Cerebral small vessel disease: Capillary pathways to stroke and cognitive decline

Pericyte dysfunction

Pericytes are embedded in layers of the basement membrane that surround the capillary endothelium. ²⁷ Pericytes are thought to cover most capillaries in the central nervous system where they regulate BBB function ²⁸ and aspects of the brain’s immune response. ²⁹ Pericytes are involved in the regulation of capillary development (angiogenesis), stabilization, maturation and remodeling ³⁰ and communicate with endothelial cells through peg-socket contacts as they – among other functions – jointly form and maintain the basement membrane. ²⁷ Neurogenic locus notch homolog protein 3 (NOTCH3) signalling is crucial for the postnatal differentiation of vascular cells into their ‘correct’ arterial, capillary and venous phenotypes^27,31 and their ability to adapt to changes in pressure and vascular strain.^32,33 While pericytes are characterized by their relation to microvessels, they share cellular and functional characteristics with vascular smooth muscle cells (VSMCs) encircling arterioles and venules. The distinction between VSMC and pericytes recently became a matter of debate with regards to the attribution of CBF-regulation^19,34,35 – see discussion in the literature. ³⁶

Cerebral pericytes are contractile, and they have been shown to contract and relax in response to neuromediators, vasoactive drugs and, importantly, to sensory stimulation in brain slices as well as in vivo.^18,19,35 Thus, cerebral pericytes have been shown to regulate capillary diameter during functional activation, ¹⁸ dilating about 1 s before arteriolar dilation and thereby possibly controlling both CBF and CTH. ¹⁹ Retinal pericytes have been characterized extensively in vitro: retinal pericytes constrict in response to high oxygen tension and relax in response to lactate and low pH, ³⁷ possibly providing a mechanism by which capillary flows can redistribute to meet local cellular metabolic demands during activation. ³⁷ Much like VSMCs, retinal pericytes react to a range of vasoactive substances, constricting when exposed to mechanical stretch, angiotensin II (AT2) ³⁸ and endothelin-1 (ET1) ³⁹ by a Ca⁺⁺-dependent mechanism ⁴⁰ and relaxing when exposed to adenosine, ⁴¹ ATP ⁴² and nitric oxide (NO)^43,44 and in response to cholinergic ⁴⁵ and adrenergic ⁴⁰ stimulation. See the study by Attwell et al. ⁴⁶ for a review of neurovascular coupling mechanisms and the control of VSMC and pericyte tone.

Pericyte loss and basement membrane thickening are observed in conditions that represent major risk factors for SVD, such as ageing, hypertension and diabetes – see Table 2. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL – Table 3) is associated with mutations in the NOTCH3 gene. ⁴⁷ The receptor protein encoded by the NOTCH3 gene is expressed in both VSMCs and pericytes, ⁴⁸ and recent evidence suggests that CADASIL is associated not only with degeneration and damage to VSMCs in small arteries and arterioles but also to microvascular pericytes. Dziewulska and Lewandowska ⁴⁹ observed pericyte loss and pericyte fragments within thickened basement membranes in skin and muscle biopsies in CADASIL. They reported that pericyte-endothelial peg-socket contacts were disrupted, seemingly giving rise to basement membrane thickening, endothelial swelling and protrusions into the capillary lumen. ⁴⁹ Recent animal models of CADASIL show evidence of reduced capillary density ⁵⁰ and pericyte degeneration ⁵¹ and suggest that reduced pericyte coverage is related to impaired BBB function. ⁵²

When exposed to viral and bacterial proteins, pericytes initiate inflammatory responses that facilitate the recruitment of immune cells from the blood stream – see the study by Hill et al. ⁵³ for a recent review. As neutrophils pass through the surrounding basement membrane, they pass between embedded pericytes, which in turn remodel the laminin-rich basement membrane to permit extravasation. ⁵⁴ Importantly, pericytes seemingly change their phenotype during inflammation to become migratory, ⁵⁴ a phenomenon also observed in CNS injury. ⁵⁵ The ability of pericytes to undertake BBB function ²⁸ and capillary flow control ¹⁹ may therefore be compromised during infection and inflammation.

Pericyte exposure to parenchymal waste: Amyloid and hemoglobin

Molecules the size of haemoglobin and amyloid β (Aβ) are cleared from the subarachnoid space and brain parenchyma along the basement membranes of arteries and capillaries.^56,57 Indeed, impaired glymphatic clearance has recently emerged as a potential therapeutic target. ⁵⁸ Located in the layers of capillary basement membrane, pericytes are therefore exposed to amyloid during its perivascular removal and clearance across the BBB.^59–61 Pericytes undergo degeneration when exposed to certain Aβ types in vitro,^62,63 and although the role of pericytes in the pathogenesis of cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD) remains poorly understood, evidence from Aβ transgenic mice and in vitro models suggest they may be involved in neurodegeneration.^64,65 For recent reviews, see the study by Hamilton et al. ⁶⁶ and Winkler et al. ⁶⁷

Microbleeds are associated with SVD, and the vasoactive properties of hemoglobin breakdown-products are described in detail in the literature.^68,69 Briefly, spontaneous autoxidation of oxyhemoglobin (HgbO) to methemoglobin and the iron released from hemoglobin cause the release of highly reactive superoxide radicals.^68,69 Superoxides are thought to cause vasoconstriction by depleting vascular NO levels^70,71 and to induce lipid peroxidation and peroxynitrite formation, which in turn cause vasoconstriction and structural damage to cerebral microvessels, including the endothelial cell layer. ⁷² The breakdown of heme into bilirubin under such oxidative conditions results in the formation of bilirubin oxidation products (BOXes) that change the contractility, signalling and metabolism in large vessels – see also the study by Pyne-Geithman et al. ⁷³

Endothelial function

Endothelial cells are mechanically coupled by tight junctions, which ensure BBB integrity and prevent leakage of toxic molecules into the brain interstitium – see discussion in the literature.^3,4 Endothelial cells are also electrically and metabolically coupled to each other as well as to nearby VSMCs via gap junctions composed of connexins. ⁷⁴ This rapid, bidirectional signalling pathway seemingly provides efficient coordination of vessel function across the microvascular bed.^75–77 Disruption of the signalling between endothelial cells has been shown to cause profound breakdowns in vascular control across the capillary bed, resulting in extreme degrees of capillary shunting through the shortest arteriolo-venular pathways. ⁷⁸

In small-vessel vasculitides (Table 4) associated with antineutrophilic cytoplasmic antibodies (ANCAs), neutrophils adhere to capillary endothelial cells and cause the release of reactive oxygen species (ROS) and lysosomal enzymes. This abnormal inflammatory reaction causes endothelial cells to undergo necrosis and detach from the basement membrane, after which they can be found in peripheral blood. ⁷⁹ While the activation of neutrophils and endothelial cells in the capillary lumen may disturb capillary flow patterns in itself, the disruption of endothelial cell-to-cell signalling described above is expected to cause severe capillary dysfunction.

Glycocalyx dysfunction

The luminal surface of the capillary endothelium is covered by a 0.5-µm thick glycocalyx.^80,81 This carbohydrate-rich matrix affects the passage of blood cells through the capillary bed. ⁸² reducing capillary haematocrit to 20–50% of that found in the systemic circulation. Glycocalyx damage, in turn, disrupts capillary flow regulation, causing capillary hematocrit to approach that of the systemic circulation.^83,84 The glycocalyx constitutes a fluid barrier in the vascular system and has been implicated in oedema formation.^85,86 The glycocalyx is degraded by direct oxidative stress and exposure to oxidized lipoproteins,^83,87,88 by hyperglycaemia ⁸⁹ and by ischemia.^88,90

Blood viscosity

The dimensions of white blood cells (WBC) and erythrocytes exceed the average capillary diameter. Experimental studies have shown that capillary flow patterns are sensitive to the size, deformability, viscosity, number and endothelial adhesion of blood cells. In infections and low-grade vascular inflammation, blood is hence increasingly redirected to thoroughfare channels which act as functional shunts. ⁹¹ In a classical study, hyperviscosity was demonstrated in diabetic patients (Table 2) compared to age-matched controls and the viscosity found to correlate with the extent of microvascular diabetic complications. Accordingly, erythrocyte deformability was lower in those diabetic patients who had the most extensive microangiopathy compared to either diabetics with no complications or to controls. ⁹²

In cryoglobulinaemic vasculitis (Table 5), cryoglobulins precipitate and lead to hyperviscosity. ²⁶ Hematocrit is lower in capillaries than in the systemic circulation, and since cryoglobulins precipitate more easily under conditions of serum excess, capillary flows may be particularly sensitive to this phenomenon.

Mild capillary dysfunction: CBF increases in conditions that represent risk factors for SVD

For mild capillary disturbances, the reduction in oxygen extraction efficacy is so small that it can be compensated for by elevated CBF. Observations of increased resting CBF or increased CBF responses early in the course of SVD precursors therefore suggest that capillary dysfunction (elevated CTH), rather than primary changes in the morphology or function of upstream arterioles, is involved in the early etiology of the condition. Meanwhile, the BOLD signal is often used to localize brain activity through its sensitivity to tissue deoxyhemoglobin concentrations [dHgb]. Mild capillary dysfunction is characterized by reduced OEF and proportionately higher CBF responses during functional activations, both of which reduce [dHgb] and thereby increase BOLD signal amplitudes before resting CBF and OEF become affected. In asymptomatic subjects presented with identical tasks, BOLD responses are therefore expected to be higher in those with mild capillary dysfunction than in controls, despite identical changes in metabolic activity. CBF and BOLD responses are recorded in grey matter and are hence sensitive to changes in capillary function in the cortex and subcortical nuclei. Subcortical lesions may result in secondary changes in cortical function, and, in theory, even compensatory hyperactivity in some regions.

In streptozotocin (STZ)-induced diabetes (Table 1) in rats, both total and cortical CBF values are indeed elevated compared to control animals early after induction of the disease,^94–96 and cortical oxygen tension elevated. ⁹⁶ In early-stage hypertension (Table 2), elevated CBF and BOLD responses to hypercapnia have been reported in spontaneously hypertensive rats compared to age matched control animals. ⁹⁷ The apolipoprotein (APOE) ɛ4 allele is associated with both CAA and the development of AD ⁹⁸ (Table 2), and carriers of this allele have therefore been studied extensively. In asymptomatic APOE ɛ4 carriers aged 19–28, both resting- and activity-related CBF levels are elevated,^99,100 and BOLD signal changes during memory encoding tasks are elevated in the asymptomatic APOE ɛ4 carriers,^101–103 consistent with reduced OEF and compensatory hyperaemia. Similarly, BOLD responses are elevated in patients with systemic lupus erythematosus (SLE – Table 6) but little or no cognitive defects, compared to controls. ¹⁰⁴ In asymptomatic human immunodeficiency virus 1 (HIV-1) infected patients (Table 5), elevated BOLD signals can be observed ¹⁰⁵ in proportion to signs of glial activation. ¹⁰⁶ The notion that viral replication in brain parenchyma is associated with mild capillary dysfunction is consistent with findings that BOLD signal amplitudes are elevated in seropositive patients with low BBB penetration of combination antiretroviral therapy, but comparable to those found in controls and in patients with high penetrance and thereby virological control. ¹⁰⁷ It should be noted that relative BOLD signal changes depend on both resting and activation-related CBF and OEF levels. The interpretation of such changes in terms of the underlying microvascular pathology therefore requires detailed analysis of the underlying physiology and magnetic resonance signal mechanisms.^17,108

Moderate capillary dysfunction: Transition from hyperperfusion to CBF suppression

If capillary flow disturbances become more severe, then hyperemia fails as a means to compensate for reduced oxygen extraction efficacy. Instead, CBF responses – and ultimately resting CBF – must be attenuated in order to limit functional shunting. The transition from mild to moderate capillary dysfunction is therefore predicted to require dramatic, yet characteristic changes in CBF in order to maintain flow-metabolism coupling.

Such a transition, from hyper- to hypoperfusion, was indeed observed in a follow-up study of asymptomatic APOE ɛ4 carriers and controls. ¹⁰⁹ At the time of their initial examination, APOE ɛ4 carriers showed higher resting CBF values in vulnerable brain regions than did control subjects, while CBF reductions in these regions 8 years later were significantly larger in APOE ɛ4 carriers than in controls. ¹⁰⁹

If flow responses are limited by a physical, flow-limiting condition, then CBF cannot increase beyond a certain upper limit, irrespective of the metabolic requirements of brain tissue. If CBF suppression instead serves to maintain flow-metabolism coupling, then CBF, tissue metabolism and the extent of capillary dysfunction determine whether flow suppression is necessary. We briefly discuss how this phenomenon might have revealed itself in studies of SVD and its precursor states.

In a mouse genetic model of CADASIL, Joutel et al. ⁵⁰ examined CBF responses to functional activation, CO₂ inhalation and reduced perfusion pressure in 5- to 6-month-old animals, at a time-point where no changes in arterial structure or signs of BBB breakdown could be observed. Animals with and without the CADASIL-causing NOTCH3 point-mutation had similar blood pressure, similar resting CBF and similar CBF responses to CO₂ inhalation, a vasodilatory stimulus. CBF responses to functional activation, however, were attenuated in CADASIL mice. ⁵⁰ These findings are consistent with capillary dysfunction that only limits tissue oxygenation during functional activation – either by deficient pericyte-mediated capillary dilation (and CTH reduction) during functional activation, ¹⁹ or because only the combination of elevated CBF and increased metabolic demands ‘unmasked’ capillary dysfunction at this early point in the development of characteristic disease signs.

In asymptomatic APOE ɛ4 carriers aged 50–65, elevated resting CBF values have been reported at a time where their CBF- and BOLD-responses to functional activation had been suppressed. ¹¹⁰ Suppression of CBF-responses to sensory stimulation at a time where resting CBF is elevated has also been observed in spontaneously hypertensive rats, prior to any changes in their microvasculature. ¹¹¹ These findings are again consistent with the gradual transition from mild to moderate capillary dysfunction which first becomes apparent in states of high metabolic demand.

The unmasking of capillary dysfunction by combinations of high CBF and CTH that necessitate flow suppression was recently illustrated in a study by Suri et al. ¹¹² who observed flow suppression during hypercapnia (a strong vasodilator) in young APOE ɛ4 carriers compared to noncarriers. These young APOE ɛ4 carriers showed increased hippocampal BOLD responses to memory tasks, and the attenuation of their CBF responses during hypercapnia accounted for 70% of this increase, ¹¹² consistent with the prediction that mild (asymptomatic) capillary dysfunction links the two findings.

Attenuation of functional hyperemia can also be observed immediately after administration of AT2 and Aβ in animal models of hypertension and AD/amyloidosis, respectively (Table 2)^113–115 and antedates any morphological changes in the vessel wall or brain parenchyma and even the development of high blood pressure in the model of hypertension. ¹¹⁶ Although the effects of AT2 and Aβ on pericyte tone in living brain remain to be studied, these findings are consistent with capillary dysfunction caused by pericyte constrictions and compensatory increase in VSMC tone to limit flow responses.

Flow suppression and small vessel changes

The flow suppression observed in animal models of hypertension and AD/amyloidosis is caused by vascular production of ROS,^117,118 which reacts with NO to form peroxynitrite. ¹¹⁹ Both NO depletion and peroxynitrite cause vasoconstriction by impairing normal smooth muscle cell relaxation, ¹²⁰ but also long-term remodelling and thickening of the vessel walls and VSMC damage. ¹²¹ By evoking flow suppression, capillary dysfunction may therefore contribute to – or even antedate – the wall damage observed in small arteries and arterioles before SVD becomes overt. Note that wall thickening narrows the vascular lumen and may reduce CBF and attenuate CBF responses. This ‘mechanical’ flow suppression would therefore be expected to make flow suppression by oxidative stress superfluous over time.

Oxygen diffuses through arteriolar walls to supply the capillary-free area around arterioles, and it can reach tissue with capillary supply as well. In fact, recent studies suggest that arterioles account for as much as 50% of the total oxygen extraction during rest, while capillaries serve as the primary site of oxygen extraction during functional hyperemia. ¹²² Arteriolar oxygen extraction is insensitive to CTH downstream, and the increased arteriolar tortuosity and length observed in some SVD precursor states ¹²³ may therefore, paradoxically, increase arteriolar oxygen extraction capacity by increasing arteriolar surface area and transit time. The long, tortuous medullary arteries observed in SVD, however, are generally thought to cause hemodynamic insufficiency. Studies of retinal vessels in SVD patients suggest that venules are generally wide in SVD precursor states.^124,125 While the restricted venular lumen observed in venous collagenosis ¹²³ (Table 7) would be expected to facilitate tissue oxygen extraction by prolonging blood’s transit time through the capillary bed, complete venous occlusions, instead, cause venous infarcts to develop.

Moderate capillary dysfunction: Failure to suppress CBF

If the microcirculation cannot evoke intrinsic mechanisms to limit CBF and CBF responses, then functional shunting can become so severe that stroke-like symptoms and hypoxic tissue injury may develop at CBF values well above the classical ischemic threshold.

Fabry’s Disease (Table 3) is associated with cerebral hyperperfusion,^126–128 which is reversed or attenuated by therapies that remove the capillary deposits shown in Figure 2.^126,127 This hyperperfusion might, in principle, represent flow metabolism coupling, with hyperaemia compensating for mild capillary dysfunction. The relative hyperemia is, however, observed in patients with severe neurological symptoms ¹²⁷ and seemingly antedates the development of white matter lesions that may occur in the disease, ¹²⁹ suggesting that tissue damage is the result of insufficient suppression of excessive vasodilation and functional shunting in this disease.

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Figure 2.

Panel (a) illustrates the organization of endothelial cells, basement membrane and pericytes in the vessel wall. Capillaries are ensheathed by astrocytic endfeet, and neuronal terminals are closely apposed to capillaries and pericytes. ⁶⁶ Source: Reproduced from Hamilton et al. ⁶⁶ according to the Creative Commons terms. Panel (b) shows a cross section of normal capillary with a thin basement membrane (arrow) and normal appearing endothelial cell (e). In ageing (Panel (c)), thickened basement membranes (arrows), pericapillary fibrosis and pericyte loss are often found. Source: Panels (b) and (c) are reproduced from Farkas et al. ¹⁸⁸ Panel (d) shows a capillary cross section from the skin of a patient with Fabry’s disease. Note the lamellar sphingolipid inclusions in the capillary endothelium (arrow). These inclusions disappear upon enzyme replacement therapy. Source: Reproduced from Eng et al. ¹⁸⁹ Panel (e) shows typical cerebral capillary wall pathology in human AD. The arrow indicates pericyte degeneration. The symbols denote lumen (l), endothelial cell (e), basement membrane (*) and pericyte (p). Source: Reproduced from Farkas et al. ¹⁹⁰ Panel (f) shows a cross section of a muscle capillary from a patient with MELAS. Note the thickened basement membrane and increased number and size of mitochondria in the pericyte. Source: Reproduced from Sakuta and Nonaka. ¹⁹¹ Panel (g) shows a cross section of a cerebral capillary from the motor cortex of a MELAS patient with accumulation of mitochondria in the endothelial cell. Source: Reproduced from Ohama et al. ¹⁹² with permission from the publisher. AD: Alzheimer’s disease; MELAS: mitochondrial encephalopathy with lactic acidosis and stroke-like episodes.

Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS – Table 3) is also associated with severe hyperperfusion, which seemingly contributes to tissue infarction. Studies have revealed globally elevated CBF, low OEF and reduced cerebral metabolic rate of oxygen (CMRO₂) in MELAS patients both before^130–133 and after^131,132,134 stroke. In these patients, the mitochondrial enzymes needed for oxidative phosphorylation are deficient, and it is therefore unclear how tissue levels of oxygen, ATP and lactate affect neurovascular coupling. The lack of metabolic feedback mechanisms to limit excessive vasodilation in this condition is underscored by the finding that normal vasodilation is preserved, even in hyperperfused stroke lesions. ¹³⁵

Vascular endothelium is extremely vulnerable to radiation and post-radiation angiopathy (Table 7) is associated with capillary rarefaction and tissue hypoxia.^136,137 Mineura et al. ¹³⁸ found hyperperfusion and low OEF early after radiation therapy in humans, and Hahn et al. ¹³⁹ demonstrated a dose-dependent CBF increase three months after irradiation. If this hyperaemia was a compensatory response to mild capillary dysfunction, then tissue oxygen tension would be elevated rather than reduced and hyperaemia limited by flow-metabolism coupling rather than radiation dose. Instead, these observations suggest that microvascular signalling is severely disturbed, possibly due to a loss of endothelial regulatory signalling. After radiation exposure, initial hyperperfusion is often followed by normalization of CBF, ¹³⁸ but OEF remains low, ¹³⁸ indicating reduced tissue metabolism as a result of tissue damage. Hahn et al. ¹³⁹ observed that neuropsychological performance deteriorated when the dose-dependent CBF increase three months after irradiation was followed by a reduction in CBF by six months. These findings suggest that uncontrolled hyperemia contributes to on-going tissue damage at least three months after radiation, but also lends hope to the notion that dose fractionation might ameliorate tissue damage and cognitive decline.

Severe capillary dysfunction

In severe capillary dysfunction, oxygen availability gradually approaches the metabolic needs of brain tissue. The parallel reduction in tissue oxygen tension, in turn, is highly conducive to BBB breakdown, Aβ deposition and loss of trophic support. See literature^7,140 for a discussion of capillary dysfunction in dementia and preliminary data.

If capillary changes become so severe that CTH approaches CTH^max, then even increases in viscosity might reduce tissue oxygenation enough to trigger neurological symptoms or tissue injury. This suggests a mechanism by which dehydration or bacterial infections (during which WBC count is elevated) can cause neurological deterioration or stroke-like symptoms in patients with preexisting, capillary dysfunction. ⁶ We discuss therapeutic implications of this pathophysiological process below.

In severe capillary dysfunction, resting CBF is predicted to approach the classical ischemic threshold at which oxygen extraction is optimal, even for high CTH values. This biophysical feature implies that, paradoxically, tissue oxygenation may be improved to meet the metabolic demands of functional activation by reducing CBF to reduce physiological shunting. Indeed, Ferraccioli et al. ¹⁴¹ observed inverted CBF responses to painful stimuli (Raynaud’s phenomenon) in the sensorimotor cortex of patients with scleroderma or SLE vasculitis (Table 6).

Cognitive decline or stroke-like phenotype?

Both capillary dysfunction and arteriolar narrowing can lead to hypoxic tissue injury – but what determines whether a SVD precursor state develops along a ‘dementia-like’ ⁷ or a ‘stroke-like’ ⁶ pathway? Although ‘mixed’ cases exist, chronic spirochete infections by Treponema pallidum and Borrelia burgdorferi both come in a meningovascular form, which is dominated by lymphoplasmacytic infiltrates and intima-proliferation in the walls of leptomeningeal arteries, veins and vasa vasorum and associated with the development of multiple cerebral infarcts, that is, a stroke-like phenotype. In their parenchymal form, spirochetes invade brain tissue to aggregate around microvessels, and particularly capillaries. ¹⁴⁷ In this form, the infection is instead associated with cortical atrophy and dementia – and often amyloid deposits and neurofibrillary tangles. In severe neurosyphillis, antibacterial treatment in some cases leads to significant increases in CMRO₂ without increases in CBF from its near-ischemic levels. ¹⁴⁷ Such an ‘isolated’ improvement of OEF and cerebral metabolism is difficult to reconcile with flow-limiting SVD, or the reversal of infection-specific suppression of neuronal function. ¹⁴⁷ We speculate that the pericapillary invasion of spirochetes may be associated with severe capillary dysfunction, causing CTH to exceed CTH^max in general paresis. Reduction of capillary flow disturbances by antibiotic therapy would then be expected to improve CMRO₂ and neurological function, but only to normalize CBF if CTH was reduced considerably. In patients with neuroborreliosis and less severe neurological symptoms, cerebral hypoperfusion is partially reversed by antibiotic therapy. ¹⁴⁸

Similar correlates between microvascular histopathology and the progression along pathways dominated by stroke-like symptoms or cognitive decline may exist for other SVD risk factors and help elucidate what separates these etiologically related, but clinically separate, presentations.

Blood viscosity

Dehydration and infection-induced leukocytosis increase blood viscosity. These common occurrences can therefore reduce the brain’s oxygen supply by increasing CTH. Influenza vaccinations are offered to the elderly in order to reduce the incidence of influenza and secondary infections, and this is known to reduce the number of stroke deaths.^158–160 Infections may trigger thromboembolism by destabilizing atheromatous plaques in the walls of cerebral vessels, but we speculate that increases in blood viscosity may elicit stroke-like symptoms in patients with preexisting, severe capillary dysfunction as well. Therefore, influenza vaccinations may be beneficial for SVD patients, irrespective of age. The impact of bacterial infections on cerebral oxygenation and thereby cognition may also be reflected in the observation that eradication of chronic helicobacter pylori infections in AD patients dramatically improves their cognitive scores and overall survival.^161,162

CTH may be reduced by lowering blood viscosity, and aggressive management of hyperlipidaemia may therefore be warranted in SVD patients. Similarly, high homocysteine levels increase blood viscosity, increase the adhesion of monocytes to the capillary wall and cause oxidation of low-density lipoproteins ¹⁶³ and could therefore represent a source of capillary dysfunction. Indeed, Hassan et al. ¹⁶⁴ showed that elevated homocysteine levels represent an independent risk factor of SVD. A meta-analysis has suggested that homocysteine-lowering therapy may reduce stroke risk in regions where folate levels are low. ¹⁶⁵

Phosphodiesterase (PDE) inhibitors reduce platelet aggregation, ¹⁶⁶ decrease blood viscosity ¹⁶⁷ and increase the flexibility of erythrocytes. ¹⁶⁷ While reduced platelet aggregation might increase bleeding risk, the haemorheologic PDE inhibitor effects would be expected to reduce CTH and thereby improve tissue oxygenation. For a recent review of pharmacological approaches to SVD management, see literature. ¹⁶⁸

Nicotine up-regulates the expression of adhesion molecules in the capillary endothelium ¹⁶⁹ and increases leukocyte rolling, ¹⁷⁰ keeping in mind that the latter is observed mainly in post-capillary venules where selectin density and glycocalyx properties provide optimal adhesion for leukocyte recruitment. ¹⁷¹ In additions to nicotine’s effects on larger vessels and large vessel atheromatous plaques, smoking would therefore be expected to worsen capillary flow disturbances, to accelerate the development of SVD from its risk factors and to increase the risk of an ischemia-like event. Indeed, pack years of smoking are associated with an increased risk of stroke in CADASIL ¹⁷² and with a higher burden of SVD lesions in patients with sporadic lacunar stroke. ¹⁷³ Patients with SVD precursor states should therefore receive help to reduce not only smoking, but also nicotine consumption in general, in order to reduce their risk of later cognitive decline or stroke.

Hyperaemia, anaemia and poor oxygen saturation

Hyperaemia is predicted to be harmful in patients with capillary dysfunction.

Obstructive sleep apnea (OSA) is associated with periods of severe nocturnal hypercapnia and hypoxemia, both of which cause dramatic increases in CBF in the normal brain. In addition, reductions in oxygen saturation cause a proportionate reduction in the net oxygen metabolism that can be supported for a given level of capillary dysfunction – increasing the risk of neurological symptoms. The risk that hyperaemia poses to patients who suffer from capillary dysfunction may in part be reflected in the observation that continuous positive airway pressure (CPAP) treatment reduces the incidence of strokes. ¹⁷⁴

The vulnerability of patients with capillary dysfunction to increased blood viscosity and reduced arterial oxygen content may contribute to the strong association between delirium and dementia: ¹⁷⁵ declining haemoglobin levels, dehydration and minor infections are known to herald delirium in the elderly. In patients with severe capillary dysfunction, small reductions in haemoglobin concentration or blood saturation, as well as increases in blood viscosity, may trigger regional cerebral hypoxia and thus, in principle, contribute to delirium symptoms. For patients with SVD precursor states, stricter definitions of anaemia and special attention to pulmonary function may therefore be warranted to reduce the risk of delirium and to alleviate the long-term consequences of chronic brain tissue hypoxia.

NO depletion

Capillary NO depletion due to oxidative stress and tissue hypoxia may represent a modifiable aspect of capillary dysfunction. Mediterranean diet is rich in green-leafed vegetables, a major source of dietary nitrate (see above). One might expect this diet to offer some protection towards NO depletion in patients with capillary dysfunction, and hence the development of SVD pathology. Preference for MD is indeed associated with a lower burden of white matter hyperintensities ¹⁷⁶ and, more generally, with a lower risk of ischemic stroke.^177,178 Keeping in mind that this protective effect may be attributable to other MD constituents, these observations may warrant further studies of dietary interventions in SVD and its risk factors. See also the study by Bath and Wardlaw. ¹⁶⁸

Stroke management in SVD patients

Given the deleterious effects of dehydration and poor saturation on tissue oxygenation, pre-hospital rehydration and efforts to reach full blood saturation may be warranted in patients with capillary dysfunction. While recanalization therapy clearly limits infarct size if large vessel occlusion is the cause of tissue hypoxia, it is important to keep in mind that means of restoring capillary flow patterns should also be explored.^19,24,179 Since SVD risk factors are generally prevalent in the stroke population irrespective of mechanisms of individual events, these interventions may be of general benefit.