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| REVIEW ARTICLE |
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| Year : 2017 | Volume
: 1
| Issue : 1 | Page : 22-35 |
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Updates in vascular dementia
Nora Olazabal Eizaguirre1, Gerardo Priego Rementeria2, Miguel Ángel González-Torres1, Moises Gaviria3
1 Department of Psychiatry, Hospital Universitario Basurto, Bilbao; Department of Neuroscience, University of the Basque Country, Leioa, Bizkaia, Spain
2 Department of Psychiatry, Hospital Universitario Basurto, Bilbao, Spain
3 Department of Psychiatry, The University of Illinois at Chicago, Chicago, Illinois, USA
| Date of Web Publication | 24-May-2017 |
Correspondence Address:
Nora Olazabal Eizaguirre
Pabellón Eskuza, Hospital Basurto, Avenida Montevideo 18, 48013 Bilbao, Bizkaia
Spain
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/hm.hm_4_16
It has been more than a hundred years since Alzheimer and Binswanger's first description of vascular dementia (VaD). Ever since then, histopathology research and neuroimaging techniques have allowed the development of new pathogenic, etiologic, and treatment hypotheses. The “vascular cognitive impairment (VCI)” concept has also been developed, and it includes all grades of cognitive dysfunction of a vascular origin. Early detection of dementia as well as its primary prevention is the main goals for clinicians. For this reason, new scales, new diagnostic criteria, and preventive treatments have been proposed. The association between stroke and VaD is already known, but a comprehensive review of this relationship reveals a bidirectional causality. Depression has been hypothesized as a risk factor for later dementia development. Late-life depression is the most associated condition; however, studies have found it works as a prodromal state symptom. Deep knowledge in vascular risk factors that are involved in vascular origin cognitive decline is the most important prevention tool. Hypertension, Type II diabetes, cholesterol, and inflammation markers have demonstrated to increase the risk of VaD. Evidence supporting treatments for primary and secondary prevention of VaD and VCI are presented. Keywords: Prevention, risk factor, vascular cognitive impairment, vascular dementia
How to cite this article:
Eizaguirre NO, Rementeria GP, González-Torres M&, Gaviria M. Updates in vascular dementia. Heart Mind 2017;1:22-35 |
| Introduction | |  |
Historical perspective
The first clinical description of vascular dementia (VaD) comes from Thomas Willis whose careful attention to the cerebral vasculature led to his description of the circle of Willis in 1684. Under the heading “A palsie often succeeds stupidity, or becoming foolish,” he describes: “I have observed in many that when the brain being first indisposed, they have been distempered with a dullness of mind, and forgetfulness, and afterward with a stupidity and foolishness, after that, have fallen into a palsie, which I often did predict.”[1]
Otto Binswanger and Alois Alzheimer, in their clinicopathological correlations, separated dementia paralytica (neurosyphilis), a common disease at that time, from VaD and proposed the term “atherosclerotic brain degeneration” for the disease.[2] Alzheimer wrote “New studies on senile dementia and brain diseases caused by atheromatous vascular diseases” in 1898, describing widespread atheromatosis of the vascular system, substantial brain weight loss, and dilated ventricles; relating these disturbances with VaD. Some years later, he described presenile dementia (Alzheimer's disease [AD]) after finding demented people with little vascular disease and a presence of neuritic plaques and neurofibrillary changes in their brains.[3],[4]
In 1910, Emil Kraepelin divided the dementias into senile and presenile in his classification and including the term “arteriosclerotic dementia” among the senile dementias in his book “Psychiatrie.” The main conclusion was that cerebral arteriosclerosis or arteriosclerotic insanity was the most frequent form of senile dementia. Nowadays, AD is considered the most frequent cause of dementia.[5]
VaD has been present in all versions of the Diagnostic and Statistical Manuals (DSMs): In DSM I (1951), it was called “chronic brain syndrome associated with senile brain disease;” in DSM II (1968), psychosis with cerebral arteriosclerosis; in DSM III (1980), it was classified as “multiinfarct dementia (MID).” In DSM IV, it was called “VaD.” Finally, in DSM V, the diagnosis is called “major neurocognitive disorder” specifying that it is due to vascular disease.[6]
In 1970, Tomlinson examined the brains of demented and nondemented patients and concluded that arteriosclerotic dementia had been over diagnosed in the past and defined new pathologic features in the examined brains: cortical atrophy, ventricular dilatation, senile plaque formation, Alzheimer's neurofibrillary changes, etc.[7]
V. Hachinski, in 1974, changed previous theories about the etiology of senile dementia and affirmed that it was small or large cerebral infarctions, and not cerebral atherosclerosis, the etiological cause of the mental deterioration. He proposed the term “MID” for this concept. He also noted that these cumulative strokes were sometimes symptomatic, but they could be silent and occur progressively.[8] At that time, computed tomography (CT) and magnetic resonance (MR) were introduced and allowed the detection of noninfarction vascular changes such as white matter lesions (WMLs), small subcortical lacunae, and microhemorrhages.[9]
Concept and terminology
A deepening knowledge and the development of new concepts in the field of dementia have led to the creation of different terms beyond “VaD” or “atherosclerotic dementia” used in older texts.
Nowadays, the most commonly used term for any cognitive disorder of a vascular origin is vascular cognitive impairment (VCI).[10] VCI syndrome is a heterogeneous construct that includes VaD, mixed-origin dementia (AD and VaD), and “VCI, not dementia” (VCInD).[11] VCInD is the term used for patients that, while suffering from cognitive deficits associated with vascular disease, do not meet criteria for the diagnosis of dementia. The VCI diagnosis also includes classical cerebrovascular disorders resulting in VaD: poststroke dementia, MID, and leukoaraiosis.[9],[12] Some authors have called this “the VaD spectrum,” and its main aim is to detect patients with a minimal cognitive impairment to prevent the development of dementia.[13]
Mild cognitive impairment (MCI) is a cognitive decline greater than expected for a patient's age and education level, which does not interfere notably with their daily life activities.[14] Even the concept's definition does not imply a specific outcome or an etiology; this term has been applied the most to the risk state of progression to AD. It was later demonstrated that AD is characterized by episodic and semantic memory loss, whereas VCI is associated with other signs of cognitive impairment such as executive dysfunction (an impairment in planning and execution of activities) also called nonamnesic MCI.[15] Either way, the nonamnesic subtype of MCI and vascular origin MCI (VaMCI) can be included in the VCI concept.[16]
Mixed dementias can include cerebrovascular disease with concomitant AD, Parkinson's disease, frontotemporal dementia or Lewy's Bodies disease. Vascular impairment can also contribute to cognitive decline in all kinds of neurodegenerative dementias.[15] VaD can be the primary cause of dementia or an important contributing factor to the course of other types of dementias such as AD.[17]
| Methods | | |
The main aim of this revision is to provide a concise and useful update on the topic of VaD, including its etiology, macroscopic and microscopic features as well as an overview from a diagnostic and clinical point of view.
A comprehensive search was performed on the Medline, Ovid, EMBASE, and PsycINFO databases using the terms “VaD” and “VCI.” From a total of 11,657 papers, those focusing on AD were excluded from the study, leaving 6964. The authors read the abstracts and looked for papers focusing on the “epidemiology,” “risk factor,” “pathogenesis,” “neuroradiology,” “neuropsychology,” and “treatment” topics. Original research, specific review articles, and consensus statements were analyzed, and the most relevant ones were used to extract updates.
| Epidemiology | | |
VaD is the second cause of dementia after AD. Population studies indicate that vascular risk factors (VRFs) increase the risk for suffering all types of dementia. Moreover, cerebrovascular lesions are present in most of the patients diagnosed with AD, and therefore mixed dementia (AD in patients suffering from cerebrovascular disease) could be considered the most frequent etiology leading to cognitive impairment.[18],[19]
The Rotterdam study revealed a 6.3% prevalence of dementia in the general population, which increases exponentially from age 55–59 (0%–4%) to age 95 and over (43.2%). AD represents three-quarters of all dementia cases, while VaD accounts for 16%.[20] European samples reveal a dementia prevalence between 5.9% and 9.4% for patients older than 65.[21] Neurological Diseases in The Elderly Research Group found that 4.4% of the population was suffering from AD and 1.6% from VaD.[22] The prevalences of both AD and VaD increase with age. The prevalence of AD doubles every 4.3 years while that of VaD does so every 5.3 years.[16] Postmortem neuropathology studies are consistent with these results.[23] The prevalence of VaD has been established as ranging from 1.2% to 4.2% in people over 65 years of age. Survival of patients suffering from VaD is shorter than that of AD patients because of the cerebrovascular and cardio VRFs as well as concomitant diseases.[24]
Meta-analyses in this area reveal a big difference between studies regarding incidence and prevalence of VaD. The prevalence in dementia varies depending on the classification systems used (ICD, DSM IV, DSM III, etc.,)[25],[26] and on the diagnostic threshold selected in the spectrum of cognitive disorders. No homogeneous diagnostic criteria are used, and samples are of different education levels, incomes, countries, and ethnic groups.[19],[27] The general consensus among researchers is that the prevalence of VaD has been underestimated using specific, but not sensitive, clinical criteria.[19],[23],[28]
The incidence of all-type dementia doubles every 5 years from ages 65–90, growing from 7/1000 at the age of 65 to 118/1000 in ages 85–89, according to the Framingham study.[29] The 90+ study reveals the same rate of increasing incidence for patients of over 90 years of age.[30],[31]
In studies comparing the AD and VaD's incidence rates, those for AD are higher (1.59/1000 person-years) than for VaD (0.99/1000 py).[32] Other samples, such as the Canadian Study of Health and Aging reveal a VaD incidence rate of 3.79/1000 person-years by including deceased patients.[24]
No consistent differences among races were found regarding the incidence and prevalence of dementia in population-based studies for any type of dementia,[33],[34],[35] or for VCI. Stroke rates are higher in Asian countries, so VCI rates may also be higher.[35],[36]
| Etiology | | |
Risk factors
Several studies have revealed that VRFs are common risk factors for AD, VaD, and related diagnoses (including VCI, MCI, and age-related cognitive decline).[37] VRFs were thought to be at the origin of cerebral ischemia, and thus also at that of VaD, but studies have found that cerebral ischemia and amyloid deposits interact in a synergistic pathogenic mechanism so that VCI and AD occur together in mixed-origin dementias as well as in strokes. In the same way, VCI may unmask previously subclinical AD and other neurodegenerative processes. This relationship between VRFs and AD can be due to increased amyloid deposition in vascular injuries.[38],[39]
VRFs are interesting in the efforts for dementia prevention as they are the only known modifiable risk factors.[40] Type II diabetes, hypertension, cholesterol, and inflammation markers have demonstrated to increase the risk for dementia, AD, MCI, and cognitive decline.[24],[37],[41]
Hypertension is the most studied risk factor [38] and has been linked to both an increased incidence (odds ratio [OR]: 1.59; confidence interval [CI]: 1.29–1.95) and increased prevalence of VaD (OR: 4.84; CI: 3.52–6.67). Both midlife and later-life hypertension have shown to increase the risk for VaD although the relationship between long-standing hypertension during the midlife and VaD is the strongest.[42],[43] Late-life hypotension has also been identified as a risk factor for dementia development, showing a U-shaped relationship with systolic arterial pressure.[44]
Hypertension affects blood vessels' elasticity over the long-term, leading to atherosclerotic changes that diminishes the capacity of the vessels to respond to changes in irrigation requirements in the brain.[45],[46] Preventive treatment of hypertension with antihypertensive agents in patients older than 60 has revealed a risk reduction for developing dementia of 55%.[47] The benefits of antihypertensive treatment in patients already exhibiting cognitive impairment remain unclear.
Neuropathologic studies have revealed that diabetes doubles the risk for developing dementia, AD and VaD as well as increases mortality in elderly patients.[48] Diabetes mellitus during the midlife has been associated with an increased risk for developing dementia three decades later (OR: 2.83; CI: 1.40–5.71).[49] Inadequate glycemic control is associated with cognitive decline affecting psychomotor speed and efficiency. Hemoglobin Ac1 levels in nondiabetic patients have also been linked to cognitive impairment.[50],[51]
Dyslipidemia is associated with atherosclerotic vascular disease and dementia. Increased low-density lipoprotein levels and decreased high-density lipoprotein levels have been linked with higher rates of atherosclerotic vascular disease and dementia.[52] Midlife high total cholesterol levels are associated with an increased risk of all types of dementia.[53] Adherence to a mediterranean diet is associated with a lower incidence of cognitive impairment in a large population-based study (REGARDS), especially in nondiabetic individuals.[54] Some studies have hypothesized the benefits of taking preventive statins for hyperlipidemic and nonhyperlipidemic patients to diminish the risk for developing dementia.[55] Recent placebo-controlled prospective studies conclude that the effect of statins in the incidence of dementia is negligible.[56]
Blood inflammatory markers, serum C-reactive protein (CRP), serum interleukin 6, and plasma alpha-1-antichymotrypsin have been linked to the risk of developing dementia. Hyperhomocysteinemia is associated with AD, but there is no evidence to link it to VaD.[34],[57],[58]
Demographic factors such as race and sex have not revealed clear results; it was commonly thought that men would show a higher incidence of VaD, and that people of black race would exhibit higher rates of VaD, but the evidence for these associations remains unclear.[33],[59]
Genetic factors include nonmodifiable risk factors, such as Apolipoprotein E4 (APOE4). APOE4 has been linked to increased cardio VRFs and is also strongly associated with AD.[60],[61]
Low educational level and sedentary habits have been found to be associated to higher rates of VaD. Heavy alcohol consumption and cigarette smoking have been linked to cognitive decline.[62],[63],[64],[65] Obesity during the midlife is linked to VaD, and a higher waist-hip ratio increases the risk as well. However, in later life, obesity appears to be a protective factor for cognitive impairment and presents a U-shaped relationship.[66]
Patients suffering from moderate and severe chronic kidney disease have an increased the prevalence of cognitive impairment, even for those patients that are under adequate dialysis treatments.[67],[68] Coronary artery disease and atrial fibrillation are independent risk factors for VaD as well as for all other types of dementia.[69],[70] Peripheral arterial disease as measured by the Ankle–Brachial Index is associated with an increased risk of VaD.[71] Cardiac dysfunction and cerebral hypoperfusion as measured by the Cardiac Index have shown a relationship with accelerated brain aging in the Framingham heart study.[72]
Risk factors for VCI and VaD are similar to those for stroke and have been classified into demographic, atherosclerotic, genetic, and stroke-related factors as shown in [Table 1].[34],[37] Evidence for VCI prevention as well as treatment options are summarized in [Table 2]. | Table 2: Differential features of Alzheimer disease and vascular dementia
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Poststroke dementia
Poststroke dementia occurs in 20%–30% of patients who have had a stroke,[73],[74],[75],[76] 51% of them being diagnosed with VaD or mixed VaD-AD (37%), showing no gender differences.[77],[78] Cognitive deficits are observed in 10%–82% of these patients, depending on the evaluation method and diagnostic criteria used.[79],[80] VCI is seen in 45.1% of the patients who suffer from a stroke, and it develops more frequently in patients with low education levels, those who suffer from strategic strokes, those that exhibit greater white matter changes, and in those whose strokes are moderate to severe.[81],[82] The risk is higher for patients suffering from concurrent illnesses that determine a poststroke cerebral hypoxia or ischemia, such as cardiac arrhythmias or seizures.[77],[83],[84] Some other risk factors for the subsequent development of dementia are a prior stroke (OR 3.1), a left carotid vascular territory location (OR: 12.5), an age higher than 65 years (OR: 6.6), a low education level (OR: 3.3), and a previous low functional state (OR: 4.5).[85] Recurrent strokes seem to be the strongest risk factor for long-term cognitive decline.[86] Life expectancy is affected in poststroke dementia mainly due to the increased risk of cardiovascular mortality and stroke recurrence.[87]
Having a previous cognitive impairment diagnosis is associated to a 2-fold increase in the risk of suffering a stroke. This observation lends credibility to the hypothesis that VCI is a manifestation of vascular brain injury.[88],[89] Nevertheless, having a previous diagnosis of AD is not considered a risk factor for subsequent stroke.[90]
Subclinical or silent brain infarctions seen in MR images (MRIs) are also considered a risk factor for later cognitive impairment;[91] these patients exhibit a doubled risk of dementia in the subsequent 5 years of follow-up.[92]
Depression
Depression and dementia are common pathologies among elderly individuals. The previous histories of depressive symptoms and higher rates of dementia have been observed for both VaD and AD.[93],[94],[95] The complex relationship between depression and dementia has been studied through different hypotheses: depression as risk factor, depression as a prodromal stage of dementia, or considering them as two different and concomitant pathologies.[96]
The underlying mechanisms that have been hypothesized to be responsible for such a high concurrency are cerebrovascular pathology, such as WMLs, monoamine deficits, inflammatory activity, and corticosteroid-related disturbances. These studies have not revealed consistent findings that would allow to elucidate with certainty the common neurobiological mechanisms.[97],[98] Depression is common in patients after suffering a stroke, and longitudinal studies have found prevalence rates of 31.7% that remain high even 10 years after the event. The rate of depression is higher among patients with prestroke dementia.[99]
Late-life depression (LLD) and early life depression (ELD) have been studied in longitudinal studies as risk factors for developing later dementia. A history of either LLD or ELD has been found to be associated to a 3-fold risk of VaD.[100] ELD by itself is not clearly linked with later dementia development, with contradictory results in different studies. On the other hand, LLD could be understood as a prodromal phase, or an early manifestation of dementia, due to the strong temporal association, especially with VaD.[101],[102],[103] The evidence of a link between depression and the incidence of MCI is contradictory;[94],[104],[105] however, there is evidence for a link between depression and prevalent MCI.[106] Some studies have demonstrated higher dementia rates in patients suffering from more severe and frequent depressive episodes.[105],[107],[108] LLD and VaD have both demonstrated a higher prevalence of WMLs, suggesting a common neuropathologic mechanism,[109] with WML being responsible for the persistence of cognitive deficits following a depressive episode.[110],[111],[112] This common neurovascular etiology [113] is supported by the studies that found a higher risk of stroke in elderly patients suffering from depression.[114]
Cognitive performance is affected in both dementia and depression, but a temporal relationship between incident depression and dementia has not yet been demonstrated.[115],[116] Patients suffering from LLD exhibit a slowed processing speed and disturbances in executive function.[117] Depression in patients suffering from dementia has demonstrated to accelerate cognitive decline.[118]
Antidepressant treatment has not proven efficacious in people suffering from depression with a the previous diagnosis of dementia.[119] Most studies have not found antidepressant agents to be more effective than placebo for this condition.[120]
Neuropathology and neuroradiology
The diagnosis of VaD is mainly clinical as radiologic criteria alone are not enough for the diagnosis of VaD or VCI. Some diagnostic criteria such as NINDS-AIREN include neuroradiological findings as a key element for the diagnosis of VaD. Moreover, clinical and imaging findings do not need to coincide in their anatomical locations.[34],[121],[122]
MRI is more sensitive than CT in the detection of cerebrovascular disease. Newer technological advances such as 7 Teslas MRI have shown an even greater sensitivity and represent a hopeful demonstration for the future as tools that may allow for the early detection of small vessel lesions in microinfarctions and microhemorrhages.[123]
Small vessel disease
The term leukoaraiosis or WMLs are a descriptive term introduced in 1987 by Hachinski et al. to indicate the periventricular white matter MR hyperintensities frequently found in elderly people. It is a nonspecific radiological finding that may be present in both normal and demented populations. WMLs are associated with cerebrovascular disease and nonvascular pathology such as demyelinating disorders, infections, and neoplasic processes. Cerebral hypoperfusion and ischemia are purported to be responsible for WML in patients with VRFs or suspected of suffering from VaD.[124]
WMLs are linked to old age and hypertension and are more frequent in patients suffering from stroke, for both symptomatic and nonsymptomatic ischemic strokes.[125],[126] In research like the Framingham study, a high inheritability in the accumulation of WML has been found.[127]
The relationship between WML in neuroimaging (TC and MR) and dementia is controversial. Patients exhibiting WMLs have alterations in some cognitive domains such as executive function and processing speed but may not fulfill the dementia diagnosis criteria.[128] It has been suggested that a certain volume of WML correlates with cognitive impairment; however, further studies are needed to determine the threshold.[129]
WML location is an important factor that influences the severity of cognitive impairment; periventricular lesions have demonstrated greater association with cognitive decline over subcortical WML.[130] This phenomenon has been explained by WML close to the cerebral ventricles damaging periventricular long association fibers, resulting in cholinergic denervation in the cerebral cortex.[131] WMLs appear as hypodense (dark) on CT, hypointense (dark) on T1-weighted MRI, and hyperintense (bright) on T2-weighted MRI sequences.[132] The Fazekas scale was developed to unify criteria and measure white matter changes and basal ganglia lesions in both CT and MRI. Interrater reliability for CT is moderate for CT (Ҡ = 0.48) and good for MRI (0.67) with different sensitivities for specific cerebral regions [Figure 1].[133],[134]
Lacunes are subcortical small artery infarctions measuring up to 10 mm and affect the caudate, thalamus, internal capsule, cerebellum, and brainstem.[135],[136] Several studies suggest that SVD in the form of silent lacunes correlates to poorer executive functioning.[137],[138] This is consistent with the hypothesis that small vessel disease (SVD) disrupts frontal-subcortical circuits.[139] Lacunes visible in MRI may also have important implications for the successful execution of activities fundamental to the maintenance of an independent lifestyle, due to their association with executive dysfunction.[140] Large numbers of lacunes located in gray matter are referred to as “état lacunaire” or “status lacunaris;” and it is called “éstat criblé” or “status cribosus” if the location is in white matter.[141] MRIs of lacunes are hyperintense on T2 and fluid-attenuated inversion recovery (FLAIR).[122]
Silent cerebral infarctions are strokes which occur without focal neurological or classical signs or symptoms. They present with subtle cognitive function disturbances that can go unnoticed.[122] The presence of silent infarctions doubles the risk of dementia.[92] These silent infarctions are common in the nondemented elderly population, with 8%–28% of the population exhibiting them in neuroimaging.[142] Infarction anatomic location and disrupted white matter connections are the key matters that determine the functional impact of silent infarcts.[122]
Large vessel disease
Single or multiple infarctions (MID) are caused by the occlusion of large and medium-sized arteries such as the internal carotid artery, mild cerebral artery, or proximal perforating arteries.[121] VaD may develop depending on the location and the volume of the affected brain parenchyma.[34] CT angiography and MR angiography are very sensitive in revealing the size and the location for both symptomatic and asymptomatic strokes.[128] MR reveals hyperintensity in T1 and FLAIR images.[122] Thalamic infarctions must be especially taken into account because of the peculiar form of VaD that develops from them, leading to slowness, apathy and impairments in attention, motivation, and initiative.[143]
Watershed infarctions occur in the distal areas of major cerebral arteries, in the border regions between two or three main cerebral arterial territories.[144] The etiology is still controversial, but systemic hypotension, cardiac arrest, internal carotid artery occlusion, and emboli are known to cause them.[145],[146] Cortical watershed infarctions, located in the lateral margins of the lateral ventricle, are hyperintense in MR. Internal watershed infarctions are also hyperintense, running parallel to the lateral ventricles.[122]
Global cerebral hypoperfusion is often found in patients with cardiac dysfunction and large artery disease; cardiac arrest, profound hypotension, and large vessel atherosclerosis are good examples. Vessels in the circle of Willis and carotid arteries degenerate in the presence of VRFs, such as hypertension or dyslipidemia, and correlate with high dementia rates.[147],[148] Atherosclerosis can lead to white matter hypoperfusion, WMLs, and diffuse white matter changes. Chronic hypoperfusion can also lead to brain atrophy and hippocampal neuronal loss.[15],[121]
Pathogenesis
The role of cerebrovascular disease has further implications than just VaD. It may regulate the clinical expression of dementia caused by other underlying factors, including AD.[149],[150] Pathophysiological studies have revealed that neurons, glia, and vascular cells are synergistically responsible for the alterations in cerebral blood vessels and neuronal dysfunction that leads to cognitive impairment.[149],[151]
The main responsible mechanisms of brain tissue damage are described below:
- Deep white matter is vulnerable to vascular insufficiency due to its location at the distal border between vascular territories.[152] Reduced blood flow has been linked with leukoaraiosis areas and reduced vascular reactivity.[153],[154] White matter is susceptible to damage during blood pressure fluctuations.[155] This impaired cerebrovascular self-regulation is thought to precede WMLs and to be responsible for them.[156] A lowered cerebral blood flow can be observed before the onset of the clinical features of dementia.[157] An impairment of nitric oxide-dependent vasodilatation and a greater rigidity in large vessels have been suggested as the mechanisms responsible for reduced blood flow and vascular reactivity in large vessels [108],[158]
- Blood–brain barrier (BBB) permeability is altered due to endothelial dysfunction, especially in WML areas.[159],[160] This BBB dysfunction could even precede white matter injury.[161] Endothelial cells are damaged following ischemia and hypoxia. Oxidative stress and vascular inflammation can alter BBB permeability [149]
- Oxidative stress, free radicals, and inflammation are observed in the damaged white matter in patients suffering from VCI.[162] VRFs are associated to vascular oxidative stress and inflammation, and functional hyperemia, as well as endothelium-dependent responses, are attenuated in these patients.[163] Free radicals affect angiotensin II leading to the impairment of neurovascular coupling, which affects the neuronal activity-induced cerebral blood flow functional increase [164]
- BBB alterations lead to the extravasation of plasma proteins (fibrinogen, inmunoglobulins, and complement), which can activate inflammation and free radical production.[149] Neurons and glia have a prosurvival and protective effect on endothelial cells. Free radicals and inflammation reduce brain-derived neurotrophic factor levels, which leads to a negative trophic effect on vascular cells, leading to endothelial cell atrophy, and microvascular rarefaction.[152] Capillary density is reduced in damaged tissue; however, it is also reduced in apparently normal white matter in patients with VCI. Vessels that lack an endothelium are also observed.[149] These processes are thought to be related to brain volume loss [165]
- Axon myelination allows for faster neural conduction and reduced energy expenditure in white matter tracts. Pro-inflammatory environments lead to demyelination with two main consequences: the slowing of axonal potential transmission, and axonal loss.[149],[166] Connections between deep white matter, thalamus, and the forebrain cholinergic neuronal system can be damaged, with executive dysfunction being the major consequence.[167],[168]
The kind of vascular lesions that lead to VCI are diverse. Cognitive decline is commonly associated with widespread small ischemic vascular lesions involving subcortical brain areas (the basal ganglia and hemispherical white matter).[169] Leukoaraiosis is the term used to describe these confluent WMLs. The main mechanisms involved are as follows: (a) atherosclerotic plaques affecting small cerebral vessels, (b) lipohyalinosis affecting the vascular walls, (c) the stiffening and microvascular distortion (arteriolosclerosis), and (d) fibrinoid necrosis.[170]
Microinfarctions and microhemorrhages are usually associated with leukoaraiosis, lacunar infarctions, large infarctions, and hemorrhage.[135],[171] Furthermore, stenosis of the internal carotid arteries is associated with chronic ischemia and cognitive impairment.[172] Systemic factors affecting global cerebral perfusion such as cardiac arrest, cardiac failure, arrhythmias, or hypotension have also been related to transient or permanent cognitive impaired function.[173],[174]
Cognitive impairment in VaD is heterogeneous, potentially affecting almost all of the cognitive domains.[175] Two different clinical patterns have been recognized depending on the predominant pathology and clinical symptoms: the cortical and subcortical VaD subtypes.[176]
In the cortical VaD, clinical features are specific to affected anatomic areas as seen in strokes. Pathology involving the frontal lobe leads to executive dysfunction, apathy, and abulia. On the other hand, dominant temporal lesions induce aphasia, apraxia, and agnosia whereas nondominant lesions lead to anosognosia, confusion, and visuospatial difficulties.[177] Anterograde amnesia is seen when the medial temporal lobe is affected. The onset of these clinical features is not typically abrupt but insidious and progressive.[121] Subcortical dementia has been largely studied in terms of its pathophysiology and clinical aspects, and it has been associated to small vessel disease in subcortical areas.[176] Pathophysiological studies have identified two further different types of subcortical vascular dementia: Binswanger disease with extensive WML in subcortical white matter regions; and the multiple lacunar infarction subtype.[178],[179] Both subtypes affect the deep cerebral nuclei and white matter pathways, disrupting connections with remote cortical areas such as the frontal lobe.[130] Gait disturbances, urinary symptoms, apathy, abulia, depression, and psychomotor retardation are the typical clinical features in patients suffering from subcortical vascular dementia.[177]
Preclinical biomarkers
VaD biomarkers can be found in both serum and cerebrospinal fluid (CSF) of patients. The purpose of the study of these biomarkers is to facilitate the differential diagnosis of different dementia subtypes and to help in the development of early detection and treatment strategies.[180]
CSF biomarkers have great sensitivity and low specificity for VaD based on the presence of proteins that indicate increased BBB permeability (serum/albumin ratio, total protein, etc.).[181] These are not specific for VaD and can be present in AD as well. The matrix metalloproteases (MMP) are thought to respond to changes indicating inflammation in extracellular matrix. Elevated MMP levels are associated to demyelination phenomena in VaD.[182] Serum-CSF folate ratio is lower in VaD patients than in those suffering from AD.[181]
Serum and plasma biomarkers for VaD include inflammation biomarkers such as hyperhomocysteinemia and CRP. Lipoprotein-A is related to atheromatosis process and subsequently to VaD. Similarly, indicators of cerebral thrombosis such as D-dimer, thrombin, etc., are associated to VaD.[183],[184]
Genetic factors are known for some vascular diseases, such as CADALSIL. AD and VaD have some causal pathways in common including, presenilin, amyloid, and APOE.[185]
Polymorphism in angiotensine receptors have been linked to VaD. Genes involved in inflammation cascades are possible future investigation targets.[181]
These prodromal indicators show promise as potential targets for the prevention of progression of VaD.
| Diagnosis | | |
Clinical diagnostic
The differential diagnosis between AD and VaD, as well as the early detection of cognitive disturbances, such as VCI, is the main objectives of all the diagnostic criteria and diagnostic scales proposed for VaD. The differential features for AD and VaD are summarized in [Table 1].[34],[121] There is a lack of satisfactory diagnostic criteria for VCI and most of the definitions used for the diagnosis of dementia include memory loss, but executive dysfunction remains the most typical feature of vascular-origin cognitive disorders,[10] showing memory loss only in the more severe stages.
Hachinski published in 1974, the original Hachinski Ischemic Score (HIS), provided criteria for the differential diagnosis of VaD from AD.[8],[186] Patients scoring 7 or more in the (HIS) are labeled as VaD and patients scoring lower than 4 are labeled as AD. Patients with scores between 5 or 6 are considered mixed dementias [Table 2].[187]
The most relevant clinical diagnostic criteria are presented in [Table 3]. The patient classification has been revealed to have low correlation rates across the different available diagnostic criteria.[26],[188],[189],[190] Different classification systems identify the same size samples, but results reveal low-reliability rates measured by the Kappa index.[188],[190]
The Hachinski Ischemic Scale does not include any neuroimaging criteria. HIS performs well for differential diagnosis between VaD and AD, with a sensitivity and specificity near 0.9. Mixed dementias are more problematic. Interrater reliability has been established as 0.61 of K value.[188]
In the NINDS-AIREN criteria, memory impairment is needed to diagnose dementia, leading to a diagnostic overlap with AD and mixed dementias.[190] These criteria have demonstrated a high specificity for the diagnosis of VaD, but a low sensitivity is its biggest drawback.[35],[191] The NINDS-AIREN criteria are nowadays the most widely used diagnostic criteria for research.[192]
The American Stroke Association-American Heart Association (ASA-AHA) criteria are thought to be more sensitive than NINDS-AIREN's because they do not require memory loss and require fewer impaired cognitive domains. There are not any clinical, pathologic studies available to reach any conclusions about sensitivity and specificity of the ASA-AHA criteria.[34],[35]
Neuropsychological assessment
The principal aim of neuropsychological assessments is to distinguish between AD and VaD, but a high prevalence of mixed dementias lowers the specificity of all the available neuropsychological tests.[11] Furthermore, neuropsychological profiles are heterogeneous among patients suffering from VCI, with a typical expression including executive dysfunction and psychomotor slowing.[193],[194] The clinical manifestations of this frontal executive dysfunction are due to the early involvement of cortico-subcortical circuits and include impaired attention, difficulties in planning of complex activities, as well as disorganized thought, emotions, and behavior.[15],[195] The specific tasks for executive dysfunction should assess working memory, abstraction, reasoning, mental flexibility, and fluency.[179],[196]
Patients with VCI show a greater retention of new information and lower rates of forgetting as compared to AD patients, but they exhibit higher rates of disturbances on visual memory and encoding new information.[193],[196] Patients suffering from VaD show disturbances in verbal memory tasks; however, this change is not applicable to patients with VCI. Regarding subjective perceived cognitive dysfunction complaints, patients suffering from VaMCI have shown higher frequency of complaints than patients suffering from other types of MCI, reinforcing the idea that vascular origin cognitive impairments are different in their clinical profile.[197]
The mini-mental state examination (MMSE) test, the most widely used bedside test for the screening of dementias, is not sensitive in distinguishing between AD and VaD; cortical functions such as language, calculation, and orientation tend to be relatively preserved in VaD, and executive functions are not included in MMSE. The Montreal Cognitive Assessment (MOCA) achieves a more comprehensive assessment of major cognitive domains and includes executive functioning tasks with a good discriminant validity, resulting in a higher sensitivity and specificity.[198],[199] The Neuropsychiatric Inventory was developed in 1994 by Cummings and focuses the attention on the behavioral disturbances in dementia classified in 10 domains (apathy, anxiety irritability…) and assesses a wider psychopathology than tests centered in memory.[200],[201] The NINDS-AIREN working group has proposed the shortened version of MOCA for the screening of VaD which includes 12 items.[10] Three subtests have been selected: A six-item orientation task, a five-word immediate and delayed recall task, and a phonemic fluency test.[10],[175]
Functional scales can also be useful to assess instrumental and self-care activities in daily living. The Activities of Daily Living Questionnaire (ADLQ) measures the functioning in six areas (employment, self-care…). ADLQ has demonstrated accurate detection of temporal decline in patients with probable dementia.[201]
| Prevention and Treatment | | |
The primary prevention of VCI aims to achieve the control of known risk factors. VRFs are modifiable, and their control has demonstrated efficacy in preventing VCI [Table 4]. Secondary prevention has two main objectives: an early diagnosis and treatment of acute stroke, and the prevention of stroke recurrence.[15],[35],[47]
Currently, there are no Food and Drug Administration - approved drugs for the treatment of VaD. Two-thirds of stroke survivors suffer from behavioral and cognitive changes such as depression, apathy, and intellectual decline, but few stroke trials include cognitive and behavioral end-points for the evaluation of new treatments.
Cholinesterase inhibitors may be useful in VaD. Subcortical cerebrovascular disease may disrupt cholinergic pathways from nucleus basalis of Meynert. Cholinesterase inhibitors increase the amount of acetylcholine at the synapse gaps, possibly overriding the disruption caused by CVD;[178],[202] however, large clinical trials show inconsistent benefits, and the available data shows beneficial effects in mixed VaD-AD.[35] Donepezil has been studied in the largest clinical trial of pure VaD to date, and statistically significant improvements were found in cognitive function.[12] Galantamine has not demonstrated major improvements in daily living activities in patients with probable VaD.[203] Rivastigmine and memantine have shown improvements in cognitive and behavioral areas, but further studies are needed.[204],[205]
Patients treated with nimodipine demonstrated an improved performance on lexical production and showed less deterioration on the MMSE and the Global Deterioration Scale.[206] Poststroke-administered actovegin has shown an improved functional recovery and reduced neurological deficits as measured in Global Impression-Schizophrenia, MMSE, and other cognitive scales.[207] There is no current evidence for aspirin in VaD;[208] however, the Aspirin in Reducing Events in the Elderly study is still underway.
Cerebrolysin administered in poststroke patients has contradictory results in trials that have tried to demonstrate improvement in clinical global improvement, cognitive performance, and the activities of daily living.[209] The intensive management of preexisting risk factors such as homocysteine levels has demonstrated some benefits. Fasting total homocysteine is an independent predictor of cognitive decline. Elevated homocysteine is a marker of folate/B12 deficiency; significant improvement in cognition has been shown after supplementation in patients with mild to moderate all-type dementia.[210]
| Conclusions | | |
VCI as a complex clinicopathological entity is the second leading cause of dementia nowadays. Vascular origin cognitive impairment acts synergistically with other causes of dementia, giving rise to what is known as “mixed dementias.” The most often used diagnostic criteria show a low diagnostic concordance between them, and available screening tests fail to take into account dominions that characterize VaDs, being above all centered in evaluating memory. As of the writing of this paper, there are not any approved treatments, and therefore, efforts should be focused on primary prevention by controlling cardio VRFs. Because of all of this, vascular origin cognitive impairment is an entity on which further research and robust conclusions are still sorely needed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1]
[Table 1], [Table 2], [Table 3], [Table 4]
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