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Small Vessel Disease: A Whole Brain Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 54812

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Prof. Dr. Rita Moretti

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Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy
Interests: small vessel disease; neurovascular coupling; liver–brain axis; NAFLD and brain; bilirubin and antioxidative properties; neuroinflammation
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Dr. Paola Caruso

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Università degli Studi di Trieste, Trieste, Italy

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Dear Colleagues,

Cerebral small vessel disease (SVD) is an umbrella term covering a variety of abnormalities related to small blood vessels in the brain. SVD results from damage to the small penetrating arteries and arterioles in the brain, and its prevalence increases exponentially with aging: From approximately 6% to 7% at age 60 to 28% at age 80.
SVD is a common cause of stroke, cognitive impairment, and gait disturbances, which slowly progress to vascular Parkinsonism and dementia, but can be differentiated from Alzheimer's disease considering neuroimaging findings (it is associated with more extensive white matter lesions, less severe hippocampal atrophy, and the absence of cerebral amyloid angiopathy). Substantial evidence shows that small vessel disease shares many risk factors and prognostic impacts in specific clinical settings. In fact, the presence of small vessel disease confers a risk of hemorrhagic transformation in brain ischemia in 10% of cases. SVD increases the morbidity, disability, and healthcare costs of the growing elderly population, decreasing their quality of life. Its prevention and treatment are critical research and clinical priorities. Our work purposes would be to view the small vessel disease as a whole-brain pathology, with possible new biological markers, hemodynamic complex alterations, and cholinergic dysfunction, pointing out the dynamic process that links small vessel disease to subcortical dementia.

Prof. Dr. Rita Moretti
Dr. Paola Caruso
Guest Editors

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Keywords

small vessel disease
neuroinflammation
biological markers
neuroimaging
hemodynamic

Related Special Issue

Small Vessel Disease: New Perspectives on an Emerging Reality in International Journal of Molecular Sciences (5 articles)

Published Papers (12 papers)

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Research

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23 pages, 7515 KiB

Open AccessArticle

Exploring the Potential of Mesenchymal Stem Cell-Based Therapy in Mouse Models of Vascular Cognitive Impairment

by Na Kyung Lee, Hyeongseop Kim, Jong Wook Chang, Hyemin Jang, Hunnyun Kim, Jehoon Yang, Jeyun Kim, Jeong Pyo Son and Duk L. Na

Int. J. Mol. Sci. 2020, 21(15), 5524; https://doi.org/10.3390/ijms21155524 - 1 Aug 2020

Cited by 2 | Viewed by 2850

Abstract

Closely linked to Alzheimer’s disease (AD), the pathological spectrum of vascular cognitive impairment (VCI) is known to be wide and complex. Considering that multiple instead of a single targeting approach is considered a treatment option for such complicated diseases, the multifaceted aspects of mesenchymal stem cells (MSCs) make them a suitable candidate to tackle the heterogeneity of VCI. MSCs were delivered via the intracerebroventricular (ICV) route in mice that were subjected to VCI by carotid artery stenosis. VCI was induced in C57BL6/J mice wild type (C57VCI) mice by applying a combination of ameroid constrictors and microcoils, while ameroid constrictors alone were bilaterally applied to 5xFAD (transgenic AD mouse model) mice (5xVCI). Compared to the controls (minimal essential medium (MEM)-injected C57VCI mice), changes in spatial working memory were not noted in the MSC-injected C57VCI mice, and unexpectedly, the mortality rate was higher. In contrast, compared to the MEM-injected 5xVCI mice, mortality was not observed, and the spatial working memory was also improved in MSC-injected 5xVCI mice. Disease progression of the VCI-induced mice seems to be affected by the method of carotid artery stenosis and due to this heterogeneity, various factors must be considered to maximize the therapeutic benefits exerted by MSCs. Factors, such as the optimal MSC injection time point, cell concentration, sacrifice time point, and immunogenicity of the transplanted cells, must all be adequately addressed so that MSCs can be appropriately and effectively used as a treatment option for VCI. Full article

(This article belongs to the Special Issue Small Vessel Disease: A Whole Brain Disease)

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13 pages, 1898 KiB

Open AccessArticle

ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes

by Abby Keable, Ronan O’Neill, Matthew MacGregor Sharp, Maureen Gatherer, Ho Ming Yuen, David Annandale Johnston, Roy Oliver Weller and Roxana Octavia Carare

Int. J. Mol. Sci. 2020, 21(12), 4371; https://doi.org/10.3390/ijms21124371 - 19 Jun 2020

Cited by 8 | Viewed by 3553

Abstract

The accumulation of amyloid-β (Aβ) in the walls of capillaries and arteries as cerebral amyloid angiopathy (CAA) is part of the small vessel disease spectrum, related to a failure of elimination of Aβ from the brain. Aβ is eliminated along basement membranes in walls of cerebral capillaries and arteries (Intramural Peri-Arterial Drainage—IPAD), a pathway that fails with age and ApolipoproteinEε4 (ApoE4) genotype. IPAD is along basement membranes formed by capillary endothelial cells and surrounding astrocytes. Here, we examine (1) the composition of basement membranes synthesised by ApoE4 astrocytes; (2) structural differences between ApoE4 and ApoE3 astrocytes, and (3) how flow of Aβ affects Apo3/4 astrocytes. Using cultured astrocytes expressing ApoE3 or ApoE4, immunofluorescence, confocal, correlative light and electron microscopy (CLEM), and a millifluidic flow system, we show that ApoE4 astrocytes synthesise more fibronectin, possess smaller processes, and become rarefied when Aβ flows over them, as compared to ApoE3 astrocytes. Our results suggest that basement membranes synthesised by ApoE4 astrocytes favour the aggregation of Aβ, its reduced clearance via IPAD, thus promoting cerebral amyloid angiopathy. Full article

(This article belongs to the Special Issue Small Vessel Disease: A Whole Brain Disease)

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18 pages, 3350 KiB

Open AccessArticle

Heterogeneous Disease Progression in a Mouse Model of Vascular Cognitive Impairment

by Na Kyung Lee, Hunnyun Kim, Jehoon Yang, Jeyun Kim, Jeong Pyo Son, Hyemin Jang and Duk L. Na

Int. J. Mol. Sci. 2020, 21(8), 2820; https://doi.org/10.3390/ijms21082820 - 17 Apr 2020

Cited by 2 | Viewed by 2660

Abstract

Recently, an asymmetric vascular compromise approach that replicates many aspects of human vascular cognitive impairment (VCI) has been reported. The present study aimed to first investigate on the reproducibility in the disease progression of this newly reported VCI model using wild-type C57BL6/J mice. The second aim was to assess how this approach will affect the disease progression of transgenic Alzheimer’s disease (AD) 5XFAD mice subjected to VCI. C57BL6/J and 5XFAD mice were subjected to VCI by placing an ameroid constrictor on the right CCA and a microcoil on the left CCA. Infarcts and hippocampal neuronal loss did not appear predominantly in the right (ameroid side) as expected but randomly in both hemispheres. The mortality rate of C57BL6/J mice was unexpectedly high. Inducing VCI reduced amyloid burden in the hippocampi of 5XFAD mice. Since VCI is known to be complex and complicated, the heterogeneous disease progression observed from this current study shares close resemblance to the clinical manifestation of VCI. This heterogeneity, however, makes it challenging to test novel treatment options using this model. Further study is warranted to tackle the heterogeneous nature of VCI. Full article

(This article belongs to the Special Issue Small Vessel Disease: A Whole Brain Disease)

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12 pages, 1236 KiB

Open AccessArticle

The Predictive Value of Salt Sensitivity and Osmotic Fragility in the Development of Cerebral Small Vessel Disease

by Larisa A. Dobrynina, Alla A. Shabalina, Kamila V. Shamtieva, Elena V. Gnedovskaya, Alexander B. Berdalin and Marina V. Krotenkova

Int. J. Mol. Sci. 2020, 21(6), 2036; https://doi.org/10.3390/ijms21062036 - 16 Mar 2020

Cited by 4 | Viewed by 2751

Abstract

Increased salt intake in food probably affects the progression of cerebral small vessel disease (CSVD), which justifies the study of disturbances in sodium homeostasis associated with the development of CSVD. We aimed to clarify the role of salt sensitivity and osmotic fragility in the development of CSVD. Erythrocyte salt sensitivity was measured using the modified salt blood test, and osmotic fragility was measured using the classic osmotic fragility test in 73 patients with CSVD (48 women; 60.1 ± 6.5 years) and 19 healthy volunteers (14 women; 56.9 ± 6.4 years). Salt sensitivity and osmotic fragility exhibited a predictive value in relation to CSVD. These parameters were associated with an increase in white matter hyperintensities (p = 0.019 and 0.004, respectively). Their simultaneous use increased their predictive ability for CSVD (p < 0.000001; AUC (95% CI), 0.824 (0.724–0.923)). The possibility of predicting CSVD using erythrocyte salt sensitivity and osmotic fragility indicates the value of the individual glycocalyx buffer capacity in relation to sodium and the activity of sodium channels in the development of CSVD. Increased salt sensitivity and osmotic fragility seem to be risk factors for CSVD. Full article

(This article belongs to the Special Issue Small Vessel Disease: A Whole Brain Disease)

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17 pages, 4020 KiB

Open AccessArticle

Astaxanthin Ameliorates Ischemic-Hypoxic-Induced Neurotrophin Receptor p75 Upregulation in the Endothelial Cells of Neonatal Mouse Brains

by Min-Hsun Kuo, Hung-Fu Lee, Yi-Fang Tu, Li-Hsuan Lin, Ya-Yun Cheng and Hsueh-Te Lee

Int. J. Mol. Sci. 2019, 20(24), 6168; https://doi.org/10.3390/ijms20246168 - 6 Dec 2019

Cited by 13 | Viewed by 3472

Abstract

Ischemic stroke is a leading cause of human death in present times. Two phases of pathological impact occur during an ischemic stroke, namely, ischemia and reperfusion. Both periods include individual characteristic effects on cell injury and apoptosis. Moreover, these conditions can cause severe cell defects and harm the blood-brain barrier (BBB). Also, the BBB components are the major targets in ischemia-reperfusion injury. The BBB owes its enhanced protective roles to capillary endothelial cells, which maintain BBB permeability. One of the nerve growth factor (NGF) receptors initiating cell signaling, once activated, is the p75 neurotrophin receptor (p75NTR). This receptor is involved in both the survival and apoptosis of neurons. Although many studies have attempted to explain the role of p75NTR in neurons, the mechanisms in endothelial cells remain unclear. Endothelial cells are the first cells to encounter p75NTR stimuli. In this study, we found the upregulated p75NTR expression and reductive expression of tight junction proteins after in vivo and in vitro ischemia-reperfusion injury. Moreover, astaxanthin (AXT), an antioxidant drug, was utilized and was found to reduce p75NTR expression and the number of apoptotic cells. This study verified that p75NTR plays a prominent role in endothelial cell death and provides a novel downstream target for AXT. Full article

(This article belongs to the Special Issue Small Vessel Disease: A Whole Brain Disease)

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17 pages, 3079 KiB

Open AccessArticle

Lipid Reshaping and Lipophagy Are Induced in a Modeled Ischemia-Reperfusion Injury of Blood Brain Barrier

by Elena Lonati, Paola Antonia Corsetto, Gigliola Montorfano, Stefania Zava, Tatiana Carrozzini, Anna Brambilla, Laura Botto, Paola Palestini, Angela Maria Rizzo and Alessandra Bulbarelli

Int. J. Mol. Sci. 2019, 20(15), 3752; https://doi.org/10.3390/ijms20153752 - 31 Jul 2019

Cited by 17 | Viewed by 3769

Abstract

Ischemic-reperfusion (I/R) injury induced a remodeling of protein and lipid homeostasis, under oxidative stress and inflammatory status. Starvation occurring during I/R is a condition leading to autophagy activation, which allows abnormal material clearance or amino acid, or both, and fatty acid (FA) recycling essential for survival. This study investigated the lipid reshaping, peroxidation, and related-signaling pathways, in rat brain endothelial cells (RBE4) subjected to 3 h of oxygen and glucose deprivation (OGD) and restoration of standard condition (I/R in vitro model). Lipids and proteins were analyzed after 1 or 24 h of oxygen and nutrient restoration. Together with the oxidative stress and inflammatory status, I/R injury induced a reshaping of neutral lipids and biogenesis of lipid droplets (LD) with excessive lipid storage. The increase of LC3-II/LC3-I ratio, an autophagy marker, and LC3 co-localization with LD suggest the activation of lipophagy machinery to counteract the cell engulfment. Lipophagy leads to cholesterol ester (CE) hydrolysis, increasing free cholesterol (FC) secretion, which occurred by specific transporters or unconventional exocytosis pathways, or both. Here, we propose that an unconventional spreading of FC and other lipid metabolites may influence the neurovascular unit (NVU) cells, contributing to Blood brain barrier (BBB) alteration or adaptation, or both, to the cumulative effects of several transient ischemia. Full article

(This article belongs to the Special Issue Small Vessel Disease: A Whole Brain Disease)

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15 pages, 2306 KiB

Open AccessArticle

Ureaplasma Species Modulate Cytokine and Chemokine Responses in Human Brain Microvascular Endothelial Cells

by Christine Silwedel, Christian P. Speer, Axel Haarmann, Markus Fehrholz, Heike Claus, Nicolas Schlegel and Kirsten Glaser

Int. J. Mol. Sci. 2019, 20(14), 3583; https://doi.org/10.3390/ijms20143583 - 22 Jul 2019

Cited by 6 | Viewed by 4181

Abstract

Ureaplasma species are common colonizers of the adult genitourinary tract and often considered as low-virulence commensals. Intraamniotic Ureaplasma infections, however, facilitate chorioamnionitis and preterm birth, and cases of Ureaplasma-induced neonatal sepsis, pneumonia, and meningitis raise a growing awareness of their clinical relevance. In vitro studies are scarce but demonstrate distinct Ureaplasma-driven impacts on immune mechanisms. The current study addressed cytokine and chemokine responses upon exposure of native or lipopolysaccharide (LPS) co-stimulated human brain microvascular endothelial cells (HBMEC) to Ureaplasma urealyticum or U. parvum, using qRT-PCR, RNA sequencing, multi-analyte immunoassay, and flow cytometry. Ureaplasma exposure in native HBMEC reduced monocyte chemoattractant protein (MCP)-3 mRNA expression (p < 0.01, vs. broth). In co-stimulated HBMEC, Ureaplasma spp. attenuated LPS-evoked mRNA responses for C-X-C chemokine ligand 5, MCP-1, and MCP-3 (p < 0.05, vs. LPS) and mitigated LPS-driven interleukin (IL)-1α protein secretion, as well as IL-8 mRNA and protein responses (p < 0.05). Furthermore, Ureaplasma isolates increased C-X-C chemokine receptor 4 mRNA levels in native and LPS co-stimulated HBMEC (p < 0.05). The presented results may imply immunomodulatory capacities of Ureaplasma spp. which may ultimately promote chronic colonization and long-term neuroinflammation. Full article

(This article belongs to the Special Issue Small Vessel Disease: A Whole Brain Disease)

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Review

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21 pages, 321 KiB

Open AccessReview

An Iatrogenic Model of Brain Small-Vessel Disease: Post-Radiation Encephalopathy

by Rita Moretti and Paola Caruso

Int. J. Mol. Sci. 2020, 21(18), 6506; https://doi.org/10.3390/ijms21186506 - 5 Sep 2020

Cited by 11 | Viewed by 3201

Abstract

We studied 114 primitive cerebral neoplasia, that were surgically treated, and underwent radiotherapy (RT), and compared their results to those obtained by 190 patients diagnosed with subcortical vascular dementia (sVAD). Patients with any form of primitive cerebral neoplasia underwent whole-brain radiotherapy. All the tumor patients had regional field partial brain RT, which encompassed each tumor, with an average margin of 2.6 cm from the initial target tumor volume. We observed in our patients who have been exposed to a higher dose of RT (30–65 Gy) a cognitive and behavior decline similar to that observed in sVAD, with the frontal dysexecutive syndrome, apathy, and gait alterations, but with a more rapid onset and with an overwhelming effect. Multiple mechanisms are likely to be involved in radiation-induced cognitive impairment. The active site of RT brain damage is the white matter areas, particularly the internal capsule, basal ganglia, caudate, hippocampus, and subventricular zone. In all cases, radiation damage inside the brain mainly focuses on the cortical–subcortical frontal loops, which integrate and process the flow of information from the cortical areas, where executive functions are “elaborated” and prepared, towards the thalamus, subthalamus, and cerebellum, where they are continuously refined and executed. The active mechanisms that RT drives are similar to those observed in cerebral small vessel disease (SVD), leading to sVAD. The RT’s primary targets, outside the tumor mass, are the blood–brain barrier (BBB), the small vessels, and putative mechanisms that can be taken into account are oxidative stress and neuro-inflammation, strongly associated with the alteration of NMDA receptor subunit composition. Full article

(This article belongs to the Special Issue Small Vessel Disease: A Whole Brain Disease)

39 pages, 3576 KiB

Open AccessReview

Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies

by Jayant Patwa and Swaran Jeet Singh Flora

Int. J. Mol. Sci. 2020, 21(11), 3862; https://doi.org/10.3390/ijms21113862 - 29 May 2020

Cited by 28 | Viewed by 8100

Abstract

Heavy metals are considered a continuous threat to humanity, as they cannot be eradicated. Prolonged exposure to heavy metals/metalloids in humans has been associated with several health risks, including neurodegeneration, vascular dysfunction, metabolic disorders, cancer, etc. Small blood vessels are highly vulnerable to heavy metals as they are directly exposed to the blood circulatory system, which has comparatively higher concentration of heavy metals than other organs. Cerebral small vessel disease (CSVD) is an umbrella term used to describe various pathological processes that affect the cerebral small blood vessels and is accepted as a primary contributor in associated disorders, such as dementia, cognitive disabilities, mood disorder, and ischemic, as well as a hemorrhagic stroke. In this review, we discuss the possible implication of heavy metals/metalloid exposure in CSVD and its associated disorders based on in-vitro, preclinical, and clinical evidences. We briefly discuss the CSVD, prevalence, epidemiology, and risk factors for development such as genetic, traditional, and environmental factors. Toxic effects of specific heavy metal/metalloid intoxication (As, Cd, Pb, Hg, and Cu) in the small vessel associated endothelium and vascular dysfunction too have been reviewed. An attempt has been made to highlight the possible molecular mechanism involved in the pathophysiology, such as oxidative stress, inflammatory pathway, matrix metalloproteinases (MMPs) expression, and amyloid angiopathy in the CSVD and related disorders. Finally, we discussed the role of cellular antioxidant defense enzymes to neutralize the toxic effect, and also highlighted the potential reversal strategies to combat heavy metal-induced vascular changes. In conclusion, heavy metals in small vessels are strongly associated with the development as well as the progression of CSVD. Chelation therapy may be an effective strategy to reduce the toxic metal load and the associated complications. Full article

(This article belongs to the Special Issue Small Vessel Disease: A Whole Brain Disease)

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26 pages, 858 KiB

Open AccessReview

Update on the Neurobiology of Vascular Cognitive Impairment: From Lab to Clinic

by Luisa Vinciguerra, Giuseppe Lanza, Valentina Puglisi, Francesco Fisicaro, Manuela Pennisi, Rita Bella and Mariagiovanna Cantone

Int. J. Mol. Sci. 2020, 21(8), 2977; https://doi.org/10.3390/ijms21082977 - 23 Apr 2020

Cited by 51 | Viewed by 4477

Abstract

In the last years, there has been a significant growth in the literature exploring the pathophysiology of vascular cognitive impairment (VCI). As an “umbrella term” encompassing any degree of vascular-related cognitive decline, VCI is deemed to be the most common cognitive disorder in the elderly, with a significant impact on social and healthcare expenses. Interestingly, some of the molecular, biochemical, and electrophysiological abnormalities detected in VCI seem to correlate with disease process and progression, eventually promoting an adaptive plasticity in some patients and a maladaptive, dysfunctional response in others. However, the exact relationships between vascular lesion, cognition, and neuroplasticity are not completely understood. Recent findings point out also the possibility to identify a panel of markers able to predict cognitive deterioration in the so-called “brain at risk” for vascular or mixed dementia. This will be of pivotal importance when designing trials of disease-modifying drugs or non-pharmacological approaches, including non-invasive neuromodulatory techniques. Taken together, these advances could make VCI a potentially preventable cause of both vascular and degenerative dementia in late life. This review provides a timely update on the recent serological, cerebrospinal fluid, histopathological, imaging, and neurophysiological studies on this “cutting-edge” topic, including the limitations, future perspectives and translational implications in the diagnosis and management of VCI patients. Full article

(This article belongs to the Special Issue Small Vessel Disease: A Whole Brain Disease)

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35 pages, 1506 KiB

Open AccessReview

Small Vessel Disease-Related Dementia: An Invalid Neurovascular Coupling?

by Rita Moretti and Paola Caruso

Int. J. Mol. Sci. 2020, 21(3), 1095; https://doi.org/10.3390/ijms21031095 - 7 Feb 2020

Cited by 37 | Viewed by 7060

Abstract

The arteriosclerosis-dependent alteration of brain perfusion is one of the major determinants in small vessel disease, since small vessels have a pivotal role in the brain’s autoregulation. Nevertheless, as far as we know, endothelium distress can potentiate the flow dysregulation and lead to subcortical vascular dementia that is related to small vessel disease (SVD), also being defined as subcortical vascular dementia (sVAD), as well as microglia activation, chronic hypoxia and hypoperfusion, vessel-tone dysregulation, altered astrocytes, and pericytes functioning blood-brain barrier disruption. The molecular basis of this pathology remains controversial. The apparent consequence (or a first event, too) is the macroscopic alteration of the neurovascular coupling. Here, we examined the possible mechanisms that lead a healthy aging process towards subcortical dementia. We remarked that SVD and white matter abnormalities related to age could be accelerated and potentiated by different vascular risk factors. Vascular function changes can be heavily influenced by genetic and epigenetic factors, which are, to the best of our knowledge, mostly unknown. Metabolic demands, active neurovascular coupling, correct glymphatic process, and adequate oxidative and inflammatory responses could be bulwarks in defense of the correct aging process; their impairments lead to a potentially catastrophic and non-reversible condition. Full article

(This article belongs to the Special Issue Small Vessel Disease: A Whole Brain Disease)

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20 pages, 1439 KiB

Open AccessReview

Pericytes in Microvessels: From “Mural” Function to Brain and Retina Regeneration

by Nunzia Caporarello, Floriana D’Angeli, Maria Teresa Cambria, Saverio Candido, Cesarina Giallongo, Mario Salmeri, Cinzia Lombardo, Anna Longo, Giovanni Giurdanella, Carmelina Daniela Anfuso and Gabriella Lupo

Int. J. Mol. Sci. 2019, 20(24), 6351; https://doi.org/10.3390/ijms20246351 - 17 Dec 2019

Cited by 85 | Viewed by 7838

Abstract

Pericytes are branched cells located in the wall of capillary blood vessels that are found throughout the body, embedded within the microvascular basement membrane and wrapping endothelial cells, with which they establish a strong physical contact. Pericytes regulate angiogenesis, vessel stabilization, and contribute to the formation of both the blood-brain and blood-retina barriers by Angiopoietin-1/Tie-2, platelet derived growth factor (PDGF) and transforming growth factor (TGF) signaling pathways, regulating pericyte-endothelial cell communication. Human pericytes that have been cultured for a long period give rise to multilineage progenitor cells and exhibit mesenchymal stem cell (MSC) features. We focused our attention on the roles of pericytes in brain and ocular diseases. In particular, pericyte involvement in brain ischemia, brain tumors, diabetic retinopathy, and uveal melanoma is described. Several molecules, such as adenosine and nitric oxide, are responsible for pericyte shrinkage during ischemia-reperfusion. Anti-inflammatory molecules, such as IL-10, TGFβ, and MHC-II, which are increased in glioblastoma-activated pericytes, are responsible for tumor growth. As regards the eye, pericytes play a role not only in ocular vessel stabilization, but also as a stem cell niche that contributes to regenerative processes in diabetic retinopathy. Moreover, pericytes participate in melanoma cell extravasation and the genetic ablation of the PDGF receptor reduces the number of pericytes and aberrant tumor microvessel formation with important implications for therapy efficacy. Thanks to their MSC features, pericytes could be considered excellent candidates to promote nervous tissue repair and for regenerative medicine. Full article

(This article belongs to the Special Issue Small Vessel Disease: A Whole Brain Disease)

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