Pathogenesis and treatment of vascular cognitive impairment.

REVIEW For reprint orders, please contact: [email protected]

Pathogenesis and treatment of vascular cognitive impairment Kurt A Jellinger*

Practice points

Definition ●●

Vascular cognitive impairment (VCI) is a continuum of cognitive disorders ranging from mild cognitive impairment

to overt dementia (VaD), caused by cerebrovascular lesions either alone or in (frequent) conjunction with Alzheimer disease (AD) or other pathologies. Classification ●●

Current clinical classification criteria, distinguishing possible, probable and proven vascular dementia and mixed

dementia show limitations due to the heterogeneous underlying pathology and pathogenesis. Recent proposals for assessment of cerebrovascular lesions related to cognitive impairment await confirmation and validation. Morphology ●●

Cerebrovascular lesions associated with cognitive impairment are focal, multifocal, diffuse or combined, resulting from systemic, cardiac and local large or small vessel disease.

Pathogenesis ●●

Major pathogenic factors are cerebral atherosclerosis, small vessel disease and cardiovascular dysfunction resulting in multiple disseminated small infarcts and white matter lesions due to hypoperfusion and related disorders, involving neuronal circuits and networks important for memory, cognition, executive functions and behavior. These lesions frequently coexist with Alzheimer-type and other pathologies that synergetically promote dementia.

Risk factors ●●

Major risk factors like hypertension, diabetes, atherosklerosis, cardiovascular disease, hyperlipidemia, aging and physical inactivity are common to both VaD and AD.

Improved diagnosis ●●

Assessment of clinical data with fusion of modern neuroimaging and biological markers will improve the clinical diagnostic accuracy of VCI and its distinction from AD and mixed dementia (AD + cerebrovascular or other pathologies), the latter being most frequent in aged demented but also nondemented subjects.

Management ●●

Treatment of VCI with cholinesterase inhibitors and memantine produces only small cognitive improvement, but currently there are no FDA-approved treatments for this disorder.

Future prospects ●●

Therapy and control of hypertension, cardiovascular and other risk factors and in particular, lifestyle modification are essential for the prevention of VCI and mixed dementia.

*Institute of Clinical Neurobiology, 18, Kenyongasse, A-1070 Vienna, Austria; Tel./Fax: +43 1 526 6534; [email protected]

10.2217/NMT.14.37 © 2014 Future Medicine Ltd

Neurodegener. Dis. Manag. (2014) 4(6), 471–490

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Review Jellinger SUMMARY Vascular cognitive impairment (VCI) defines a continuum of disorders ranging from mild cognitive impairment to full-blown dementia, attributable to cerebrovascular causes. Major morphological types – multi-infarct encephalopathy, strategic infarct type, subcortical arteriosclerotic leukoencephalopathy, multilacunar state, postischemic encephalopathy – result from systemic, cardiac and local large or small vessel disease. Cognitive decline is commonly caused by widespread small cerebrovascular lesions (CVLs) affecting regions/networks essential for cognition, memory and behavior. CVLs often coexist with Alzheimer-type and other pathologies, which interact in promoting dementia, but in many nondemented elderly individuals, mixed brain pathologies are also present. Due to the high variability of CVLs, no validated clinical and neuropathological criteria for VCI are available. Cholinesterase inhibitors and memantine produce small cognitive improvement but without essential effect. Antihypertensive treatment, cardiovascular control and lifestyle modifications reducing vascular risk factors are essential. Given its growing health, social and economic burden, prevention and treatment of VCI are a major challenge of neuroscience. KEYWORDS

• cerebrovascular lesions • large and small vessel disease • neuropathology • pathogenic factors • prevention and therapeutics • subcortical vascular lesions • vascular

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Dementia, a neurocognitive disorder in which there is objective evidence of cognitive impairment (CI) in more than one domains that are interfering with activities of daily living, has emerged as a leading health problem of our time. Advances in prevention and healthcare have increased life expectancy and produced a shift in the burden of dementing diseases worldwide. It was estimated that 35.6 million people lived with dementia worldwide in 2010, with numbers expected to double every 20 years to 115.4 million in 2050 [1] . While some data suggest a decline in prevalence [2] , others showed an increasing incidence of dementia in the oldest-old [3–5] . Thus, it remains a devastating and costly disease; the total estimated worldwide costs of dementia were US$604 billion in 2010 [6] . Cerebrovascular disease (CVD) is increasingly recognized as a cause of CI in later life either alone or in conjunction with Alzheimer disease (AD) and other pathologies. Vascular cognitive impairment (VCI) [7–10] describes a heterogeneous group of disorders related to cerebrovascular lesions (CVLs) contributing to cognitive decline ranging from mild cognitive impairment (VCI, no dementia/VCIND [11]) finally to the development of dementia – vascular dementia (VaD) [12–14] ; while ‘subcortical vascular dementia’ (SVaD) means a more homogeneous syndrome [15–18] . ‘Vascular cognitive disorder’ (VCD) [19] is a global category encompassing all disorders of presumed vascular cause. Its pathobiology has been reviewed recently [20,21] . VCI/VaD increases the morbidity, disability and healthcare costs of the growing elderly population, and decreases the quality of life and survival [22–26] . Given the substantial health and economic burden of VCI, its prevention and treatment are critical research and clinical priorities, that

Neurodegener. Dis. Manag. (2014) 4(6)

provide many challenges to modern neuroscience, because evidence-based studies that seek to provide definite answers often lack clear definitions and validated consensus criteria of the disease [27–29] . The present paper, after discussing limitations of the current diagnostic criteria, the epidemiology, major morphological substrates and pathogenic mechanisms of VCI/VaD, will critically review the current evidence for the prevention and treatment of this devastating disorder, based on recent overviews [10,20–21] and new relevant data. The limitations of current classification criteria ●●Clinical criteria

Previous diagnostic criteria for VCI/VaD required the presence of memory loss and a severity of CI sufficient to adversely affect independent functioning consistent with dementia. The four commonly used sets of criteria for VaD are: the National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN) criteria [30] , the State of California Alzheimer Disease Diagnostic and Treatment Centers (ADDTC) criteria [31] , the ICD-10 criteria [32] and the DSM-V criteria [33] . These distinguish between: possible VaD, clinical criteria of dementia with focal clinical or imaging signs of one or more infarcts, gait disorders, pseudobulbar palsy, personality and mood changes; probable VaD, all signs of dementia, two or more infarcts followed by dementia and imaging signs of at least one extracerebellar infarct; proven VaD with clinically proven dementia and pathological demonstration of multiple CVLs and mixed dementia,

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Pathogenesis & treatment of vascular cognitive impairment a combination of AD and VaD. These criteria may not capture the executive dysfunction or less severe decline in VCI. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) published harmonization standards for VCI to address these potential limitations and to provide a first step toward developing diagnostic criteria for VCI [34] . Other diagnostic algorithms for VCI [35] , the NINDS-AIREN DSM IV [36] , the new EFNSENS guidelines for the diagnosis and treatment of disorders associated with dementia [37] , a proposal of the VASCOG (International Society for Vascular Behavior and Cognitive Disorders) for new criteria for vascular cognitive disorders [38] and the comprehensive consensus statement on VCI of the American Stroke Association [36] are suggested to be suitable clinical approaches for assessing VCI patients, but await further validation. In contrast to recently updated consensus criteria for the clinical diagnosis of AD, for example, the revised NINCDS-ADRDA and EFNS criteria for AD [37,39] , the National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria for AD [40–43] and other degenerative dementias [44,45] , no generally accepted and validated criteria for the clinical diagnosis of VCI/VaD are currently available. Vascular mild cognitive impairment, no dementia (VCIND) describes an abnormal condition, which is caused by vascular diseases and in which the patients present with cognitive deficits not severe enough to fit the criteria for dementia [11] . As in neurodegenerative mild cognitive impairment (MCI), essential features of vascular MCI are currently under discussion [46–48] . Pure amnestic MCI is probably less associated with CVD and may be more consistent with evolving AD. However, vascular risk factors are common in these patients [49] . The limitations of current diagnostic criteria sets for VaD that poorly reflect underlying pathology, have been outlined recently [38] . ●●Pathological criteria

Due to the high variability of CVLs related with CI, despite many attempts, no generally accepted morphological schemes for quantifying CVD associated with cognitive disturbances and no validated neuropathological criteria for VaD/VCI have been established so far [21,50] . Therefore, the need to unify neuropathological assessment of vascular lesions in the aging brain has been emphasized [51,52] .


Review

Mixed type dementia, being frequent in elderly demented persons, is diagnosed when a combination of several pathologies, for example, AD with cerebrovascular and/or Lewy pathology, is present [27,53] . Vascular brain injury is commonly encountered in seniors with and without AD pathology [27,53–55] ; but uniform and reproducible criteria are not available. Clinico-pathological studies reported moderate sensitivity of currently used clinical criteria (average 50–56%) and variable specificity (range 64–98%, average 87%) with variable inter-rater reliability [27,56–58] , while the Mayo clinical criteria had 75% sensitivity and 81% specificity for autopsy-proven VaD [59] . However, the demonstration of CVLs and white matter lesions (WMLs) by neuroimaging and autopsies does not prove that they definitely cause dementia [60] . Although cerebrovascular pathology is usually present in cases with a clinical diagnosis of VCI/VaD, it is also frequently found in people with no dementia or other clinical diagnoses [61–65] . Prevalence & epidemiology CI occurs after stroke in 6–41.3% of patients but can also arise from covert CVD [53,66–68] ; a recent study found an incidence of dementia after stroke in 23.9% over an average follow-up of 3.8 years [68] . High levels of variation between studies on the prevalence of poststroke dementia are influenced by differences in methodology and definitions [69] . In clinical studies, the prevalence of VCI/ VaD ranges from 4.5 to 39%, in Western memory clinic- and population-based series averages 8–15.8%, with standardized incidence rates (SIR) between 0.42 and 2.68, increasing with age [70,71] . VCI is strongly age related. In European clinical studies, prevalence rates of VaD between age 65 years and 80+ years ranged from 2.2 to 16.3%, 20–40 to 200–700/100,000 and 0.7 to 6–8.1/1000 p/years [72] or 39.0/1000 p/years at age 85+ years [73] , prevalence doubling every 5.3 years. In the USA, it increased from 0.2 to 19% [8,74] , while in Japan its prevalence decreased after age 85+ years (from 5.3 to 3.9%) [75] . Pathological studies showed a prevalence of VaD ranging from 0.03 to 85.2% with means around 11% [27] , while in recent autopsy series from Japanese geriatric hospitals, it was 23.6– 35% [76] . In elderly subjects with and without dementia, the prevalence of ‘pure’ VaD (without concomitant cerebral pathologies) ranged from

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Review Jellinger 5 to 78%, in the oldest-old from 4.5 to 46.8% [77] . The majority of patients (24–93%) showed mixed pathologies [21,78] . In the age group 70 to 90+ years, the prevalence of VaD increased from 13 to 44.8%, compared with AD (23.6 to 57%) and mixed dementia (2 to 86%) [77] . In an autopsy series of 1700 elderly demented, AD without other pathologies and mixed dementia increased with age, whereas the prevalence of ‘pure’ VaD decreased after age 80+ years [21] . However, the prevalence studies must be interpreted cautiously due to referral biases, confounding effect of their comparison by the lack of common diagnostic criteria for VaD, small numbers of very old individuals in most studies [79–82] and the fact that a large percentage of nondemented elderly subjects show AD-related, vascular and/or mixed pathologies and co-morbidities [21,83–86] . In conclusion, VCI/VaD and mixed dementias may be the most underdiagnosed and undertreated forms of dementia in the elderly [19,27,54] . Vascular lesions associated with cognitive impairment VCI can stem from a wide variety of cardiovascular and cerebrovascular pathologies [20–21,27,53] . The most frequent causative vessel disorders are: atherosclerosis of large- and medium-sized arteries inducing local thrombosis or embolism that cause brain infarcts, whereas embolism of atherogenic thrombi can lead to a broad variety of infarcts [55] ; cerebral small-vessel disease (SVD) (arteriolosclerosis, fibrohyalinosis and fibrinoid necrosis of small arteries) predominantly in the basal ganglia and cerebral white matter that can result in lacunar or microinfarcts, microbleeds and white matter lesions [87–92] . Another frequent form is cerebral amyloid angiopathy (CAA) due to deposition of β-amyloid (Aβ) in leptomeningeal and intracerebral vessels, causing thickening of the vessel wall that can lead to rupture with hemorrhages, microbleeds, capillary occlusion, blood flow disturbances and microinfarcts [93,94] . These disorders increasingly occur in the brains of elderly individuals and become more prevalent and severe with advancing age [95] , changes in brain function occurring years before the onset of CI [96] . In nondemented elderly subjects, lacunes, microbleeds and WMHs have been associated with cognitive decline, including reduced mental speed and impaired executive functions [97] or other neuropsychiatric

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symptoms. SVD might interact with the neurodegenerative changes in AD as either independent of each other [98] or due to additive or synergistic effects on cognitive decline [99] . However, there is much that still needs to be classified in understanding the pathophysiology of VCI in relation to SVD [91,100] . Less common forms include vasculitis and hereditary forms, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) [101,102] . Morphological substrates of VCI/VaD VCI/VaD is the net result of vascular lesions that lead to impairment of brain function [26– 27,53,70–71] . Pathological changes in patients with VCI representing a variety of small and large cerebrovascular and ischemic lesions involving various cerebral lesions are multifold; they include focal, multifocal and diffuse lesions (Box 1) . The patterns of the vascular brain lesions leading to cognitive impairment distinguish major forms of VaD: ●● Multi-infarct dementia (MID), with multiple large or small infarcts in the cortex and subcortical areas due to severe atherosclerosis of cerebral and extracerebral vasculature; ●● Strategic infarct dementia (SID) caused by

small infarcts in strategic brain regions (e.g., thalamus, hippocampus and basal forebrain); ●● Subcortical vascular dementia (SVaD,

Binswanger’s disease) with diffuse white matter lesions sparing U-fibers, caused by severe small-vessel disease, disturbances of the blood–brain barrier and hypotension; ●● Mixed type dementia due to neurodegenera-

tive, vascular and other pathologies as the most frequent form in the elderly. Other forms of VaD include postischemic encephalopathy with two types of predominant distribution patterns [21,53,71] : ●● Cortical laminar necrosis and their sequelae resulting from cardiac or respiratory arrest, often occurring in arterial border zones and associated with diffuse white matter damage; ●● Multiple postischemic lesions after hypoten-

sion, cardiac arrest and narrowing of brainfeeding vessels, leading to multiple cortical and subcortical (micro)infarcts or cortical necrosis. Hippocampal sclerosis (HS), a relatively common neuropathological finding (~10%) in


Pathogenesis & treatment of vascular cognitive impairment

Review

Box 1. Classification of vascular dementia according to major morphologic lesions. Multifocal/diffuse disease ●● LVD ●● MID: multiple large artery/borderline infarcts, cortical and subcortical, microinfarcts, disseminated lesions in gray and white matter ●● SVD ●● Subcortical infarct dementia ūū Multiple small lacunar infarcts in subcortical gray and white matter ūū Lacunes and multilacunar state ūū ‘Granular atrophy’ of cortex (multifocal cortical microinfarcts) - rare ūū Binswanger’s arteriopathic subcortical leukoencephalopathy ūū Hereditary angiopathies - CADASIL and others ●● Cortical and/or subcortical infarct dementia: multiple small or microinfarcts due to: ūū Hypertensive and arteriosclerotic angiopathy ūū Cerebral amyloid angiopathy (sporadic, hereditary) ūū Collagen or inflammatory vascular disease (angiitis, PCNSA, FMD), infectious, non-infectious ●● HHD ●● Diffuse hypoxic-ischemic encephalopathy (cortical laminar necrosis, after cardiac arrest, hypotension) ●● Venous infarct dementia ●● Large hemorrhagic, bilateral infarcts due to thrombosis of the sagittal sinus or the great vein of Galen ●● Hemorrhagic dementia ●● Subdural or subarachnoid hemorrhage ●● Intracerebral hemorrhage ●● Multiple microbleeds Focal disease/SID ●● Small infarcts restricted to strategically important regions ●● Mesial temporal (hippocampal) infarcts/ischemia/sclerosis ūū Caudate and thalamic infarcts (especially DM nucleus) ūū Fronto-cingulate infarcts (basal forebrain, ACA) ūū Angular gyrus infarct (dominant cerebral hemisphere – ACA and MCA territories) ūū White matter key areas (particularly subfrontal) ACA: Anterior cerebral artery; CAA: Cerebral amyloid angiopathy; CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; DM: Dorsomedial; FMD: Fibromuscular dysplasia; HHD: Hypoperfusive, hypoxic– ischemic dementia; LVD: Large vessel dementia; MCA: Medial cerebral artery; MID: Multiple infarct dementia; PCNSA: Primary angiitis of the CNS; SID: Strategic infarct dementia; SVD: Small vessel dementia.

individuals over age 85 years, is characterized by cell loss and gliosis that is not explained by AD. Caused by hypoxia-ischemia in old subjects with cardiac failure and cerebral hypoperfusion, it is often associated with dementia [34,53,103] . However, HS is also associated with a variety of neurodegenerative disorders, such as frontotemporal lobar degeneration (FTLD), most frequently associated with TDP-43 pathology [104] and taupathies [105] . Thus, HS may incorporate different subtypes: hippocampal sclerosis - CVD [106] , HS in epilepsy [107] , HS-tau [108,109] , HS-FTLD [110] , HS-TDP-43 [104] and HS associated with advanced age [111] , the latter being linked to arteriosclerosis that affects multiple brain regions [112] .


As for other pathologies underlying VCI, there is general consensus that cognitive impairment results from the brain dysfunction caused by cumulative tissue damage [20–21,36] . Does ‘pure’ VCI/VaD exist? ’Pure’ VaD is morphologically characterized by multiple CVLs without essential concomitant AD-type (Braak neuritic stage >2.0 and negative amyloid imaging) or other pathologies. PIB-PET studies showed that subcortical VaD without abnormal amyloid imaging was more common than expected [113] . In an autopsy series of elderly patients, its prevalence ranged from 5 to 78% and from 4.5 to 46.8% in the age group 90+ years. In a large autopsy series of elderly


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Review Jellinger demented, pure VaD accounted for 10.8% [77,95] ; in another smaller series for only 5.8% [26] , while cases of mixed dementia showed a reverse lesion pattern. In other series, 66% showed infarcts, suggesting that atherosclerosis-related thrombosis and embolism are important for this type of VaD. In contrast to AD and mixed dementia, the prevalence of ‘pure’ VaD decreased after 80 years of age [21,95] . The thresholds for vascular and degenerative lesions for distinguishing ‘pure’ VaD or AD from mixed cases have been critically discussed [114] . Furthermore, there are particular syndromes within the ‘VaD’ category that can reasonably be considered as discrete diagnoses. They include genetic disorders such as CADASIL manifesting as recurrent strokes usually in the 4th to 6th decade, occurring in the absence of other vascular risk factors, or other hereditary forms [69,115] . Risk factors for VCI/VaD ●●General

A large body of evidence suggests that risk factors for CVD are also risk factors for dementia - due to both AD and VaD. Advanced age is a powerful risk factor for VCI, and the prevalence and incidence of cognitive impairment increase exponentially after age 65 years [36] . Vascular risk factors (midlife hypertension, dyslipidemia, diabetes) and behavioral factors (obesity, physical inactivity) are associated with MCI, CVD and dementia [116–121] . Vascular risk factors have been shown to promote conversion of MCI to AD [118,122] . Studies in middle-aged or older adults have found associations between VCI and hypertension [74,123–124] , hyperlipidemia [125] , obesity [126,127] , diabetes [128–130] , metabolic syndrome [131,132] , cardiovascular risk factors [118,133] , smoking [119,134–135] and physical inactivity [136] (Figure 1) , while others suggested hypotension to be a risk factor for VaD [137] . Cerebrovascular dysfunction and blood–brain barrier (BBB) alterations may compromise the cerebral microenvironment and increase the vulnerability of regions critical for cognition to ischemic-hypoxic brain damage leading to neuronal dysfunction and cognitive deficits [138] , but hippocampal atrophy suggested no specific vulnerability towards vascular risk factors in normal elders [139] . Atrial fibrillation may cause microembolic complications that lead to VCI [118,140] or accelerate cognitive and functional decline [141] . Recurrent stroke is one of the strongest predictors of dementia onset [67,142] , but clinically

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asymptomatic vascular brain injury (infarction and WMLs) in midlife also increase the likelihood of late life dementia [143] . Although for a given level of neuropathology higher education is associated with less cognitive deficits [144] , being a surrogate marker of cognitive reserve [145–147] , the educational level does not influence the rate of progression of VCI and no longer has an impact in advanced disease [144] . Atherosclerosis of the intracranial arteries is an independent and important risk factor for dementia, suggesting potentially reversible pathways unrelated to AD pathology and stroke through which vascular changes influence dementia risk [148] . Remarkably, in VCI as in AD, the increase in risk afforded by vascular factors is observed decades later, a finding that may explain why some studies did not find a cognitive improvement with risk factor control later in life [142] . In terms of population attributable risks, hypertension, diabetes, cardiovascular and lifestyle factors are probably the most important ones [36,118,121,149–152] . ●●Genetic

Genetic factors may influence the development or course of VCI. ApoE ε4 and ε2 with their potential amyloidogenic role may be responsible for some of the microvascular changes in VaD [153–155] . Recent genome-wide association studies of VaD showed a novel genetic locus on the X chromosome [156] and on chromosome 17q25 [157] . However, a link between ApoE and sporadic VCI has not been established [158] . CADASIL is a genetic form of SVD associated with Notch3 mutations whose location may differ by geography or demography [101] . The identification of phenotypes that can be reliably and effectively determined in large samples of subjects is a critical challenge for genetic studies [159] , but the diversity of pathologies underlying VCI and the overlap with AD complicate the interpretation of these studies [20] . SVaD without hypertension may be a unique subtype and can be a target group for studies of unknown risk factors [160] . Cerebrovascular lesions & Alzheimer disease Cerebrovascular function is reduced in early AD [161,162] , implicating reduced cerebral perfusion in the pathobiology of the disease. Conversely, some studies have reported increased amyloid deposition in stroke patients, suggesting that ischemia promotes AD pathology [163] . Recent



Genetic factors

Hypertension

Cardiovascular problems

Diabetes Aging

Atherosclerosis

Amyloid deposition

Cerebrovascular disease Vascular cognitive impairment

Hyperlipidemia

Physical inactivity

Review

Endothelial dysfunction

BBB alterations

Oxidative stress

Inflamation Dementia

Figure 1. Potential mechanisms between vascular risk factors, cerebrovascular disease and cognitive impairment. BBB: Blood–brain barrier.

emphasis on co-morbidity of AD and CVD in 30–90% of AD brains and showing a large variety of lesions [84–85,164–165] , the link between AD and atherosclerosis [130,166] , association of cognitive impairment with CAA, present in up to 100% in AD brains [93,167] , effects of cerebral microangiopathy [168] , deficient clearance of amyloid across the BBB [169] and many other data indicate an association between CVD and AD [165] . The association between circle of Willis atherosclerosis and AD-type pathology provides further evidence for overlap between CVD and AD [170] . Experimental studies indicate that Aβ clearance mechanisms are altered in the presence of vascular dysfunction, contributing to parenchymal and vascular Aβ accumulation [171] . CVD is known to induce amyloid deposition, which has been shown to cause cerebrovascular degeneration, indicating a positive feedback between both lesions [172] . These and other observations suggest a link between cerebrovascular health and brain Aβ clearance [20] . Furthermore, AD and CVD may have common risk factors, such as hypertension, hyperlipidemia, diabetes and insulin resistance, among others [125,130,135,165,173,135] ; this correlation being strongest when risk factors were considered together. It was strongest for VaD and weakest for AD, suggesting that vascular risk factors may independently increase the likelihood of dementia without exacerbating AD pathology. In contrast, studies that have prospectively evaluated patient cohorts with autopsy-confirmed clinical diagnosis failed to establish a link between the burden of AD pathology and vascular risk factors [174] . Neurovascular dysfunction could play a major role in the pathogenesis of AD [169,175]


that, by some authors, has been considered a primary vascular disorder [176] . In elderly patients with subclinical or mild AD and little functional brain reserve (with frequent entorhinal tangles and moderate cortical plaques), either critically located CVLs or cortical watershed microinfarcts may worsen cognitive impairment [177,178] . However, in advanced or full-blown stages of AD, concomitant small vascular lesions do not significantly influence the overall state and progression of cognitive decline that is mainly related to the severity and extent of AD pathology overwhelming the effects of CVD [27,165,179–180] . Cerebral atherosclerosis is associated with cystic and microinfarcts but not with AD-type pathologic changes [181] , and microinfarcts as an important correlate of age-related VCI are not associated with an increased burden of AD pathology [182] . Cerebral microbleeds due to microangiopathy (CAA) are an important factor inducing cognitive impairment [183,184] . Increased WMLs are associated with decreased glucose metabolism and decline in executive function, but do not affect AD-pathology progression, suggesting that vascular contribution to dementia is probably additive although not necessarily independent of the amyloid pathway [185] . Other authors found accumulation of brain Aβ increasing with age in VaD subjects more than in those without CVD [186] , but there is no evidence that vascular brain injury increases the likelihood of Aβ deposition [187] . There is considerable clinical and MRI overlap in patients with SVD with and without abnormal Aβ imaging [113] . In general, elevated CVD burden may lower the threshold of AD pathology necessary to produce cognitive deficits [188–190] . However, others


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Review Jellinger observed no major differences in neurodegenerative lesion load between AD and AD+CVLs, except when these are located in the temporal lobe and hippocampus, suggesting that this location may be important in the pathophysiology of both VaD and mixed dementia [191,192] . Concurrent CVD is common in neuropathological findings in aged subjects with dementia, more common in AD than in other neurodegenerative disorders, and lowers the threshold for dementia due to AD and α-synucleinopathies [193] . New imaging and biomarkers for the in vivo diagnosis of AD may provide additional insights into whether vascular factors are pathogenetically linked with AD [174,194] . Pathogenic factors Important pathogenic factors of VaD/VCD include the volume of brain destruction, its location and the number of CVLs, although the overlap between vascular and degenerative mechanisms and a frequent lack of correlation between clinical and pathology findings was emphasized [52] . Severe ischemia resulting from arterial occlusion can lead to brain damage and VCI, for example, multi-infarct dementia, but cognitive dysfunction is most often associated with more subtle vascular alterations targeting predominantly the subcortical gray and white matter [91,165]. Hippocampal infarcts and sclerosis either alone or in combination with other (vascular) lesions have been related to dementia [34,103] . The interaction between hypertensive SVD and CAA may explain the development of VCI [195] due to synergistic effects of ischemia and Aβ burden [196] . Recent studies showed a significant correlation between SVD pathology severity and CI [91,100,197–198] . Brain atrophy accelerates cognitive decline in cerebral SVD [199] . The impact of small CVLs in autopsy series with vascular pathology confined to microinfarcts [200] and lacunes showed a strong association between the extent and location of cerebral microinfarcts and cognitive findings, cortical microinfarcts representing the only consistent determinant of cognitive decline, while deep and periventricular WMLs did not significantly predict cognitive impairment [58,201–203] . MCI subjects showed large cystic infarcts in 31%, multiple subcortical lacunes in 52, the others had multiple infarcts of various volumes, while of 20 cognitively unimpaired controls, two-thirds had cystic solitary hemispheral

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infarcts and 30% multiple subcortical lacunes with preserved thalamus [71] . In a large autopsy series of demented subjects, those with ‘pure’ VaD showed a significantly higher frequency of small subcortical lesions (volume 50 ml loss of tissue); multi-infarct dementia Multiple small or microinfarcts (>3 with minimum diameter 5 mm); small vessel disease† (involving greater than three coronal levels; hyalinization, CAA, lacunar infarcts, perivascular changes, microhemorrhages); white matter lesions/ leukoaraiosis/Binswanger disease Strategic infarcts (e.g., thalamus, hippocampus and basal forebrain) Cerebral hypoperfusion (hippocampal sclerosis, ischemic–anoxic damage, cortical laminar necrosis, borderzone infarcts involving three different coronal levels) Cerebral hemorrhages (lobar, intracerebral and subarachnoidal) Cerebrovascular changes with Alzheimer pathology (above Braak stage III); mixed dementia (according to the author’s experience stage IV would be appropriate); combined cerebrovascular lesions

I II

III IV V VI

The age of the vascular lesion(s) should correspond with the time when disease began. Poststroke cases are usually included in subtypes I–III. † Subtype I may result from large vessel occlusion (atherothromboembolism), artery-to-artery embolism or cardioembolism. Subtype II usually involves descriptions of arteriosclerosis, lipohyalinosis, hypertensive, arteriosclerotic, amyloid or collagen angiopathy. Subtypes I, II and V may result from aneurysms, arterial dissections, arteriovenous malformations and various forms of vasculitis. CAA: Cerebral amyloid angiopathy. Data taken from [205].

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Table 2. Staging of the cerebrovascular lesions. Score

Staging

Frontal & temporal lobes 0 I II

Normal appearance of brain, vessels, white matter and cortex Mild modification of vessel walls, perivascular spaces or white matter Moderate to severe but isolated modification of the vessel walls (arteriolosclerosis or amyloid angiopathy), usually associated with hemosiderin deposits in the perivascular spaces Moderate to severe perivascular space dilatations either in the deep or the juxtacortical white matter Moderate to severe myelin loss Presence of cortical microinfarcts Presence of large infarcts

III IV V VI Hippocampus 0 I II III IV

Normal appearance Mild modification of vessel walls or perivascular spaces Moderate to severe perivascular space dilatations Presence of microinfarcts (usually in Ammon horn or the subiculum) Presence of large infarcts

Basal ganglia

0 I II III IV Total vascular score

Normal appearance Mild modification of vessel walls or perivascular spaces Moderate to severe perivascular space dilatations Presence of microinfarcts Presence of large infarcts Frontal lobe + temporal lobe + hippocampus + basal ganglia/20

Data taken from [237].

Prospects for therapy & prevention The development of treatment for VCI has been hampered by the lack of suitable animal models recapitulating the multifaceted features of the disease [36] . Several animal models of hypoperfused white matter damage have been developed [239–242] that have demonstrated that counteracting some of the pathogenic factors, for example, chronic ischemia, inflammation and oxidation, reduce WMLs and/or behavioral deficits [240,243] . Despite some positive results in these models, there are no FDA-approved treatments for VCI/VaD [244,245] . Application of antioxidants, anti-inflammatory agents or those increasing cerebral perfusion has not led to consistent results [244] . ●●Current treatment strategies

Currently, cognitive dysfunction of VaD is treated with classic cholinesterase inhibitors, in particular, donepezil and an N-methylD-aspartate antagonist (Memantine ® [Merz Pharma, Frankfurt am Main, Germany]), which produce small cognitive improvements in VaD patients, likely due to their action on coexistent AD pathology, but they have not


been shown to improve global clinical outcome [246] . Galantamine and rivastigmine cannot be recommended with high priority due to side effects [247,248] , while the effectiveness of Ginkgo biloba and Cerebrolysin® (Ebewe Pharma, Vienna, Austria) has not been studied adequately. However, a recent meta-analysis reported improvement of global clinical function after Cerebrolysin® treatment [249] . In 2010, the British Association for Psychopharmacology (BAP) recommended against prescribing these drugs to patients with VaD, although those with AD and mixed VaD+AD may benefit. Acupuncture treatment may have some effect on VaD [250–253] . Clinical trials are currently exploring other agents, inducing cholinergic stimulation (choline alphoscerate), vasodilators (Udenafil), inhibitor of platelet aggregation (cilostazol) and delta-9-tetrahydrocannabinol (a complete list can be found in [254]). Huperzine A (Hup A) could improve cognitive performance in patients with AD and VaD, but needs to be used with caution [255] . Revised recommendations for management of VaD were published recently [256] .


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Review Jellinger ●●Prevention challenges

Increasing evidence suggests that VCI/VaD can be reduced by preventive measures. A study in the UK suggests that the prevalence of dementia may be decreasing by rigorous blood pressure control [2,257] , and antihypertensive therapy together with a cholinesterase inhibitor may prevent poststroke cognitive decline, while selective serotonin-uptake inhibitors and dihydropyridine calcium channel blockers may improve short-term cognitive functions in patients with VaD [26] . Medications for hypertension, diabetes, hypercholesterolemia and modification of cardiovascular risk factors have been recommended, but randomized clinical trials have not convincingly shown that these treatments can prevent or postpone cognitive decline [121,258–259] . There is insufficient evidence to recommend statins for the treatment and prevention of VaD [260] . The effectiveness of nutrition, dietary factors, vitamins and other compounds for VCI/VaD has been critically discussed [261–264] . Physical and mental activity, social engagement and a diet rich in antioxidants and polyunsaturated fatty acids may reduce dementia risk [155,265– 267] . Therefore, life style changes, controlling vascular risk factors, promoting a healthy diet, non-smoking, exercise and mental activity are promising strategies to reduce VCI and may be associated with better cognitive performance in later life [268–271] . However, most of the evidence is based on observational studies, which have not been confirmed by randomized clinical trials of risk factor modification, stressing the need for fu rther long-scale studies [134,259,272] . Conclusion & future perspective VCI/VaD are major contributors to age-related dementias and comprise a heterogenous group of cognitive disorders attributable to a variety of vascular causes. Vascular pathology is also an integral part of AD and other neurodegenerative dementing conditions. Despite the diversity of the underlying brain pathology, the CVLs have a similar pathogenic basis, resulting from hypoperfusion and its consecutive lesions caused by systemic cardiovascular, and focal large or small vessel disease, their pathogenesis being multifocal. Assessment of clinical data with fusion of biomarkers has improved the clinical diagnostic accuracy of AD up to 98%, while their sensitivity and specificity versus

482


other dementias is 23–88%. A combination of clinical neuropsychological data and of the best biomarkers and multimodal techniques for identifying AD (cerebrospinal fluid, MRI and PET markers) will lead to more precise diagnosis of AD [273–276] . However, for VCI/VaD, further development of homogenous and harmonized clinical and neuropathological definitions and procedures in classifying and characterizing cerebrovascular and other pathologies remain an important priority for the future, and fundamental questions concerning the interaction of AD and vascular pathology remain unanswered. Novel imaging modalities will address some of these challenges and may make it possible to characterize the pathology in vivo with spatial, temporal and morphological accuracy. Concerning mixed dementia as the most common cause of cognitive impairment in the elderly, it has become increasingly important to harmonize basic science, translational and clinical approaches to AD and VaD, and the impact of both pathologies should be considered, independently of whether their contribution is add itive or sy nergistic [20] . Paradigms to drive research in new directions are integrated strategies, and new initiatives to evaluate recent advances in systems biology and network medicine [277] . Universal use of homogenous and harmonized clinical and neuropathological definitions and standards will help to identify individuals with cognitive impairment related to vascular brain injury, make clinico-pathological studies comparable and accelerate the pace of process as a basis for further successful neuroprotection and treatment of these deleterious and life-involving disorders [278] . In the absence of effective disease-modifying therapies, promoting and maintaining vascular health seems critical to prevent both the vascular and neurodegenerative components of the disease and is probably the best possible course of action at the present. Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.


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Vascular cognitive impairment and dementia.

[Pathogenesis of cognitive impairment in multiple sclerosis].

Vascular contributions to cognitive impairment.

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Retinal vascular fractals and cognitive impairment.

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Molecular Neuroimaging in Vascular Cognitive Impairment.

Vascular parkinsonism--characteristics, pathogenesis and treatment.

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Behavioural and psychological symptoms in poststroke vascular cognitive impairment.

Chronic administration of isocarbophos induces vascular cognitive impairment in rats.

Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease.

Predictors for vascular cognitive impairment in stroke patients.

Multimodal markers of inflammation in the subcortical ischemic vascular disease type of vascular cognitive impairment.

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Cognitive Impairment in Bipolar Disorder: Treatment and Prevention Strategies.

Evidence-based interventions for cancer- and treatment-related cognitive impairment.

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