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Vascular Cognitive Impairment: From Molecular Mechanisms to Preventive and Therapeutic Strategies

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 (31 July 2019) | Viewed by 55842

Special Issue Editors


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Guest Editor
1. Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
2. Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
Interests: supplement; vitamin D; depression; dementia; Alzheimer; aging; oxidative stress; inflammation
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
Interests: aging; geriatrics; nutrition; senescence; telomeres; telomerase; dementia; cognition; diabetes; metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The term vascular cognitive impairment (VCI) has been recently introduced and refers to the contribution of vascular pathology to any severity of cognitive impairment, from subjective cognitive decline through mild cognitive impairment to dementia. Although vascular pathology and its complications are common in old age subjects with cognitive decline, pure vascular dementia is uncommon. Due to the variability of cerebrovascular disease, common comorbid pathologies and diverse clinical phenotypes of VCI, no widely-accepted criteria defining the neuropathological threshold of this disorder are available. At present, the main treatment for VCI is prevention by treating vascular diseases and other risk factors for VCI, such as hypertension, diabetes mellitus, and their complications. Elucidating the underlying molecular mechanisms and intertwined pathways is important to address the question whether cognitive decline may be prevented by an adequate vascular control or even treated with drugs already available. This Special Issue aims to bring together all branches of the research community and is soliciting manuscripts in the form of original research, mini and full reviews, short communications, as well as perspectives, which address any aspect of VCI.

Potential topics include, but are not limited to:

  • Cognitive declines in old age
  • Biological mechanisms linking vascular disease to cognitive impairment
  • Oxidative stress, mitochondria and brain aging
  • Metabolism, obesity, and vascular dementia
  • Cardiovascular and lifestyle risk factors for dementia
  • Common peripheral biomarkers in vascular dementia
  • Drug management and therapeutics
  • Multidisciplinary approach
  • Risk factors

Prof. Dr. Patrizia Mecocci
Dr. Virginia Boccardi
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • aging
  • cognition
  • vascular disease
  • mitochondria
  • lifestyle
  • nutrition
  • biomarkers
  • management
  • prevention
  • therapeutics
  • risk factors
  • obesity and metabolism
  • drugs

Published Papers (10 papers)

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Research

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11 pages, 2657 KiB  
Article
The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates High-fat Induced Cognitive Decline in Tauopathy Model Mice
by Yuriko Nakaoku, Satoshi Saito, Yumi Yamamoto, Takakuni Maki, Ryosuke Takahashi and Masafumi Ihara
Int. J. Mol. Sci. 2019, 20(10), 2539; https://doi.org/10.3390/ijms20102539 - 23 May 2019
Cited by 20 | Viewed by 3565
Abstract
Vascular risk factors, such as type 2 diabetes mellitus (T2DM), are associated with the increased risk of Alzheimer’s disease. One of the common T2DM medications, dipeptidyl peptidase (DPP)-4 inhibitors, have a minimum risk for hypoglycemia and have recently been suggested to ameliorate β-amyloid [...] Read more.
Vascular risk factors, such as type 2 diabetes mellitus (T2DM), are associated with the increased risk of Alzheimer’s disease. One of the common T2DM medications, dipeptidyl peptidase (DPP)-4 inhibitors, have a minimum risk for hypoglycemia and have recently been suggested to ameliorate β-amyloid pathology. However, conflicting results have been reported regarding the effects of DPP-4 inhibition on cognitive function and tau pathology. Thus, we investigated whether inhibiting DPP-4 affects tau pathology and cognition in a mouse model of tauopathy with hyperglycemia. Male mice overexpressing the P301S mutant human microtubule-associated protein tau gene (PS19) were fed either a low or high-fat diet. PS19 mice were then administered either linagliptin, a DPP-4 inhibitor, or vehicle, from 6 weeks to 8 months of age. Linagliptin-treated mice exhibited higher levels of glucagon-like peptide-1 and decreased fasting blood glucose, compared with the vehicle-treated mice at 8 months. Linagliptin treatment significantly restored spatial reference memory and increased cerebral blood flow without affecting phosphorylation levels of tau or endothelial nitric oxide synthase (eNOS) in the brain. Linagliptin may ameliorate HFD-induced cognitive worsening in tauopathy, at least partially, by increasing cerebral perfusion via the eNOS-independent pathway. Full article
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12 pages, 549 KiB  
Article
Low-Grade Inflammation Is Associated with Apathy Indirectly via Deep White Matter Lesions in Community-Dwelling Older Adults: The Sefuri Study
by Hiroshi Yao, Yoshito Mizoguchi, Akira Monji, Yusuke Yakushiji, Yuki Takashima, Akira Uchino, Takefumi Yuzuriha and Manabu Hashimoto
Int. J. Mol. Sci. 2019, 20(8), 1905; https://doi.org/10.3390/ijms20081905 - 17 Apr 2019
Cited by 14 | Viewed by 3593
Abstract
Low-grade inflammation is implicated in the pathogenesis of atherosclerosis, metabolic syndrome, and apathy as a form of vascular depression. We analyzed the brain magnetic resonance imaging findings in 259 community-dwelling older adults (122 men and 137 women, with a mean age of 68.4 [...] Read more.
Low-grade inflammation is implicated in the pathogenesis of atherosclerosis, metabolic syndrome, and apathy as a form of vascular depression. We analyzed the brain magnetic resonance imaging findings in 259 community-dwelling older adults (122 men and 137 women, with a mean age of 68.4 years). The serum concentrations of high-sensitivity C-reactive protein (hsCRP) were measured by a quantitative enzyme-linked immunosorbent assay. Logistic regression analysis revealed that the log10 hsCRP value and the presence of a metabolic syndrome were independently associated with confluent but not punctate deep white matter lesions (DWMLs). Path analysis based on structural equation modeling (SEM) indicated that the direct path from the log10 hsCRP to the DWMLs was significant (β = 0.119, p = 0.039). The direct paths from the metabolic syndrome to the log10 hsCRP and to the DWMLs were also significant. The direct path from the DWMLs to apathy (β = −0.165, p = 0.007) was significant, but the direct path from the log10 hsCRP to apathy was not significant. Inflammation (i.e., elevated serum hsCRP levels) was associated with DWMLs independent of common vascular risk factors, while DWMLs were associated with apathy. The present analysis with SEM revealed the more realistic scheme that low-grade inflammation was associated with apathy indirectly via DWMLs in community-dwelling older adults. Full article
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19 pages, 1948 KiB  
Article
Association between Striatal Brain Iron Deposition, Microbleeds and Cognition 1 Year After a Minor Ischaemic Stroke
by Maria del C. Valdés Hernández, Tessa Case, Francesca M. Chappell, Andreas Glatz, Stephen Makin, Fergus Doubal and Joanna M. Wardlaw
Int. J. Mol. Sci. 2019, 20(6), 1293; https://doi.org/10.3390/ijms20061293 - 14 Mar 2019
Cited by 16 | Viewed by 3491
Abstract
Brain iron deposits (IDs) are inversely associated with cognitive function in community-dwelling older people, but their association with cognition after ischemic stroke, and whether that differs from microbleeds, is unknown. We quantified basal ganglia IDs (BGID) and microbleeds (BMBs) semi-automatically on brain magnetic [...] Read more.
Brain iron deposits (IDs) are inversely associated with cognitive function in community-dwelling older people, but their association with cognition after ischemic stroke, and whether that differs from microbleeds, is unknown. We quantified basal ganglia IDs (BGID) and microbleeds (BMBs) semi-automatically on brain magnetic resonance images from patients with minor stroke (NIHSS < 7), at presentation and 12 months after stroke. We administered the National Adult Reading Test (NART, estimates premorbid or peak adult cognition) and the Revised Addenbrooke’s Cognitive Examination (ACE-R; current cognition) at 1 and 12 months after stroke. We adjusted analyses for baseline cognition, age, gender, white matter hyperintensity (WMH) volume and vascular risk factors. In 200 patients, mean age 65 years, striatal IDs and BMBs volumes did not change over the 12 months. Baseline BGID volumes correlated positively with NART scores at both times (ρ = 0.19, p < 0.01). Baseline and follow-up BGID volumes correlated positively with age (ρ = 0.248, p < 0.001 and ρ = 0.271, p < 0.001 respectively), but only baseline (and not follow-up) BMB volume correlated with age (ρ = 0.129, p < 0.05). Both smoking and baseline WMH burden predicted verbal fluency and visuospatial abilities scores (B = −1.13, p < 0.02 and B = −0.22, p = 0.001 respectively) at 12 months after stroke. BGIDs and BMBs are associated differently with cognition post-stroke; studies of imaging and post-stroke cognition should adjust for premorbid cognition. The positive correlation of BGID with NART may reflect the lower premorbid cognition in patients with stroke at younger vs older ages. Full article
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Review

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20 pages, 26600 KiB  
Review
Animal Models of Chronic Cerebral Hypoperfusion: From Mouse to Primate
by Kazuo Washida, Yorito Hattori and Masafumi Ihara
Int. J. Mol. Sci. 2019, 20(24), 6176; https://doi.org/10.3390/ijms20246176 - 7 Dec 2019
Cited by 87 | Viewed by 10276
Abstract
Vascular cognitive impairment (VCI) or vascular dementia occurs as a result of brain ischemia and represents the second most common type of dementia after Alzheimer’s disease. To explore the underlying mechanisms of VCI, several animal models of chronic cerebral hypoperfusion have been developed [...] Read more.
Vascular cognitive impairment (VCI) or vascular dementia occurs as a result of brain ischemia and represents the second most common type of dementia after Alzheimer’s disease. To explore the underlying mechanisms of VCI, several animal models of chronic cerebral hypoperfusion have been developed in rats, mice, and primates. We established a mouse model of chronic cerebral hypoperfusion by narrowing the bilateral common carotid arteries with microcoils, eventually resulting in hippocampal atrophy. In addition, a mouse model of white matter infarct-related damage with cognitive and motor dysfunction has also been established by asymmetric common carotid artery surgery. Although most experiments studying chronic cerebral hypoperfusion have been performed in rodents because of the ease of handling and greater ethical acceptability, non-human primates appear to represent the best model for the study of VCI, due to their similarities in much larger white matter volume and amyloid β depositions like humans. Therefore, we also recently developed a baboon model of VCI through three-vessel occlusion (both the internal carotid arteries and the left vertebral artery). In this review, several animal models of chronic cerebral hypoperfusion, from mouse to primate, are extensively discussed to aid in better understanding of pathophysiology of VCI. Full article
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14 pages, 439 KiB  
Review
Behavioral Disturbances in Dementia and Beyond: Time for a New Conceptual Frame?
by Federico Ambrogio, Lucia Anna Martella, Patrizio Odetti and Fiammetta Monacelli
Int. J. Mol. Sci. 2019, 20(15), 3647; https://doi.org/10.3390/ijms20153647 - 25 Jul 2019
Cited by 14 | Viewed by 5715
Abstract
Alzheimer’s disease and vascular dementia are estimated to be the most common causes of dementia, although mixed dementia could represent the most prevalent form of dementia in older adults aged more than 80 years. Behavioral disturbances are common in the natural history of [...] Read more.
Alzheimer’s disease and vascular dementia are estimated to be the most common causes of dementia, although mixed dementia could represent the most prevalent form of dementia in older adults aged more than 80 years. Behavioral disturbances are common in the natural history of dementia. However, so far, there is a paucity of studies that investigated the causal association between behavioral psychological symptoms of dementia and dementia sub-types, due to the high heterogeneity of methodology, study design and type of clinical assessment. To understand the scant evidence on such a relevant clinical issue, it could be hypothesized that a new shifting paradigm could result in a better identification of the relationship between behavioral disturbances and dementia. This narrative review provides an update of evidence on the behavioral patterns associated with different dementia sub-types and offers a potential future perspective as common ground for the development of new translational studies in the field of behavioral disturbances in dementia and the appropriateness of psychoactive treatments. Full article
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27 pages, 528 KiB  
Review
Emerging Biomarkers in Vascular Cognitive Impairment and Dementia: From Pathophysiological Pathways to Clinical Application
by Virginia Cipollini, Fernanda Troili and Franco Giubilei
Int. J. Mol. Sci. 2019, 20(11), 2812; https://doi.org/10.3390/ijms20112812 - 8 Jun 2019
Cited by 60 | Viewed by 8807
Abstract
Vascular pathology is the second most common neuropathology of dementia after Alzheimer’s disease (AD), with small vessels disease (SVD) being considered the major cause of vascular cognitive impairment and dementia (VCID). This review aims to evaluate pathophysiological pathways underlying a diagnosis of VCID. [...] Read more.
Vascular pathology is the second most common neuropathology of dementia after Alzheimer’s disease (AD), with small vessels disease (SVD) being considered the major cause of vascular cognitive impairment and dementia (VCID). This review aims to evaluate pathophysiological pathways underlying a diagnosis of VCID. Firstly, we will discuss the role of endothelial dysfunction, blood-brain barrier disruption and neuroinflammation in its pathogenesis. Then, we will analyse different biomarkers including the ones of inflammatory responses to central nervous system tissue injuries, of coagulation and thrombosis and of circulating microRNA. Evidences on peripheral biomarkers for VCID are still poor and large-scale, prospectively designed studies are needed to translate these findings into clinical practice, in order to set different combinations of biomarkers to use for differential diagnosis among types of dementia. Full article
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15 pages, 267 KiB  
Review
Innovative MRI Techniques in Neuroimaging Approaches for Cerebrovascular Diseases and Vascular Cognitive Impairment
by Lorenzo Carnevale and Giuseppe Lembo
Int. J. Mol. Sci. 2019, 20(11), 2656; https://doi.org/10.3390/ijms20112656 - 30 May 2019
Cited by 19 | Viewed by 3726
Abstract
Cognitive impairment and dementia are recognized as major threats to public health. Many studies have shown the important role played by challenges to the cerebral vasculature and the neurovascular unit. To investigate the structural and functional characteristics of the brain, MRI has proven [...] Read more.
Cognitive impairment and dementia are recognized as major threats to public health. Many studies have shown the important role played by challenges to the cerebral vasculature and the neurovascular unit. To investigate the structural and functional characteristics of the brain, MRI has proven an invaluable tool for visualizing the internal organs of patients and analyzing the parameters related to neuronal activation and blood flow in vivo. Different strategies of imaging can be combined to obtain various parameters: (i) measures of cortical and subcortical structures (cortical thickness, subcortical structures volume); (ii) evaluation of microstructural characteristics of the white matter (fractional anisotropy, mean diffusivity); (iii) neuronal activation and synchronicity to identify functional networks across different regions (functional connectivity between specific regions, graph measures of specific nodes); and (iv) structure of the cerebral vasculature and its efficacy in irrorating the brain (main vessel diameter, cerebral perfusion). The high amount of data obtainable from multi-modal sources calls for methods of advanced analysis, like machine-learning algorithms that allow the discrimination of the most informative features, to comprehensively characterize the cerebrovascular network into specific and sensitive biomarkers. By using the same techniques of human imaging in pre-clinical research, we can also investigate the mechanisms underlying the pathophysiological alterations identified in patients by imaging, with the chance of looking for molecular mechanisms to recover the pathology or hamper its progression. Full article
12 pages, 1206 KiB  
Review
Disturbance of Intracerebral Fluid Clearance and Blood–Brain Barrier in Vascular Cognitive Impairment
by Masaki Ueno, Yoichi Chiba, Ryuta Murakami, Koichi Matsumoto, Ryuji Fujihara, Naoya Uemura, Ken Yanase and Masaki Kamada
Int. J. Mol. Sci. 2019, 20(10), 2600; https://doi.org/10.3390/ijms20102600 - 27 May 2019
Cited by 21 | Viewed by 4250
Abstract
The entry of blood-borne macromolecular substances into the brain parenchyma from cerebral vessels is blocked by the blood–brain barrier (BBB) function. Accordingly, increased permeability of the vessels induced by insult noted in patients suffering from vascular dementia likely contributes to the cognitive impairment. [...] Read more.
The entry of blood-borne macromolecular substances into the brain parenchyma from cerebral vessels is blocked by the blood–brain barrier (BBB) function. Accordingly, increased permeability of the vessels induced by insult noted in patients suffering from vascular dementia likely contributes to the cognitive impairment. On the other hand, blood-borne substances can enter extracellular spaces of the brain via endothelial cells at specific sites without the BBB, and can move to brain parenchyma, such as the hippocampus and periventricular areas, adjacent to specific sites, indicating the contribution of increased permeability of vessels in the specific sites to brain function. It is necessary to consider influx and efflux of interstitial fluid (ISF) and cerebrospinal fluid (CSF) in considering effects of brain transfer of intravascular substances on brain function. Two pathways of ISF and CSF are recently being established. One is the intramural peri-arterial drainage (IPAD) pathway of ISF. The other is the glymphatic system of CSF. Dysfunction of the two pathways could also contribute to brain dysfunction. We review the effects of several kinds of insult on vascular permeability and the failure of fluid clearance on the brain function. Full article
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8 pages, 716 KiB  
Review
The Blood Pressure Pendulum following Spinal Cord Injury: Implications for Vascular Cognitive Impairment
by Rahul Sachdeva, Tom E. Nightingale and Andrei V. Krassioukov
Int. J. Mol. Sci. 2019, 20(10), 2464; https://doi.org/10.3390/ijms20102464 - 18 May 2019
Cited by 29 | Viewed by 7266
Abstract
Cognitive impairment following spinal cord injury (SCI) has received considerable attention in recent years. Among the various systemic effects of SCI that contribute towards cognitive decline in this population, cardiovascular dysfunction is arguably one of the most significant. The majority of individuals with [...] Read more.
Cognitive impairment following spinal cord injury (SCI) has received considerable attention in recent years. Among the various systemic effects of SCI that contribute towards cognitive decline in this population, cardiovascular dysfunction is arguably one of the most significant. The majority of individuals with a cervical or upper-thoracic SCI commonly experience conditions called orthostatic hypotension and autonomic dysreflexia, which are characterized by dangerous fluctuations in systemic blood pressure (BP). Herein, we review the potential impact of extreme BP lability on vascular cognitive impairment (VCI) in individuals with SCI. Albeit preliminary in the SCI population, there is convincing evidence that chronic hypotension and hypertension in able-bodied individuals results in devastating impairments in cerebrovascular health, leading to VCI. We discuss the pertinent literature, and while drawing mechanistic comparisons between able-bodied cohorts and individuals with SCI, we emphasize the need for additional research to elucidate the mechanisms of cognitive impairment specific to the SCI population. Lastly, we highlight the current and potential future therapies to manage and treat BP instability, thereby possibly mitigating VCI in the SCI population. Full article
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17 pages, 495 KiB  
Review
Vascular Cognitive Impairment: Information from Animal Models on the Pathogenic Mechanisms of Cognitive Deficits
by Jakub Hort, Martin Vališ, Kamil Kuča and Francesco Angelucci
Int. J. Mol. Sci. 2019, 20(10), 2405; https://doi.org/10.3390/ijms20102405 - 15 May 2019
Cited by 18 | Viewed by 4360
Abstract
Vascular cognitive impairment (VCI) is the second most common cause of cognitive deficit after Alzheimer’s disease. Since VCI patients represent an important target population for prevention, an ongoing effort has been made to elucidate the pathogenesis of this disorder. In this review, we [...] Read more.
Vascular cognitive impairment (VCI) is the second most common cause of cognitive deficit after Alzheimer’s disease. Since VCI patients represent an important target population for prevention, an ongoing effort has been made to elucidate the pathogenesis of this disorder. In this review, we summarize the information from animal models on the molecular changes that occur in the brain during a cerebral vascular insult and ultimately lead to cognitive deficits in VCI. Animal models cannot effectively represent the complex clinical picture of VCI in humans. Nonetheless, they allow some understanding of the important molecular mechanisms leading to cognitive deficits. VCI may be caused by various mechanisms and metabolic pathways. The pathological mechanisms, in terms of cognitive deficits, may span from oxidative stress to vascular clearance of toxic waste products (such as amyloid beta) and from neuroinflammation to impaired function of microglia, astrocytes, pericytes, and endothelial cells. Impaired production of elements of the immune response, such as cytokines, and vascular factors, such as insulin-like growth factor 1 (IGF-1), may also affect cognitive functions. No single event could be seen as being the unique cause of cognitive deficits in VCI. These events are interconnected, and may produce cascade effects resulting in cognitive impairment. Full article
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