Cognitive impairment and cardiovascular disease: so near, so far.

IJCA-18176; No of Pages 9 International Journal of Cardiology xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Review

Cognitive impairment and cardiovascular disease: So near, so far☆ Eugenio Picano a, Rosa Maria Bruno a,⁎, Gian Franco Ferrari b, Ubaldo Bonuccelli c a b c

Institute of Clinical Physiology, CNR, Pisa, Italy Institute of Clinical Physiology, CNR, Rome, Italy Department of Clinical and Experimental Medicine, Neurology Unit, University of Pisa, Pisa, Italy

a r t i c l e

i n f o

Article history: Received 24 October 2013 Received in revised form 30 April 2014 Accepted 5 May 2014 Available online xxxx Keywords: Atherosclerosis Brain Dementia Vessels

a b s t r a c t In the spectrum of cognitive impairment, ranging from “pure” vascular dementia to Alzheimer's disease (AD), clinical interest has recently expanded from the brain to also include the vessels, shifting the pathophysiological focus from the leaves of synaptic dysfunction to the sap of cerebral microcirculation and the roots of cardiovascular function. From a diagnostic viewpoint, a thorough clinical evaluation of individuals presenting cognitive impairment might systematically include the assessment of the major cardiovascular rings of the chain linking regional perfusion to brain function: 1) lung (with assessment of asthma, chronic obstructive pulmonary disease, obstructive sleep apnea syndrome); 2) heart function (with clinical examination and echocardiography) and cardiovascular risk factors; 3) orthostatic hypotension (with medical history and measurement of heart rate and blood pressure in supine and upright positions); 4) aorta and large artery stiffness (with assessment of pulse wave velocity); 5) large cerebro-vascular vessel status (with neuroimaging techniques); 6) assessment of microcirculation (with cerebrovascular reactivity testing with transcranial Doppler sonography or MRI perfusion imaging); and 7) assessment of venous cerebral circulation. The apparent difference in approaches to “brain” and “vascular” environmental enrichment with physical, cognitive and sensorial training is conceptually identical to that of a constant gardener caring for an unhealthy tree, watering the leaves (“train the brain”) or simply the roots (“mind the vessel”). The therapeutic difference probably consists in the amount and quality of water added to the tree, rather than by where one pours it, with either a top-down (leaves to roots) or bottom-up (roots to leaves) approach. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Alzheimer's disease (AD) is nowadays only one part of the whole dementia scenario, encompassing primary neurodegenerative dementias, vascular dementia and mixed dementia. The number of patients affected by AD has been growing steadily over the last decade, and neurodegenerative processes are a significant threat and health burden for the elderly — it is estimated that by 2040, there will be more than

Abbreviations: AD, Alzheimer's disease; CABG, coronary artery bypass surgery; CNR, Consiglio Nazionale delle Ricerche - National Research Council; COPD, Chronic Obstructive Pulmonary Disease; C-PAP, continuous positive airway pressure CVD, Cardiovascular disease; DCM, Dilated cardiomyopathy; EE, Environmental enrichment; MRI, Magnetic resonance imaging; NO, nitric oxide; OH, orthostatic hypotension; OSAS, Obstructive sleep apnea syndrome; SVD, small vessel disease; VCI, vascular cognitive impairment. ☆ Acknowledgments: The study was funded by “Train the Brain”, grant agreement (B55E09000520007) from Fondazione Pisa, Pisa, Italy and “Ageing” project from MIURCNR (grant agreement B65E12000480001). ⁎ Corresponding author at: Institute of Clinical Physiology, CNR, Via Moruzzi 1-56124 Pisa, Italy. Tel.: +39 50 3152377; fax: +39 50 3152374. E-mail address: [email protected] (R.M. Bruno).

80 million people with dementia worldwide [1]. It is still unclear exactly what proportion of dementias are driven by amyloid plaques (50–80%) and by vascular pathology (20–30%) [2]. They often coexist in brains of people with dementia, although neuro-pathological criteria for AD can be found in 50% of the brains of aged individuals who were never cognitively impaired during life; even in symptomatic individuals, there is no correlation between severity of disease and pathological burden [3]. The link between vascular disease and AD is certainly present and probably strong [4], but is neither simple nor entirely clear, with a blurred pathological divide between cognitive decline and normal healthy brain and vessel aging. 2. The vascular basis of brain aging and dementia With normal aging, both cognitive function and cognitive reserve decline. Cognitive reserve refers to the brain's ability to cope with either increasing activities or damage. The concept of cognitive reserve is a predominantly functional one. It follows the concept that brain plasticity allows increasing brain connectivity after mental exercise, from early infancy throughout life, and this prolongs maintenance of function

http://dx.doi.org/10.1016/j.ijcard.2014.05.004 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

Please cite this article as: Picano E, et al, Cognitive impairment and cardiovascular disease: So near, so far, Int J Cardiol (2014), http://dx.doi.org/ 10.1016/j.ijcard.2014.05.004

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E. Picano et al. / International Journal of Cardiology xxx (2014) xxx–xxx

despite cell degeneration in older life. There is a threshold after which cognitive reserve finishes and cognitive impairment becomes evident [5]. There is no direct measure of reserve, but it is commonly reflected by proxies such as education, type of job and brain volume [6] or by more sophisticated and technology-demanding approaches evaluating brain perfusion and metabolic reserve during cognitive tasks [7]. Normal aging causes brain atrophy, with MRI studies showing a 4% reduction in brain volume for every 10 years above age 65 years [8]. The physiological descent is earlier and steeper in neurodegenerative diseases such as AD (Fig. 1a). Vascular reserve refers to the vessel's ability to cope with increasing activity or damage, and is commonly measured as the ability to increase regional flow after a hyperemic stimulus, such as carbon dioxide in the brain, adenosine in myocardium or ischemia in the forearm. The cerebral, coronary and systemic vascular flow reserve also decline with aging [9–11], with a shape and rate of change of the trajectory not dissimilar from that of cognitive reserve decline (Fig. 1b). Since it is unable to store energy, the brain function depends on continuous delivery of oxygen and glucose through blood flow. Under physiological conditions, essential for neuronal functional activity, there is a systematic coupling between activation of specific brain function and microcirculation flow activation, within the concept of the neurovascular unit with microvessels, endothelial cells, neurons and glial cells all closely integrated with continuous bidirectional signaling [12,13]. The brain is a high-flow, low-impedance organ with a high metabolic rate, and typically receives 15% of total cardiac output and 25 to 50% of total body glucose utilization despite accounting for only 2% of total body weight [14,15]. Blood flow to critical organs with high resting demand, such as the brain, is normally autoregulated, meaning that flow remains relatively constant over a wide range of mean perfusion pressures. If blood pressure falls below a certain point, termed the lower limit of autoregulation, cerebral blood flow decreases. Because of the high metabolic demand for oxygen in the brain, limited cerebral blood flow may lead to neurovascular unit energy crisis [4] and cerebral hypoperfusion is a very early event in the hypothetical cascade leading

Fig. 1. The parallel lives of cognitive (left side, panel a) and vascular (right side, panel b) reserve in normal elderly healthy persons and in those with premature dementia (red line in panel a) or atherosclerosis (red line in panel b). ATS: atherosclerotic. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2. The cascade of events: regional hypoperfusion of brain and heart respectively is an upstream event in natural history of dementia (panel 2a) and dilated cardiomyopathy (panel 2b).

to cognitive decline (Fig. 2a). Early involvement of microcirculation in the natural history of degenerative disease is also found in the heart (Fig. 2b), where reduction of coronary flow reserve due to coronary small vessel disease is a proximal harbinger of late myocardial dysfunction in both ischemic and non-ischemic cardiomyopathies [16,17]. For several decades the traditional classification of dementia have distinguished those forms of clinically relevant cognitive impairment in which the evidence of clinical stroke or subclinical vascular brain injury can be identified (namely vascular cognitive impairment, VCI) from AD, describing different pathophysiological pathways in the two conditions. More recently, de la Torre hypothesized that AD can be viewed as a predominantly vascular disorder [18]. The hypothesis was based on several converging lines of evidence, including: 1) epidemiological studies showing that AD shares with cardiovascular disease a number of risk factors (from hypertension to diabetes) and virtually all reported risk factors for AD lower cerebral perfusion [19]; 2) detection of regional cerebral hypoperfusion with the use of neuroimaging techniques is capable to identify AD candidates preclinically; 3) the presence of regional brain microvascular abnormalities appear before hypometabolism, cognitive decline and neurodegenerative changes; 4) clinical overlap between AD and vascular dementia; 5) improvement of cerebral perfusion is obtained from drugs (such as cholinesterase inhibitors) used to reduce the symptoms of AD [20] in patients who respond to treatment [21]. However, the interpretation of the cause–effect relationship between hypoperfusion and cognitive decline remains uncertain, since following the metabolism-flow coupling concept, decreased flow is conventionally interpreted as an epiphenomenon or a consequence of reduced neuronal activity. However, the reverse can be true, turning cerebral hypoperfusion from bystander to killer — and a potential target of therapeutic intervention with far-reaching implications. Evidence supporting the vascular hypothesis of AD has been reinforced and extended in the last decade (Table 1). Brain and vessel premature aging share similar molecular, cellular and tissue


E. Picano et al. / International Journal of Cardiology xxx (2014) xxx–xxx Table 1 AD and CVD: epidemiological, biological, pathological and clinical similarities. AD Common risk factors Common protective factors Environmental stressors Environmental protectors Pathology Pathophysiology Clinical syndromes Molecular mechanisms Cellular mechanisms Genetic mechanisms

CVD

Hypertension, diabetes, obesity, dyslipidemia, depression High income, low stress, social links, estrogens, androgens Overeating, X-rays, particulate matter, ozone Physical exercise, community links, Mediterranean diet Large/small vessel disease Large/small vessel disease Dementia cascade Heart failure cascade AD and VaD overlap Ischemic and DCM overlap Epigenetic damage of DNA, inflammation, reduced NO production Altered endothelial function Common hub genes, common miRNA family (mir 17, 21, 29, 34)

AD = Alzheimer's disease; CVD = cardiovascular cardiomyopathy; NO = nitric oxide.

disease;

DCM = dilated

mechanisms, such as abnormal intracellular calcium handling, epigenetic DNA damage, and low-level systemic and local inflammation with altered redox state [22], with imbalance between reduced trophicprotective factors and increased inhibitory factors and reduced endothelial nitric oxide production. In a systems biology perspective, AD and atherosclerosis show several common signaling pathways, with common genes, common miRNA family (mR17, miR21, miR29b, miR34), and common molecular links [23,24]. However, the clinical diagnostic

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and therapeutic implications of this improved understanding of the disease remain elusive, and usually no systematic cardiovascular workup is recommended in AD. 3. Links between cardiovascular disease and cognitive impairment: a patho-physiological perspective Changed cardiovascular conditions can induce changes in organs and above all in brain perfusion [25], possibly one of the determinants of cognitive impairment. In a clinically oriented approach, the system can be usefully simplified and conceptualized as shown in Fig. 3: normal brain perfusion requires that all rings of the physiological chain be intact, since a chain can only lift the weight that its weakest link can bear. In this simplified description of cardiovascular hemodynamics, it is possible to identify seven distinct segments in series, contributing to normal perfusion with well-oxygenated blood in the healthy aging brain (Fig. 3): the lungs, the heart, the large elastic vessels (aorta) [26], the baroreflex (indispensable for short-term, high-gain blood pressure control) [27], the cerebrovascular arteries (carotid, middle cerebral and vertebral arteries) [28], the small cerebral vessels (contributing to 50% of the overall cerebral resistance of the healthy brain) [29], and the cerebrospinal venous system [30]. An anatomic or functional alteration of each segment can lead to impaired cerebrovascular perfusion and increased risk of dementia, although frequently these conditions are not isolated and are often mutually interrelated. The risk of critical cerebral hypoperfusion increases in a clinically relevant way when each of the rings of the adequate cardiovascular

Fig. 3. A simplified model of normal hemodynamics, with seven distinct rings of the normal circulatory chain that in a diseased condition may lead – separately or in association – to cerebral hypoperfusion or hypoxia and eventually to AD. In clockwise order: obstructive apnea syndrome or chronic asthma; heart failure (of ischemic or non-ischemic nature) or atrial fibrillation; increased aortic stiffness (e.g., due to hypertension); impaired baroreflex function (with orthostatic hypotension); athero-thrombo-embolic vessel occlusion or occlusion of major cerebral arteries; cerebral microvascular disease; cerebrospinal venous hypertension (as can occur in dural arterovenous fistula). All these conditions can increase the risk of dementia, and are amenable to treatment, which in some cases has been shown to be effective in treating or preventing an evolution towards cognitive decay.


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cerebral perfusion chain is weakened. No matter how brain hypoperfusion occurs, it may eventually enter a final common pathological pathway, provoking β-amyloid (Aβ) accumulation through several possible mechanisms [31]. Effective therapeutic interventions targeting cardiovascular disease may beneficially affect cognitive decline. We will now briefly zoom on each of the seven rings of the cardiovascular circle of cerebral perfusion: lungs, heart, baroreflex, aorta, macro- and micro-cerebrovascular circulation, venous system. 3.1. Lung failure and obstructive sleep apnea syndrome Untreated chronic lung disease can be associated with declining cognitive function, especially in serious chronic obstructive pulmonary disease (COPD) patients [32] and in elderly asthma sufferers with compromised arterial oxygen saturation [33,34]. Obstructive sleep apnea syndrome (OSAS) is a common disease characterized by repeated episodes of upper airway obstruction during sleep that result in intermittent hypoxemia and arousal, affecting 25% of the general population and 50% of AD. Untreated, OSAS can have dire health consequences and can increase the risk of dementia [35]. Furthermore, OSAS can negatively impact cerebral and vascular health not only by compromising blood oxygenation, but also favoring the development of hypertension, diabetes, atrial fibrillation and stroke [36]. 3.2. Heart failure and cardiac arrhythmias Heart failure and dementia are common medical conditions in elderly persons. Heart failure (of ischemic and non-ischemic origins) and lower ejection fraction are related to poorer cognitive function [37,38] and are a risk factor for dementia [39]. In 1504 elderly subjects enrolled in the Framingham Offspring Cohort study, cardiac index was correlated with brain volume in aging, with lower values of cardiac index being associated with lower brain volumes [40]. Heart failure patients show loss of gray matter in brain areas believed to be important for memory, reasoning, and planning [41]. The same changes can be observed in children with pediatric heart failure without comorbid cerebrovascular disease [42]. Heart failure is also a risk factor for multiple cerebral emboli, which could lead to cognitive impairment [43]. Atrial fibrillation (AF) is the most common cardiac arrhythmia in the elderly, increases by 4–5 times the risk of ischemic stroke, and accounts for about 30% of strokes in patients 80–90 years of age. In a prospective cohort study enrolling 3045 community-dwelling adults aged 65 and older without dementia or clinical stroke, followed up for 6 years, AF was associated with an increased incidence of all-cause dementia and AD, even independent of stroke onset [44]. Post-procedural cognitive dysfunction occurs in close to 30% of patients undergoing ablation for atrial fibrillation [45]. Not only overt heart disease, but also cardiovascular risk factors have been associated with cognitive impairment, both of vascular and Alzheimer origins: the evidence is stronger for hypertension and diabetes, whereas is less consistent for other risk factors [43,46,47]. 3.3. Aorta Aortic wall stiffness increases throughout the normal human lifespan, particularly in the presence of cardiovascular disease risk factors. Disproportionate stiffening of the proximal aorta as compared with the carotid arteries, which typically occurs with aging, reduces wave reflection at this important interface and thereby facilitates transmission of excessive pulsatile energy into the cerebral microcirculation, leading to microvascular damage and impaired function. The velocity profile in cerebral vessels shows high flow throughout diastole. Consequently, flow and pressure pulsations travel well into the arterial tree, similar to kidney circulation, and reach smaller, more fragile vessels [48]. Changes to central circulation, such as increased arterial stiffness, would be of greater detriment to these vascular beds than in blood

vessels in skeletal muscle, for instance, whose highly resistant arterioles prevent large pulse pressures from reaching the microcirculation [49]. Arterial stiffness (expressed by pulse wave velocity) progressively increases in groups with normal cognitive function, mild cognitive impairment, AD and vascular dementia, even independent of traditional cardiovascular risk factors [50]. In the elderly population of the Baltimore Longitudinal Study of aging, the higher the arterial stiffness, the steeper the cognitive decline [51]. In elderly participants in the community-based Age, Gene/Environment Susceptibility Reykjavik study, who had no history of stroke, transient ischemic attack or dementia, marked stiffening of the aorta was associated with reduced wave reflection at the interface between carotid and aorta, transmission of excessive flow pulsatility into the brain, microvascular structural brain damage and lower scores in various cognitive domains [52]. 3.4. Baroreflex dysfunction and orthostatic hypotension Baroreflex is one of the most important neural mechanisms involved in blood pressure regulation: its dysfunction can lead to instability in blood pressure levels, which in AD can cause critical intermittent brain hypoperfusion, especially during orthostatic stress [53]. Impaired baroreceptor sensitivity plays an important role in the pathogenesis of orthostatic hypotension (OH), whose consequences regarding cerebral perfusion are magnified during aging, when there is a progressive reshaping of cerebral autoregulation from a sigmoid curve to a straight line. This implies that any abrupt change in blood pressure will result in a significant change in cerebral blood flow [4]. Consistently with this pathophysiological background, OH is three to five times more frequent in AD and vascular dementia than in healthy age-matched controls [54] — although in other studies the association was no longer significant after correction for cardiovascular risk factors [55]. 3.5. Cerebrovascular disease Cerebrovascular disease is recognized as the pathophysiological basis for VCI, ranging from mild impairment to full-blown dementia. VCI accounts for 20–30% of all dementias, and its clinical manifestations range from overt, repeated strokes to dementia accompanied by neuroimaging findings, showing brain small vessel disease (SVD) including dilated Virchow–Robin spaces, micro-infarcts, white matter degeneration and microbleeds. Indeed, neuroimaging abnormalities can be found in both AD and VCI, as well as in asymptomatic individuals [46]. Both micro- and macrocirculation can be involved. At pathology verification, atherosclerotic changes in circle of Willis and intracranial arteries are more extensive in the AD group than in people without dementia [56]. Atherosclerosis of the extracranial carotid arteries is associated with increased prevalence of both vascular and Alzheimer dementia in the Rotterdam study population [57]. Arteriolosclerosis and, more in general, cerebral SVD, are also involved in cognitive impairment and it is thought to be a major component of degenerative brain disease [58]. Age and hypertension appear to be the main factors inducing microvascular rarefaction and remodeling, but also AD and environmental stress, such as X-ray exposure for radiotherapy, have been associated to SVD [58]. Cerebral amyloid angiopathy and ereditary small-vessel syndromes are also important contributors to VCI [46]. 3.6. Elevated cerebral venous pressure A role for cerebral venous pathology in pathogenesis of cognitive decline has been recently hypothesized. Dural arterovenous fistulas and jugular venous reflux may lead to chronic cerebral venous hypertension and decreased cerebral blood flow [59,60]. In particular, jugular venous reflux has been associated with leukoaraiosis, a major cause of vascular dementia in the elderly [60]. To date, the role of the venous circulation in pathophysiology of cognitive impairment is largely unknown and current evidence is contradictory [61].



4. Clinical implications: diagnosis and therapy of the vascular component of cognitive impairment From a diagnostic viewpoint, a thorough evaluation of patients with cognitive impairment might systematically include the assessment of the seven major cardiovascular rings of the chain linking blood perfusion to brain function: this systematic screening may also lead to identification of potentially treatable factors enhancing cognitive decay. Asthma in AD is commonly under-diagnosed and under-treated, and a proper anti-asthmatic treatment improves cognitive function after 1 year [62]. Coexistence of COPD and cognitive impairment is associated with worse global prognosis in the community-dwelling elderly population [63], but the impact of COPD treatment on cognitive outcomes is unknown. OSAS diagnosis typically involves the use of screening questionnaires, physical exam, and an overnight polysomnography or a much simpler portable home study. Individuals with sleep apnea are often unaware of their sleep disorder. Treatment options include lifestyle changes, continuous positive airway pressure (C-PAP), surgery, and dental appliances [64]. OSAS can exacerbate cognitive dysfunction in dementia, while sustained C-PAP use in AD patients might result in moderate-to-large effect sizes in cognitive decline [65]. Systolic heart failure can be readily identified on the basis of clinical symptoms and with a resting echocardiogram showing ejection fraction b40%, indicating at least a moderate left ventricular dysfunction [66]. Patients with end-stage heart failure awaiting heart transplantation are more likely to have cognitive impairment, which could improve after cardiac surgery [67]. In patients with heart failure with coronary artery disease, complete revascularization (immediate, early or late) can also improve cognitive scores — although post-interventional cognitive dysfunction is frequent after coronary artery bypass surgery (CABG), possibly also due to increased neuro-inflammatory stress and microembolic phenomena [68]. In middle-age subjects, an abnormally high pressure is a risk factor for long-term development of dementia, and in hypertensive patients, antihypertensive therapy may protect from hypertension-associated dementia, although it is still unclear if different classes of anti-hypertensive agents have a different effect on the development of cognitive decline [69,70]. However, in elderly patients the risk of mental deterioration may also be enhanced when diastolic pressure becomes too low, for example below 70 mm Hg, since the relationship between blood pressure and cognitive function appears to be curvilinear, so that a low diastolic blood pressure and mean blood pressure are associated with more progression of sub-cortical brain atrophy in patients with manifest arterial disease, irrespective of the course of blood pressure over time [71]. There is no convincing evidence that effective glucose control or lipid lowering therapy could prevent cognitive impairment [72,73]. The treatment of OH, defined as a fall in systolic blood pressure below 20 mm Hg and diastolic blood pressure below 10 mm Hg of baseline within 3 min in upright position, can be challenging, and usually consist of a combination of non-pharmacological approaches, with drug treatment as second-line [74]. The effect of OH treatment on cognitive function is unknown. Cerebrovascular disease can involve both large and small vessels. Elderly symptomatic patients with severe carotid lesions, easily diagnosed by ultrasound, had significant improvement in cognitive performance scores after carotid endarterectomy [75]. Cerebral small vessel disease can be indirectly detected through its functional consequences via Transcranial Doppler sonography, which although not as accurate as computed tomography or MRI imaging is a noninvasive imaging technique assessing mean arterial blood flow velocity (an accepted proxy for cerebral blood flow) and the pulsatility index (a surrogate for cerebrovascular resistance and intracranial compliance). Patients with AD have a reduced cerebral blood flow velocity and increased pulsatility index when compared to healthy controls, and these changes are even more obvious in vascular dementia [76]. Asymptomatic spontaneous cerebral emboli measured by continuous Transcranial Doppler of

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the middle cerebral artery are more common in both AD and vascular dementia than in healthy controls [77]. Potential sources of asymptomatic emboli include unstable carotid disease, valvular heart disease, atrial fibrillation, and paradoxical embolization of venous emboli into the arterial circulation, associated with migraine, obstructive sleep apnea, patent foramen ovale, and decompression sickness in scuba divers, which may favor cognitive disorders [78]. Cognitive dysfunction is common in elderly patients with atrial fibrillation and related to less effective anticoagulation [79], but no prospective data are available. Dural arteriovenous fistulas are arterio-venous shunts within the wall of the dural venous sinuses and represent 10–15% of cerebrovascular malformations. Although the commonly recognized initial symptoms are tinnitus, headache, and decreased cognitive function, it may also present with progressive dementia as the initial symptom caused by venous hypertensive encephalopathy [80]. Apart from this rare but curable cause [81], the hypothesis that hypertensive venous encephalopathy could be a much more frequent mechanism of dementia than is currently supposed remains largely speculative to date [60]. Driven by a better understanding of underlying mechanisms, the core of therapeutic intervention can also shift from individual treatment to aggressive prevention of environmental causes for both individual and social benefits. The clinician, as a “constant gardener” treating the desiccated plant of cognitive impairment not only looks at the leaves, but also assesses the vascular roots of the cognitive tree. In other words, a neurologist should be familiar with the main cardiovascular causes contributing to the progression of cognitive impairment, proactively rule out most common causes with targeted diagnostic testing driven by clinical history, and be familiar with the most effective treatments. In a chronically hypoperfused, dry and wasted brain, the return of warm cerebral blood flow could contribute to slowing the progression of cognitive decay (Fig. 4). 5. Environmental nurturing of brain and vessel plasticity Environment can both protect and inhibit the aging brain and vessel plasticity. As a plant's health also depends on the quality of air and soil in the habitat where it grows, the chance of suffering from atherosclerotic and neurodegenerative diseases increases with the degree of environmental pollution. Many factors exert their influence in a similar direction for both brain and vessel function. Premature brain and vessel aging can be promoted by environmental factors such as sedentary lifestyle, heavy ecosystem pressure (high urban and industrial pollution, agriculture, military and medical toxicants), brain drain (stress, isolation, depression), and eating habits (overeating, junk food). For instance, there is a causal relationship between air pollution with particulate matter b2.5 μm in diameter and cardiovascular morbidity and mortality [82], and between severe air pollution and AD [83]. Head and neck exposure to ionizing radiation is a recognized carcinogen for brain cancer [84] but is also responsible for non-cancer effects such as atherosclerosis [85] and neuro-degeneration [86]. Environmental enrichment (EE) is known to profoundly affect the central nervous system at the functional, anatomical and molecular levels, during the critical early growth period, during adulthood, in the aging brain and even in neurodegenerative states, such as the early stages of Alzheimer's disease. The efficacy of this therapeutic approach has been demonstrated in the experimental setting [87], although more clinical data are needed, and a recent US National Institute of Health Consensus panel on AD concluded that it is too soon to tell whether lifestyle changes including physical, cognitive, sensory and social training or any other prevention strategy can affect the development or course of AD [88]. Lifestyle changes are likely to have only limited benefit if a garden variety of overt AD is enrolled, without appropriate exclusion of patients with important comorbidities. On the contrary, benefits might be magnified in early stages of disease without critical comorbidities. Even small gains in cognitive function or slight delays in the development


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Fig. 4. The shared therapeutic approach to AD and atherosclerosis-mediated AD though lifestyle modulation and environmental enrichment: the constant gardener approach. The same lifestyle changes (physical exercise, healthy diet, social relationships and mental activity) will benefit brain and vessels.

of symptoms could greatly reduce the burden of disease. Obviously an aging brain in the pre-dementia stage cannot have the same synaptic and vascular plasticity as an adult brain, which even in normal conditions will suffer a 20% reduction in functional capacity by about 68 years of age [9] (Fig. 5, blue line). However, assuming that environmental enrichment might produce a reduction of the rate of decline of only 0.1% per year from young adulthood onward, functional decline is then delayed until age 88 years (Fig. 5, green line). Negative environmental nurturing can advance the 20% cognitive decay to the age of 58 (Fig. 5, red line). In addition, the same lifestyle and environmental factors modulating cognitive function also modulate vascular function. This model explains why even trivial improvements can add up over time to exert significant consequences for the individual. The recommendations of neurobiologists to prevent cognitive decay by lifestyle and environmental intervention closely mirror those of cardiologists to prevent vascular disease progression: quitting smoking, achievement and maintenance of ideal body weight, regular exercise, reduced intake of saturated fats and sugars, and decreasing the level of stress which is best achieved by improving one's family, community and societal relationships [90]. An integrated physical, cognitive, and dietary program of environmental enrichment allows the neurobiologist and the cardiologist to kill but two birds (brain and vessel protection) with one stone (lifestyle changes). On the other hand, a program of environmental enrichment is most effective when other risk factors and predisposing conditions have been ruled out and/or effectively treated, when indicated. To date, research on nonpharmacological treatment for AD and VCI is limited, despite preliminary evidence that these approaches are no less efficacious than the antidementia drugs [91]: exercise program

[92], cognitive intervention [93] and sensorial enrichment [94], either alone or combined, can slow the progression of MCI and AD, with a beneficial impact on lower health care costs [95].

Fig. 5. Different rates of decline with aging based on cerebral blood flow and oxygen consumption (based on Kety, ref. [9]), from early adulthood to senescence. The green line represents the outcome of slowing this process, for instance via environmental enrichment, by 0.1% per year. The red line represents the effects of accelerating this process, for instance in the presence of a highly polluted urban environment with intense social stress, by 0.1% per year (based on Weiss, ref [89]). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)



Within this conceptual framework, the Italian National Research Council (CNR) recently launched a multimillion-euro prospective, randomized, parallel-group, open-label clinical trial called “Train the Brain”, and enrolled (between March 2012 and January 2014) 118 patients (aged 69–89 years) with Mild Cognitive Impairment or mild AD randomized to standard vs. environmental enrichment therapy (Fig. 6). In the enrollment phase, a thorough cardiovascular characterization (including resting echocardiography, flow-mediated dilation of brachial artery and aortic stiffness) is made, in order to better define the study cohort from the cardiovascular viewpoint. A complete clinical, neuropsychological and brain (anatomic, perfusion and functional) MRI assessment is performed at study entry, following 7-month treatment and again (for all exams except MRI) at 18 months. The study design will provide insight into the neuropsychological, cerebral microvascular and cardiovascular alterations present in mild cognitive impairment, as well as their modification by an environmental enrichment program. This will involve a 3-h environmental enrichment session 3 times a week for 7 months, consisting of tailored, stepwise physical, cognitive and social training, including music therapy and dance, under the close supervision of highly specialized personnel in an ad-hoc facility built within the Pisa CNR Research campus. 6. Train the brain, and mind the vessel! It remains uncertain whether AD is a vascular disorder with neurodegenerative consequences or a neurodegenerative disorder with vascular consequences. It is certain that the cardiovascular system and the central nervous system are two complex systems whose functions are deeply intertwined, with similar processes participating in the phase of involution, the same markers indicating vulnerability to

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decay, and possibly similar factors slowing progression and promoting resilience to disease. In AD, decreased neuronal function requires less energy, and cerebral perfusion is reduced because less blood is demanded by affected brain tissue [96]. The opposite is true in cerebral hypoperfusion, when decreased blood flow goes below a critical threshold, causing tissue injury resulting in decreased brain metabolism in surviving areas. Therefore, hypoperfusion causes cognitive dysfunction, and cognitive dysfunction causes cerebral hypoperfusion, in an inextricably vicious circle [97]. The concepts of pure vascular and pure neurodegenerative dementia have been replaced with the recognition that many patients exhibit a spectrum of neurodegenerative and vascular processes. In some ways, this may lead to a resurrection of the old term “cardiogenic dementia” coined in 1977 [98], suggesting that this disorder might at least in some instances be secondary to cerebrovascular disease [99]. In particular, endothelial NO is a well known major vasodilator playing a key role in regulating local blood flow, and altered in many vascular conditions. Recently, however, endothelial NO has shown the ability to affect synaptic plasticity, mitochondrial biogenesis, and function of neural progenitor cells, also modulating processing of amyloid precursor protein. It has been suggested that endothelial NO is the key molecule linking cerebrovascular and neuronal function and the “protector of a healthy mind” (and also of a healthy vessel, probably a prerequisite for the preservation of a healthy mind) [100]. 7. Conclusions Vascular contribution to cognitive impairment and dementia are now extensively recognized. In particular, the vascular hypothesis of AD usefully complements the amyloid hypothesis, and at present both

Fig. 6. The flow-chart of Train the Brain study project.


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are necessary for understanding different aspects of the disease, in the same way as the quantum and wave theory are both useful for understanding the different physical phenomena of light. However, even the vascular hypothesis is a heterogeneous umbrella term covering pathophysiologically and clinically heterogeneous entities converging into the pathogenetic mechanism of cerebral hypoperfusion and neuroglial unit energy crisis. Considering this heterogeneity and complexity, it is not surprising that therapeutic carpet bombing with a one-size-fits-all approach will yield disappointing results. Our understanding of pathophysiology of cognitive impairment is still largely unsatisfactory, and substantial benefits are more likely to come from a multidisciplinary and integrated rather than monocultural and hyper-specialized approach. Heterogeneous pathophysiology and the underlying complexity of apparently similar clinical syndromes can be plainly ignored to make our life easier as clinicians, but the risk of oversimplification and generalization will certainly impact on the quality of our scientific efforts and clinical care. From a clinical viewpoint, cognitive performance is tightly associated with the maximal aerobic exercise capacity, and the maintenance of cerebrovascular endothelial function through regular exercise and healthy lifestyle is a key element for successful brain aging [101]. According to Shakespeare, “the brain may derive laws for the blood” (The Merchant of Venice, Act 1, Scene 2), but the blood and vessels may just as well derive laws for the brain. References [1] Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a delphi consensus study. Lancet 2005;366:2112–7. [2] Abbott A. Dementia: a problem for our age. Nature 2011;475:S2–4. [3] Wharton SB, Brayne C, Savva GM, et al. Epidemiological neuropathology: the MRC cognitive function and aging study experience. J Alzheimers Dis 2011;25:359–72. [4] de la Torre JC. Cardiovascular risk factors promote brain hypoperfusion leading to cognitive decline and dementia. Cardiovasc Psychiatry Neurol 2012;2012:367516. [5] Snowdon DA. Healthy aging and dementia: findings from the Nun study. Ann Intern Med 2003;139:450–4. [6] Staff RT. Reserve, brain changes, and decline. Neuroimaging Clin N Am 2012;22:99–105 [viii–iv]. [7] Stern Y. Cognitive reserve. Neuropsychologia 2009;47:2015–28. [8] Fotenos AF, Mintun MA, Snyder AZ, Morris JC, Buckner RL. Brain volume decline in aging: evidence for a relation between socioeconomic status, preclinical Alzheimer disease, and reserve. Arch Neurol 2008;65:113–20. [9] Kety SS. Human cerebral blood flow and oxygen consumption as related to aging. J Chronic Dis 1956;3:478–86. [10] Galderisi M, Rigo F, Gherardi S, et al. The impact of aging and atherosclerotic risk factors on transthoracic coronary flow reserve in subjects with normal coronary angiography. Cardiovasc Ultrasound 2012;10:20. [11] Taddei S, Virdis A, Mattei P, et al. Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation 1995;91:1981–7. [12] Iadecola C. The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathol 2010;120:287–96. [13] Del Zoppo GJ. Toward the neurovascular unit. A journey in clinical translation: 2012 Thomas Willis lecture. Stroke 2013;44:263–9. [14] Wolff CB. Normal cardiac output, oxygen delivery and oxygen extraction. Adv Exp Med Biol 2007;599:169–82. [15] Fehm HL, Kern W, Peters A. The selfish brain: competition for energy resources. Prog Brain Res 2006;153:129–40. [16] Neglia D, Michelassi C, Trivieri MG, et al. Prognostic role of myocardial blood flow impairment in idiopathic left ventricular dysfunction. Circulation 2002;105: 186–93. [17] Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007; 356:830–40. [18] de la Torre JC. Alzheimer disease as a vascular disorder: nosological evidence. Stroke 2002;33:1152–62. [19] Kaffashian S, Dugravot A, Elbaz A, et al. Predicting cognitive decline: a dementia risk score vs. the Framingham vascular risk scores. Neurology 2013;80:1300–6. [20] Geaney DP, Soper N, Shepstone BJ, Cowen PJ. Effect of central cholinergic stimulation on regional cerebral blood flow in Alzheimer disease. Lancet 1990;335: 1484–7. [21] Van Beek AH, Claassen JA. The cerebrovascular role of the cholinergic neural system in Alzheimer's disease. Behav Brain Res 2011;221:537–42. [22] Pizza V, Agresta A, D'Acunto CW, Festa M, Capasso A. Neuroinflammation and ageing: current theories and an overview of the data. Rev Recent Clin Trials 2011; 6:189–203. [23] Ray M, Ruan J, Zhang W. Variations in the transcriptome of Alzheimer's disease reveal molecular networks involved in cardiovascular diseases. Genome Biol 2008;9: R148.

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Non-alcoholic fatty liver disease and psoriasis: So far, so near.

Brexpiprazole: so far so good.

Cancer Metastases: So Close and So Far.

Global maternal, newborn, and child health--so near and yet so far.

So near and yet so far: harmonic radar reveals reduced homing ability of Nosema infected honeybees.

Nanomedicine and neurodegenerative disorders: so close yet so far.

Tapentadol--the evidence so far.

My Journey in Cardiology - So far.

Esophageal testing: What we have so far.

Commentary on "Still so far to go".

Extracontractual referrals: the story so far.

New OV training arrangements: progress so far.

Biology Open: The story so far….

Genomics and pharmacogenomics of sepsis: so close and yet so far.

Things we still haven't learned (so far).

My adventure in tRNA biology, so far.

In an open publishing house not so far, far away….

THERAPY OF ENDOCRINE DISEASE: Islet transplantation for type 1 diabetes: so close and yet so far away.

So close and yet so far - Molecular Microbiology of Campylobacter fetus subspecies.

Perspectives on modelling the distribution of ticks for large areas: so far so good?

Treatment of dyslipidemia and cardiovascular outcomes: the journey so far--is this the end for statins?

Diagnosis biomarkers in acute intestinal ischemic injury: so close, yet so far.

ESC-derived retinal pigmented epithelial cell transplants in patients: so far, so good.

The superficial femoral artery conundrum: so close, yet so far away!