About the Heart-Brain Connection

Vascular dementia (VaD)

Vascular disease is increasingly recognized as an independent cause of and contributor to cognitive decline in the elderly [1]. In 1993, international diagnostic criteria of vascular dementia (VaD) were accepted to identify patients who developed dementia attributable to cerebral vascular disease [2]. Using these criteria, VaD accounts for 16% of dementia cases in the elderly [3].

More recently, evidence has accumulated that vascular pathology also plays a role in people with a diagnosis of Alzheimer’s disease (AD) that has long been regarded as being primarily neurodegenerative. Infarcts and white matter lesions are observed in brains of 60–90% of patients with AD [4]. Since a diagnosis of AD accounts for 72% of demented elderly 3], vascular pathology may play a role in the majority of elderly patients with dementia. This is supported by a community-based population study, finding a frequency of cerebrovascular disease at autopsy as high as 75% [5].

Vascular coginitive impairment (VCI)

Vascular disease does not only cause dementia, but it also is a main contributor to milder forms of cognitive impairment. In 1993, the construct vascular cognitive impairment (VCI) was introduced to capture the whole spectrum of cognitive disorders related to vascular disease [6], and in 2011 the definition of VCI was further refined [1]. VCI is generally thought to be the result of irreversible changes in the brain [7]. Based on this view, treatment is often restricted to secondary prevention by treating risk factors.

Recent observations, however, suggest that hemodynamic factors can influence cell function in the brain, before structural changes occur [7]. In patients with heart failure (HF), cerebral perfusion and cognitive dysfunction can be improved by improving cardiac function [8–11]. Moreover, the frequently observed cognitive impairment in patients with carotid occlusive disease (COD) without frank infarction also suggests a causal relationship between reduced cerebral blood flow (CBF) and cognition, independent of cerebral structural damage [12].

Thus, cardiac and vascular (cardiovascular) pathology affecting hemodynamics in the brain might influence its cellular functions before structures are irreversibly altered, but this contribution to VCI is relatively unexplored. Exploring this contribution may be important, since it could identify treatment targets for the improvement of patients with cognitive impairment in the foreseeable future. This expectation is realistic because drugs that are able to influence hemodynamic changes are available, in contrast to the unavailability of drugs effectively targeting primary neurodegenerative changes, despite huge investments.

The brain depends on a continuous and adequate blood supply, and interruption of CBF leads to brain dysfunction and death [13]. There is ample evidence that sufficient cerebral perfusion is a prerequisite for adequate cognitive functioning, and in a number of studies cerebral hypoperfusion has been observed in different types of dementia [1]. Cerebral perfusion is a function of cardiac output, arterial stiffness, patency of cerebropetal arteries, cerebral autoregulation, patency of small cerebral vessels, and venous patency. For each of these parameters, there is evidence that, if changed, it can affect cognition.

The control mechanisms of CBF include chemoreceptors and autoregulation, endothelium-mediated signaling, and neurovascular coupling [14, 15]. Cerebrovascular autoregulation (CA) is the mechanism that is responsible for securing CBF over a range of blood pressures [16]. CA can be triggered by a host of stimuli, comprising changes in wall shear stress and chemical stimuli that are detected by endothelial receptors [17]. These stimuli ultimately result in changes in the tone of the smooth muscle cells of cerebral arterioles, leading to changes in arteriolar diameter that affect the brain’s resistance to blood flow. By adapting the flow resistance to local needs or changes of the systemic blood pressure, the brain secures its blood supply. There is evidence that the autonomous nervous system and the neurovascular unit also contribute to CA [18].

Chemoregulation is another mechanism that rules CBF. It involves the strong cerebrovascular responsiveness to changes in the arterial carbon dioxide partial pressure (Pa CO2) in direct relation to the pH [15]. Finally, the increased local metabolic needs that occur during neural activity are met by a powerful local increase in blood flow due to a mechanism called neurovascular coupling, also known as functional hyperemia [19]. Neurovascular coupling is executed at the level of the so-called neurovascular unit (interplay between neurons, vascular cells, and glia), ensuring that the brain’s blood supply matches its energy requirements [20, 21].

However, CA is not always able to compensate for hemodynamic challenges. The most drastic example is acute arrest of CBF, due to cardiac arrest [13], or occlusion of a large cerebral artery, which leads to infarction of brain tissue [22]. Apart from being overwhelmed, the efficacy of the CA can be reduced by microvascular diseases including those affecting the neurovascular unit. Endothelium-dependent responses in the microcirculation may be impaired in atherosclerosis, hypertension, diabetes, and old age (discussed in [1]). Oxidative stress and inflammation may play an important role in dysfunction of the neurovascular unit. Oxidative stress induces endothelial dysfunction, opening of the blood-brain barrier, and cytokine production [23]. Inflammation, in turn, enhances oxidative stress by upregulating the expression of reactive oxygen species-producing enzymes and down-regulating antioxidant defenses [24]. Furthermore, oxidative stress and inflammation compromise the repair mechanism of the damaged white matter, by interfering with proliferation, migration, and differentiation of oligodendrocyte progenitor cells [25–27]. The loss of growth factors produced by the brain, observed in both AD and VCI, further compromises repair mechanisms [28]. Finally, apolipoprotein E .4 genotype seems to have an influence on the neurovascular unit via the pericytes, giving rise to blood-brain barrier breakdown and microvascular flow changes that precede and initiate neurodegenerative changes [29, 30]. All these mechanisms affect cerebral arterioles in particular and can contribute to the development of small vessel diseases such as cerebral amyloid angiopathy and arteriolosclerosis. Diseases affecting the neurovascular unit cause blunting of the cerebral vasomotor reactivity [31, 32]. This, in turn, creates an increased vulnerability to changes in systemic blood pressure. Impaired cognition, stroke-like symptoms, and structural brain changes (white matter lesions, lacunar infarcts, and parenchymal hemorrhages) are the clinical consequences (discussed in [1]).

The amount of blood reaching the cerebral circulation further depends on cardiac function and patency of the cerebropetal arteries. In patients with HF, reduced CBF was observed, and reduced CBF correlated with a rising prevalence (of up to 25%) of cognitive dysfunction [33, 34]. Even a subclinical decrease in cardiac output has been shown to be associated with impaired cognitive functioning [35], while improvement of cardiac function by transplantation or resynchronization improved cognitive functioning [8, 10, 11]. These observations cannot be explained by the limited blood supply due to extracerebral factors beyond normally functioning CA. There is experimental evidence that reduced cardiac output hampers CA efficacy, challenging cerebral perfusion [36]. More evidence for the assumption that insufficient blood supply to the cerebral circulation can lead to cognitive impairment comes from observations in patients with blocked internal carotid arteries [37]. In a well-documented study, about half of these patients were cognitively impaired [37, 38]. Cognitive impairment could not be explained by the presence of structural brain damage, but rather by—potentially reversible—lactate accumulation in non-infarcted brain regions [39].

Apart from the amount of blood reaching the cerebral circulation, the arterial pulse profile, which is influenced by the arterial elasticity, may be an important hemodynamic parameter for the brain. Due to the so-called “Windkessel function”, the wall of a healthy, elastic aorta absorbs the pulsatile energy during systole and releases it during diastole. Due to the lower stiffness of a normal aorta as compared to the carotids (impedance mismatch), a portion of the pulsatile energy is reflected at the origin of the common carotid artery and therefore is not transmitted into the distal vasculature [40]. With increasing age and vascular risk factor exposure aortic stiffness increases, with two important hemodynamic effects [40].

First, the loss of Windkessel function causes an increase of pulsatile energy. Second, due to a decreased impedance mismatch, transmission of the increased pulsatile energy into the cerebral microcirculation is facilitated, leading to microvascular damage and impaired function. Aortic stiffness can be determined noninvasively, using ultrasound or magnetic resonance imaging (MRI), and is reflected by the pulse-wave velocity (PWV). In patients with cognitive impairment, increased PWV has been observed [34]. An inverse relationship between PWV and cognitive performance was reported cross-sectionally [41–43]. PWV was found to be an independent predictor of longitudinal changes in cognitive function in older individuals [43, 44]. Furthermore, correlations have been found between PWV and structural changes on neuroimaging studies, such as white matter lesions, atrophy, and subcortical infarcts [40]. Atherosclerosis can also contribute to the development of VCI by affecting the wall of the carotids and vertebral arteries.

In the Rotterdam Study, intracranial carotid artery calcification measured by CT is present in more than 80% of the participants [45]. Larger calcification volume is associated with smaller brain volumes, higher white matter hyperintensity loads, cerebral infarcts, and loss of microstructural brain integrity on MRI on the one hand, and on the other worse cognitive performance [46, 47]. In addition, there is evidence that atherosclerosis affects the neurovascular unit with consequences for local cerebral perfusion-metabolism (mis)matching [1]. And, finally, atherosclerosis can result in hemodynamic compromise of the brain through steno-occlusive disease and plaque rupture with thrombotic occlusion of large arteries and emboli originating from ruptured plaques [1].

Currently, the only disease-modifying treatment that can be offered to VCI patients is targeted at secondary prevention of progression of cerebrovascular disease by treating risk factors or, in some cases, prescribing antithrombotic agents. Potentially reversible, hemodynamic causes of VCI provide a more optimistic outlook for VCI patients regarding possible treatment. Observations in several studies suggest that hemodynamic improvement gives rise to improved cognitive functioning and even reversal of structural changes. In patients with significant cerebrovascular steno-occlusive disease, surgical revascularization (extracranial-intracranial bypass or carotid endarterectomy) resulted in cognitive improvement associated with an increase of CBF and cerebral vascular resistance [12] or even in restoration of cortical thickness [48], although results are not uniform [49]. Improvement of cognition has also been observed in patients with HF who were treated with angiotensin-converting enzyme inhibitors (which have a positive effect on CBF) [9], and in patients who underwent cardiac transplantation or resynchronization [8, 10], conditions that were associated with improvement of CBF.

Unresolved issues in VCI: The Heart-Brain Connection

It is currently unknown how often hemodynamic changes based on cardiovascular pathology occur in elderly patients with cognitive impairment. Conversely, it is also unclear to what extent cognitive impairment occurs in patients with cardiovascular disease and whether this is determined by hemodynamic changes. Various cardiovascular factors, such as cardiac output, blood pressure, PWV, aortic and carotid stiffness, carotid patency, and cerebrovascular autoregulation, may influence CBF. However, little is known about how these factors, separate or in concert, influence cognitive performance and for which of these treatment is most promising. Since individual patterns of disturbed cardiovascular factors leading to VCI will be highly variable, treatment of these patients probably requires a personalized approach to a high degree. For such an approach, a diagnostic protocol is required that allows assessment of the different factors contributing to the hemodynamic status in individual patients. What such a protocol should assess and how is currently unknown.

Recently, both the American Heart Association/American Stroke Association (AHA/ASA)

[1] and the National Institutes of Health (NIH) mentioned several reasons for this knowledge gap [50]. The monodisciplinary way health care and research is often organized results in neglecting the cardiovascular status in patients presenting with cognitive impairment in memory clinics and, vice versa, in neglecting cognition in patients presenting with cardiovascular disease in cardiology or vascular medicine departments. Guidelines for diagnostic protocols that provide a combined comprehensive assessment of the cardiovascular and cerebral status are lacking. Thus, it is not surprising that welldesigned, largescale clinical studies with focus on the heart-brain axis do not as yet exist. The heart-brain axis provides a clear unmet clinical and basic research need, which can only be met by truly multidisciplinary and translational approach. Clinical trials that assess the efficacy of improving hemodynamics have not been performed because of an incomplete understanding of the mechanisms involved and because of the absence of methods to identify patients who might benefit from it. These observations in combination with the availability of drugs that are able to improve the hemodynamic status by various mechanisms make the hemodynamic status a promising, but still underexplored, target for treatment of VCI [7].

We have designed and recently started a multidiciplinary comprehensive research program involving neurologists, cardiologists, epidemiologists, neuropsychologists, radiologists, pathologists, and basic neuroscientists. It focuses on the cardiovascular contribution to cognitive impairment. In addition, novel diagnostic tools will be developed and new treatment options will be proposed for cognitive impairment in the elderly. The following expected results meet the unmet clinical and basic research needs that are currently recognized [1, 50].

In September 2011, the AHA/ASA published a scientific statement providing an overview of the evidence on vascular contributions to cognitive impairment and dementia [1]. These vascular contributions are recognized as important. In the statement a clear need was identified to further improve our understanding of VCI. A specific recommendation was to develop nationally funded centers of excellence with transdisciplinary programs within and between centers. Also in an NIH Consensus and State-of-the-Science Statement on Preventing AD and Cognitive Decline that was published by the NIH in 2010, the development of such centers was recommended [50]. The basis for these recommendations is the recognition that full exploration of the interaction of the cardiovascular system and the brain is currently hampered by the fact that in patient care these systems are rarely analyzed together. The rather monodisciplinary approach of many cardiolo gists and neurologists in their clinical work also reflects on research. Importantly, there is a lack of animal models that enable studying the contribution of car- diovascular pathology to cognitive dysfunction [51]. In this program, we follow the AHA/ASA and NIH recommendations and aim to develop a national interdisciplinary collaborative network in the Netherlands linking complementary groups with different disciplines sharing excellent track records that are relevant to the study of VCI.
A comprehensive diagnostic protocol will be developed a) to capture vulnerable neuropsychological functions in patients with VCI, b) to detect the hemodynamic changes that, apart and in concert, contribute to brain dysfunction, c) to have an inventory of diseasemodifying factors and d) to define targets for treatment. Furthermore, cardio- and cerebrovascular parameters will be collected as part of our protocol to detect hemodynamic changes relevant for the diagnosis and therapy of VCI. Moreover, relevant biomarkers will be sought, enhancing the diagnostic performance of our model.
Although hemodynamic changes based on cardiovascular pathology were found to contribute to the development of VCI, the mechanisms involved are incompletely understood. We will use different approaches:

  • Cross-sectionally, we will assess the relationship between hemodynamic status and cognitive performance in three hospital-based patient populations with VCI, HF, or COD. In addition to clinical assessment, measuring biomarkers and a protocol measuring cognition, we will perform extensive functional phenotyping with a comprehensive MRI protocol that will enable us to obtain mechanistic insight into the relationship between hemodynamic status and cognitive performance.
  • In the same patients, we will perform a follow-up study to assess the predictive value of the hemodynamic status for future cognitive decline.
  • Using an epidemiological approach, we will assess the relationship between hemodynamic status and cognitive function in the elderly population at large of the Rotterdam Study.
Currently, we cannot select patients with VCI who might benefit from treatment. We envisage developing a diagnostic protocol that allows assessing and measuring the hemodynamic changes that are responsible for actual or pending cognitive impairment in individual patients. In addition, we will assess the role of additional risk factors for identifying such patients. Such information can help to identify patients needing treatment and is also helpful to install person- alized treatment by addressing the specific disturbed mechanisms in individual patients. The ability to measure such mechanisms provides tools that enable tailoring treatment at follow up based on objective targets.
The overarching goal of this study is to pave the way for randomized controlled treatment trials assessing the effect of treatment aimed at changing the hemodynamic status on cognitive functioning in VCI. This study will meet the following, currently unfulfilled needs for such trials:

  • Candidate treatments aimed at improving cognition in VCI based on a pathomechanistical model of hemodynamic influence on cognition.
  • Definition of subcategories of VCI patients that could benefit from such treatment.
  • Availability of a comprehensive but clinically feasible diagnostic protocol to identify these patients.
  • Availability of a protocol to monitor treatment effects based on primary outcome (cognitive functioning) and relevant mechanistic parameters (hemodynamic status).