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Small Vessel Disease: New Perspectives on an Emerging Reality
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Small Vessel Disease: New Perspectives on an Emerging Reality

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 December 2021) | Viewed by 30584

Special Issue Editor

Prof. Dr. Rita Moretti

E-Mail Website
Guest Editor
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
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Small vessel disease (SVD) is an umbrella term that starts in para-physiological healthy aging and ends into related subcortical vascular dementia (sVAD). 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 mostly unknown to the best of our knowledge. 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.

The arteriosclerosis‐dependent alteration of brain perfusion is one of the major determinants in small vessel disease, with degeneration of the smooth muscle layer and replacement by hyaline fibrosis, leading to a subtotal luminal occlusion, but also 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 SVD, also being defined as subcortical vascular dementia, as well as microglia activation, chronic hypoxia and hypoperfusion, vessel‐tone dysregulation, altered astrocytes, and pericyte functioning blood–brain barrier disruption. The molecular basis of this pathology remains controversial. The apparent consequence is the macroscopic alteration of neurovascular coupling. SVD is an ongoing process, which begins with altered microvessels and pial arteries and ends in subcortical dementia; CBF regional selective decrease seems to be one of the critical factors for the progression from small vessel disease to small vessel disease‐related dementia. The most relevant aspects still under debate are the modality of changing from typical aging small vessel disease toward dementia; the impact of aging and age–gene interactions in arteriolosclerosis, endothelium dysfunction, pericyte alterations, and astrocyte modifications, which are caused, promoted, or potentiated by hypoperfusion and metabolic disruption; altered neurovascular coupling, a secondary or a causative (primary) defect in SVD; and potential clinical rescue from SVD, knowing different times of its development, probably by acting precociously, simultaneously via various strategies (anti‐inflammatory, anti‐oxidant, anti‐thrombotic, and perhaps via nutraceutical promotions, acting as co‐enzymatic promoters).

This Special Issue will aim to shed some light on these fascinating aspects.

Prof. Dr. Rita Moretti
Guest Editor

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Keywords

  • biological markers
  • vitamin
  • endothelium
  • blood brain barrier
  • CAA
  • astrocytes
  • neurovascular coupling
  • neuro-inflammation
  • glymphatic system

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Related Special Issue

Published Papers (5 papers)

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Review

22 pages, 957 KiB  
Review
Small Vessel Disease: Ancient Description, Novel Biomarkers
by Rita Moretti and Paola Caruso
Int. J. Mol. Sci. 2022, 23(7), 3508; https://doi.org/10.3390/ijms23073508 - 23 Mar 2022
Cited by 16 | Viewed by 5773
Abstract
Small vessel disease (SVD) is one of the most frequent pathological conditions which lead to dementia. Biochemical and neuroimaging might help correctly identify the clinical diagnosis of this relevant brain disease. The microvascular alterations which underlie SVD have common origins, similar cognitive outcomes, [...] Read more.
Small vessel disease (SVD) is one of the most frequent pathological conditions which lead to dementia. Biochemical and neuroimaging might help correctly identify the clinical diagnosis of this relevant brain disease. The microvascular alterations which underlie SVD have common origins, similar cognitive outcomes, and common vascular risk factors. Nevertheless, the arteriolosclerosis process, which underlines SVD development, is based on different mechanisms, not all completely understood, which start from a chronic hypoperfusion state and pass through a chronic brain inflammatory condition, inducing a significant endothelium activation and a consequent tissue remodeling action. In a recent review, we focused on the pathophysiology of SVD, which is complex, involving genetic conditions and different co-morbidities (i.e., diabetes, chronic hypoxia condition, and obesity). Currently, many points still remain unclear and discordant. In this paper, we wanted to focus on new biomarkers, which can be the expression of the endothelial dysfunction, or of the oxidative damage, which could be employed as markers of disease progression or for future targets of therapies. Therefore, we described the altered response to the endothelium-derived nitric oxide-vasodilators (ENOV), prostacyclin, C-reactive proteins, and endothelium-derived hyperpolarizing factors (EDHF). At the same time, due to the concomitant endothelial activation and chronic neuroinflammatory status, we described hypoxia-endothelial-related markers, such as HIF 1 alpha, VEGFR2, and neuroglobin, and MMPs. We also described blood–brain barrier disruption biomarkers and imaging techniques, which can also describe perivascular spaces enlargement and dysfunction. More studies should be necessary, in order to implement these results and give them a clinical benefit. Full article
(This article belongs to the Special Issue Small Vessel Disease: New Perspectives on an Emerging Reality)
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14 pages, 614 KiB  
Review
The Contribution of Small Vessel Disease to Neurodegeneration: Focus on Alzheimer’s Disease, Parkinson’s Disease and Multiple Sclerosis
by Federico Paolini Paoletti, Simone Simoni, Lucilla Parnetti and Lorenzo Gaetani
Int. J. Mol. Sci. 2021, 22(9), 4958; https://doi.org/10.3390/ijms22094958 - 7 May 2021
Cited by 41 | Viewed by 4993
Abstract
Brain small vessel disease (SVD) refers to a variety of structural and functional changes affecting small arteries and micro vessels, and manifesting as white matter changes, microbleeds and lacunar infarcts. Growing evidence indicates that SVD might play a significant role in the neurobiology [...] Read more.
Brain small vessel disease (SVD) refers to a variety of structural and functional changes affecting small arteries and micro vessels, and manifesting as white matter changes, microbleeds and lacunar infarcts. Growing evidence indicates that SVD might play a significant role in the neurobiology of central nervous system (CNS) neurodegenerative disorders, namely Alzheimer’s disease (AD) and Parkinson’s disease (PD), and neuroinflammatory diseases, such as multiple sclerosis (MS). These disorders share different pathophysiological pathways and molecular mechanisms (i.e., protein misfolding, derangement of cellular clearance systems, mitochondrial impairment and immune system activation) having neurodegeneration as biological outcome. In these diseases, the actual contribution of SVD to the clinical picture, and its impact on response to pharmacological treatments, is not known yet. Due to the high frequency of SVD in adult-aged patients, it is important to address this issue. In this review, we report preclinical and clinical data on the impact of SVD in AD, PD and MS, with the main aim of clarifying the predictability of SVD on clinical manifestations and treatment response. Full article
(This article belongs to the Special Issue Small Vessel Disease: New Perspectives on an Emerging Reality)
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22 pages, 1202 KiB  
Review
Homocysteine in Neurology: A Possible Contributing Factor to Small Vessel Disease
by Rita Moretti, Mauro Giuffré, Paola Caruso, Silvia Gazzin and Claudio Tiribelli
Int. J. Mol. Sci. 2021, 22(4), 2051; https://doi.org/10.3390/ijms22042051 - 19 Feb 2021
Cited by 37 | Viewed by 6587
Abstract
Homocysteine (Hcy) is a sulfur-containing amino acid generated during methionine metabolism, accumulation of which may be caused by genetic defects or the deficit of vitamin B12 and folate. A serum level greater than 15 micro-mols/L is defined as hyperhomocysteinemia (HHcy). Hcy has many [...] Read more.
Homocysteine (Hcy) is a sulfur-containing amino acid generated during methionine metabolism, accumulation of which may be caused by genetic defects or the deficit of vitamin B12 and folate. A serum level greater than 15 micro-mols/L is defined as hyperhomocysteinemia (HHcy). Hcy has many roles, the most important being the active participation in the transmethylation reactions, fundamental for the brain. Many studies focused on the role of homocysteine accumulation in vascular or degenerative neurological diseases, but the results are still undefined. More is known in cardiovascular disease. HHcy is a determinant for the development and progression of inflammation, atherosclerotic plaque formation, endothelium, arteriolar damage, smooth muscle cell proliferation, and altered-oxidative stress response. Conversely, few studies focused on the relationship between HHcy and small vessel disease (SVD), despite the evidence that mice with HHcy showed a significant end-feet disruption of astrocytes with a diffuse SVD. A severe reduction of vascular aquaporin-4-water channels, lower levels of high-functioning potassium channels, and higher metalloproteinases are also observed. HHcy modulates the N-homocysteinylation process, promoting a pro-coagulative state and damage of the cellular protein integrity. This altered process could be directly involved in the altered endothelium activation, typical of SVD and protein quality, inhibiting the ubiquitin-proteasome system control. HHcy also promotes a constant enhancement of microglia activation, inducing the sustained pro-inflammatory status observed in SVD. This review article addresses the possible role of HHcy in small-vessel disease and understands its pathogenic impact. Full article
(This article belongs to the Special Issue Small Vessel Disease: New Perspectives on an Emerging Reality)
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15 pages, 3510 KiB  
Review
From Brain to Heart: Possible Role of Amyloid-β in Ischemic Heart Disease and Ischemia-Reperfusion Injury
by Giulia Gagno, Federico Ferro, Alessandra Lucia Fluca, Milijana Janjusevic, Maddalena Rossi, Gianfranco Sinagra, Antonio Paolo Beltrami, Rita Moretti and Aneta Aleksova
Int. J. Mol. Sci. 2020, 21(24), 9655; https://doi.org/10.3390/ijms21249655 - 17 Dec 2020
Cited by 22 | Viewed by 4502
Abstract
Ischemic heart disease (IHD) is among the leading causes of death in developed countries. Its pathological origin is traced back to coronary atherosclerosis, a lipid-driven immuno-inflammatory disease of the arteries that leads to multifocal plaque development. The primary clinical manifestation of IHD is [...] Read more.
Ischemic heart disease (IHD) is among the leading causes of death in developed countries. Its pathological origin is traced back to coronary atherosclerosis, a lipid-driven immuno-inflammatory disease of the arteries that leads to multifocal plaque development. The primary clinical manifestation of IHD is acute myocardial infarction (AMI),) whose prognosis is ameliorated with optimal timing of revascularization. Paradoxically, myocardium re-perfusion can be detrimental because of ischemia-reperfusion injury (IRI), an oxidative-driven process that damages other organs. Amyloid-β (Aβ) plays a physiological role in the central nervous system (CNS). Alterations in its synthesis, concentration and clearance have been connected to several pathologies, such as Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Aβ has been suggested to play a role in the pathogenesis of IHD and cerebral IRI. The purpose of this review is to summarize what is known about the pathological role of Aβ in the CNS; starting from this evidence, we will illustrate the role played by Aβ in the development of coronary atherosclerosis and its possible implications in the pathophysiology of IHD and myocardial IRI. Better elucidation of Aβ’s contribution to the molecular pathways underlying IHD and IRI could be of great help in developing new therapeutic strategies. Full article
(This article belongs to the Special Issue Small Vessel Disease: New Perspectives on an Emerging Reality)
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Graphical abstract

15 pages, 3948 KiB  
Review
Sleep as a Novel Biomarker and a Promising Therapeutic Target for Cerebral Small Vessel Disease: A Review Focusing on Alzheimer’s Disease and the Blood-Brain Barrier
by Oxana Semyachkina-Glushkovskaya, Dmitry Postnov, Thomas Penzel and Jürgen Kurths
Int. J. Mol. Sci. 2020, 21(17), 6293; https://doi.org/10.3390/ijms21176293 - 31 Aug 2020
Cited by 42 | Viewed by 7770
Abstract
Cerebral small vessel disease (CSVD) is a leading cause of cognitive decline in elderly people and development of Alzheimer’s disease (AD). Blood–brain barrier (BBB) leakage is a key pathophysiological mechanism of amyloidal CSVD. Sleep plays a crucial role in keeping health of the [...] Read more.
Cerebral small vessel disease (CSVD) is a leading cause of cognitive decline in elderly people and development of Alzheimer’s disease (AD). Blood–brain barrier (BBB) leakage is a key pathophysiological mechanism of amyloidal CSVD. Sleep plays a crucial role in keeping health of the central nervous system and in resistance to CSVD. The deficit of sleep contributes to accumulation of metabolites and toxins such as beta-amyloid in the brain and can lead to BBB disruption. Currently, sleep is considered as an important informative platform for diagnosis and therapy of AD. However, there are no effective methods for extracting of diagnostic information from sleep characteristics. In this review, we show strong evidence that slow wave activity (SWA) (0–0.5 Hz) during deep sleep reflects glymphatic pathology, the BBB leakage and memory deficit in AD. We also discuss that diagnostic and therapeutic targeting of SWA in AD might lead to be a novel era in effective therapy of AD. Moreover, we demonstrate that SWA can be pioneering non-invasive and bed–side technology for express diagnosis of the BBB permeability. Finally, we review the novel data about the methods of detection and enhancement of SWA that can be biomarker and a promising therapy of amyloidal CSVD and CSVD associated with the BBB disorders. Full article
(This article belongs to the Special Issue Small Vessel Disease: New Perspectives on an Emerging Reality)
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