Relationship between Cognitive Impairment and Echocardiographic Parameters: A Review

Relationship between Cognitive Impairment and Echocardiographic Parameters: A Review Dimitri Arangalage, MD, St
ephane Ederhy, MD, Laurie Dufour, MD, J
er
emie Joffre, MD, Cl
elie Van der Vynckt, MD, Sylvie Lang, PhD, Christophe Tzourio, MD, PhD, and Ariel Cohen, MD, PhD, Paris and Bordeaux, France

With >24 million people affected worldwide, dementia is one of the main public health challenges modern medicine has to face. The path leading to dementia is often long, with a wide spectrum of clinical presentations, and preceded by a long preclinical phase. Previous studies have demonstrated that clinical strokes and covert vascular lesions of the brain contribute to the risk for developing dementia. Although it is not yet known whether preventing such lesions reduces the risk for dementia, it is likely that starting preventive measures early in the course of the disease may be beneficial. Echocardiography is a widely available, relatively inexpensive, noninvasive imaging modality whereby morphologically or hemodynamically derived parameters may be integrated easily into a risk assessment model for dementia. The aim of this review is to analyze the information that has accumulated over the past two decades on the prognostic value of echocardiographic factors in cognitive impairment. The associations between cognitive impairment and echocardiographic parameters, including left ventricular systolic and diastolic indices, left atrial morphologic parameters, cardiac output, left ventricular mass, and aortic root diameter, have previously been reported. In the light of these studies, it appears that echocardiography may help further improve currently used risk assessment models by allowing detection of subclinical cardiac abnormalities associated with future cognitive impairment. However, many limitations, including methodologic heterogeneity and the observational designs of these studies, restrict the scope of these results. Further prospective studies are required before integrating echocardiography into a preventive strategy. (J Am Soc Echocardiogr 2014;-:---.) Keywords: Echocardiography, Mild cognitive impairment, Dementia, Prevention

Since the early 1990s, many cross-sectional and longitudinal epidemiologic studies have revealed an association between vascular factors, including clinical, biologic, and echocardiographic parameters, and risk for cardiovascular events. The results of these studies have allowed the stratification of patients according to their individual risk, the aim being to develop treatments and preventive measures for use at an early stage of the disease. With >24 million people affected worldwide and considering the increasing life expectancy of the population, dementia is becoming one of the main public health challenges modern medicine has to ^ pital Saint Antoine, Assistance Publique – From the Service de Cardiologie, Ho ^ pitaux de Paris, Paris, France (D.A., S.E., L.D., J.J., C.V.d.V., S.L., A.C.); Ho
de Me
decine Pierre et Marie Curie, Paris, France University Paris 6, Faculte (D.A., L.D., C.V.d.V., A.C.); and INSERM Research Center for Epidemiology and Biostatistics (U897), Team Neuroepidemiology, and University of Bordeaux, Bordeaux, France (C.T.). Dr Tzourio has received fees from Fondation de Recherche sur l’Hypertension
rielle for participating in a scientific committee. Dr Cohen has received a Arte research grant from RESICARD (research nurses) and consulting and lecturing fees from AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Daiichi-Sankyo, GlaxoSmithKline, and Sanofi. All other authors report no conflicts of interest. Reprint requests: Ariel Cohen, MD, PhD, Department of Cardiology, Saint Antoine
Pierre et Marie Curie, 184 rue du University and Medical School, Universite Faubourg Saint-Antoine, 75571 Paris Cedex 12, France (E-mail: ariel.cohen@sat. aphp.fr). 0894-7317/$36.00 Copyright 2014 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2014.11.009

face.1 It is one of the primary causes of loss of autonomy and institutionalization of elderly patients in many countries.1 The path leading to dementia is often long, with a wide spectrum of initial clinical presentations. Moreover, an extended period exists during which subjects do not exhibit clinically noticeable symptoms despite the presence of neurodegenerative lesions.2 Identifying early determinants of this process may lead to the initiation of specific treatments to slow the progress of the disease.3 More particularly, clinical strokes and covert vascular lesions of the brain contribute to the risk for developing all types of dementia.4-6 Although it is not yet known whether preventing such lesions reduces the risk for dementia, it is very likely that starting preventive measures early in the course of the disease may be beneficial. Prevention has had a significant role in the decline of many cardiovascular diseases, and the application of such measures to cognitive impairment could have major medical and economic impacts.7,8 An increasing volume of information has accumulated over the past two decades on the prognostic value of echocardiographic factors in cognitive impairment. In this article, we seek to provide an up-to-date review on the link between the two.

CLINICAL DETERMINANTS OF COGNITIVE IMPAIRMENT The main clinical factors associated with cognitive impairment are advanced age, hypertension, diabetes mellitus, high plasma cholesterol levels, obesity, tobacco smoking, and the presence of atherosclerotic vascular disease.9-14 In addition to these risk factors, 1

2 Arangalage et al

hyperhomocysteinemia, diets comprising high levels of AF = Atrial fibrillation saturated fats, excessive alcohol consumption, and physical CO = Cardiac output inactivity increase the risk for GLS = Global longitudinal developing Alzheimer’s disstrain ease.15 These risk factors are also associated with an increase LA = Left atrial in the incidence of cerebrovascuLV = Left ventricular lar diseases.15 Although the exact mechanisms are still unknown, LVEF = Left ventricular ejection fraction heart failure16,17 and the occurrence of acute coronary MRI = Magnetic resonance syndromes18 are also associated imaging with risk for cognitive impairment, probably because of the increased risk for vascular disease in this category of patients.19 The occurrence of cardioembolic strokes and reduced cardiac output (CO) leading to decreased cerebral perfusion may also explain the increased risk for cognitive impairment in patients with heart failure.16,17 Atrial fibrillation (AF) is also independently associated with the onset of cognitive impairment and Alzheimer’s disease, although the exact mechanism explaining this link remains unclear.20,21 With an annual incidence of 4.5%, AF is the primary cause of ischemic stroke, causing up to 15% of reported events.22 The development of brain imaging techniques including magnetic resonance imaging (MRI) has revealed the occurrence of silent brain infarctions in patients with AF, causing damage to the brain parenchyma, leading to further cognitive impairment.21 Moreover, patients with mild cognitive impairment face an increased risk for conversion to dementia if they have associated diagnoses of AF.23 Another important determinant of cognitive impairment is the presence of cerebral white matter lesions detected on brain MRI. These lesions are associated with reduced performance of many cognitive functions, such as executive functions, processing speed, and immediate and delayed memory.24,25 Abbreviations

COGNITIVE IMPAIRMENT RISK EVALUATION MODELS It is now accepted that a preclinical phase exists in dementia, hence the early identification of patients at risk for developing the disease is likely to be a key step.2 In 2006, Kivipelto et al.26 proposed a cognitive impairment risk evaluation model, the Cardiovascular Risk Factors, Aging and Dementia risk score, to predict the 20-year risk for dementia in middle-aged people. This model stratifies patients by age, sex, education, hypertension, body weight, physical activity, hyperlipidemia, and apolipoprotein E genotype.27 Since then, several studies have assessed the usefulness of different risk scores to predict the onset of cognitive impairment and dementia.28-34 It is worthy of note that most of the risk factors associated with dementia used in these algorithms, such as diabetes mellitus, hypertension, hypercholesterolemia, and obesity, are modifiable and are shared with cardiovascular diseases, illustrating the close link between the brain and the heart.13,35-41 This link was further strengthened when the Framingham general cardiovascular disease risk score and the Framingham stroke risk score were compared with the Cardiovascular Risk Factors, Aging and Dementia risk score.27 Following the examples of risk scores used in AF, acute coronary syndromes, or cardiac surgical risk evaluation algorithms, creating a multimodal risk evaluation model on the basis of various parameters including ultrasound-based measures is an appealing idea that may

Journal of the American Society of Echocardiography - 2014

help further enhance our capacity to predict cognitive impairment. However, the usefulness of integrating echocardiographic parameters in a cognitive impairment risk evaluation model has never been assessed.

CONVENTIONAL ECHOCARDIOGRAPHIC PARAMETERS OF THE LEFT VENTRICLE AND COGNITIVE IMPAIRMENT The presence of a heart disease may alter left ventricular (LV) function, leading to a reduction in cerebrovascular blood flow causing subclinical brain injury and cognitive impairment.42-45 It was described previously that patients with severe chronic heart failure may have reduced cerebral blood flow, by approximately 30%, despite the activation of physiologic neurohormonal counterregulatory mechanisms such as the renin-angiotensin system and the sympathetic nervous system.46 LV Systolic Function LV systolic dysfunction, measured by the LV ejection fraction (LVEF), appears to be particularly correlated with cognitive impairment (Table 1, Figure 1).47-53 Jerskey et al.49 found that reduced sustained attention and vigilance is correlated with an LVEF # 55%. In the Framingham Heart Study cohort, comprising participants free of stroke or dementia, a nonlinear association between LVEF and measures of cognitive impairment was suggested.48 In that study, LVEF was not linearly associated with white matter lesions on brain MRI or with any neuropsychological variables, although patients in the lowest and highest LVEF quintiles had abnormal cognitive changes.48 Interestingly, patients belonging to the highest LVEF quintile also had a significant association with reduced cognitive functions in verbal and visuospatial memory, executive functioning, and visuoperceptual abilities. This association persisted despite adjustment for many confounding factors and after the inclusion of multiple covariates. The exact mechanism explaining this phenomenon is unknown.48 Furthermore, an increased risk for future cognitive impairment and stroke is associated with white matter lesions and silent brain infarcts.5,54-57 It is worth mentioning that in several studies, an association between white matter lesions on brain MRI and LV systolic dysfunction has been demonstrated.42,58,59 Recently, Russo et al.60 published the first article studying the association between LV global longitudinal strain (GLS) and subclinical brain disease in a community-based cohort (Table 1). The definition of an abnormal LV GLS value was based on a measure lower outside the 95th percentile of the LV GLS distribution in a subgroup of healthy participants and corresponded to LV GLS $
14%. This article highlighted an association between lower LV GLS and the existence of subclinical cerebral white matter lesions on brain MRI in subjects without dementia symptoms and without overt cardiac disease independently of LVEF. Moreover, significantly lower LV GLS values were observed in participants with silent brain infarcts despite having similar LVEF values.60 LV Diastolic Function LV diastolic dysfunction appears particularly associated with lower cognitive function in patients with heart diseases (Table 1).47,61 Van den Hurk et al.47 showed, in a cohort of healthy people, that LV diastolic dysfunction assessed by E/e0 ratio62-64 at baseline was associated with lower scores on attention and executive functioning at follow-up. Similarly, in a population of patients with cardiovascular

Arangalage et al 3

Journal of the American Society of Echocardiography Volume - Number -

Table 1 Main studies analyzing the link between cognitive impairment and LVEF, GLS, and diastolic function Cardiac imaging parameters

Study

Population

Age (y)*

Cognitive parameters

Results

Russo et al. (2013)

LV GLS

436 stroke-free patients without CVD

69.3 6 9.7

White matter lesions and silent brain infarctions in brain MRI

 Lower GLS associated with silent brain infarctions and white matter lesions  LVEF not associated

Van den Hurk et al. (2011)47

LV diastolic function: ratio of early mitral valve flow velocity and early diastolic lengthening velocity

313 healthy people

67 (59–87)

 Attention and executive functioning  Informationprocessing speed

LV diastolic dysfunction at baseline associated with lower scores on attention and executive functioning at follow-up

Jefferson et al. (2011)48

LVEF

1114 patients from the Framingham Heart Study Offspring Cohort free from stroke or dementia

67 6 9

 Delayed memory, language, executive functioning, verbal reasoning, visuoperceptual abilities  White matter lesions

 LVEF not linearly associated with white matter lesions or neuropsychologic variables  Lowest and highest LVEF quintiles had abnormal cognitive changes

Jerskey et al. (2009)49

LVEF

67 outpatients with stable CVD without neurologic diseases

68.5 6 7.4

Sustained attention and vigilance

Reduced LVEF associated with reduced sustained attention and vigilance

Suwa and Ito (2009)61

LV diastolic function

81 outpatients with stable CVD and LVEF $ 40%

Minimum, 65

MMSE score # 24

LV diastolic dysfunction related to cognitive impairment

Moser et al. (1999)52

LVEF

93 patients with CVD enrolled in a cardiac rehabilitation program

60.9

 Response generation memory  Verbal abstraction  Verbal fluency

LVEF associated with cognitive impairment

 et al. (1997)53 Zuccala

LVEF

57 patients with chronic heart failure

 MMSE score < 24  Mental deterioration battery  CES-D score  Katz activities of daily living  Instrumental activities of daily living

LVEF associated with cognitive impairment

60

Mean, 76.7

CES-D, Center for Epidemiological Studies Depression Scale; CVD, cardiovascular disease; GLS, global longitudinal strain; LV, left ventricular; LVEF, left ventricular ejection fraction; MMSE, Mini-Mental State Examination. *Data are expressed as mean 6 SD or mean (range) unless otherwise stated.

diseases, risk factors, and LVEF $40%, Suwa and Ito61 found a significant association between diastolic function and cognitive impairment. More recently, Shimizu et al.65 identified an association between LV diastolic function and white matter lesions on brain MRI in a population of elderly patients with normal LV contraction and no signs or history of cardiac disease, stroke, or cognitive dysfunction.

LEFT ATRIAL ENLARGEMENT PARAMETERS AND COGNITIVE IMPAIRMENT Left atrial (LA) function can be considered as a three-component model.66 The first component occurs during LV systole and is called

the reservoir phase, in which the left atrium receives blood from the pulmonary veins. The second component is called the passive conduit phase, occurring during LV early diastole and diastasis. The LA contraction phase is the third component, in which the left atrium acts as a contractile pump during late diastole LV filling, contributing to the increase in LV stroke volume.66 Silent brain infarcts caused by AF and reduced cerebral perfusion due to lowered CO are the two main possible mechanisms explaining cognitive impairment caused by LA enlargement.67,68 LA dilation is mainly observed in pressure- or volumeoverload situations. The relationship between increased LV filling pressures, secondary to LV dysfunction or mitral valve disease, and increased LA size due to increased LA afterload has previously been described.68-70 The same applies to the association between LA

4 Arangalage et al

Journal of the American Society of Echocardiography - 2014

Figure 1 Two- and three-dimensional LVEF calculation according to Simpson’s method. (A, B) Normal LVEF in an elderly patient with normal cognitive function. (C, D) Impaired LVEF in an elderly patient diagnosed with dementia. LVEF, Left ventricular ejection fraction. enlargement and LA chronic volume overload observed in valvular regurgitations.71,72 LA enlargement usually involves several of the aforementioned parameters that are independently associated with cognitive impairment (Figure 2). Thus, the relationship between increased LA diameter and the risk for developing AF has previously been described.73,74 LA enlargement is also a significant predictor of stroke and death75,76 and a strong predictor of cardiovascular outcome.68 Furthermore, LV pressures are increased in abnormal LV relaxation situations, causing an increase in LA pressure to maintain efficient LV filling.77 Therefore, the augmentation of atrial wall tension leads to LA dilation. Thus, increased LA volume was found to express the severity of LV diastolic dysfunction.77 Finally, LA enlargement has been found to be a predictor of congestive heart failure.68,78,79 The main studies that analyzed the link between LA parameters and cognitive impairment are detailed in Table 2. Oh et al.67 showed that LA enlargement, defined as a LA diameter on two-dimensional echocardiography > 40 mm in men and > 38 mm in women, was correlated with impaired cognitive functions and white matter lesions. In addition, Karadag et al.80 found that in patients with cognitive impairment, LA volume index was increased by $34 mL/m2. Van den Hurk et al.47 showed that a higher LA volume index was associated with a lower information-processing speed.

CARDIAC OUTPUT AND COGNITIVE IMPAIRMENT The exact mechanism governing the link between cognitive impairment and reduced CO remains unknown.43,67,81 It has previously been reported that counterregulatory mechanisms contribute to the increase of cerebral blood flow during acute periods of reduced CO.82 However, chronic CO reduction may decrease cerebral blood flow, overwhelming autoregulatory phenomena and leading to brain

injury, particularly in elderly individuals with hypertension, in whom a shift of the cerebral autoregulation curve is observed.43,83,84 Interestingly, cerebral blood flow appeared to increase significantly by 53.3%, and returned to normal values after cardiac transplantation in patients with refractory congestive heart failure.85 The main studies that analyzed the link between CO parameters and cognitive impairment are shown in Table 3. Cohen et al.86 found that CO was correlated with overall attention and executive functioning. In the Framingham Offspring Cohort, a subclinical decrease in MRI-assessed cardiac index (CO/body surface area) was associated with impaired cognitive function and positively related to total brain volume and lateral ventricular volume on brain MRI, both markers of brain aging.87-89 Reduced CO < 4 L/min was shown to be associated with poorer executive functioning, mainly sequencing and planning.81 The association between decreased CO and a lower Mini-Mental State Examination score was also recently reported.67 Furthermore, a decrease in CO is associated with the presence of white matter lesions adjacent to the subcortical nuclei in brain MRI.90

LEFT VENTRICULAR MASS AND COGNITIVE IMPAIRMENT The main hypothesis linking cognitive impairment to increased LV mass is the fact that LV mass may be a reflection of chronic exposure to high blood pressure, a recognized risk factor for dementia.91,92 Table 4 details the main studies that investigated the link between LV mass and cognitive impairment. Scuteri et al.92 found that an increased LV mass index was associated with cognitive impairment and a higher probability of developing dementia independently of blood pressure in a population of geriatric outpatients. In the community-based Framingham Offspring Study, LV mass was inversely associated with abstract reasoning, verbal memory,

Arangalage et al 5

Journal of the American Society of Echocardiography Volume - Number -

Figure 2 LA volume assessed by two-dimensional echocardiography. (A, B) Normal LA volume in an elderly patient with normal cognitive function. (C, D) LA enlargement in an elderly patient diagnosed with dementia. LA, Left atrial.

Table 2 Main studies analyzing the link between LA parameters and cognitive impairment Study

Cardiac imaging parameters

Population

Age (y)*

Cognitive parameters

74.8 6 6.9 MMSE score # 25

Karadag et al. (2013)80 LA volume index $ 34 mL/m2

108 stroke-free healthy people without CVD

Oh et al. (2012)67

LA diameter: > 40 mm (men) and > 38 mm (women)

 54 Alzheimer’s disease 74.1 (52–96)  White matter lesions  23 Parkinson’s disease MMSE score  16 vascular dementia

Van den Hurk et al. (2011)47

LA volume index

313 healthy people

Results

Larger LA associated with cognitive impairment LA enlargement correlated with white matter lesions

67 (59–87)  Attention and executive Higher LA volume index functioning associated with lower  Information-processing informationspeed processing speed

CVD, Cardiovascular disease; LA, left atrial; MMSE, Mini-Mental State Examination. *Data are expressed as mean 6 SD or mean (range).

visuospatial memory, and organization.93 Moreover, LV mass has been associated with lower information processing speed.47 Finally, LV hypertrophy has previously been linked to white matter lesions and to the risk for stroke and transient ischemic attack.94,95 This result is probably linked to the fact that hypertension is associated with thickening of the media of intracerebral vessels causing cerebral white matter lesions and ischemic brain injury.94

AORTIC ROOT DIAMETER AND COGNITIVE IMPAIRMENT Paul et al.51 found that an increased aortic root diameter was associated with both impaired cognitive function and cerebral abnormalities on brain MRI, including white matter lesions and whole-brain volume. The relationship between ischemic brain infarction and aortic arch morphology has been described previously.96-100 This link may be explained by the fact that dilation of the aorta has been associated with the presence of atherosclerotic plaques in the vessel, which are known to be positively related to the risk for

stroke.96-100 Aortic root enlargement is also observed in the context of hypertension, and it may therefore also be considered a marker of vascular disease.101

EPICARDIAL FAT THICKNESS AND COGNITIVE IMPAIRMENT Recently, a growing amount of interest has been focused on the link between the amount of visceral adiposity and cognition.102 The epicardial adipose tissue is a recognized index of visceral adiposity,103 a marker of cardiovascular risk,104 and has been associated with inflammation modulators that may play a role in coronary atherosclerosis and in vasculopathic effects mediated by systemic inflammation.105 Considering that chronic inflammation is associated with systemic vasculopathy and progressive cerebral deterioration,106 Mazzoccoli et al.107 recently showed that increased epicardial fat thickness assessed by transthoracic echocardiography was associated with lower cognitive performance evaluated by the Mini-Mental State

6 Arangalage et al

Journal of the American Society of Echocardiography - 2014

Table 3 Main studies analyzing the link between CO and cognitive impairment Cardiac imaging parameters

Study 67

Oh et al. (2012)

CO

Population

Age (y)*

Cognitive parameters

 54 Alzheimer’s disease 74.1 (52–96)  MMSE score  23 Parkinson’s  White matter lesions disease  16 vascular dementia

Results

Lower CO associated with MMSE score

Jefferson et al. (2010)87 MRI-assessed cardiac index (CO/body surface area)

1,504 patients from the Framingham Heart Study Offspring Cohort free from stroke and dementia

61 6 9

Cardiac MRI-assessed  Verbal memory, cardiac index visuospatial memory, associated with verbal learning, neuropsychological executive functioning, and total brain volume information and lateral ventricular processing, language, volume in MRI object recognition  Brain MRI

Cohen et al. (2009)86

CO

88 geriatric outpatients with documented stable CVD and no history of neurologic disease

70 6 7.7

 MMSE score, CO correlated with language, visuospatial attention and abilities, learning, executive functioning memory, attention, executive function.  White matter lesions

Jefferson et al. (2007)90 CO

36 patients with CVD and free of dementia

71.5 6 7.5

Jefferson et al. (2007)81 CO and LVEF

72 geriatric outpatients with treated stable CVD and no history of neurologic disease

69 6 7.5

White matter lesions

Inverse relationship between white matter lesions adjacent to subcortical nuclei and CO

Tasks sensitive to  Reduced CO is cognitive functions associated with mediated by frontalpoorer executive subcortical systems: functioning executive functioning,  No association with other measures LVEF including learning and memory

CO, Cardiac output; CVD, cardiovascular disease; LVEF, left ventricular ejection fraction; MMSE, Mini-Mental State Examination. *Data are expressed as mean 6 SD (range).

Examination score independently of the presence of a metabolic syndrome or obesity. In that study, epicardial fat was defined as the echofree space between the outer wall of the myocardium and visceral layer of pericardium at end-systole measured on the free wall of the right ventricle.107

IS THERE ENOUGH EVIDENCE TO INTEGRATE ECHOCARDIOGRAPHY INTO A PREVENTIVE STRATEGY? In this review, we found strong evidence in favor of the existence of an association between echocardiographic parameters and cognitive impairment. One of the most interesting, but arduous, questions that subsequently arises focuses on the nature of the underlying mechanisms governing this relationship. Echocardiographic evidence such as LA enlargement, systolic and/or diastolic LV dysfunction, and increased LV mass may simply reflect an underlying cardiac condition that predisposes to developing cognitive impairment. On the other hand, cardiac dysfunction itself may be considered as the cause of cognitive impairment. Based only on the results of cross-sectional studies, all answers remain hypothetical, and the exact pathophysiologic mechanisms, as well as the nature of this relationship—direct

and causal or influenced by other factors—needs to be further studied. Therefore, accumulating data on vascular risk factors, brain MRI, and echocardiographic parameters, before the onset of the disease, is of utmost importance. Gathering data on prospective cohorts that include echocardiographic parameters and performing replication studies are essential in order to increase the statistical strength and scope of the results of these studies. Nevertheless, regardless of the mechanism, previous publications suggest that early institution of preventive measures may lower the risk for developing cognitive impairment. In light of the articles we analyzed in this review, it is tempting to hypothesize that cardiac morphologic and functional modifications exist in patients with cognitive impairment and that they may be detected at an early stage using cardiovascular imaging techniques. Echocardiography is a widely available, relatively inexpensive, portable, safe, noninvasive imaging modality whereby morphologically or hemodynamically derived parameters may be easily integrated into a risk model.108 In addition, even though the benefit of such a strategy has never been precisely assessed, integrating a systematic cardiac ultrasound examination in patients with vascular risk factors may be useful to detect not only early determinants of cognitive impairment but other cardiac conditions as well.108

Arangalage et al 7

Journal of the American Society of Echocardiography Volume - Number -

Table 4 Main studies analyzing the link between cognitive impairment and aortic root diameter or LV mass Study

Cardiac imaging parameters

Population

Age (y)*

Cognitive parameters

Results

67 (59–87)

 Attention and executive functioning  Informationprocessing speed

LV mass index associated with lower information processing speed

Van den Hurk et al. (2011)47

LV mass index

313 healthy people

Scuteri et al. (2009)92

LV mass index

400 geriatric outpatients

79 6 6

MMSE score < 21

LV mass index associated with lower MMSE score

Elias et al. (2007)93

LV mass

1,673 patients from the Framingham Offspring Study free from stroke

57 6 9

Abstract reasoning, visual-spatial memory and organization, verbal memory

LV mass inversely associated with abstract reasoning, visual-spatial memory and organization, and verbal memory

Paul et al. (2005)51

 Aortic root diameter from 2D parasternal long-axis view  Left aortic wall thickness  LVEF  Stroke volume

27 patients with evidence of CVD and mild ischemic vascular disease free of dementia

68.8 6 8.1

 DRS-2  Whole-brain volume and white matter lesions in brain MRI

 Increased aortic root diameter related to the DRS-2 and brain MRI abnormalities  LVEF and stroke volume not related to cognitive impairment

CVD, Cardiovascular disease; DRS-2, Dementia Rating Scale 2; LV, left ventricular; LVEF, left ventricular ejection fraction; MMSE, Mini-Mental State Examination; 2D, two-dimensional. *Data are expressed as mean 6 SD or mean (range).

One hypothesis regarding the implementation of echocardiography in clinical practice is that it may be used as a first-line screening tool. Thus, the detection of abnormal echocardiographic prognostic parameters in patients addressed for routine investigation would lead to early orientation toward a cognitive impairment prevention program. Considering the considerable number of examinations performed, echocardiography may therefore become a formidable screening tool. A more plausible hypothesis is that echocardiography may be integrated into a risk stratification algorithm including various clinical, biologic, and perhaps even brain imaging parameters. The optimal role of echocardiography in this algorithm remains to be determined. Echocardiography may also be considered as a reflection of the efficacy of preventive measures and may represent an interesting follow-up method of patients with cognitive impairment. Although these scenarios seem realistic, it is worth remembering that convincing evidence proving the usefulness of such large-scale strategies involving echocardiography is still lacking. Several issues must be taken into account when analyzing all of the studies that investigated the link between echocardiographic parameters and cognitive function. First, it needs to be stressed that there are no precise diagnostic criteria to define cognitive impairment and dementia. Thus, dementia is defined as a loss of brain function and involves a group of symptoms that affect global cognitive function, leading to the loss of ability to perform daily living tasks. It includes several types of dementia, the most common and frequent being Alzheimer’s disease and vascular dementia.9,109 Cognitive impairment is a more generic term, defined by a decline in cognitive functions, and ranges from mild cognitive impairment to dementia.9 Mild cognitive impairment is an intermediate state between normal cognition and dementia. In comparison with subjects with normal cognition, the rate of progression from mild cognitive impairment to dementia is higher.110 The studies analyzed in this

review focused on different cognitive functions, ranging from verbal memory to abstract reasoning and executive functions, and assessed the impairment in cognitive functions using different scales such as the Trail Making Test or the Mini-Mental State Examination score.111 Among studies using a reduced Mini-Mental State Examination score as the main end point, the threshold defining cognitive impairment varied from <21 to #25. The methodologic heterogeneity observed limits the scope of these studies and weakens the strength of the link between the alteration of echocardiographic parameters and cognitive impairment. This task is further complicated by the existence of many types of dementia, defined by different diagnostic criteria,109 which may be linked to varying extents to cardiac morphologic and functional alterations. Consequently, this article must be considered as a plea for a more systematic approach, on the basis of consensual definitions and standardized methodologic approaches that would allow one to gather and pool data from prospective cohorts across the world and drastically increase the power of future studies. Considering that dementia is a multifactorial disease, most studies did not take into account many of the confounding factors, such as cardiovascular risk factors, making it very difficult to assess the direct link with echocardiographic parameters. Given the highly complex nature of the relationship, it seems unlikely that echocardiography will be found to integrate all potential factors involved in the mechanism linking the heart to the brain. Thus, echocardiographic parameters may predict cognitive impairment through intermediate and complex mechanisms involving cardiovascular risk factors. In this context, combining clinical, biologic, and echocardiographic parameters to assess the risk for developing dementia is a path that needs exploring. Furthermore, knowing that cognitive impairment is preceded by a long preclinical phase, it is conceivable that the alteration of echocardiographic indices associated with cognitive impairment may develop late in the disease process.

8 Arangalage et al

However, detection of such changes may still provide some window of opportunity, or perhaps incentive, for greater risk management efforts. A major point that needs to be considered is the absence of an effective treatment for dementia. Therefore, it may be argued that the association between cognitive impairment and echocardiographic parameters has only theoretical and academic interest and no proven practical value. Although no cure is available for the moment, many efficient preventive therapeutic modalities may slow the progress of the disease or prolong the preclinical phase. At present, the first step remains to precisely identify patients at risk for developing cognitive impairment. This task requires a transversal and multidisciplinary approach involving neurologists, geriatricians, cardiologists, epidemiologists, radiologists, and many other disciplines. Moreover, large-scale, multicenter, collaborative studies are necessary to implement algorithms combining clinical, biologic, and imaging data. Defining the population of patients that would benefit from systematic echocardiographic screening is another question that needs to be investigated. From an echocardiographic point of view, assessing the predictive role of a combination of echocardiographic parameters on the occurrence of cognitive impairment is a path that needs exploring. Only then will investigators be able to justify the initiation of relevant randomized trials studying the impact of preventive measures on the onset of cognitive impairment. The exact clinical impact of such measures remains unclear, but most articles analyzed in this review suggest potentially positive consequences. Identifying early determinants of cognitive impairment is a fast-evolving, major field of interest, generating a considerable number of publications and in which echocardiographers may play a significant role. We hope that this review will stimulate investigators and echocardiographers to give more attention to the potential value of echocardiographic observations in screening patients at risk for developing cognitive impairment. Nevertheless, it must be stressed that benefits, detriments, and the potential harm that may be caused by systematic population screening remains unknown. From an economic standpoint, the financial impact of such a large-scale screening process has not yet been studied, and unless an effective treatment for dementia is discovered, the cost may outweigh the effectiveness. Finally, although large community-based cohorts, such as the Framingham cohort, were included in our analysis, it is important to mention that observational data cannot establish causality; therefore, further prospective investigation is required before integrating echocardiography into a preventive strategy.

CONCLUSIONS Dementia is an increasingly important public health challenge, and no curative treatment has thus far been identified. Focusing on the detection of preclinical signs announcing the onset of the disease is, however, highly important in view of the possibility that starting preventive measures early in the course of the disease may prove beneficial. The inclusion of echocardiography may further improve currently used risk assessment models by allowing the detection of subclinical cardiac functional and morphologic abnormalities associated with future cognitive impairment. Further prospective studies are required before echocardiography can be integrated into a preventive strategy at a larger scale.

Journal of the American Society of Echocardiography - 2014

ACKNOWLEDGMENTS Sophie Rushton-Smith, PhD, provided editorial support for the final version of this review and was funded by the authors.

REFERENCES 1. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112-7. 2. Vos SJ, Xiong C, Visser PJ, Jasielec MS, Hassenstab J, Grant EA, et al. Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study. Lancet Neurol 2013;12:957-65. 3. Patterson C, Feightner JW, Garcia A, Hsiung GY, MacKnight C, Sadovnick AD. Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease. CMAJ 2008;178: 548-56. 4. Schneider JA, Wilson RS, Cochran EJ, Bienias JL, Arnold SE, Evans DA, et al. Relation of cerebral infarctions to dementia and cognitive function in older persons. Neurology 2003;60:1082-8. 5. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348:1215-22. 6. Reitz C, Bos MJ, Hofman A, Koudstaal PJ, Breteler MM. Prestroke cognitive performance, incident stroke, and risk of dementia: the Rotterdam Study. Stroke 2008;39:36-41. 7. Langa KM, Chernew ME, Kabeto MU, Herzog AR, Ofstedal MB, Willis RJ, et al. National estimates of the quantity and cost of informal caregiving for the elderly with dementia. J Gen Intern Med 2001;16: 770-8. 8. Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol 2011;10:819-28. 9. Justin BN, Turek M, Hakim AM. Heart disease as a risk factor for dementia. Clin Epidemiol 2013;5:135-45. 10. Moon Y, Kim H, Ok Kim J, Han SH. Vascular factors are associated with the severity of the neuropsychiatric symptoms in Alzheimer’s disease. Int J Neurosci 2014;124:512-7. 11. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999;53:1937-42. 12. Molinuevo JL, Casado-Naranjo I. Clinical profile of Alzheimer’s disease: is the age of the patient a decisive factor? results of the INFLUENCE study. J Alzheimers Dis 2014;39:227-32. 13. Kalmijn S, Foley D, White L, Burchfiel CM, Curb JD, Petrovitch H, et al. Metabolic cardiovascular syndrome and risk of dementia in JapaneseAmerican elderly men. The Honolulu-Asia aging study. Arterioscler Thromb Vasc Biol 2000;20:2255-60. 14. Exalto LG, Quesenberry CP, Barnes D, Kivipelto M, Biessels GJ, Whitmer RA. Midlife risk score for the prediction of dementia four decades later. Alzheimers Dement 2014;10:562-70. 15. Fillit H, Nash DT, Rundek T, Zuckerman A. Cardiovascular risk factors and dementia. Am J Geriatr Pharmacother 2008;6:100-18. 16. Hajduk AM, Kiefe CI, Person SD, Gore JG, Saczynski JS. Cognitive change in heart failure: a systematic review. Circ Cardiovasc Qual Outcomes 2013;6:451-60. 17. Vogels RL, Scheltens P, Schroeder-Tanka JM, Weinstein HC. Cognitive impairment in heart failure: a systematic review of the literature. Eur J Heart Fail 2007;9:440-9. 18. Volonghi I, Pendlebury ST, Welch SJ, Mehta Z, Rothwell PM. Cognitive outcomes after acute coronary syndrome: a population based comparison with transient ischaemic attack and minor stroke. Heart 2013;99: 1509-14. 19. Picano E, Bruno RM, Ferrari GF, Bonuccelli U. Cognitive impairment and cardiovascular disease: so near, so far. Int J Cardiol 2014;175:21-9.

Journal of the American Society of Echocardiography Volume - Number -

20. Kilander L, Andren B, Nyman H, Lind L, Boberg M, Lithell H. Atrial fibrillation is an independent determinant of low cognitive function: a crosssectional study in elderly men. Stroke 1998;29:1816-20. 21. Bunch TJ, Weiss JP, Crandall BG, May HT, Bair TL, Osborn JS, et al. Atrial fibrillation is independently associated with senile, vascular, and Alzheimer’s dementia. Heart Rhythm 2010;7:433-7. 22. Rosendorff C, Beeri MS, Silverman JM. Cardiovascular risk factors for Alzheimer’s disease. Am J Geriatr Cardiol 2007;16:143-9. 23. Forti P, Maioli F, Pisacane N, Rietti E, Montesi F, Ravaglia G. Atrial fibrillation and risk of dementia in non-demented elderly subjects with and without mild cognitive impairment (MCI). Arch Gerontol Geriatr 2007;44(Suppl 1):155-65. 24. Charlton RA, Barrick TR, McIntyre DJ, Shen Y, O’Sullivan M, Howe FA, et al. White matter damage on diffusion tensor imaging correlates with age-related cognitive decline. Neurology 2006;66:217-22. 25. Sullivan EV, Rohlfing T, Pfefferbaum A. Quantitative fiber tracking of lateral and interhemispheric white matter systems in normal aging: relations to timed performance. Neurobiol Aging 2010;31: 464-81. 26. Kivipelto M, Ngandu T, Laatikainen T, Winblad B, Soininen H, Tuomilehto J. Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. Lancet Neurol 2006;5:735-41. 27. Kaffashian S, Dugravot A, Elbaz A, Shipley MJ, Sabia S, Kivimaki M, et al. Predicting cognitive decline: a dementia risk score vs. the Framingham vascular risk scores. Neurology 2013;80:1300-6. 28. Elias MF, Sullivan LM, D’Agostino RB, Elias PK, Beiser A, Au R, et al. Framingham stroke risk profile and lowered cognitive performance. Stroke 2004;35:404-9. 29. Llewellyn DJ, Lang IA, Xie J, Huppert FA, Melzer D, Langa KM. Framingham Stroke Risk Profile and poor cognitive function: a population-based study. BMC Neurol 2008;8:12. 30. Reijmer YD, van den Berg E, van Sonsbeek S, Dekker JM, Nijpels G, Stehouwer CD, et al. Dementia risk score predicts cognitive impairment after a period of 15 years in a nondemented population. Dement Geriatr Cogn Disord 2011;31:152-7. 31. Seshadri S, Wolf PA, Beiser A, Elias MF, Au R, Kase CS, et al. Stroke risk profile, brain volume, and cognitive function: the Framingham Offspring Study. Neurology 2004;63:1591-9. 32. Unverzagt FW, McClure LA, Wadley VG, Jenny NS, Go RC, Cushman M, et al. Vascular risk factors and cognitive impairment in a stroke-free cohort. Neurology 2011;77:1729-36. 33. Kaffashian S, Dugravot A, Nabi H, Batty GD, Brunner E, Kivimaki M, et al. Predictive utility of the Framingham general cardiovascular disease risk profile for cognitive function: evidence from the Whitehall II study. Eur Heart J 2011;32:2326-32. 34. Percy M, Somerville MJ, Hicks M, Garcia A, Colelli T, Wright E, et al. Risk factors for development of dementia in a unique six-year cohort study. I. An exploratory, pilot study of involvement of the E4 allele of apolipoprotein E, mutations of the hemochromatosis-HFE gene, type 2 diabetes, and stroke. J Alzheimers Dis 2014;38:907-22. 35. Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, et al. Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population based study. BMJ 2001;322: 1447-51. 36. Ott A, Stolk RP, Hofman A, van Harskamp F, Grobbee DE, Breteler MM. Association of diabetes mellitus and dementia: the Rotterdam Study. Diabetologia 1996;39:1392-7. 37. Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K. Midlife cardiovascular risk factors and risk of dementia in late life. Neurology 2005;64: 277-81. 38. Debette S, Seshadri S, Beiser A, Au R, Himali JJ, Palumbo C, et al. Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline. Neurology 2011;77:461-8. 39. Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kareholt I, Winblad B, et al. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol 2005;62:1556-60.

Arangalage et al 9

40. Xu WL, Atti AR, Gatz M, Pedersen NL, Johansson B, Fratiglioni L. Midlife overweight and obesity increase late-life dementia risk: a populationbased twin study. Neurology 2011;76:1568-74. 41. Zeki Al Hazzouri A, Haan MN, Neuhaus JM, Pletcher M, Peralta CA, Lopez L, et al. Cardiovascular risk score, cognitive decline, and dementia in older Mexican Americans: the role of sex and education. J Am Heart Assoc 2013;2:e004978. 42. Shibata M, Ohtani R, Ihara M, Tomimoto H. White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion. Stroke 2004;35:2598-603. 43. Tranmer BI, Keller TS, Kindt GW, Archer D. Loss of cerebral regulation during cardiac output variations in focal cerebral ischemia. J Neurosurg 1992;77:253-9. 44. Vogels RL, van der Flier WM, van Harten B, Gouw AA, Scheltens P, Schroeder-Tanka JM, et al. Brain magnetic resonance imaging abnormalities in patients with heart failure. Eur J Heart Fail 2007;9:1003-9. 45. Qiu C, Winblad B, Marengoni A, Klarin I, Fastbom J, Fratiglioni L. Heart failure and risk of dementia and Alzheimer disease: a population-based cohort study. Arch Intern Med 2006;166:1003-8. 46. Gruhn N, Larsen FS, Boesgaard S, Knudsen GM, Mortensen SA, Thomsen G, et al. Cerebral blood flow in patients with chronic heart failure before and after heart transplantation. Stroke 2001;32:2530-3. 47. van den Hurk K, Reijmer YD, van den Berg E, Alssema M, Nijpels G, Kostense PJ, et al. Heart failure and cognitive function in the general population: the Hoorn Study. Eur J Heart Fail 2011;13:1362-9. 48. Jefferson AL, Himali JJ, Au R, Seshadri S, Decarli C, O’Donnell CJ, et al. Relation of left ventricular ejection fraction to cognitive aging (from the Framingham Heart Study). Am J Cardiol 2011;108:1346-51. 49. Jerskey BA, Cohen RA, Jefferson AL, Hoth KF, Haley AP, Gunstad JJ, et al. Sustained attention is associated with left ventricular ejection fraction in older adults with heart disease. J Int Neuropsychol Soc 2009;15: 137-41. 50. Jefferson AL. Cardiac output as a potential risk factor for abnormal brain aging. J Alzheimers Dis 2010;20:813-21. 51. Paul RH, Gunstad J, Poppas A, Tate DF, Foreman D, Brickman AM, et al. Neuroimaging and cardiac correlates of cognitive function among patients with cardiac disease. Cerebrovasc Dis 2005;20:129-33. 52. Moser DJ, Cohen RA, Clark MM, Aloia MS, Tate BA, Stefanik S, et al. Neuropsychological functioning among cardiac rehabilitation patients. J Cardiopulm Rehabil 1999;19:91-7. 53. Zuccala G, Cattel C, Manes-Gravina E, Di Niro MG, Cocchi A, Bernabei R. Left ventricular dysfunction: a clue to cognitive impairment in older patients with heart failure. J Neurol Neurosurg Psychiatry 1997; 63:509-12. 54. Kuller LH, Longstreth WT Jr., Arnold AM, Bernick C, Bryan RN, Beauchamp NJ Jr. White matter hyperintensity on cranial magnetic resonance imaging: a predictor of stroke. Stroke 2004;35:1821-5. 55. Vermeer SE, Hollander M, van Dijk EJ, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke 2003;34:1126-9. 56. Bernick C, Kuller L, Dulberg C, Longstreth WT Jr., Manolio T, Beauchamp N, et al. Silent MRI infarcts and the risk of future stroke: the cardiovascular health study. Neurology 2001;57:1222-9. 57. Kobayashi S, Okada K, Koide H, Bokura H, Yamaguchi S. Subcortical silent brain infarction as a risk factor for clinical stroke. Stroke 1997;28: 1932-9. 58. Hatazawa J, Shimosegawa E, Satoh T, Toyoshima H, Okudera T. Subcortical hypoperfusion associated with asymptomatic white matter lesions on magnetic resonance imaging. Stroke 1997;28:1944-7. 59. Marstrand JR, Garde E, Rostrup E, Ring P, Rosenbaum S, Mortensen EL, et al. Cerebral perfusion and cerebrovascular reactivity are reduced in white matter hyperintensities. Stroke 2002;33:972-6. 60. Russo C, Jin Z, Homma S, Elkind MS, Rundek T, Yoshita M, et al. Subclinical left ventricular dysfunction and silent cerebrovascular disease: the Cardiovascular Abnormalities and Brain Lesions (CABL) study. Circulation 2013;128:1105-11.

10 Arangalage et al

61. Suwa M, Ito T. Correlation between cognitive impairment and left ventricular diastolic dysfunction in patients with cardiovascular diseases. Int J Cardiol 2009;136:351-4. 62. Little WC, Oh JK. Echocardiographic evaluation of diastolic function can be used to guide clinical care. Circulation 2009;120:802-9. 63. Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007;28:2539-50. 64. Tschope C, Paulus WJ. Is echocardiographic evaluation of diastolic function useful in determining clinical care? Doppler echocardiography yields dubious estimates of left ventricular diastolic pressures. Circulation 2009;120:810-20. discussion 20. 65. Shimizu A, Sakurai T, Mitsui T, Miyagi M, Nomoto K, Kokubo M, et al. Left ventricular diastolic dysfunction is associated with cerebral white matter lesions (leukoaraiosis) in elderly patients without ischemic heart disease and stroke. Geriatr Gerontol Int 2014;14(Suppl 2):71-6. 66. Cianciulli TF, Saccheri MC, Lax JA, Bermann AM, Ferreiro DE. Twodimensional speckle tracking echocardiography for the assessment of atrial function. World J Cardiol 2010;2:163-70. 67. Oh JE, Shin JW, Sohn EH, Jung JO, Jeong SH, Song HJ, et al. Effect of cardiac function on cognition and brain structural changes in dementia. J Clin Neurol 2012;8:123-9. 68. Abhayaratna WP, Seward JB, Appleton CP, Douglas PS, Oh JK, Tajik AJ, et al. Left atrial size: physiologic determinants and clinical applications. J Am Coll Cardiol 2006;47:2357-63. 69. Appleton CP, Galloway JM, Gonzalez MS, Gaballa M, Basnight MA. Estimation of left ventricular filling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease. Additional value of analyzing left atrial size, left atrial ejection fraction and the difference in duration of pulmonary venous and mitral flow velocity at atrial contraction. J Am Coll Cardiol 1993;22:1972-82. 70. Simek CL, Feldman MD, Haber HL, Wu CC, Jayaweera AR, Kaul S. Relationship between left ventricular wall thickness and left atrial size: comparison with other measures of diastolic function. J Am Soc Echocardiogr 1995;8:37-47. 71. Hoogsteen J, Hoogeveen A, Schaffers H, Wijn PF, van der Wall EE. Left atrial and ventricular dimensions in highly trained cyclists. Int J Cardiovasc Imaging 2003;19:211-7. 72. Lai ZY, Chang NC, Tsai MC, Lin CS, Chang SH, Wang TC. Left ventricular filling profiles and angiotensin system activity in elite baseball players. Int J Cardiol 1998;67:155-60. 73. Psaty BM, Manolio TA, Kuller LH, Kronmal RA, Cushman M, Fried LP, et al. Incidence of and risk factors for atrial fibrillation in older adults. Circulation 1997;96:2455-61. 74. Vaziri SM, Larson MG, Benjamin EJ, Levy D. Echocardiographic predictors of nonrheumatic atrial fibrillation. The Framingham Heart Study. Circulation 1994;89:724-30. 75. Benjamin EJ, D’Agostino RB, Belanger AJ, Wolf PA, Levy D. Left atrial size and the risk of stroke and death. The Framingham Heart Study. Circulation 1995;92:835-41. 76. Barnes ME, Miyasaka Y, Seward JB, Gersh BJ, Rosales AG, Bailey KR, et al. Left atrial volume in the prediction of first ischemic stroke in an elderly cohort without atrial fibrillation. Mayo Clin Proc 2004;79: 1008-14. 77. Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden. Am J Cardiol 2002;90: 1284-9. 78. Gottdiener JS, Kitzman DW, Aurigemma GP, Arnold AM, Manolio TA. Left atrial volume, geometry, and function in systolic and diastolic heart failure of persons > or =65 years of age (the cardiovascular health study). Am J Cardiol 2006;97:83-9. 79. Takemoto Y, Barnes ME, Seward JB, Lester SJ, Appleton CA, Gersh BJ, et al. Usefulness of left atrial volume in predicting first congestive heart

Journal of the American Society of Echocardiography - 2014

80.

81.

82. 83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99. 100.

failure in patients > or = 65 years of age with well-preserved left ventricular systolic function. Am J Cardiol 2005;96:832-6. Karadag B, Ozyigit T, Ozben B, Kayaoglu S, Altuntas Y. Relationship between left atrial volume index and cognitive decline in elderly patients with sinus rhythm. J Clin Neurosci 2013;20:1074-8. Jefferson AL, Poppas A, Paul RH, Cohen RA. Systemic hypoperfusion is associated with executive dysfunction in geriatric cardiac patients. Neurobiol Aging 2007;28:477-83. Saxena PR, Schoemaker RG. Organ blood flow protection in hypertension and congestive heart failure. Am J Med 1993;94:4S-12. Zhang R, Witkowski S, Fu Q, Claassen JA, Levine BD. Cerebral hemodynamics after short- and long-term reduction in blood pressure in mild and moderate hypertension. Hypertension 2007;49:1149-55. Immink RV, van den Born BJ, van Montfrans GA, Koopmans RP, Karemaker JM, van Lieshout JJ. Impaired cerebral autoregulation in patients with malignant hypertension. Circulation 2004;110:2241-5. Massaro AR, Dutra AP, Almeida DR, Diniz RV, Malheiros SM. Transcranial Doppler assessment of cerebral blood flow: effect of cardiac transplantation. Neurology 2006;66:124-6. Cohen RA, Poppas A, Forman DE, Hoth KF, Haley AP, Gunstad J, et al. Vascular and cognitive functions associated with cardiovascular disease in the elderly. J Clin Exp Neuropsychol 2009;31:96-110. Jefferson AL, Himali JJ, Beiser AS, Au R, Massaro JM, Seshadri S, et al. Cardiac index is associated with brain aging: the Framingham Heart Study. Circulation 2010;122:690-7. Jefferson AL, Massaro JM, Wolf PA, Seshadri S, Au R, Vasan RS, et al. Inflammatory biomarkers are associated with total brain volume: the Framingham Heart Study. Neurology 2007;68:1032-8. DeCarli C, Massaro J, Harvey D, Hald J, Tullberg M, Au R, et al. Measures of brain morphology and infarction in the framingham heart study: establishing what is normal. Neurobiol Aging 2005;26:491-510. Jefferson AL, Tate DF, Poppas A, Brickman AM, Paul RH, Gunstad J, et al. Lower cardiac output is associated with greater white matter hyperintensities in older adults with cardiovascular disease. J Am Geriatr Soc 2007; 55:1044-8. Verdecchia P, Carini G, Circo A, Dovellini E, Giovannini E, Lombardo M, et al. Left ventricular mass and cardiovascular morbidity in essential hypertension: the MAVI study. J Am Coll Cardiol 2001;38:1829-35. Scuteri A, Coluccia R, Castello L, Nevola E, Brancati AM, Volpe M. Left ventricular mass increase is associated with cognitive decline and dementia in the elderly independently of blood pressure. Eur Heart J 2009;30: 1525-9. Elias MF, Sullivan LM, Elias PK, D’Agostino RB Sr., Wolf PA, Seshadri S, et al. Left ventricular mass, blood pressure, and lowered cognitive performance in the Framingham offspring. Hypertension 2007;49:439-45. Selvetella G, Notte A, Maffei A, Calistri V, Scamardella V, Frati G, et al. Left ventricular hypertrophy is associated with asymptomatic cerebral damage in hypertensive patients. Stroke 2003;34:1766-70. Bikkina M, Levy D, Evans JC, Larson MG, Benjamin EJ, Wolf PA, et al. Left ventricular mass and risk of stroke in an elderly cohort. The Framingham Heart Study. JAMA 1994;272:33-6. Sen S, Wu K, McNamara R, Lima J, Piantadosi S, Oppenheimer SM. Distribution, severity and risk factors for aortic atherosclerosis in cerebral ischemia. Cerebrovasc Dis 2000;10:102-9. Amarenco P, Cohen A, Tzourio C, Bertrand B, Hommel M, Besson G, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994;331:1474-9. Cohen A, Tzourio C, Bertrand B, Chauvel C, Bousser MG, Amarenco P. Aortic plaque morphology and vascular events: a follow-up study in patients with ischemic stroke. FAPS Investigators. French Study of Aortic Plaques in Stroke. Circulation 1997;96:3838-41. Heinzlef O, Cohen A, Amarenco P. An update on aortic causes of ischemic stroke. Curr Opin Neurol 1997;10:64-72. Agmon Y, Khandheria BK, Meissner I, Schwartz GL, Sicks JD, Fought AJ, et al. Is aortic dilatation an atherosclerosis-related process? Clinical, laboratory, and transesophageal echocardiographic correlates of thoracic

Journal of the American Society of Echocardiography Volume - Number -

101. 102.

103. 104.

105.

aortic dimensions in the population with implications for thoracic aortic aneurysm formation. J Am Coll Cardiol 2003;42:1076-83. Vasan RS, Larson MG, Levy D. Determinants of echocardiographic aortic root size. The Framingham Heart Study. Circulation 1995;91:734-40. Kamogawa K, Kohara K, Tabara Y, Uetani E, Nagai T, Yamamoto M, et al. Abdominal fat, adipose-derived hormones and mild cognitive impairment: the J-SHIPP study. Dement Geriatr Cogn Disord 2010;30:432-9. Rabkin SW. Epicardial fat: properties, function and relationship to obesity. Obes Rev 2007;8:253-61. Iacobellis G, Ribaudo MC, Assael F, Vecci E, Tiberti C, Zappaterreno A, et al. Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk. J Clin Endocrinol Metab 2003;88:5163-8. Cottam DR, Mattar SG, Barinas-Mitchell E, Eid G, Kuller L, Kelley DE, et al. The chronic inflammatory hypothesis for the morbidity associated with morbid obesity: implications and effects of weight loss. Obes Surg 2004;14:589-600.

Arangalage et al 11

106. Rosano C, Marsland AL, Gianaros PJ. Maintaining brain health by monitoring inflammatory processes: a mechanism to promote successful aging. Aging Dis 2012;3:16-33. 107. Mazzoccoli G, Dagostino MP, Vinciguerra M, Ciccone F, Paroni G, Seripa D, et al. An association study between epicardial fat thickness and cognitive impairment in the elderly. Am J Physiol Heart Circ Physiol 2014. Epub ahead of print. 108. Tsang TS. Echocardiography in cardiovascular public health: the Feigenbaum Lecture 2008. J Am Soc Echocardiogr 2009;22:649-56. quiz 751–2. 109. Ritchie K, Lovestone S. The dementias. Lancet 2002;360:1759-66. 110. Ganguli M, Snitz BE, Saxton JA, Chang CC, Lee CW, Vander Bilt J, et al. Outcomes of mild cognitive impairment by definition: a population study. Arch Neurol 2011;68:761-7. 111. Folstein MF, Folstein SE, McHugh PR. ‘‘Mini-Mental State’’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-98.