Vascular dementia (VaD) is widely recognised as the second most common type of dementia. Consensus and accurate diagnosis of clinically suspected VaD relies on wide-ranging clinical, ...neuropsychological and neuroimaging measures in life but more importantly pathological confirmation. Factors defining subtypes of VaD include the nature and extent of vascular pathologies, degree of involvement of extra and intracranial vessels and the anatomical location of tissue changes as well as time after the initial vascular event. Atherosclerotic and cardioembolic diseases combined appear the most common subtypes of vascular brain injury. In recent years, cerebral small vessel disease (SVD) has gained prominence worldwide as an important substrate of cognitive impairment. SVD is characterised by arteriolosclerosis, lacunar infarcts and cortical and subcortical microinfarcts and diffuse white matter changes, which involve myelin loss and axonal abnormalities. Global brain atrophy and focal degeneration of the cerebrum including medial temporal lobe atrophy are also features of VaD similar to Alzheimer's disease. Hereditary arteriopathies have provided insights into the mechanisms of dementia particularly how arteriolosclerosis, a major contributor of SVD promotes cognitive impairment. Recently developed and validated neuropathology guidelines indicated that the best predictors of vascular cognitive impairment were small or lacunar infarcts, microinfarcts, perivascular space dilation, myelin loss, arteriolosclerosis and leptomeningeal cerebral amyloid angiopathy. While these substrates do not suggest high specificity, VaD is likely defined by key neuronal and dendro-synaptic changes resulting in executive dysfunction and related cognitive deficits. Greater understanding of the molecular pathology is needed to clearly define microvascular disease and vascular substrates of dementia.
This article is part of the Special Issue entitled ‘Cerebral Ischemia’.
•VaD resulting from severe VCI or from delayed impairment after stroke.•Diagnosis relies on adequate clinical information and rigorous pathological examination.•Small vessel disease is a common cause of VaD.•Consensus suggests cortical infarcts, lacunes and microinfarcts are best correlates.•Diffuse WM changes involving periventricular and deep regions are frequent in VaD.
Vascular dementia (VaD) is recognised as a neurocognitive disorder, which is explained by numerous vascular causes in the general absence of other pathologies. The heterogeneity of cerebrovascular ...disease makes it challenging to elucidate the neuropathological substrates and mechanisms of VaD as well as vascular cognitive impairment (VCI). Consensus and accurate diagnosis of VaD relies on wide-ranging clinical, neuropsychometric and neuroimaging measures with subsequent pathological confirmation. Pathological diagnosis of suspected clinical VaD requires adequate postmortem brain sampling and rigorous assessment methods to identify important substrates. Factors that define the subtypes of VaD include the nature and extent of vascular pathologies, degree of involvement of extra and intracranial vessels and the anatomical location of tissue changes. Atherosclerotic and cardioembolic diseases appear the most common substrates of vascular brain injury or infarction. Small vessel disease characterised by arteriolosclerosis and lacunar infarcts also causes cortical and subcortical microinfarcts, which appear to be the most robust substrates of cognitive impairment. Diffuse WM changes with loss of myelin and axonal abnormalities are common to almost all subtypes of VaD. Medial temporal lobe and hippocampal atrophy accompanied by variable hippocampal sclerosis are also features of VaD as they are of Alzheimer’s disease. Recent observations suggest that there is a vascular basis for neuronal atrophy in both the temporal and frontal lobes in VaD that is entirely independent of any Alzheimer pathology. Further knowledge on specific neuronal and dendro-synaptic changes in key regions resulting in executive dysfunction and other cognitive deficits, which define VCI and VaD, needs to be gathered. Hereditary arteriopathies such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy or CADASIL have provided insights into the mechanisms of dementia associated with cerebral small vessel disease. Greater understanding of the neurochemical and molecular investigations is needed to better define microvascular disease and vascular substrates of dementia. The investigation of relevant animal models would be valuable in exploring the pathogenesis as well as prevention of the vascular causes of cognitive impairment.
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.
The global burden of ischaemic strokes is almost 4-fold greater than haemorrhagic strokes. Current evidence suggests that 25–30% of ischaemic stroke survivors develop immediate or delayed vascular ...cognitive impairment (VCI) or vascular dementia (VaD). Dementia after stroke injury may encompass all types of cognitive disorders. States of cognitive dysfunction before the index stroke are described under the umbrella of pre-stroke dementia, which may entail vascular changes as well as insidious neurodegenerative processes. Risk factors for cognitive impairment and dementia after stroke are multifactorial including older age, family history, genetic variants, low educational status, vascular comorbidities, prior transient ischaemic attack or recurrent stroke and depressive illness. Neuroimaging determinants of dementia after stroke comprise silent brain infarcts, white matter changes, lacunar infarcts and medial temporal lobe atrophy. Until recently, the neuropathology of dementia after stroke was poorly defined. Most of post-stroke dementia is consistent with VaD involving multiple substrates. Microinfarction, microvascular changes related to blood–brain barrier damage, focal neuronal atrophy and low burden of co-existing neurodegenerative pathology appear key substrates of dementia after stroke injury. The elucidation of mechanisms of dementia after stroke injury will enable establishment of effective strategy for symptomatic relief and prevention. Controlling vascular disease risk factors is essential to reduce the burden of cognitive dysfunction after stroke. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.
•Ischaemic injury is common among long-term stroke survivors•About 25% stroke survivors develop dementia with a much greater proportion developing cognitive impairment•Risk factors of dementia after stroke include older age, vascular comorbidities, prior stroke and pre-stroke impairment•Current imaging and pathological studies suggest 70% of dementia after stroke is vascular dementia•Severe white matter changes and medial temporal lobe atrophy as sequelae after ischaemic injury are substrates of dementia•Controlling vascular risk factors and prevention strategies related to lifestyle factors would reduce dementia after stroke
The integrity of the vascular system is essential for the efficient functioning of the brain. Aging‐related structural and functional disturbances in the macro‐ or microcirculation of the brain make ...it vulnerable to cognitive dysfunction, leading to brain degeneration and dementing illness. Several faltering controls, including impairment in autoregulation, neurovascular coupling, blood‐brain barrier leakage, decreased cerebrospinal fluid, and reduced vascular tone, appear to be responsible for varying degrees of neurodegeneration in old age. There is ample evidence to indicate vascular risk factors are also linked to neurodegenerative processes preceding cognitive decline and dementia. The strongest risk factor for brain degeneration, whether it results from vascular or neurodegenerative mechanisms or both, is age. However, several modifiable risks such as cardiovascular disease, hypertension, dyslipidemia, diabetes, and obesity enhance the rate of cognitive decline and increase the risk of Alzheimer's disease in particular. The ultimate accumulation of brain pathological lesions may be modified by genetic influences, such as the apolipoprotein E ε4 allele and the environment. Lifestyle measures that maintain or improve cardiovascular health, including consumption of healthy diets, moderate use of alcohol, and implementation of regular physical exercise are important factors for brain protection.
Advances in neuroimaging have enabled greater understanding of the progression of cerebral degenerative processes associated with ageing‐related dementias. Leukoaraiosis or rarefied white matter (WM) ...originally described on computed tomography is one of the most prominent changes which occurs in older age. White matter hyperintensities (WMH) evident on magnetic resonance imaging have become commonplace to describe WM changes in relation to cognitive dysfunction, types of stroke injury, cerebral small vessel disease and neurodegenerative disorders including Alzheimer's disease. Substrates of WM degeneration collectively include myelin loss, axonal abnormalities, arteriolosclerosis and parenchymal changes resulting from lacunar infarcts, microinfarcts, microbleeds and perivascular spacing. WM cells incorporating astrocytes, oligodendrocytes, pericytes and microglia are recognized as key cellular components of the gliovascular unit. They respond to ongoing pathological processes in different ways leading to disruption of the gliovascular unit. The most robust alterations involve oligodendrocyte loss and astrocytic clasmatodendrosis with displacement of the water channel protein, aquaporin 4. These modifications likely precede arteriolosclerosis and capillary degeneration and involve tissue oedema, breach of the blood–brain barrier and induction of a chronic hypoxic state in the deep WM. Several pathophysiological mechanisms are proposed to explain how WM changes commencing with haemodynamic changes within the vascular system impact on cognitive dysfunction. Animal models simulating cerebral hypoperfusion in man have paved the way for several translational opportunities. Various compounds with variable efficacies have been tested to reduce oxidative stress, inflammation and blood–brain barrier damage in the WM. Our review demonstrates that WM degeneration encompasses multiple substrates and therefore more than one pharmacological approach is necessary to preserve axonal function and prevent cognitive impairment.
This article is part of the Special Issue “Vascular Dementia”.
In this review, we discuss disintegration of the cellular components of the gliovascular unit in the white matter. This has consequences on blood–brain barrier integrity and is a strong correlate of white matter damage associated with cognitive impairment. Animal models of cerebral hypoperfusion replicate several features of white matter changes in man. They have been valuable in identifying various agents which target oxidative stress, inflammation and BBB damage.
This article is part of the Special Issue “Vascular Dementia”.
Abstract In recent years there has been increased interest in whether vascular disease contributes to Alzheimer's disease (AD). This review considers how modifiable risk factors such as hypertension, ...atherosclerosis, diabetes, dyslipidaemia and adiposity may impact on vascular structure and function to promote neurodegenerative processes and instigate AD. The presence of vascular pathology involving arterial stiffness, arteriolosclerosis, endothelial degeneration and blood–brain barrier dysfunction leads to chronic cerebral hypoperfusion. Pathological changes in human brain and animal studies suggest cerebral hypoperfusion which in turn induces several features of AD pathology including selective brain atrophy, white matter changes and accumulation of abnormal proteins such as amyloid β. Cerebral pathological changes may be further modified by genetic factors such as the apoliopoprotein E ε4 allele. Although tau hyperphosphorylation and tangle formation still needs robust explanation further support for the notion that vascular pathology influences AD changes is provided by the evidence that interventions which improve vascular function attenuate AD pathology.
Lewy Body Disorders (LBDs) lie within the spectrum of age-related neurodegenerative diseases now frequently categorized as the synucleinopathies. LBDs are considered to be among the second most ...common form of neurodegenerative dementias after Alzheimer's disease. They are progressive conditions with variable clinical symptoms embodied within specific cognitive and behavioral disorders. There are currently no effective treatments for LBDs. LBDs are histopathologically characterized by the presence of abnormal neuronal inclusions commonly known as Lewy Bodies (LBs) and extracellular Lewy Neurites (LNs). The inclusions predominantly comprise aggregates of alpha-synuclein (aSyn). It has been proposed that post-translational modifications (PTMs) such as aSyn phosphorylation, ubiquitination SUMOylation, Nitration, o-GlcNacylation, and Truncation play important roles in the formation of toxic forms of the protein, which consequently facilitates the formation of these inclusions. This review focuses on the role of different PTMs in aSyn in the pathogenesis of LBDs. We highlight how these PTMs interact with aSyn to promote misfolding and aggregation and interplay with cell membranes leading to the potential functional and pathogenic consequences detected so far, and their involvement in the development of LBDs.
Age is the strongest risk factor for brain degeneration whether it results from vascular or neurodegenerative mechanisms or both. To evaluate the current views on the impact of vascular disease on ...the most common causes of dementia, most relevant articles to the selected subject headings were reviewed until November 2011 from the popularly used databases including Pubmed, Cochrane Database and Biological Abstracts. Within the past decade, there has been four-fold increased interest in the vascular basis of neurodegeneration and dementia. Vascular ageing involving arterial stiffness, endothelial changes and blood-brain barrier dysfunction affects neuronal survival by impairing several intracellular protective mechanisms leading to chronic hypoperfusion. Modifiable risk factors such as hypertension, diabetes, dyslipidaemia and adiposity linked to Alzheimer's disease and vascular dementia promote the degeneration and reduce the regenerative capacity of the vascular system. These in tandem with accumulation of abnormal proteins such as amyloid β likely disrupt cerebral autoregulation, neurovascular coupling and perfusion of the deeper structures to variable degrees to produce white matter changes and selective brain atrophy. Brain pathological changes may be further modified by genetic factors such as the apoliopoprotein E ε4 allele. Lifestyle measures that maintain or improve vascular health including consumption of healthy diets, moderate use of alcohol and implementing regular physical exercise in general appear effective for reducing dementia risk. Interventions that improve vascular function are important to sustain cognitive status even during ageing whereas preventative measures that reduce risk of vascular disease are predicted to lessen the burden of dementia in the long-term.
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