corresponded strongly with levels of PSGL-positive platelets. Control of plaque numbers with appropriate therapy such as statin treatment may thus delay or prevent the progression of cognitive decline to dementia. Our findings also indicated that carotid atherosclerosis correlates with MCI as well as increased numbers of PSGL-expressing platelets. Analysis of blood factors using ultrasonography may aid clinicians in determining the most appropriate treatment strategy for patients with cognitive decline with vessel disease. Our simple assessment of vascular risk factors does not seem to be a fully satisfactory approach for adequately counteracting the risk of developing dementia, when compared to other largescale studies [86]. Nevertheless, we suggest that analysis of circulating adhesion factors may aid in predicting the risk of progressive cognitive impairment. Additionally, aggressive treatments for vascular disease should be considered for individuals with a predisposition toward dementia. Despite these limitations, our findings provide a basis for a future study regarding biomarkers of both cerebrovascular disease and cognitive dysfunction.

In conclusion, our findings demonstrate that circulating adhesion molecule levels and interaction between factors present significant differences in patient with MCI or dementia. Alterations in IMT and plaque number are associated with an increased risk of cognitive decline as well as conversion from MCI to dementia. These results suggest that ultrasound findings may aid in identifying older individuals at increased risk for the progression of cognitive decline when there is cerebrovascular damage. Moreover, our findings suggest that the presence of atherosclerotic changes and changes in blood factors such as p-selectin, PSGL, PLA, and PMA can be used to predict the progression of MCI and dementia.

#### **4.3. Prevalence and incidence of MCI and dementia in atherosclerosis**

The World Alzheimer Report 2015 announced the estimate that 46.8 million people worldwide have dementia, and this number is expected to increase to 74.7 million by 2030 and 131.5 million by 2050 [76]. Accordingly, due to concerns about the increasing incidence of dementia, dementia is predicted to be 'epidemic' and a consequent economic burden. The G8 dementia summit in 2013 and the WHO Ministerial Conference in 2015 decided to engage in a global action against dementia. The Atherosclerosis Risk in Communities (ARIC) study performed in 1987–1989 enrolled 15,792 individuals: they were a bi-racial group, with an age range from 45 to 64 years, from 4 US communities. Cognitive assessments were performed in the second ARIC examination in 1990–1992 [74]. A comprehensive dementia study, Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), was used as the fifth ARIC examination in 2011–2013. They evaluated what happens to participants with extensive cardiovascular disease and cognitive dysfunction after a long history of ARIC and for the participants who died. This is a longitudinal cohort depicting the association of cognitive function, cardiovascular condition, cerebrovascular condition, and mortality. In ARIC-NCS, they reported that the overall prevalence of dementia in living ARIC participants is similar to the estimate of the World Alzheimer Report 2015. Although the prevalence of MCI in ARIC-NCS and the prevalence of MCI have been reporting to be at a similar level, there is a variation in MCI prevalence because of different MCI definitions [74]. Therefore, longitudinal studies of incident dementia in this cohort are required for validation of the MCI definition.

formation. When the rapamycin derivative everolimus is delivered from a stent in atherosclerotic plaques, in the lesion site of cholesterol-fed rabbits, autophagic macrophage death occurred due to macrophage reduction. In contrast, the amounts of VSMCs were sustained without change [89]. An mTOR-mediated pathway induces dephosphorylation of p70 S6 kinase, which is responsible for selective induction of macrophage death. On the other hand, the protein synthesis inhibitor cycloheximide induced selective macrophage death in plaques of cholesterol-fed rabbits. In this case, apoptosis occurred not only via autophagy, because plaque macrophages might be highly metabolic active and vulnerable to protein synthesis

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As another therapeutic case of rapamycin, inhibited translation of VSMCs leads to upregulation of smooth muscle B-actin, calponin, and myosin heavy chain, which modulates VSMCs to be differentiated, quiescent, and have a contractile phenotype. As a result, VSMCs undergo cell death. It has been suggested that restricted protein translation might selectively induce macrophage cell death rather than cell death protein expression. mTOR gene silencing is another therapeutic approach. Transfection of mTOR-specific small interfering RNA selectively induces macrophage cell death [89]. The recent evidence shows that the transcription factor TFEB works as a transcriptional activator for a network of autophagy and lysosomal genes [91]. The studies show that macrophage specific gene activator of TFEB has the ability of lysosomal biogenesis, recovering lysosomal dysfunction via atherogenic lipids. It allows some functions such as increasing cholesterol efflux, inhibiting inflammation activation, and clearing abnormal protein aggregate [16]. This study provides the possibility that over-

Lipid reduction is the one of the well-known ways to eradicate macrophages from atherosclerotic plaques [36]. One of recent studies using a rabbit atherosclerosis model suggested that the lower levels of lipid led not to macrophage apoptosis but instead monocyte recruiting impairment because of a decrease in macrophage replication. Statins are generally used in myocardial infarction patients. In SMCs treated with the autophagy inducer 7-ketocholesterol, fluvastatin failed to activate caspases. It has been suggested there is a possibility that activation of autophagy interferes with the statin-induced apoptotic pathway [36]. Another suggestion that has been proposed is that defective mitochondria are engulfed by autophagosomes, which limits the relocation of pro-apoptotic molecules from mitochondria into the

Currently, statin drugs are major therapeutics to prevent acute coronary events. Statins inhibit cholesterol biosynthesis, reduce LDL receptors (LDLRs), and consequently trigger a reduction in blood cholesterol levels [92]. Statins work at multiple stages in atherosclerotic plaque formation. Among these stages, statins have effects at earlier atherosclerosis development stages because they hinder cholesterol accumulation, monocyte infiltration, and inflammation in arteries [92]. Carotid atherosclerosis is measured by two distinct characteristics: carotid intimamedia thickness (cIMT) and carotid plaque burden quantified by plaque presence or localization. A recent study suggests that plaque burden may act as a predictor of cardiovascular

expressed TFEB in macrophages alleviates atherosclerosis [16].

**5.2. Treating atherosclerosis as a therapy for cognitive impairment**

inhibitors relative to SMCs [90].

cytosol or nucleus [36].

From some studies, it is obvious that the prevalence of dementia is related to stroke, heart disease, hypertension, and diabetes. These results are limited because many medications used to treat cardiovascular disease and other vascular diseases have been observed to have an effect on dementia prevalence and incidence. This is why no single factor has been identified to fully explain the changes in dementia prevalence and incidence. However, it is important to identify multiple risk factors and protective factors throughout a personal whole life-course relating to physical, mental, and cognitive health. In particular, atherosclerotic and vascular risk factors need to be well-controlled for reducing the risk of dementia in later life.
