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Chronic cerebral hypoperfusion: An undefined, relevant entity
Journal of Clinical Neuroscience xxx (xxxx) xxx
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Review article
Chronic cerebral hypoperfusion: An undefined, relevant entity Antonio Ciacciarelli ⇑, Giuliano Sette, Franco Giubilei, Francesco Orzi Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), ‘‘SAPIENZA” University of Rome, Sant’Andrea University Hospital, Rome, Italy
a r t i c l e
i n f o
Article history: Received 17 October 2019 Accepted 6 January 2020 Available online xxxx Keywords: Chronic cerebral hypoperfusion Neurocognitive disorders Alzheimer’s disease Heart failure Hypotension Carotid stenosis
a b s t r a c t Despite the large body of data available, chronic cerebral hypoperfusion lacks an operative definition. In a tautological way, the term hypoperfusion is being referred to conditions of ‘‘inadequate blood flow”, ‘‘defects of perfusion” or ‘‘dysfunction of autoregulation”. The chronicity refers to sustained conditions or wavering states characterized by repeated phases of inefficient functional hyperemia. The phenomenon may affect the whole brain or defined areas. A few defined clinical disorders, including heart failure, hypotension, atherosclerosis of large or small vessels and carotid stenosis are thought to cause progressive brain disorders due to chronic hypoperfusion. The clinical relevance manifests mostly as neurocognitive disorders associated with neuroimaging changes. The available data support a conceptual framework that considers chronic cerebral hypoperfusion a likely, relevant pathogenic mechanism for the neurodegeneration-like progression of the neurocognitive disorders. The relationship between neuropathology, cerebral perfusion, and symptoms progression is, however, elusive for several aspects. Typical microangiopathy findings, such as MRI white matter hyperintensities, may appear in individuals without any cerebrovascular risk or vascular lesions. Pathology features of the MRI changes, such as demyelination and gliosis, may result from dysfunction of the neuro-vascular unit not directly associated with vascular mechanisms. In this review, we aim to overview the most common clinical conditions thought to reflect chronic hypoperfusion. Ó 2020 Elsevier Ltd. All rights reserved.
1. Introduction Considerable interest has grown in the recent years concerning the role of chronic cerebral hypoperfusion (CCH) or misery perfusion on the development and progression of neurocognitive disorders, including Alzheimer’s disease (AD). A large body of evidence does in fact account for the interaction between vascular and neurodegenerative mechanisms. The interaction has been shown on experimental ground by exploiting the susceptibility of different animal models to developing Alzheimer-like pathology under conditions of reduced or altered brain perfusion [1]. In parallel, experimental data specifically have provided evidence for the deleterious effects of Ab on cerebrovascular function. Accumulation of Ab, either because of increased production or altered clearance, increases arterial vasoconstriction, reduces resting cerebral blood flow (CBF) and impairs functional hyperemia [2], by interfering with the function of the neurovascular unit (NVU) [3,4]. Altered Ab clearance itself may ⇑ Corresponding author at: Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), ‘‘SAPIENZA” University of Rome, Sant’Andrea University Hospital, via di Grottarossa 1035, 00189 Rome, Italy. E-mail address: [email protected] (A. Ciacciarelli).
result from arterial stiffness, which reduces the exchange between interstitial fluid and cerebrospinal fluid (CSF) [5]. The Abneurovascular interaction, therefore, likely encompasses mechanisms that fuel deleterious vicious circles. Endothelial and immune cells, neurons, glia, pericytes and other components of the NVU may promote the pathogenesis of neurodegenerative diseases by means of different mechanisms [6], and it is unclear whether changes in CBF precede or follow the neurovascular dysfunction, or whether the hypoperfusion is a cause or a consequence, or just an epiphenomenon. Epidemiological data, by showing the co-presence of vascular risk factors and neurocognitive disorders [7], support the causal link between vascular and neurodegenerative mechanisms. For instance, major and mild neurocognitive disorders due to AD are consistently associated with vascular risk factors such as hypertension, ischemic heart disease, hypercholesterolemia, atrial fibrillation, smoking and obesity [8,9]. Whether the association is a causal one is uncertain. Still, in large population-based studies, the CBF reduction precedes the cognitive decline and hippocampal atrophy [10] as to suggest a causality. Pathology studies have largely proven the frequent coexistence of extracellular amyloid Ab deposits, intracellular tau tangles or
https://doi.org/10.1016/j.jocn.2020.01.026 0967-5868/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: A. Ciacciarelli, G. Sette, F. Giubilei et al., Chronic cerebral hypoperfusion: An undefined, relevant entity, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.026
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A. Ciacciarelli et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
structural changes such as atrophy together with cerebrovascular lesions [11]. The nature of the ‘‘ischemic” lesions is variegated. The lesions typically include lacunes, infarcts, white matter hyperintensities (WMH), microbleeds and enlarged perivascular spaces [12,13]. All these lesions are thought to express cerebral microangiopathies, but mechanisms underlying the formation and progression of these lesions are not fully understood and likely include a broad range of dysfunctions affecting NVU [14]. These observations, altogether, support a conceptual framework that considers CCH a likely, relevant pathogenic mechanism for the neurodegeneration-like progression of the neurocognitive disorders [15,16]. The relationship between neuropathology, cerebral perfusion and symptoms progression, however, is elusive for several aspects. Extensive AD-type lesions may exist without dementia [17]. Typical microangiopathy findings, such as WMH, may appear in individuals without any cerebrovascular risk or vascular lesions [18]. Pathology features of the white matter lesions, such as demyelination and gliosis, may result from NVU dysfunction not directly associated with hypoperfusion [19]. Most notably, CCH is generally inferred, not measured. Despite the potential relevance of the disorder, as reflected by the large body of literature data, an operative definition is missing. CCH is told to embrace conditions of ‘‘inadequate” blood flow, or conditions characterized by ‘‘defects” of perfusion or by ‘‘dysfunctions” in mechanisms associated with the autoregulation. The hypoperfusion, in addition, bears a dynamic dimension, as the chronicity may refer either to sustained conditions (for instance caused by vessel stenosis or cardiac insufficiency) or to repeated phases during which local blood flow fails to meet increments of energy supply demands (inefficient functional hyperemia). Reports in the literature often do not specify the temporal dimension of the hypoperfusion, whether persistent, sustained or phasic in nature. In addition, the phenomenon may pertain the whole brain or be limited to defined areas. Thus, hypoperfusion encompasses many different conditions, which range from mild phasic or temporary mismatch between energy tissue demand and blood flow supply to a persistent inadequate perfusion. An operative definition of hypoperfusion is, therefore, missing. Despite such fundamental uncertainty, a pubmed search of ‘‘chronic cerebral hypoperfusion” or ‘‘misery perfusion” resulted in almost one thousand entries, which have been increasing until our days reaching 75 entries in 2018. In this short review, we refer to animal models of hypoperfusion and to clinical conditions of chronically hypothetically altered cerebral perfusion caused by definite conditions, such as chronic heart failure [20,21], hypotension [22,23] and carotid stenosis [24,25]. 2. Background The brain takes approximately ¼ of the whole-body oxygen and glucose consumption. The average whole CBF, is about 57 ml/100gr/min, in the healthy adult individual, which is 800 ml/min, or approximately 15% of the total basal cardiac output [26]. Since the amount of oxygen stored in brain is small, an increase in CBF is mandatory whenever there is increased energy demand. The exploitation of several methods and techniques for measuring local rates of CBF and energy metabolism under a variety of physiological conditions has shown that rates of CBF and energy metabolism are heterogeneously distributed within the brain. CBF and energy metabolism vary not only from area to area, but they also vary with time, conformably to the dynamic changes of the brain function. Thus, any local increase in functional activity, under physiological conditions, is associated with local increase in CBF to meet the energy demand (functional hyperemia).
CCH seems, therefore, to refer to inadequate supply of nutrients (essentially, glucose and oxygen) to meet the energy demand of the tissue, including conditions of altered functional hyperemia. The mismatch results in increased extraction of oxygen, from the blood, by the brain, at least in the early phases when the brain function is maintained normal (or near normal) despite the reduced perfusion. 3. Animal models of hypoperfusion A fundamental approach to model CCH is based on manipulating the neck large blood vessels. Rats and baboons are usually submitted to permanent bilateral occlusion (2VO) of the carotids [27– 29], while mice are usually submitted to stenosis. The models cause persistent reduction of the global or regional CBF. Bilateral occlusion of the common carotid arteries in the rat causes decrease of CBF to 35–45% of control in cortical areas and to about 60% in the hippocampus. A partial recovery occurs in the days following the occlusion. The recovery is almost complete in 2– 3 months. Six months following the occlusion the flow is completely recovered [30]. The progressive restitution to normal flow and energy metabolism is inconsistent with the constant or progressive cerebral hypoperfusion observed in aging and dementia. Despite such a difference, the persistent oligemia causes structural and functional brain changes consistent with the clinical findings. The 2VO animals develop white matter lesions, which are typically evident two weeks following ligation of the arteries. The lesions, characterized by vacuolation of myelin, axonal damage, demyelination, BBB opening [31] and persistent activation of the microglia and lymphocyte infiltration [32], resemble the diffuse white matter radiological changes frequently associated with hypertension or diabetes. Grey matter alterations are inconsistent. Neural and synaptic contact loss may occur later and may not correlate with CBF changes [33]. The 2VO animals develop behavioral changes, which share similarities with the cognitive disorders in humans. The behavioral alterations are measurable a few weeks following occlusion and seem to progress with time [34], even when flow has recovered to normal values. Thus, while most of the changes occur during the chronic phase of the hypoperfusion, the progression of the behavioral changes seems to support the hypothesis of a neurodegenerative-like mechanism that may ‘‘survive” to the hypoperfusion. In mice, microcoils placed in both carotid arteries cause variable CBF drops, according to the coil diameter. In all the cases, bilateral carotid stenosis causes white matter lesions correlated with the extent of CBF reduction. The lesions consist in rarefaction of myelinated fibers in the corpus callosum, caudate putamen, internal capsule, and in the optic tract, associated with inflammation and BBB permeability. Grey matter involvement is inconsistent [1,27]. A few studies were carried out in models of CCH based on longlasting manipulation of cerebrovascular risk factors. For instance, authors carried out studies following high-salt/high-fat diet or elevated dietary levels of the amino acid homocysteine. Other studies were carried out in aged or CADASIL-like animals, or in models of atherosclerosis [35]. Other studies are focused on causing inadequate heart function, such as surgery-induced models of aortic constriction, cardiac arrest, or myocardial infarct models [27]. 4. Hypoperfusion in humans A few defined clinical conditions are thought to be associated with or cause CCH in humans [36,37] (Table 1). 4.1. Heart failure There is an inherent difficulty in providing operative definitions of Heart Failure (HF). The diagnosis and the New York Heart Asso-
Please cite this article as: A. Ciacciarelli, G. Sette, F. Giubilei et al., Chronic cerebral hypoperfusion: An undefined, relevant entity, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.026
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A. Ciacciarelli et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx Table 1 Clinical Conditions Associated with Chronic Hypoperfusion. Clinical Condition
Hypoperfusion Inferred from:
Findings
Defined as:
Ref.
Heart Failure
99mTc SPECT 133Xe SPECT TCD MRI TCD at rest and after stimulation Perfusion MRI
rCBF reduction in posterior cortical areas Global CBF reduction MCA-CBF velocity reduction Higher T2-relaxation values Lower MCA Blood flow velocity at rest and lower increase after stimulation Increased MTT
NYHA II/III NYHA III/IV NYHA II/III/IV NYHA II sBP < 100 mmHg
[38] [39] [40] [41] [42] [43]
TCD
Lower CBF velocity and CVR during head up tilt
ASL-MRI CT perfusion
Post-CAS CBF higher than pre-CAS CBF Ipsilateral MTT and CBV increase and CBF reduction compared to contralateral Ipsilateral Impaired VMR, recovered after CEA Ipsilateral Increased OEF ratio
Orthostatic ;sBP 20 or dBP 10 mmHg Orthostatic ;sBP 30 or dBP 10 mmHg Unilateral 68–96% stenosis Unilateral > 70% stenosis Unilateral > 70% stenosis Complete ICA occlusion
[48] [49]
Essential Hypotension Orthostatic Hypotension
Carotid Stenosis
TCD 15O-PET
[44] [45] [46]
Cerebral Vascular Resistance (CVR) = Mean Blood Pressure (MBP)/ Mean Flow Velocity (MFV); rCBF = regional Cerebral Blood Flow; MCA = Middle Cerebral Artery; MTT = Mean Time Transit; VMR = Vasomotor reactivity; TCD = Transcranial Doppler; CAS = Carotid Artery Stenting; sBP = Systolic Blood Pressure; dBP = Diastolic Blood Pressure; ; OEF = Oxygen Extraction Fraction.
ciation (NYHA) classification are based on clinical signs and symptoms, and several confounding variables are typically associated with the different causes of HF. NYHA class III/IV is associated with whole-brain CBF reduction of about 30% [39]. Patients with NYHA class II/III show regional CBF changes, mostly represented by reductions in the posterior cortical areas of the brain [38]. HF is often inferred by measuring the ejection fraction (EF). Different degrees of EF reduction may cause brain damage depending on the presence of risk factors, such as aging or increased systolic pressure [50]. Duration of the heart disease seems to be also a sensible variable [20], although most studies do not provide information on the time length of EF reduction. Lesions occur both in white and grey matter. Different areas are differentially affected, suggesting that different variables account for different distribution patterns of the brain damage [41]. HF may, however, occur with preserved heart function [51]. The term ‘‘cardiogenic dementia” appeared in the literature almost forty years ago and since than several findings have supported the association between HF and cognitive impairment [21]. In a case-control study Sauvé et al. found that in subjects with HF there is a 4-fold increased risk of cognitive impairment as compared to matched controls [52]. In a prospective cohort study of a total of 577 patients, 79% of them resulted impaired at least in one cognitive domain [53]. In a meta-analysis Cannon et al. estimated a 40% prevalence of cognitive impairment in subjects with HF, thus confirming the association between HF and cognitive impairment [54]. The pathophysiological mechanism behind this relationship is, however, unclear. It is a question whether the hypoperfusion per se, and the consequent hypoxia, is the cause of the neurocognitive disorders. A few studies, carried out in small groups of patients who underwent heart transplant, reported partial recovery of neuropsychological performances following intervention, supporting the clinical relevance of the improved cerebral perfusion [55]. Other variables, however, including changes in cerebrovascular reactivity, potentially associated with endothelial dysfunction or coagulation, are also relevant. 4.2. Hypotension Research is mainly focused on essential hypotension or orthostatic hypotension (OH). The essential hypotension (also named constitutional, primary or chronic hypotension) is a persistent condition of lowered blood pressure (BP) without any identifiable pathological factors. In most studies, however, there is not defined
BP threshold value, and hypotension is often defined in association with symptoms such as fatigue, dizziness and concentration deficits. The prevalence of the essential hypotension is probably underestimated, due to the lack of definite diagnostic criteria [56]. The Honolulu-Asia Aging Study [57] and the Kungsholmen Project [22] provided evidence that chronic hypotension, is a predictor of reduced cognitive function in elderly [58]. Data obtained in young subjects support the causal relationship between hypotension and reduced cerebral blood perfusion [42], inferred by reduced mean flow velocity at rest and reduced task-induced blood flow increment at Transcranial Doppler (TCD) [23]. OH is defined as a reduction of systolic BP of at least 20 mmHg or diastolic BP of at least 10 mmHg within 3 min of standing up. The prevalence is age-dependent and increases up to 10–30% in elderly people [59]. The hypotension is thought to cause failure of the CBF autoregulation. The failure is typically inferred when TCD changes occur following an acute hypotensive stimulus [60] or 80° head-up tilt [44]. The relationship between OH and cognitive impairment is controversial [61]. A recent clinicopathological study found a higher burden of pathological changes in the white matter in demented patients with autonomic dysfunction [62]. Moreover, a 20-year follow-up study showed a causal association between OH and neurocognitive disorders [63]. 4.3. Carotid stenosis Arteriosclerosis embraces a variety of different lesions that include sclerosis of small arteries and arterioles (arteriolosclerosis) and formation of plaques in large and medium-size arteries (atherosclerosis). The disease involves intracranial and extracranial arteries. Lacunar, subcortical and cortical infarctions determined by emboli, thromboembolism or occlusions are frequently identified in these patients, together with hemodynamic and metabolic impairments and reduction of the CBF [64]. Remarkably, the effect of intracranial atherosclerosis probably exceeds the boundaries of mechanisms directly involved in blood perfusion. For instance, vessel stiffening associated with atherosclerosis seems to affect the Ab clearance. Such a mechanism adds to those thought to link atherosclerosis and AD. The stiffening would reduce the effect of the reflection wave of the arterial wall. The arterial wave, caused by normal cardiac pulse, is thought to represent the driving force for solute drainage from the interstitial spaces, by means of the perivascular pathway [5,65]. Weakening of the wave would reduce the clearance drive.
Please cite this article as: A. Ciacciarelli, G. Sette, F. Giubilei et al., Chronic cerebral hypoperfusion: An undefined, relevant entity, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.026
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Carotid stenosis is responsible for at least 20% of all thromboembolic strokes. Carotid endarterectomy or stenting is of proven efficacy in reducing the risk of stroke and TIA, both in symptomatic and asymptomatic patients. In addition, several findings suggest that carotid stenosis leads to a condition of CCH. For instance, there is evidence that intracranial stenosis, in the range 50–99%, causes different degrees of impairment of anterograde CBF and downstream perfusion depending on efficiency of collateral vessels [66]. Consistently, Marshall and collaborators showed increased oxygen extraction fraction (OEF) ratio, interpreted as expression of hemodynamic failure, in patients with carotid stenosis. The altered perfusion was associated with cognitive impairment and brain changes seen in these subjects [49]. Removal of the arterial narrowing has been hypothesized to improve cerebral hemodynamics and provide benefits in cognitive functions, by supposedly resolving the insufficient blood supply [47,67]. There are findings suggesting that following resolution of the carotid stenosis in asymptomatic patients show a mild improvement in cognitive performance [25], likely associated with the improved perfusion [48]. However, the issue is still controversial since there is lack of systematic and prospective studies [24]. In a 7-year prospectic study Arntzen et al. found that cognitive performance scoring was inversely proportional to the number of the plaques, total plaque area, stenosis grade and carotid intimamedia thickness, suggesting an independent correlation between carotid atherosclerosis and cognitive function [68]. Buratti et al. monitored cognitive performance in subjects with bilateral asymptomatic carotid stenosis and found a linear relationship between TCD-based breath-holding index and MMSE [69]. The findings sustain the speculation that carotid endarterectomy or stenting reduce the risk of cognitive impairment in addition to reducing the risk of recurrent stroke. 5. Conclusions The findings altogether suggest that different diseases that cause altered blood perfusion of the brain promote neurodegeneration. Several mechanisms are involved in mediating the effect of hypoperfusion [70]. Most of the reported mechanisms refer to dysfunctions of the NVU [71], which may or may not cause hypoxia. An open question, therefore, regards the role of hypoxia. A few studies report an increased risk of neurocognitive disorders in subjects with anemia [72] or chronic obstructive pulmonary disease [73] suggesting that hypoxia per se, i.e. without the traditional cerebrovascular risks and apparently without defects in perfusion, causes, or contributes to, the neurocognitive disorders. Appreciation of the role of CCH may suggest novel targets for therapeutic strategy to neurodegenerative disorders. Funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] Farkas E, Luiten PGM, Bari F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev 2007;54:162–80. https://doi.org/ 10.1016/j.brainresrev.2007.01.003.
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Please cite this article as: A. Ciacciarelli, G. Sette, F. Giubilei et al., Chronic cerebral hypoperfusion: An undefined, relevant entity, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.026
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Review article
Chronic cerebral hypoperfusion: An undefined, relevant entity Antonio Ciacciarelli ⇑, Giuliano Sette, Franco Giubilei, Francesco Orzi Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), ‘‘SAPIENZA” University of Rome, Sant’Andrea University Hospital, Rome, Italy
a r t i c l e
i n f o
Article history: Received 17 October 2019 Accepted 6 January 2020 Available online xxxx Keywords: Chronic cerebral hypoperfusion Neurocognitive disorders Alzheimer’s disease Heart failure Hypotension Carotid stenosis
a b s t r a c t Despite the large body of data available, chronic cerebral hypoperfusion lacks an operative definition. In a tautological way, the term hypoperfusion is being referred to conditions of ‘‘inadequate blood flow”, ‘‘defects of perfusion” or ‘‘dysfunction of autoregulation”. The chronicity refers to sustained conditions or wavering states characterized by repeated phases of inefficient functional hyperemia. The phenomenon may affect the whole brain or defined areas. A few defined clinical disorders, including heart failure, hypotension, atherosclerosis of large or small vessels and carotid stenosis are thought to cause progressive brain disorders due to chronic hypoperfusion. The clinical relevance manifests mostly as neurocognitive disorders associated with neuroimaging changes. The available data support a conceptual framework that considers chronic cerebral hypoperfusion a likely, relevant pathogenic mechanism for the neurodegeneration-like progression of the neurocognitive disorders. The relationship between neuropathology, cerebral perfusion, and symptoms progression is, however, elusive for several aspects. Typical microangiopathy findings, such as MRI white matter hyperintensities, may appear in individuals without any cerebrovascular risk or vascular lesions. Pathology features of the MRI changes, such as demyelination and gliosis, may result from dysfunction of the neuro-vascular unit not directly associated with vascular mechanisms. In this review, we aim to overview the most common clinical conditions thought to reflect chronic hypoperfusion. Ó 2020 Elsevier Ltd. All rights reserved.
1. Introduction Considerable interest has grown in the recent years concerning the role of chronic cerebral hypoperfusion (CCH) or misery perfusion on the development and progression of neurocognitive disorders, including Alzheimer’s disease (AD). A large body of evidence does in fact account for the interaction between vascular and neurodegenerative mechanisms. The interaction has been shown on experimental ground by exploiting the susceptibility of different animal models to developing Alzheimer-like pathology under conditions of reduced or altered brain perfusion [1]. In parallel, experimental data specifically have provided evidence for the deleterious effects of Ab on cerebrovascular function. Accumulation of Ab, either because of increased production or altered clearance, increases arterial vasoconstriction, reduces resting cerebral blood flow (CBF) and impairs functional hyperemia [2], by interfering with the function of the neurovascular unit (NVU) [3,4]. Altered Ab clearance itself may ⇑ Corresponding author at: Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), ‘‘SAPIENZA” University of Rome, Sant’Andrea University Hospital, via di Grottarossa 1035, 00189 Rome, Italy. E-mail address: [email protected] (A. Ciacciarelli).
result from arterial stiffness, which reduces the exchange between interstitial fluid and cerebrospinal fluid (CSF) [5]. The Abneurovascular interaction, therefore, likely encompasses mechanisms that fuel deleterious vicious circles. Endothelial and immune cells, neurons, glia, pericytes and other components of the NVU may promote the pathogenesis of neurodegenerative diseases by means of different mechanisms [6], and it is unclear whether changes in CBF precede or follow the neurovascular dysfunction, or whether the hypoperfusion is a cause or a consequence, or just an epiphenomenon. Epidemiological data, by showing the co-presence of vascular risk factors and neurocognitive disorders [7], support the causal link between vascular and neurodegenerative mechanisms. For instance, major and mild neurocognitive disorders due to AD are consistently associated with vascular risk factors such as hypertension, ischemic heart disease, hypercholesterolemia, atrial fibrillation, smoking and obesity [8,9]. Whether the association is a causal one is uncertain. Still, in large population-based studies, the CBF reduction precedes the cognitive decline and hippocampal atrophy [10] as to suggest a causality. Pathology studies have largely proven the frequent coexistence of extracellular amyloid Ab deposits, intracellular tau tangles or
https://doi.org/10.1016/j.jocn.2020.01.026 0967-5868/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: A. Ciacciarelli, G. Sette, F. Giubilei et al., Chronic cerebral hypoperfusion: An undefined, relevant entity, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.026
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structural changes such as atrophy together with cerebrovascular lesions [11]. The nature of the ‘‘ischemic” lesions is variegated. The lesions typically include lacunes, infarcts, white matter hyperintensities (WMH), microbleeds and enlarged perivascular spaces [12,13]. All these lesions are thought to express cerebral microangiopathies, but mechanisms underlying the formation and progression of these lesions are not fully understood and likely include a broad range of dysfunctions affecting NVU [14]. These observations, altogether, support a conceptual framework that considers CCH a likely, relevant pathogenic mechanism for the neurodegeneration-like progression of the neurocognitive disorders [15,16]. The relationship between neuropathology, cerebral perfusion and symptoms progression, however, is elusive for several aspects. Extensive AD-type lesions may exist without dementia [17]. Typical microangiopathy findings, such as WMH, may appear in individuals without any cerebrovascular risk or vascular lesions [18]. Pathology features of the white matter lesions, such as demyelination and gliosis, may result from NVU dysfunction not directly associated with hypoperfusion [19]. Most notably, CCH is generally inferred, not measured. Despite the potential relevance of the disorder, as reflected by the large body of literature data, an operative definition is missing. CCH is told to embrace conditions of ‘‘inadequate” blood flow, or conditions characterized by ‘‘defects” of perfusion or by ‘‘dysfunctions” in mechanisms associated with the autoregulation. The hypoperfusion, in addition, bears a dynamic dimension, as the chronicity may refer either to sustained conditions (for instance caused by vessel stenosis or cardiac insufficiency) or to repeated phases during which local blood flow fails to meet increments of energy supply demands (inefficient functional hyperemia). Reports in the literature often do not specify the temporal dimension of the hypoperfusion, whether persistent, sustained or phasic in nature. In addition, the phenomenon may pertain the whole brain or be limited to defined areas. Thus, hypoperfusion encompasses many different conditions, which range from mild phasic or temporary mismatch between energy tissue demand and blood flow supply to a persistent inadequate perfusion. An operative definition of hypoperfusion is, therefore, missing. Despite such fundamental uncertainty, a pubmed search of ‘‘chronic cerebral hypoperfusion” or ‘‘misery perfusion” resulted in almost one thousand entries, which have been increasing until our days reaching 75 entries in 2018. In this short review, we refer to animal models of hypoperfusion and to clinical conditions of chronically hypothetically altered cerebral perfusion caused by definite conditions, such as chronic heart failure [20,21], hypotension [22,23] and carotid stenosis [24,25]. 2. Background The brain takes approximately ¼ of the whole-body oxygen and glucose consumption. The average whole CBF, is about 57 ml/100gr/min, in the healthy adult individual, which is 800 ml/min, or approximately 15% of the total basal cardiac output [26]. Since the amount of oxygen stored in brain is small, an increase in CBF is mandatory whenever there is increased energy demand. The exploitation of several methods and techniques for measuring local rates of CBF and energy metabolism under a variety of physiological conditions has shown that rates of CBF and energy metabolism are heterogeneously distributed within the brain. CBF and energy metabolism vary not only from area to area, but they also vary with time, conformably to the dynamic changes of the brain function. Thus, any local increase in functional activity, under physiological conditions, is associated with local increase in CBF to meet the energy demand (functional hyperemia).
CCH seems, therefore, to refer to inadequate supply of nutrients (essentially, glucose and oxygen) to meet the energy demand of the tissue, including conditions of altered functional hyperemia. The mismatch results in increased extraction of oxygen, from the blood, by the brain, at least in the early phases when the brain function is maintained normal (or near normal) despite the reduced perfusion. 3. Animal models of hypoperfusion A fundamental approach to model CCH is based on manipulating the neck large blood vessels. Rats and baboons are usually submitted to permanent bilateral occlusion (2VO) of the carotids [27– 29], while mice are usually submitted to stenosis. The models cause persistent reduction of the global or regional CBF. Bilateral occlusion of the common carotid arteries in the rat causes decrease of CBF to 35–45% of control in cortical areas and to about 60% in the hippocampus. A partial recovery occurs in the days following the occlusion. The recovery is almost complete in 2– 3 months. Six months following the occlusion the flow is completely recovered [30]. The progressive restitution to normal flow and energy metabolism is inconsistent with the constant or progressive cerebral hypoperfusion observed in aging and dementia. Despite such a difference, the persistent oligemia causes structural and functional brain changes consistent with the clinical findings. The 2VO animals develop white matter lesions, which are typically evident two weeks following ligation of the arteries. The lesions, characterized by vacuolation of myelin, axonal damage, demyelination, BBB opening [31] and persistent activation of the microglia and lymphocyte infiltration [32], resemble the diffuse white matter radiological changes frequently associated with hypertension or diabetes. Grey matter alterations are inconsistent. Neural and synaptic contact loss may occur later and may not correlate with CBF changes [33]. The 2VO animals develop behavioral changes, which share similarities with the cognitive disorders in humans. The behavioral alterations are measurable a few weeks following occlusion and seem to progress with time [34], even when flow has recovered to normal values. Thus, while most of the changes occur during the chronic phase of the hypoperfusion, the progression of the behavioral changes seems to support the hypothesis of a neurodegenerative-like mechanism that may ‘‘survive” to the hypoperfusion. In mice, microcoils placed in both carotid arteries cause variable CBF drops, according to the coil diameter. In all the cases, bilateral carotid stenosis causes white matter lesions correlated with the extent of CBF reduction. The lesions consist in rarefaction of myelinated fibers in the corpus callosum, caudate putamen, internal capsule, and in the optic tract, associated with inflammation and BBB permeability. Grey matter involvement is inconsistent [1,27]. A few studies were carried out in models of CCH based on longlasting manipulation of cerebrovascular risk factors. For instance, authors carried out studies following high-salt/high-fat diet or elevated dietary levels of the amino acid homocysteine. Other studies were carried out in aged or CADASIL-like animals, or in models of atherosclerosis [35]. Other studies are focused on causing inadequate heart function, such as surgery-induced models of aortic constriction, cardiac arrest, or myocardial infarct models [27]. 4. Hypoperfusion in humans A few defined clinical conditions are thought to be associated with or cause CCH in humans [36,37] (Table 1). 4.1. Heart failure There is an inherent difficulty in providing operative definitions of Heart Failure (HF). The diagnosis and the New York Heart Asso-
Please cite this article as: A. Ciacciarelli, G. Sette, F. Giubilei et al., Chronic cerebral hypoperfusion: An undefined, relevant entity, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.026
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A. Ciacciarelli et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx Table 1 Clinical Conditions Associated with Chronic Hypoperfusion. Clinical Condition
Hypoperfusion Inferred from:
Findings
Defined as:
Ref.
Heart Failure
99mTc SPECT 133Xe SPECT TCD MRI TCD at rest and after stimulation Perfusion MRI
rCBF reduction in posterior cortical areas Global CBF reduction MCA-CBF velocity reduction Higher T2-relaxation values Lower MCA Blood flow velocity at rest and lower increase after stimulation Increased MTT
NYHA II/III NYHA III/IV NYHA II/III/IV NYHA II sBP < 100 mmHg
[38] [39] [40] [41] [42] [43]
TCD
Lower CBF velocity and CVR during head up tilt
ASL-MRI CT perfusion
Post-CAS CBF higher than pre-CAS CBF Ipsilateral MTT and CBV increase and CBF reduction compared to contralateral Ipsilateral Impaired VMR, recovered after CEA Ipsilateral Increased OEF ratio
Orthostatic ;sBP 20 or dBP 10 mmHg Orthostatic ;sBP 30 or dBP 10 mmHg Unilateral 68–96% stenosis Unilateral > 70% stenosis Unilateral > 70% stenosis Complete ICA occlusion
[48] [49]
Essential Hypotension Orthostatic Hypotension
Carotid Stenosis
TCD 15O-PET
[44] [45] [46]
Cerebral Vascular Resistance (CVR) = Mean Blood Pressure (MBP)/ Mean Flow Velocity (MFV); rCBF = regional Cerebral Blood Flow; MCA = Middle Cerebral Artery; MTT = Mean Time Transit; VMR = Vasomotor reactivity; TCD = Transcranial Doppler; CAS = Carotid Artery Stenting; sBP = Systolic Blood Pressure; dBP = Diastolic Blood Pressure; ; OEF = Oxygen Extraction Fraction.
ciation (NYHA) classification are based on clinical signs and symptoms, and several confounding variables are typically associated with the different causes of HF. NYHA class III/IV is associated with whole-brain CBF reduction of about 30% [39]. Patients with NYHA class II/III show regional CBF changes, mostly represented by reductions in the posterior cortical areas of the brain [38]. HF is often inferred by measuring the ejection fraction (EF). Different degrees of EF reduction may cause brain damage depending on the presence of risk factors, such as aging or increased systolic pressure [50]. Duration of the heart disease seems to be also a sensible variable [20], although most studies do not provide information on the time length of EF reduction. Lesions occur both in white and grey matter. Different areas are differentially affected, suggesting that different variables account for different distribution patterns of the brain damage [41]. HF may, however, occur with preserved heart function [51]. The term ‘‘cardiogenic dementia” appeared in the literature almost forty years ago and since than several findings have supported the association between HF and cognitive impairment [21]. In a case-control study Sauvé et al. found that in subjects with HF there is a 4-fold increased risk of cognitive impairment as compared to matched controls [52]. In a prospective cohort study of a total of 577 patients, 79% of them resulted impaired at least in one cognitive domain [53]. In a meta-analysis Cannon et al. estimated a 40% prevalence of cognitive impairment in subjects with HF, thus confirming the association between HF and cognitive impairment [54]. The pathophysiological mechanism behind this relationship is, however, unclear. It is a question whether the hypoperfusion per se, and the consequent hypoxia, is the cause of the neurocognitive disorders. A few studies, carried out in small groups of patients who underwent heart transplant, reported partial recovery of neuropsychological performances following intervention, supporting the clinical relevance of the improved cerebral perfusion [55]. Other variables, however, including changes in cerebrovascular reactivity, potentially associated with endothelial dysfunction or coagulation, are also relevant. 4.2. Hypotension Research is mainly focused on essential hypotension or orthostatic hypotension (OH). The essential hypotension (also named constitutional, primary or chronic hypotension) is a persistent condition of lowered blood pressure (BP) without any identifiable pathological factors. In most studies, however, there is not defined
BP threshold value, and hypotension is often defined in association with symptoms such as fatigue, dizziness and concentration deficits. The prevalence of the essential hypotension is probably underestimated, due to the lack of definite diagnostic criteria [56]. The Honolulu-Asia Aging Study [57] and the Kungsholmen Project [22] provided evidence that chronic hypotension, is a predictor of reduced cognitive function in elderly [58]. Data obtained in young subjects support the causal relationship between hypotension and reduced cerebral blood perfusion [42], inferred by reduced mean flow velocity at rest and reduced task-induced blood flow increment at Transcranial Doppler (TCD) [23]. OH is defined as a reduction of systolic BP of at least 20 mmHg or diastolic BP of at least 10 mmHg within 3 min of standing up. The prevalence is age-dependent and increases up to 10–30% in elderly people [59]. The hypotension is thought to cause failure of the CBF autoregulation. The failure is typically inferred when TCD changes occur following an acute hypotensive stimulus [60] or 80° head-up tilt [44]. The relationship between OH and cognitive impairment is controversial [61]. A recent clinicopathological study found a higher burden of pathological changes in the white matter in demented patients with autonomic dysfunction [62]. Moreover, a 20-year follow-up study showed a causal association between OH and neurocognitive disorders [63]. 4.3. Carotid stenosis Arteriosclerosis embraces a variety of different lesions that include sclerosis of small arteries and arterioles (arteriolosclerosis) and formation of plaques in large and medium-size arteries (atherosclerosis). The disease involves intracranial and extracranial arteries. Lacunar, subcortical and cortical infarctions determined by emboli, thromboembolism or occlusions are frequently identified in these patients, together with hemodynamic and metabolic impairments and reduction of the CBF [64]. Remarkably, the effect of intracranial atherosclerosis probably exceeds the boundaries of mechanisms directly involved in blood perfusion. For instance, vessel stiffening associated with atherosclerosis seems to affect the Ab clearance. Such a mechanism adds to those thought to link atherosclerosis and AD. The stiffening would reduce the effect of the reflection wave of the arterial wall. The arterial wave, caused by normal cardiac pulse, is thought to represent the driving force for solute drainage from the interstitial spaces, by means of the perivascular pathway [5,65]. Weakening of the wave would reduce the clearance drive.
Please cite this article as: A. Ciacciarelli, G. Sette, F. Giubilei et al., Chronic cerebral hypoperfusion: An undefined, relevant entity, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.026
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Carotid stenosis is responsible for at least 20% of all thromboembolic strokes. Carotid endarterectomy or stenting is of proven efficacy in reducing the risk of stroke and TIA, both in symptomatic and asymptomatic patients. In addition, several findings suggest that carotid stenosis leads to a condition of CCH. For instance, there is evidence that intracranial stenosis, in the range 50–99%, causes different degrees of impairment of anterograde CBF and downstream perfusion depending on efficiency of collateral vessels [66]. Consistently, Marshall and collaborators showed increased oxygen extraction fraction (OEF) ratio, interpreted as expression of hemodynamic failure, in patients with carotid stenosis. The altered perfusion was associated with cognitive impairment and brain changes seen in these subjects [49]. Removal of the arterial narrowing has been hypothesized to improve cerebral hemodynamics and provide benefits in cognitive functions, by supposedly resolving the insufficient blood supply [47,67]. There are findings suggesting that following resolution of the carotid stenosis in asymptomatic patients show a mild improvement in cognitive performance [25], likely associated with the improved perfusion [48]. However, the issue is still controversial since there is lack of systematic and prospective studies [24]. In a 7-year prospectic study Arntzen et al. found that cognitive performance scoring was inversely proportional to the number of the plaques, total plaque area, stenosis grade and carotid intimamedia thickness, suggesting an independent correlation between carotid atherosclerosis and cognitive function [68]. Buratti et al. monitored cognitive performance in subjects with bilateral asymptomatic carotid stenosis and found a linear relationship between TCD-based breath-holding index and MMSE [69]. The findings sustain the speculation that carotid endarterectomy or stenting reduce the risk of cognitive impairment in addition to reducing the risk of recurrent stroke. 5. Conclusions The findings altogether suggest that different diseases that cause altered blood perfusion of the brain promote neurodegeneration. Several mechanisms are involved in mediating the effect of hypoperfusion [70]. Most of the reported mechanisms refer to dysfunctions of the NVU [71], which may or may not cause hypoxia. An open question, therefore, regards the role of hypoxia. A few studies report an increased risk of neurocognitive disorders in subjects with anemia [72] or chronic obstructive pulmonary disease [73] suggesting that hypoxia per se, i.e. without the traditional cerebrovascular risks and apparently without defects in perfusion, causes, or contributes to, the neurocognitive disorders. Appreciation of the role of CCH may suggest novel targets for therapeutic strategy to neurodegenerative disorders. Funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] Farkas E, Luiten PGM, Bari F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev 2007;54:162–80. https://doi.org/ 10.1016/j.brainresrev.2007.01.003.
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Please cite this article as: A. Ciacciarelli, G. Sette, F. Giubilei et al., Chronic cerebral hypoperfusion: An undefined, relevant entity, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.026