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European Review For Medical and... Sep 2020Vascular dementia is the second-most cause of dementia, characterized by cerebral infarcts, white matter lesions, myelin loss and often amyloid angiopathy. Hence,... (Review)
Review
Vascular dementia is the second-most cause of dementia, characterized by cerebral infarcts, white matter lesions, myelin loss and often amyloid angiopathy. Hence, vascular damage is a critical cause of neuronal loss and synaptic disintegration. Abnormal neuroinflammation, autophagy and apoptosis are the prerequisite factors for endothelial and neuronal cell damage. This leads to the onset and progression of cerebrovascular disorders and cognitive dysfunction. The innate immune cells, pattern recognition receptors, Toll-like receptor-4 and related inflammatory mechanisms disrupt cerebrovascular integrity via glial activation and increased pro-inflammatory interleukins and TNFα. Inflammasome polymorphisms and multi-faceted neuro-immune interactions further integrate systemic and central inflammatory pathways, which induce vascular tissue injury and neurodegeneration. Specifically, chronic cerebral hypoperfusion disrupts the self-cannibalization mechanism of autophagy via altered expression of autophagy-specific proteins, Beclin-1, LC3 and P62. The deregulated autophagy pathway causes neuronal loss, hippocampal shrinkage, and ultimate loss in synaptic plasticity. The vascular dementia models typically exhibit downregulated anti-apoptotic Bcl-2 and upregulated pro-apoptotic Bax, cleaved caspase-3, and cleaved-PARP levels in the brain, for which modulated p38 MAPK and JNK phosphorylation pathways play a vital role. Endoplasmic stress-induced apoptosis, calcium overload and glutamate excitotoxicity in combination with ASK1-MAPK signaling mechanism also contribute to the cerebrovascular pathology. Vascular injury reduces neurological scores and increases the infarct volume, DNA damage and neuronal apoptosis in ischemia/reperfusion injury. Additionally, synergistic and additive interactions between inflammasome, autophagy and apoptotic signaling pathways augment symptoms of vascular neurodegeneration. Overall, the current review enlightens the key risk factors and underlying mechanism triggering vascular dementia. The review additionally informs the challenges associated while treating vascular dysfunction, and highlights the need for targeted drugs for reducing cerebrovascular damage.
Topics: Animals; Apoptosis; Dementia, Vascular; Humans; Inflammation
PubMed: 33015803
DOI: 10.26355/eurrev_202009_23048 -
Stroke Sep 2011This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive... (Review)
Review
BACKGROUND AND PURPOSE
This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive impairment and dementia of later life are common. Definitions of vascular cognitive impairment (VCI), neuropathology, basic science and pathophysiological aspects, role of neuroimaging and vascular and other associated risk factors, and potential opportunities for prevention and treatment are reviewed. This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment.
METHODS
Writing group members were nominated by the writing group co-chairs on the basis of their previous work in relevant topic areas and were approved by the American Heart Association Stroke Council Scientific Statement Oversight Committee, the Council on Epidemiology and Prevention, and the Manuscript Oversight Committee. The writing group used systematic literature reviews (primarily covering publications from 1990 to May 1, 2010), previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, formulate recommendations using standard American Heart Association criteria. All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. After peer review by the American Heart Association, as well as review by the Stroke Council leadership, Council on Epidemiology and Prevention Council, and Scientific Statements Oversight Committee, the statement was approved by the American Heart Association Science Advisory and Coordinating Committee.
RESULTS
The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury-not solely stroke-ranging from mild cognitive impairment through fully developed dementia. Dysfunction of the neurovascular unit and mechanisms regulating cerebral blood flow are likely to be important components of the pathophysiological processes underlying VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage of the brain, and VCI. The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage, which may overlap and synergize to heighten the risk of cognitive impairment. In this regard, magnetic resonance imaging and other neuroimaging techniques play an important role in the definition and detection of VCI and provide evidence that subcortical forms of VCI with white matter hyperintensities and small deep infarcts are common. In many cases, risk markers for VCI are the same as traditional risk factors for stroke. These risks may include but are not limited to atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore, these same vascular risk factors may be risk markers for Alzheimer disease. Carotid intimal-medial thickness and arterial stiffness are emerging as markers of arterial aging and may serve as risk markers for VCI. Currently, no specific treatments for VCI have been approved by the US Food and Drug Administration. However, detection and control of the traditional risk factors for stroke and cardiovascular disease may be effective in the prevention of VCI, even in older people.
CONCLUSIONS
Vascular contributions to cognitive impairment and dementia are important. Understanding of VCI has evolved substantially in recent years, based on preclinical, neuropathologic, neuroimaging, physiological, and epidemiological studies. Transdisciplinary, translational, and transactional approaches are recommended to further our understanding of this entity and to better characterize its neuropsychological profile. There is a need for prospective, quantitative, clinical-pathological-neuroimaging studies to improve knowledge of the pathological basis of neuroimaging change and the complex interplay between vascular and Alzheimer disease pathologies in the evolution of clinical VCI and Alzheimer disease. Long-term vascular risk marker interventional studies beginning as early as midlife may be required to prevent or postpone the onset of VCI and Alzheimer disease. Studies of intensive reduction of vascular risk factors in high-risk groups are another important avenue of research.
Topics: Alzheimer Disease; American Heart Association; Cerebral Angiography; Dementia, Vascular; Humans; Male; Mental Disorders; Risk Factors; United States
PubMed: 21778438
DOI: 10.1161/STR.0b013e3182299496 -
International Journal of Molecular... Dec 2019Vascular 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... (Review)
Review
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.
Topics: Animals; Brain Ischemia; Chronic Disease; Cognition Disorders; Dementia, Vascular; Disease Models, Animal; Mice; Primates
PubMed: 31817864
DOI: 10.3390/ijms20246176 -
Theranostics 2022The prevalence of cerebrovascular disease increases with age, placing the elderly at a greater lifetime risk for dementia. Vascular cognitive impairment (VCI)... (Review)
Review
The prevalence of cerebrovascular disease increases with age, placing the elderly at a greater lifetime risk for dementia. Vascular cognitive impairment (VCI) encompasses a spectrum of cognitive deficits from mild cognitive impairment to dementia. VCI and its most severe form, vascular dementia (VaD), is becoming a major public health concern worldwide. As growing efforts are being taken to understand VCI and VaD in animal models and humans, the pathogenesis of the disease is being actively explored. It is postulated that chronic cerebral hypoperfusion (CCH) is a major cause of VCI. CCH activates a molecular and cellular injury cascade that leads to breakdown of the blood brain barrier (BBB) and neurodegeneration. The BBB tightly regulates the movement of substances between the blood and the brain, thereby regulating the microenvironment within the brain parenchyma. Here we illustrate how BBB damage is causal in the pathogenesis of VCI through the increased activation of pathways related to excitotoxicity, oxidative stress, inflammation and matrix metalloproteinases that lead to downstream perivascular damage, leukocyte infiltration and white matter changes in the brain. Thus, CCH-induced BBB damage may initiate and contribute to a vicious cycle, resulting in progressive neuropathological changes of VCI in the brain. This review outlines the molecular and cellular mechanisms that govern BBB breakdown during CCH and highlights the clinical evidence in identifying at-risk VCI patients.
Topics: Aged; Animals; Blood-Brain Barrier; Brain; Brain Ischemia; Cognitive Dysfunction; Dementia, Vascular; Humans
PubMed: 35198062
DOI: 10.7150/thno.68304 -
International Journal of Molecular... Sep 2022Population aging has challenged the treatment of cognitive impairment or dementia. Vascular dementia is the second leading cause of dementia after Alzheimer's disease.... (Review)
Review
Population aging has challenged the treatment of cognitive impairment or dementia. Vascular dementia is the second leading cause of dementia after Alzheimer's disease. Cognitive consequences after ischemic brain injury have been recognized as a preferred target for therapeutic strategies, prompting the search for potential agents. The keyword "vascular dementia" was used to search ClinicalTrials.gov to determine agents represented in phases I, II, III, and IV. The agents were classified on the basis of their mechanisms. Of the 17 randomized controlled trials meeting our inclusion criteria, 9 were completed in the past 10 years, and 8 are ongoing or in the planning stages. We also identified one trial in phase I, nine in phase II, six in phase III, and one in phase IV. Fewer trials of new drugs for improving cognition or ameliorating the behavioral and psychological symptoms of dementia target vascular dementia than Alzheimer's dementia. Drug trials on vascular dementia overlap with drug trials targeting functional outcomes in cerebrovascular disease. International pharmaceutical companies' investment in new drugs targeting VCI and vascular dementia remains insufficient.
Topics: Alzheimer Disease; Cognition Disorders; Cognitive Dysfunction; Dementia, Vascular; Humans; Pharmaceutical Preparations
PubMed: 36232368
DOI: 10.3390/ijms231911067 -
Alzheimer's & Dementia : the Journal of... Mar 2018Progress in understanding and management of vascular cognitive impairment (VCI) has been hampered by lack of consensus on diagnosis, reflecting the use of multiple...
INTRODUCTION
Progress in understanding and management of vascular cognitive impairment (VCI) has been hampered by lack of consensus on diagnosis, reflecting the use of multiple different assessment protocols. A large multinational group of clinicians and researchers participated in a two-phase Vascular Impairment of Cognition Classification Consensus Study (VICCCS) to agree on principles (VICCCS-1) and protocols (VICCCS-2) for diagnosis of VCI. We present VICCCS-2.
METHODS
We used VICCCS-1 principles and published diagnostic guidelines as points of reference for an online Delphi survey aimed at achieving consensus on clinical diagnosis of VCI.
RESULTS
Six survey rounds comprising 65-79 participants agreed guidelines for diagnosis of VICCCS-revised mild and major forms of VCI and endorsed the National Institute of Neurological Disorders-Canadian Stroke Network neuropsychological assessment protocols and recommendations for imaging.
DISCUSSION
The VICCCS-2 suggests standardized use of the National Institute of Neurological Disorders-Canadian Stroke Network recommendations on neuropsychological and imaging assessment for diagnosis of VCI so as to promote research collaboration.
Topics: Brain; Delphi Technique; Dementia, Vascular; Humans
PubMed: 29055812
DOI: 10.1016/j.jalz.2017.09.007 -
Clinical Science (London, England :... Oct 2017Increasing evidence suggests that vascular risk factors contribute to neurodegeneration, cognitive impairment and dementia. While there is considerable overlap between... (Review)
Review
Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia.
Increasing evidence suggests that vascular risk factors contribute to neurodegeneration, cognitive impairment and dementia. While there is considerable overlap between features of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD), it appears that cerebral hypoperfusion is the common underlying pathophysiological mechanism which is a major contributor to cognitive decline and degenerative processes leading to dementia. Sustained cerebral hypoperfusion is suggested to be the cause of white matter attenuation, a key feature common to both AD and dementia associated with cerebral small vessel disease (SVD). White matter changes increase the risk for stroke, dementia and disability. A major gap has been the lack of mechanistic insights into the evolution and progress of VCID. However, this gap is closing with the recent refinement of rodent models which replicate chronic cerebral hypoperfusion. In this review, we discuss the relevance and advantages of these models in elucidating the pathogenesis of VCID and explore the interplay between hypoperfusion and the deposition of amyloid β (Aβ) protein, as it relates to AD. We use examples of our recent investigations to illustrate the utility of the model in preclinical testing of candidate drugs and lifestyle factors. We propose that the use of such models is necessary for tackling the urgently needed translational gap from preclinical models to clinical treatments.
Topics: Amyloid beta-Peptides; Animals; Behavior, Animal; Brain; Cerebrovascular Circulation; Cerebrovascular Disorders; Chronic Disease; Cognition; Cognition Disorders; Dementia, Vascular; Disease Models, Animal; Disease Progression; Humans; Leukoencephalopathies; Plaque, Amyloid; Risk Factors; Species Specificity; Time Factors; Translational Research, Biomedical
PubMed: 28963120
DOI: 10.1042/CS20160727 -
Alzheimer Disease and Associated... 2014Several sets of diagnostic criteria have been published for vascular dementia since the 1960s. The continuing ambiguity in vascular dementia definition warrants a...
BACKGROUND
Several sets of diagnostic criteria have been published for vascular dementia since the 1960s. The continuing ambiguity in vascular dementia definition warrants a critical reexamination.
METHODS
Participants at a special symposium of the International Society for Vascular Behavioral and Cognitive Disorders (VASCOG) in 2009 critiqued the current criteria. They drafted a proposal for a new set of criteria, later reviewed through multiple drafts by the group, including additional experts and the members of the Neurocognitive Disorders Work Group of the fifth revision of Diagnostic and Statistical Manual (DSM-5) Task Force.
RESULTS
Cognitive disorders of vascular etiology are a heterogeneous group of disorders with diverse pathologies and clinical manifestations, discussed broadly under the rubric of vascular cognitive disorders (VCD). The continuum of vascular cognitive impairment is recognized by the categories of Mild Vascular Cognitive Disorder, and Vascular Dementia or Major Vascular Cognitive Disorder. Diagnostic thresholds are defined. Clinical and neuroimaging criteria are proposed for establishing vascular etiology. Subtypes of VCD are described, and the frequent cooccurrence of Alzheimer disease pathology emphasized.
CONCLUSIONS
The proposed criteria for VCD provide a coherent approach to the diagnosis of this diverse group of disorders, with a view to stimulating clinical and pathologic validation studies. These criteria can be harmonized with the DSM-5 criteria such that an international consensus on the criteria for VCD may be achieved.
Topics: Cognition Disorders; Dementia, Vascular; Humans
PubMed: 24632990
DOI: 10.1097/WAD.0000000000000034 -
Continuum (Minneapolis, Minn.) Feb 2019This article provides an overview of vascular cognitive impairment; discusses its epidemiology, subtypes, and associations with other neurodegenerative diseases; and... (Review)
Review
PURPOSE OF REVIEW
This article provides an overview of vascular cognitive impairment; discusses its epidemiology, subtypes, and associations with other neurodegenerative diseases; and reviews the diagnostic evaluation and management of these disorders.
RECENT FINDINGS
Cerebrovascular disease is a common cause of dementia and frequently coexists with neurodegenerative causes. The heterogeneity of mechanisms leading to vascular cognitive impairment makes developing unifying clinical and research criteria difficult. Recognizing the neuroimaging hallmarks of different forms of vascular cognitive impairment can allow for individualized treatment and management. In individuals with mild vascular cognitive impairment, aerobic exercise appears to be a promising treatment but requires further investigation.
SUMMARY
Vascular cognitive impairment can be caused by several mechanisms. While treating vascular risk factors is rational to prevent worsening of cognitive impairment, well-designed studies are needed to demonstrate efficacy.
Topics: Brain; Cerebrovascular Disorders; Cognition Disorders; Cognitive Dysfunction; Dementia, Vascular; Humans; Neurodegenerative Diseases; Neuroimaging
PubMed: 30707191
DOI: 10.1212/CON.0000000000000684 -
Psychogeriatrics : the Official Journal... Dec 2009Recently, the importance of non-pharmacological therapies for dementia has come to the fore. In the present study, we examined the curative effects of aromatherapy in...
OBJECTIVE
Recently, the importance of non-pharmacological therapies for dementia has come to the fore. In the present study, we examined the curative effects of aromatherapy in dementia in 28 elderly people, 17 of whom had Alzheimer's disease (AD).
METHODS
After a control period of 28 days, aromatherapy was performed over the following 28 days, with a wash out period of another 28 days. Aromatherapy consisted of the use of rosemary and lemon essential oils in the morning, and lavender and orange in the evening. To determine the effects of aromatherapy, patients were evaluated using the Japanese version of the Gottfries, Brane, Steen scale (GBSS-J), Functional Assessment Staging of Alzheimer's disease (FAST), a revised version of Hasegawa's Dementia Scale (HDS-R), and the Touch Panel-type Dementia Assessment Scale (TDAS) four times: before the control period, after the control period, after aromatherapy, and after the washout period.
RESULTS
All patients showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy. In particular, patients with AD showed significant improvement in total TDAS scores. Result of routine laboratory tests showed no significant changes, suggesting that there were no side-effects associated with the use of aromatherapy. Results from Zarit's score showed no significant changes, suggesting that caregivers had no effect on the improved patient scores seen in the other tests.
CONCLUSIONS
In conclusion, we found aromatherapy an efficacious non-pharmacological therapy for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aromatherapy; Arousal; Cross-Over Studies; Dementia; Dementia, Vascular; Female; Follow-Up Studies; Geriatric Assessment; Humans; Lavandula; Male; Neuropsychological Tests; Oils, Volatile; Plant Oils; Rosmarinus; Treatment Outcome
PubMed: 20377818
DOI: 10.1111/j.1479-8301.2009.00299.x