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Vascular dementia

      Abstract

      The epidemic growth of dementia causes great concern for the society. It is customary to consider Alzheimer's disease (AD) as the most common cause of dementia, followed by vascular dementia (VaD). This dichotomous view of a neurodegenerative disease as opposed to brain damage caused by extrinsic factors led to separate lines of research in these two entities. Indeed, accumulated data suggest that the two disorders have additive effects and probably interact; however it is still unknown to what degree. Furthermore, epidemiological studies have shown "vascular" risk factors to be associated with AD. Therefore, a clear distinction between AD and VaD cannot be made in most cases, and is furthermore unhelpful. In the absence of efficacious treatment for the neurodegenerative process, special attention must be given to the vascular component, even in patients with presumed mixed pathology. Symptomatic treatment of VaD and AD is similar, although the former is less effective. For prevention of dementia it is important to treat all factors aggressively, even in stroke survivors who do not show evidence of cognitive decline. In this review, we will give a clinical and pathological picture of the processes leading to VaD and discuss its interaction with AD.

      Keywords

      1. Introduction

      The dramatic increase in the proportion of elderly people worldwide has brought attention to ageing-related impairments. Dementia has a prominent presence among the chronic diseases in the elderly [
      • Sousa R.M.
      • Ferri C.P.
      • Acosta D.
      • Albanese E.
      • Guerra M.
      • Huang Y.
      • et al.
      Contribution of chronic diseases to disability in elderly people in countries with low and middle incomes: a 10/66 Dementia Research Group population-based survey.
      ], and has emerged as a major health problem worldwide [
      • Kalaria R.N.
      • Maestre G.E.
      • Arizaga R.
      • Friedland R.P.
      • Galasko D.
      • Hall K.
      • et al.
      Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors.
      ,
      • Llibre Rodriguez J.J.
      • Ferri C.P.
      • Acosta D.
      • Guerra M.
      • Huang Y.
      • Jacob K.S.
      • et al.
      Prevalence of dementia in Latin America, India, and China: a population-based cross-sectional survey.
      ], with great impact on families and national economies [
      • Wimo A.
      • Winblad B.
      • Jonsson L.
      The worldwide societal costs of dementia: estimates for 2009.
      ,
      • Brodaty H.
      • Donkin M.
      Family caregivers of people with dementia.
      ]. Due to the continuous population aging, this problem is expected to grow dramatically in the future. Therefore understanding dementia pathogenesis and developing preventative and curative treatments are top priorities.
      Dementia is a syndrome, encompassing a large number of distinctive brain disorders. Although memory dysfunction is the basis of most formal definitions of dementia, cognitive impairment can be devastating even when memory is relatively preserved, such as when speech and executive functions are affected.
      Damage to the central nervous system, from whatever cause, can lead to cognitive impairment. However an important issue is of specificity. The clinical phenotype resulting from brain insults is the result of a combination of factors, including the site and size of the lesions, amount and location of neuronal loss, as well as the particulars of the brain in which this lesion occurred. For many years, Alzheimer's disease (AD) was considered to be the most common form of dementia, followed by vascular dementia (VaD). Recently however, this concept has been challenged by the recognition that vascular-associated cognitive decline was found to be more common than previously thought either in isolation or associated with a neurodegenerative condition [
      • Grinberg L.T.
      • Heinsen H.
      Toward a pathological definition of vascular dementia.
      ,
      • Korczyn A.D.
      • Vakhapova V.
      The prevention of the dementia epidemic.
      ]. Vascular changes typically occur in elderly people, whose brains may be affected by age-related degenerative changes and additional diseases. Thus in many cases, the pathogenesis of the dementia is complex, with vascular lesions interacting with primary neurodegenerative processes [
      • Korczyn A.D.
      Mixed dementia—the most common cause of dementia.
      ,
      • Korczyn A.D.
      The complex nosological concept of vascular dementia.
      ,
      • Langa K.M.
      • Foster N.L.
      • Larson E.B.
      Mixed dementia: emerging concepts and therapeutic implications.
      ].
      Due to the fact that the brain is already considerably damaged by the time full-blown dementia is detected, attempts to capture patients with minimal cognitive impairment, have led to the introduction of broader terms, including mild cognitive impairment.
      In this review we shall use VaD as an umbrella term, describing dementia resulting from arterial brain lesions (Venous thrombosis may also cause cognitive impairment, but this topic will not be detailed here). It became evident that VaD is heterogeneous in terms of pathogenesis, pathology, and clinical phenotype.

      2. History

      Early views in the beginning of the twentieth century considered senile dementia to result from cerebral arteriosclerosis [
      • Roman G.C.
      • Sachdev P.
      • Royall D.R.
      • Bullock R.A.
      • Orgogozo J.M.
      • Lopez-Pousa S.
      • et al.
      Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia.
      ]. Alois Alzheimer's description of microscopic dementia caused by neuritic plaques and neurofibrillary changes as oppose to the vascular changes created the concept that although cerebral arteriosclerosis was associated with dementia in older subjects, in younger ones, plaques and tangles were the culprit. This concept prevailed for several decades until it was challenged by pathological findings showing plaques and neurofibrillary deposits in the brains of most demented elderly individuals, regardless of age.
      Therefore, dementia of vascular origin was progressively dismissed in dementia differential diagnosis, and only started to come back in focus after the careful analysis by Tomlinson et al. in the 1960s [
      • Tomlinson B.E.
      • Blessed G.
      • Roth M.
      Observations on the brains of non-demented old people.
      ]. These investigators concluded that a stroke of considerable volume (>100 ml) was accompanied by a great risk of dementia development. In the 1970s, Hachinski et al. went further and coined the term multi-infarct dementia (MID) implying that a cumulative result of multiple strokes, not necessarily symptomatic or occurring at the same time, could case dementia [
      • Hachinski V.C.
      • Lassen N.A.
      • Marshall J.
      Multi-infarct dementia. A cause of mental deterioration in the elderly.
      ]. This major advance was soon supported by neuroimaging, especially after the introduction of computed tomography (CT) and magnetic resonance imaging (MRI). Modern neuroimaging subsequently helped to introduced non-infarct vascular changes, such as white matter lesions (WML), small subcortical lacunes and microbleeds, as contributors to cognitive decline [
      • Hachinski V.
      Vascular dementia: a radical redefinition.
      ].

      3. Epidemiology and risk factors

      While it is universally accepted that the prevalence of dementia is increasing, reflecting the population aging, exact figures may not be reliable, particularly in developing countries [
      • Llibre Rodriguez J.J.
      • Ferri C.P.
      • Acosta D.
      • Guerra M.
      • Huang Y.
      • Jacob K.S.
      • et al.
      Prevalence of dementia in Latin America, India, and China: a population-based cross-sectional survey.
      ]. Data on the epidemiology of VaD are probably even less reliable, since different studies looked at VaD using various methods and particularly, different diagnostic criteria in several geographic areas and ethnic groups. The different clinical sets of criteria used are not interchangeable and lead to significantly discrepant results [
      • Chui H.C.
      • Mack W.
      • Jackson J.E.
      • Mungas D.
      • Reed B.R.
      • Tinklenberg J.
      • et al.
      Clinical criteria for the diagnosis of vascular dementia—a multicenter study of comparability and interrater reliability.
      ]. It is believed that in general, epidemiological studies are likely to underestimate the number of VaD cases because of restrictive clinical criteria [
      • Knopman D.S.
      • Parisi J.E.
      • Boeve B.F.
      • Cha R.H.
      • Apaydin H.
      • Salviati A.
      • et al.
      Vascular dementia in a population-based autopsy study.
      ,
      • Gold G.
      • Giannakopoulos P.
      • Montes-Paixao Junior C.
      • Herrmann F.R.
      • Mulligan R.
      • Michel J.P.
      • et al.
      Sensitivity and specificity of newly proposed clinical criteria for possible vascular dementia.
      ]. Over the years, imaging has been added as an important contributing diagnosis tool, but imaging is expensive and not readily available, limiting the population which could be studied. In addition, imaging, whenever used, usually did not consider white matter lesions (WMLs) as an indicator of vascular contribution.
      Few epidemiological studies on VaD meet criteria for real population-based studies [
      • Zaccai J.
      • Ince P.
      • Brayne C.
      Population-based neuropathological studies of dementia: design, methods and areas of investigation—a systematic review.
      ]. Data from memory clinics may underestimate VaD because of referral bias, since patients with vascular brain disease are more likely to be followed-up in stroke units. The lack of criteria differentiating VaD from mixed dementia resulted in mixed cases being variably included in epidemiological studies [
      • Chui H.C.
      • Mack W.
      • Jackson J.E.
      • Mungas D.
      • Reed B.R.
      • Tinklenberg J.
      • et al.
      Clinical criteria for the diagnosis of vascular dementia—a multicenter study of comparability and interrater reliability.
      ]. Finally few data are available for different subtypes of VaD [
      • Leys D.
      • Henon H.
      • Mackowiak-Cordoliani M.A.
      • Pasquier F.
      Poststroke dementia.
      ].
      Nevertheless, it is clear that VaD prevalence, as of dementia in general, increases steeply with age at least until age 90, after which data are unclear [
      • Leys D.
      • Pasquier F.
      • Parnetti L.
      Epidemiology of vascular dementia.
      ,
      • Middleton L.E.
      • Grinberg L.T.
      • Miller B.
      • Kawas C.
      • Yaffe K.
      Neuropathologic features associated with Alzheimer disease diagnosis: age matters.
      ]. Apparently a higher prevalence of VaD (as compared to AD) occurs in east-Asia [
      • Ikeda M.
      • Hokoishi K.
      • Maki N.
      • Nebu A.
      • Tachibana N.
      • Komori K.
      • et al.
      Increased prevalence of vascular dementia in Japan: a community-based epidemiological study.
      ], although this difference may have diminished lately [
      • Yamada M.
      • Mimori Y.
      • Kasagi F.
      • Miyachi T.
      • Ohshita T.
      • Sudoh S.
      • et al.
      Incidence of dementia, Alzheimer disease, and vascular dementia in a Japanese population: Radiation Effects Research Foundation adult health study.
      ], and men are affected more frequently than women [
      • Leys D.
      • Henon H.
      • Mackowiak-Cordoliani M.A.
      • Pasquier F.
      Poststroke dementia.
      ]. The mortality of VaD patients exceeds that of AD patients, probably because of the added coronary morbidity [
      • Kalaria R.N.
      • Maestre G.E.
      • Arizaga R.
      • Friedland R.P.
      • Galasko D.
      • Hall K.
      • et al.
      Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors.
      ].
      There are almost no data on secular trends of VaD. However, considering that stroke incidence seems to have dropped, VaD incidence may have decreased [
      • Leys D.
      • Pasquier F.
      • Parnetti L.
      Epidemiology of vascular dementia.
      ]. In the same line, the widespread decrease in smoking and common use of antihypertensive and antidyslipidaemic drugs may have contributed to a decrease in VaD prevalence. On the other hand, the increased prevalence of obesity may all affect future VaD prevalence and incidence rates [
      • Gorelick P.B.
      • Scuteri A.
      • Black S.E.
      • Decarli C.
      • Greenberg S.M.
      • Iadecola C.
      • et al.
      Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association.
      ].
      Atherosclerotic disease in general is, as expected, a risk factor for stroke and for VaD (Table 1). The realization that AD and VaD share several risk factors is one of the most important discoveries in the past two decades regarding dementia [
      • Beeri M.S.
      • Ravona-Springer R.
      • Silverman J.M.
      • Haroutunian V.
      The effects of cardiovascular risk factors on cognitive compromise.
      ,
      • Mielke M.M.
      • Rosenberg P.B.
      • Tschanz J.
      • Cook L.
      • Corcoran C.
      • Hayden K.M.
      • et al.
      Vascular factors predict rate of progression in Alzheimer disease.
      ]. This overlap may indicate that brain ischemia is an important factor contributing to AD pathogenesis. Indeed, most cases of dementia in the elderly actually do not result from a single pathogenic mechanism but represent mixed dementia [
      • Korczyn A.D.
      Mixed dementia—the most common cause of dementia.
      ,
      • Strozyk D.
      • Dickson D.W.
      • Lipton R.B.
      • Katz M.
      • Derby C.A.
      • Lee S.
      • et al.
      Contribution of vascular pathology to the clinical expression of dementia.
      ,
      • Schneider J.A.
      • Arvanitakis Z.
      • Bang W.
      • Bennett D.A.
      Mixed brain pathologies account for most dementia cases in community-dwelling older persons.
      ]. In addition, abdominal obesity, insulin resistance, hypertension and dyslipidemia, components of the metabolic syndrome, are well known risk factors for vascular diseases in general and therefore presumably for VaD [
      • Hayden K.M.
      • Zandi P.P.
      • Lyketsos C.G.
      • Khachaturian A.S.
      • Bastian L.A.
      • Charoonruk G.
      • et al.
      Vascular risk factors for incident Alzheimer disease and vascular dementia: the Cache County study.
      ,
      • Raffaitin C.
      • Gin H.
      • Empana J.P.
      • Helmer C.
      • Berr C.
      • Tzourio C.
      • et al.
      Metabolic syndrome and risk for incident Alzheimer's disease or vascular dementia: the Three-City Study.
      ,
      • Solfrizzi V.
      • Scafato E.
      • Capurso C.
      • D'Introno A.
      • Colacicco A.M.
      • Frisardi V.
      • et al.
      Metabolic syndrome and the risk of vascular dementia: the Italian Longitudinal Study on Ageing.
      ,
      • Albers G.W.
      • Goldstein L.B.
      • Hess D.C.
      • Wechsler L.R.
      • Furie K.L.
      • Gorelick P.B.
      • et al.
      Stroke Treatment Academic Industry Roundtable (STAIR) recommendations for maximizing the use of intravenous thrombolytics and expanding treatment options with intra-arterial and neuroprotective therapies.
      ]. It appears that midlife, rather than late life exposure significantly increases the risks [
      • Xu W.
      • Qiu C.
      • Gatz M.
      • Pedersen N.L.
      • Johansson B.
      • Fratiglioni L.
      Mid- and late-life diabetes in relation to the risk of dementia: a population-based twin study.
      ].
      Table 1Risk factors for dementia.
      Risk factors for both VaD and ADRisk factors for AD
      AgeFemale gender
      Coronary artery disease
      Midlife hypercholesterolaemiaApolipoprotein E status
      High dietary saturated fat and cholesterolHead trauma
      Hyperhomocysteinaemia
      Midlife diabetes mellitus
      Midlife hypertension
      Obesity
      Metabolic syndrome
      Arteriosclerosis
      Smoking
      Poor education
      Microbleeds are now easily identified in the MRI and seen more frequently among people with dementia [
      • Werring D.J.
      • Frazer D.W.
      • Coward L.J.
      • Losseff N.A.
      • Watt H.
      • Cipolotti L.
      • et al.
      Cognitive dysfunction in patients with cerebral microbleeds on T2*-weighted gradient-echo MRI.
      ,
      • De Reuck J.
      • Auger F.
      • Cordonnier C.
      • Deramecourt V.
      • Durieux N.
      • Pasquier F.
      • et al.
      Comparison of 7.0-T T*-magnetic resonance imaging of cerebral bleeds in post-mortem brain sections of Alzheimer patients with their neuropathological correlates.
      ]. It is yet unknown whether microbleeds are risk indicators for dementia or whether the hemorrhages are causally related to cognitive decline.
      Depression is observed frequently among people with vascular disease [
      • Kent L.K.
      • Shapiro P.A.
      Depression and related psychological factors in heart disease.
      ], and is commonly seen following strokes [
      • Kumar S.
      • Selim M.H.
      • Caplan L.R.
      Medical complications after stroke.
      ]. Depression may be a significant risk factor for future development of dementia [
      • Pohjasvaara T.
      • Erkinjuntti T.
      • Ylikoski R.
      • Hietanen M.
      • Vataja R.
      • Kaste M.
      Clinical determinants of poststroke dementia.
      ], but the relationship of depression to vascular disease on the one hand and to dementia on the other is complex [
      • Korczyn A.D.
      • Halperin I.
      Depression and dementia.
      ].
      Genetic factors for stroke and VaD have not been studied widely [
      • Leblanc G.G.
      • Meschia J.F.
      • Stuss D.T.
      • Hachinski V.
      Genetics of vascular cognitive impairment: the opportunity and the challenges.
      ]. Apolipoprotein E ε4 (APOE4) is a known risk factor for atherosclerotic disease in general [
      • Leblanc G.G.
      • Meschia J.F.
      • Stuss D.T.
      • Hachinski V.
      Genetics of vascular cognitive impairment: the opportunity and the challenges.
      ] as well as for AD [
      • Kivipelto M.
      • Helkala E.L.
      • Laakso M.P.
      • Hanninen T.
      • Hallikainen M.
      • Alhainen K.
      • et al.
      Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease.
      ]. Surprisingly, it has a negligible effect on stroke [
      • Abboud S.
      • Viiri L.E.
      • Lutjohann D.
      • Goebeler S.
      • Luoto T.
      • Friedrichs S.
      • et al.
      Associations of apolipoprotein E gene with ischemic stroke and intracranial atherosclerosis.
      ] and on VaD [
      • Rowan E.
      • Morris C.M.
      • Stephens S.
      • Ballard C.
      • Dickinson H.
      • Rao H.
      • et al.
      Impact of hypertension and apolipoprotein E4 on poststroke cognition in subjects >75 years of age.
      ,
      • Treves T.A.
      • Bornstein N.M.
      • Chapman J.
      • Klimovitzki S.
      • Verchovsky R.
      • Asherov A.
      • et al.
      APOE-epsilon 4 in patients with Alzheimer disease and vascular dementia.
      ] However, APOE4 may increase the risk for cognitive decline after stroke [
      • Chapman J.
      • Wang N.
      • Treves T.A.
      • Korczyn A.D.
      • Bornstein N.M.
      ACE, MTHFR, factor V Leiden, and APOE polymorphisms in patients with vascular and Alzheimer's dementia.
      ]. Rare monogenic vascular diseases can all result in stroke as well as in VaD (Table 2).
      Table 2Genetic causes of VaD.
      DiseaseAffected proteinGeneChromosomeGenetic trasmissionComments
      CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)Transmembrane receptor vascular smooth muscle cellNOTCH319q12DominantNon-hypertensive young and middle-aged adults affected
      CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, Maeda syndrome)HtrA serine protease 1HTRA110qRecessiveMay be late onset. Accompanied by alopecia and disco-vertebral degeneration. In Japanese and Chinese populations
      Cerebral amyloid angiopathiesE693G of APP D694N of APP cystatin CAPP gene21DominantCodon 693 mutation
      Hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D)BRI2 gene21Alzheimer's disease like dementia, cortical calcifications, leukoencephalopathy
      Arctic variant Iowa variant21
      HCHWA-I (Icelandic type)2012
      Familia British dementi (FBD) Familia Danish dementi12
      13
      HERNS (hereditary endotheliopathy, retinopathy, nephropathy, and stroke)3′–5′ exonucleaseTREX1 suspected3p21DominantOne of retinal vasculopathy and cerebral leukodystrophies, encompassing three conditions with a common etiology—cerebroretinal vasculopathy, hereditary vascular retinopathy and HERNS, all mapped to chr 3p21
      Hereditary haemorrhagic telangiectasia (Osler–Weber–Rendu)Type 1—ENG (endoglin) Type 2—ALK-1 (actin-like kinase receptor 1) Type 3—SMAD4ACVRL19
      ALK-112
      SMAD45DominantAffected proteins modulate transforming growth factor (TGF)-β signalling in vascular endothelial cells and lead to the development of fragile telangiectatic vessels and arteriovenous malformations. Cerebral occurrence in 10%, stroke may be ischemic or hemorrhagic
      HyperhomocysteinaemiaMethyltetrahydro-folate reductase (MTHFR)MTHFR1pRecessiveSimply modified by folate supplement C677T genotype
      Fabry diseaseα-galactosidase AGLAXX-linkedLysosomal storage disease. Accumulation of globotriaosylceramide Gb3. Enzyme replacement therapy exists
      MELAS (mitochondrial encephalopathy with lactic acidosis and seizures)A-to-G transition mutationAt position 3243 (most common), or 3271Mitochondrial genomeMaternal inheritanceMultiple systems affected. May be overlapping with other mitochondrial diseases
      Moya-moyaDifferent lociLinked to several chromosomes 3, 6, 8, 12, and 17Different transmission modesAsian population susceptibility
      Sickle-cell diseaseFoetal haemoglobinSubstitution of glutamic acid by lysine at codon 26 of the β-globin gene6qRecessiveCommon mutation
      AD—autosomal dominant, AR—autosomal recessive.

      4. Clinical phenotypes

      Vascular-related brain lesions are heterogeneous, leading to a variety of cognitive deficits. Likewise in other brain conditions, clinical manifestation is a product of the brain region involved by the pathological process. Thus, cortical lesions can cause aphasia, apraxia, and epileptic seizures, while subcortical lesions, including WMLs, are associated with bradyphrenia, executive dysfunctions, gait abnormalities, urinary incontinence and parkinsonism [
      • Koga H.
      • Takashima Y.
      • Murakawa R.
      • Uchino A.
      • Yuzuriha T.
      • Yao H.
      Cognitive consequences of multiple lacunes and leukoaraiosis as vascular cognitive impairment in community-dwelling elderly individuals.
      ,
      • Handley A.
      • Medcalf P.
      • Hellier K.
      • Dutta D.
      Movement disorders after stroke.
      ]. Recently, the term vascular cognitive impairment (VCI) was coined, to denote the spectrum of cognitive changes resulting from, or contributed to vascular lesions of the brain [
      • Roman G.C.
      • Sachdev P.
      • Royall D.R.
      • Bullock R.A.
      • Orgogozo J.M.
      • Lopez-Pousa S.
      • et al.
      Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia.
      ,
      • Hachinski V.
      • Iadecola C.
      • Petersen R.C.
      • Breteler M.M.
      • Nyenhuis D.L.
      • Black S.E.
      • et al.
      National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards.
      ]. This term expands the previously used term VaD, incorporating also more minor deficits, such as vascular MCI. MCI was first introduced to state a transitional stage between normal cognition aging and AD [
      • Petersen R.C.
      • Smith G.E.
      • Waring S.C.
      • Ivnik R.J.
      • Kokmen E.
      • Tangelos E.G.
      Aging, memory, and mild cognitive impairment.
      ]. It is unfortunately not easy to predict the outcome of a individual MCI patient. The risk of progression of vascular MCI to dementia was estimated at 50% over five years [
      • Wentzel C.
      • Rockwood K.
      • MacKnight C.
      • Hachinski V.
      • Hogan D.B.
      • Feldman H.
      • et al.
      Progression of impairment in patients with vascular cognitive impairment without dementia.
      ].

      5. Clinical diagnosis

      The diagnosis of VaD is rarely straightforward. The clinical severity is variable ranging from mild cognitive impairment (MCI) through severe dysfunction. Clinical evolution is frequently unpredictable, with acute or insidious onset, possible improvement, stabilization or subsequent decline, either step-wise or slow deterioration. In addition, the neuropsychological profile of VaD is also variable. All these factors complicate the clinical definition of cognitive impairment related to vascular-related brain lesions.
      Several clinical criteria of VaD have been proposed and used extensively (NINDS-AIREN,ICD 10, ADDTC, DSM IV, Mayo clinic) [
      • Knopman D.S.
      • Rocca W.A.
      • Cha R.H.
      • Edland S.D.
      • Kokmen E.
      Incidence of vascular dementia in Rochester, Minn, 1985–1989.
      ,
      • Chui H.C.
      • Victoroff J.I.
      • Margolin D.
      • Jagust W.
      • Shankle R.
      • Katzman R.
      Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer's Disease Diagnostic and Treatment Centers.
      ,
      • Roman G.C.
      • Tatemichi T.K.
      • Erkinjuntti T.
      • Cummings J.L.
      • Masdeu J.C.
      • Garcia J.H.
      • et al.
      Vascular dementia—diagnostic criteria for research studies—report of the NINDS-AIREN international workshop.
      ,
      • World Health Organization
      ,
      • American Psychiatric Association
      ]. These definitions focus on dementia, and thus exclude cases with milder cognitive impairment. All of them have been composed by experts, yet validation was incomplete, partly due to lack of autopsy verification, but also because it is not clear what should be the gold standard.
      The Hachinski ischemic scale (HIS) developed on the basis of the MID concept [
      • Hachinski V.
      • Lee T.Y.
      Commentary on "Alzheimer's disease drug development and the problem of the blood–brain barrier." The blood–brain barrier: a physical and conceptual challenge.
      ], has been borrowed to be used in other VaD entities in which it may be even less useful than in MID. The score is an arbitrary one, with equal weight given to individual items, and without attention to possible redundancy [
      • Moroney J.T.
      • Bagiella E.
      • Desmond D.W.
      • Hachinski V.C.
      • Molsa P.K.
      • Gustafson L.
      • et al.
      Meta-analysis of the Hachinski ischemic score in pathologically verified dementias.
      ].
      Although neuropathological assessment is frequently assumed to be the gold standard for diagnosis, no consensus criteria are available for the pathological definition of VaD [
      • Grinberg L.T.
      • Heinsen H.
      Toward a pathological definition of vascular dementia.
      ]. Brain imaging is very sensitive in demonstrating vascular changes of the brain, but is unable to differentiate on an individual level, between people with and without cognitive impairment.
      In summary, the occurrence of co-morbid changes in the brain, the availability of multiple diagnostic criteria, and the reliance on several imaging methods, (and different criteria of abnormalities), impose imprecise diagnosis [
      • Garrett K.D.
      • Paul R.H.
      • Libon D.J.
      • Cohen R.A.
      Defining the diagnosis of vascular dementia.
      ].

      6. Natural history

      Several studies have confirmed reduced survival of VaD patients, due to concomitant vascular disease (myocardial infarctions and recurrent strokes) [
      • Pendlebury S.T.
      • Rothwell P.M.
      Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis.
      ,
      • Hoffmann M.
      • Schmitt F.
      • Bromley E.
      Vascular cognitive syndromes: relation to stroke etiology and topography.
      ]. On the other hand, the cognitive deterioration may be slower in VaD than in AD [
      • Bruandet A.
      • Richard F.
      • Bombois S.
      • Maurage C.A.
      • Deramecourt V.
      • Lebert F.
      • et al.
      Alzheimer disease with cerebrovascular disease and vascular dementia: clinical features and course compared with Alzheimer disease.
      ]. This slower progression is also seen in placebo arms of drug studies in VaD patients [
      • Orgogozo J.M.
      • Rigaud A.S.
      • Stoffler A.
      • Mobius H.J.
      • Forette F.
      Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300).
      ,
      • Meyer J.S.
      • Chowdhury M.H.
      • Xu G.
      • Li Y.S.
      • Quach M.
      Donepezil treatment of vascular dementia.
      ,
      • Auchus A.P.
      • Brashear H.R.
      • Salloway S.
      • Korczyn A.D.
      • De Deyn P.P.
      • Gassmann-Mayer C.
      Galantamine treatment of vascular dementia: a randomized trial.
      ], although the measures used may not be equally sensitive to measure decrease in VaD and in AD. VaD natural history is type-specific and depends on brain preconditions For instance, the occurrence of an ischemic stroke increases the risk of developing dementia significantly [
      • Aharon-Peretz J.
      • Daskovski E.
      • Mashiach T.
      • Tomer R.
      Natural history of dementia associated with lacunar infarctions.
      ,
      • Savva G.M.
      • Stephan B.C.
      Epidemiological studies of the effect of stroke on incident dementia: a systematic review.
      ]. Pre-stroke cognitive impairment increases this risk of a more severe cognitive impairment immediately after the stroke [
      • Savva G.M.
      • Stephan B.C.
      Epidemiological studies of the effect of stroke on incident dementia: a systematic review.
      ] . Whether the existence of vascular risk factors and metabolic stress increases the risk of poor cognitive outcome after stroke is still debated [
      • Savva G.M.
      • Stephan B.C.
      Epidemiological studies of the effect of stroke on incident dementia: a systematic review.
      ,
      • Newman G.C.
      • Bang H.
      • Hussain S.I.
      • Toole J.F.
      Association of diabetes, homocysteine, and HDL with cognition and disability after stroke.
      ]. Cognitive impairment is determined partly by the occurrence of recurrent strokes [
      • Aharon-Peretz J.
      • Daskovski E.
      • Mashiach T.
      • Tomer R.
      Natural history of dementia associated with lacunar infarctions.
      ,
      • Savva G.M.
      • Stephan B.C.
      Epidemiological studies of the effect of stroke on incident dementia: a systematic review.
      ,
      • van der Linde R.
      • Stephan B.C.
      • Matthews F.E.
      • Brayne C.
      • Savva G.M.
      Behavioural and psychological symptoms in the older population without dementia—relationship with socio-demographics, health and cognition.
      ,
      • Srikanth V.K.
      • Quinn S.J.
      • Donnan G.A.
      • Saling M.M.
      • Thrift A.G.
      Long-term cognitive transitions, rates of cognitive change, and predictors of incident dementia in a population-based first-ever stroke cohort.
      ], but other factors, possibly related to accelerated AD-like processes, may also be involved [
      • Li L.
      • Zhang X.
      • Yang D.
      • Luo G.
      • Chen S.
      • Le W.
      Hypoxia increases Abeta generation by altering beta- and gamma-cleavage of APP.
      ].
      Corroborating the latter, medial temporal lobe atrophy, suggestive of preclinical AD is associated with a poorer outcome [
      • Firbank M.J.
      • Burton E.J.
      • Barber R.
      • Stephens S.
      • Kenny R.A.
      • Ballard C.
      • et al.
      Medial temporal atrophy rather than white matter hyperintensities predict cognitive decline in stroke survivors.
      ]. Epileptic seizures after stroke were also associated with increased risk of dementia [
      • Cordonnier C.
      • Henon H.
      • Derambure P.
      • Pasquier F.
      • Leys D.
      Early epileptic seizures after stroke are associated with increased risk of new-onset dementia.
      ].

      7. Neuropsychological profile

      The first cortical neuropathological changes in AD occur in the medial temporal lobes, and this correlates nicely with the memory impairment in early AD. Interestingly, medial temporal atrophy also occurs in VaD [
      • Firbank M.J.
      • Burton E.J.
      • Barber R.
      • Stephens S.
      • Kenny R.A.
      • Ballard C.
      • et al.
      Medial temporal atrophy rather than white matter hyperintensities predict cognitive decline in stroke survivors.
      ]. Nevertheless, the neuropsychological profile of VCI is heterogeneous (Table 3). The so-called typical expression of VaD is executive dysfunction, manifested as impaired attention, planning, difficulties in complex activities, and disorganized thought, behaviour, or emotion [
      • Sachdev P.S.
      • Brodaty H.
      • Valenzuela M.J.
      • Lorentz L.
      • Looi J.C.
      • Wen W.
      • et al.
      The neuropsychological profile of vascular cognitive impairment in stroke and TIA patients.
      ,
      • Nordlund A.
      • Rolstad S.
      • Klang O.
      • Lind K.
      • Hansen S.
      • Wallin A.
      Cognitive profiles of mild cognitive impairment with and without vascular disease.
      ]. However, this applies mainly to patients with subcortical white matter disease and patients with frontal lobe lesions. As mentioned above, changes following cortical strokes depend on their location. Slower reactions are the expected result of lesions in the frontal lobes or subcortical damage affecting the cortico-basal ganglionic–thalamic circuits. Unfortunately, reaction time is not measured routinely in cognitive testing of dementing individuals. Attempts to compare the neuropsychological profile of VaD and AD showed some differences, which were, however, not consistent from one study to another [
      • Laukka E.J.
      • Jones S.
      • Small B.J.
      • Fratiglioni L.
      • Backman L.
      Similar patterns of cognitive deficits in the preclinical phases of vascular dementia and Alzheimer's disease.
      ].
      Table 3Neuropsychological findings of vascular lesion.
      Neuropsychological changesAssessment toolBrain lesion suspected location
      “Patchy” cognitive profile: better oriented to time, better recall (compared to AD), poor working memory, graphomotor impairmentMattis dementia rating scale, MMSE, MoCACortical–subcortical or interhemispheric disconnection, frontal lobes, striatum diencephalon, basal forebrain, limbic paralimbic area
      Slow motor and information processingWord-list generation task, spelling backward, Rey complex figure testWhite matter, particularly affecting basal-ganglionic-frontal connections
      Visuosaptial and graphomotor impairmentClock drawing, Rey complex figure test
      Attention deficitDigit symbol substitution test, 7 serias, Trail making test B
      Executive dysfunctionTrail making, maze test, clock drawing, spelling backwardWhite matter, particularly affecting basal-ganglionic-frontal connections
      Language difficultiesWechsler Adult Intelligence Scale (similarities subtest), Boston naming testDominant hemisphere lesions
      Abrupt behavioural changesThalamus, angular gyrus, caudate nucleus or inferior genu of internal capsule
      The widespread bedside instrument used to evaluate cognitive dysfunction, the mini-mental state examination (MMSE) [
      • Folstein M.F.
      • Folstein S.E.
      • McHugh P.R.
      "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician.
      ] is frequently employed in the evaluation of VaD. However it contains few items related to executive functions and thus, may underestimate the cognitive decline. The Montreal Cognitive Assessment (MoCA) may be better suited for this purpose [
      • Smith T.
      • Gildeh N.
      • Holmes C.
      The Montreal Cognitive Assessment: validity and utility in a memory clinic setting.
      ]. These tests are both aimed to evaluate the severity of cognitive impairment, rather than to diagnose dementia, and they are more sensitive to left hemisphere than to right hemisphere dysfunction. Importantly, a given score on each of these tests may have a different significance in AD than in VaD patients. The clock-drawing test [
      • Sunderland T.
      • Hill J.L.
      • Mellow A.M.
      • Lawlor B.A.
      • Gundersheimer J.
      • Newhouse P.A.
      • et al.
      Clock drawing in Alzheimer's disease. A novel measure of dementia severity.
      ] and the trail making test [
      • Brown E.C.
      • Casey A.
      • Fisch R.I.
      • Neuringer C.
      Trial making test as a screening device for the detection of brain damage.
      ] are both short bedside tests, useful in the measurement of executive function. However, no neuropsychological test has been proven to reliably differentiate VCI from other dementia syndromes, and particularly none can distinguish mixed dementia from either VaD or pure AD. The distinction between VCI and FTD or DLB is not assisted by neuropsychological testing, since executive functions are impaired at an early stage in FTD and DLB as well.

      8. Differential diagnosis

      In many cases, dementia is clearly of vascular origin. This is particularly the case in younger individuals, where there is an abrupt cognitive decline associated with focal signs such as hemiparesis. Since mental changes are something recovered after a vascular brain injury, the term dementia should be used only when proved that the condition is permanent. The NINDS-AIREN [
      • Roman G.C.
      • Tatemichi T.K.
      • Erkinjuntti T.
      • Cummings J.L.
      • Masdeu J.C.
      • Garcia J.H.
      • et al.
      Vascular dementia—diagnostic criteria for research studies—report of the NINDS-AIREN international workshop.
      ] acknowledges cognitive deterioration up to three months after a stroke as consistent with VaD.
      As mentioned before, cognitive deterioration can develop belatedly over months following an acute stroke [
      • Pendlebury S.T.
      • Rothwell P.M.
      Risk of recurrent stroke, other vascular events and dementia after transient ischaemic attack and stroke.
      ,
      • Tatemichi T.K.
      • Paik M.
      • Bagiella E.
      • Desmond D.W.
      • Stern Y.
      • Sano M.
      • et al.
      Risk of dementia after stroke in a hospitalized cohort: results of a longitudinal study.
      ]. In many patients the decline occurs without new ischemic lesions, possibly due to enhanced deposition of Aβ in the brain following the stroke [
      • Li L.
      • Zhang X.
      • Yang D.
      • Luo G.
      • Chen S.
      • Le W.
      Hypoxia increases Abeta generation by altering beta- and gamma-cleavage of APP.
      ,
      • Bell R.D.
      • Zlokovic B.V.
      Neurovascular mechanisms and blood–brain barrier disorder in Alzheimer's disease.
      ,
      • Iadecola C.
      Cerebrovascular effects of amyloid-beta peptides: mechanisms and implications for Alzheimer's dementia.
      ], clouding the border between VaD and AD [
      • Korczyn A.D.
      The clinical differential diagnosis of dementia: concept and methodology.
      ].
      White matter changes are very frequent in the elderly, including in AD patients [
      • Henry-Feugeas M.C.
      MRI of the 'Alzheimer syndrome'.
      ], may be manifested as depression [
      • Alexopoulos G.S.
      • Meyers B.S.
      • Young R.C.
      • Campbell S.
      • Silbersweig D.
      • Charlson M.
      'Vascular depression' hypothesis.
      ], gait impairment or parkinsonism [
      • Handley A.
      • Medcalf P.
      • Hellier K.
      • Dutta D.
      Movement disorders after stroke.
      ], or cognitive decline, although many elderly patients with WML are symptom-free. In cases of WMLs, the cognitive decline is usually insidious and may mimic the clinical deterioration in AD. Subcortical VaD patients may have slow mentation, as opposed to the memory decline which is typical for AD. However, slow mentation can also occur in AD patients who have leukoaraiosis.
      Another important distinction is between VaD from DLB and FTD. Fluctuating alertness is frequent in both DLB and vascular brain disease. Parkinsonian signs, slowness, and particularly gait impairment, may be of vascular, rather than neurodegenerative origin [
      • Balash Y.
      • Korczyn A.D.
      Vascular parkinsonism.
      ]. Although language problems or behavioral changes characterize FTD they usually progress insidiously, as oppose to the abrupt deficits seen after a stroke. In this cases, brain imaging can help to discriminate vascular from neurodegenerative changes.
      A formal division of dementia cases using the dichotomy, vascular versus neurodegenerative may be inappropriate. While logical and conceptually valid, most elderly subjects have multiple brain pathologies. In an excellent series of autopsy cases studied by Schneider et al. [
      • Schneider J.A.
      • Arvanitakis Z.
      • Bang W.
      • Bennett D.A.
      Mixed brain pathologies account for most dementia cases in community-dwelling older persons.
      ,
      • Schneider J.A.
      • Arvanitakis Z.
      • Leurgans S.E.
      • Bennett D.A.
      The neuropathology of probable Alzheimer disease and mild cognitive impairment.
      ], most brains with pure AD pathology belonged to people who had not been demented, and the number of demented people who had pure AD changes was considerably fewer than those who had both AD and vascular brain pathology. An analogous picture emerged when vascular changes were looked at: most people with pure vascular brain pathology at death had not been demented, while dementia was much more common in people with dual pathology (AD and vascular) than vascular alone. Mixed dementia may even be more common than these results suggest since the investigators disregarded WMLs in the criteria for VaD [
      • Schneider J.A.
      • Arvanitakis Z.
      • Leurgans S.E.
      • Bennett D.A.
      The neuropathology of probable Alzheimer disease and mild cognitive impairment.
      ].

      9. Neuropathology

      To date there are no accepted neuropathological criteria for diagnosing VaD or VCI, as agreed for AD, DLB or FTD. Vascular lesions are rather classified based on their morphological characteristics than by their pathogenesis. A drastic change in the way these changes are defined is critical for the creation of a new set of pathological diagnostic criteria [
      • Grinberg L.T.
      • Heinsen H.
      Toward a pathological definition of vascular dementia.
      ].
      Multiple vessel disorders occur in the aging human brain, frequently in combination and with other non-vascular changes. These vessel disorders can induce various types of cerebral tissue lesions like haemorrhage, infarction, hippocampal sclerosis, and white matter lesions [
      • Grinberg L.T.
      • Thal D.R.
      Vascular pathology in the aged human brain.
      ], any of which can result in cognitive decline. Vascular changes are found frequently in brains of cognitively normal elderly [
      • Schneider J.A.
      • Arvanitakis Z.
      • Bang W.
      • Bennett D.A.
      Mixed brain pathologies account for most dementia cases in community-dwelling older persons.
      ], making it difficult to establish a causal relationship between brain lesions and cognitive decline. Therefore, a pathological diagnosis of VaD is very frequently granted when non-vascular findings are ruled out. Classifications currently in use distinguish disorders of large-sized vessels from those of small brain vessels, and also lesions due to impaired perfusion (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Major pathological findings underlying vascular dementia.
      Vascular associated lesions commonly associated with cognitive decline (Fig. 2).
      Figure thumbnail gr2
      Fig. 2Some of the major pathological changes underlying vascular dementia.
      a) Ischemic infarct. Note the wedge-shape border of the infarct (arrows). Both white and gray matter are involved. Nissl staining.
      b) Lacunar infarct characterized by an irregular cavity and a central blood vessel surrounded by a rim of gliotic, rarefied brain tissue (arrow). Hematoxylin and eosin stain (H&E).
      c) Histopathological counterpart of a white matter lesion detected by MRI in a 62 years-old male. Note the regions of myelin pallor (**) and an enlarged perivascular space (arrow). Kluever–Barrera stain.
      d) Cerebral amyloid angiopathy (CAA). The Aβ-deposition in the wall of a cortical artery is colored in brown (arrow). In this case, there is a microbleed around this artery (note the anuclear red blood cells). Immunostain with an antibody against Ab17-24 (4G8; Covance).
      e) Small vessel disease. Two white matter arteries exhibit fibrosis and hyalinization of wall (arrows). These lesions are also referred to as arteriolosclerosis, arteriohyalinosis or lipohyalinosis (arrow). H&E.
      The calibration bars correspond to:100 μm.

      9.1 Large- and medium-sized vessel disorders

      Atherosclerosis is a degenerative vessel disorder that affects large- to medium-sized arteries. The vessels of the circle of Willis are most frequently affected and the occurrence of those changes increases as a function of age and risk factors such as hypertension and dyslipidemia. Evidence shows a significant coexistence of atherosclerosis of the circle of Willis and dementia, but it is unclear if a relationship exist or if it is a coincidental finding [
      • Suemoto C.K.
      • Nitrini R.
      • Grinberg L.T.
      • Ferretti R.E.
      • Farfel J.M.
      • Leite R.E.
      • et al.
      Atherosclerosis and dementia: a cross-sectional study with pathological analysis of the carotid arteries.
      ]. Atherosclerotic plaques are prone to rupture and the resulting thrombus can lead to vessel occlusion or it can obstruct smaller arteries.

      9.2 Small sized vessel disorders

      The term small vessel disease (SVD) describes a distinct group of small vessel changes also known as: small vessel arteriosclerosis, atherosclerosis, arteriolosclerosis, arteriohyalinosis, and lipohyalinosis [
      • Grinberg L.T.
      • Thal D.R.
      Vascular pathology in the aged human brain.
      ,
      • Pantoni L.
      Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges.
      ,
      • Jellinger K.A.
      The enigma of vascular cognitive disorder and vascular dementia.
      ]. White matter arteries often show loss of smooth muscle cells, fibrosis, and thickening of the basement membrane, and enlarged perivascular spaces, with leakage of plasma proteins [
      • Simpson J.E.
      • Wharton S.B.
      • Cooper J.
      • Gelsthorpe C.
      • Baxter L.
      • Forster G.
      • et al.
      Alterations of the blood–brain barrier in cerebral white matter lesions in the ageing brain.
      ]. These changes can lead to vessel occlusion, microaneurysms, and fibrinoid necrosis of the vessel wall. SVD is an important cause of white matter destruction, but WMLs may have other origins, such as inflammatory processes [
      • Takao M.
      • Koto A.
      • Tanahashi N.
      • Fukuuchi Y.
      • Takagi M.
      • Morinaga S.
      Pathologic findings of silent, small hyperintense foci in the basal ganglia and thalamus on MRI.
      ,
      • Fazekas F.
      • Kleinert R.
      • Offenbacher H.
      • Schmidt R.
      • Kleinert G.
      • Payer F.
      • et al.
      Pathologic correlates of incidental MRI white matter signal hyperintensities.
      ] and Wallerian degeneration [
      • Leys D.
      • Pruvo J.P.
      • Parent M.
      • Vermersch P.
      • Soetaert G.
      • Steinling M.
      • et al.
      Could Wallerian degeneration contribute to "leuko-araiosis" in subjects free of any vascular disorder?.
      ].
      Sporadic cerebral amyloid angiopathy (CAA) is characterized by amyloid-β protein (Aβ) deposition in cerebral and leptomeningeal arteries, veins and capillaries. CAA is strongly associated with the development of AD-related pathology in the brain, and therefore, it will not be further discussed in this review.

      9.3 Infarcts

      Large infarcts, exceeding 10 mm in diameter, are most frequently ischemic as a consequence of artery occlusion. Approximately 10% of all brain infarcts are located between the territories of two major arteries, and are called watershed or borderzone infarct.
      Single large strokes or strokes at strategic locations are the most clinically obvious and easy to diagnose. Indeed, acute hemispheric strokes, whether cortical or thalamic, ischemic or hemorrhagic, result in cognitive deterioration in a significant proportion of patients [
      • Hoffmann M.
      • Schmitt F.
      • Bromley E.
      Vascular cognitive syndromes: relation to stroke etiology and topography.
      ]. A recent meta-analysis showed that 10% of patients had dementia before their first stroke while another 10% developed it soon after the first stroke, and more than a third developed dementia after recurrent strokes [
      • Pendlebury S.T.
      • Rothwell P.M.
      Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis.
      ]. The cognitive decline may appear insidiously within several months after the stroke [
      • Pendlebury S.T.
      • Rothwell P.M.
      Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis.
      ,
      • Hoffmann M.
      • Schmitt F.
      • Bromley E.
      Vascular cognitive syndromes: relation to stroke etiology and topography.
      ,
      • Sachdev P.S.
      • Brodaty H.
      • Valenzuela M.J.
      • Lorentz L.M.
      • Koschera A.
      Progression of cognitive impairment in stroke patients.
      ,
      • Tatemichi T.K.
      • Paik M.
      • Bagiella E.
      • Desmond D.W.
      • Pirro M.
      • Hanzawa L.K.
      Dementia after stroke is a predictor of long-term survival.
      ]. The term Multi-infarct dementia (MID) describes the cumulative effect of multiple strokes [
      • Hachinski V.C.
      • Lassen N.A.
      • Marshall J.
      Multi-infarct dementia. A cause of mental deterioration in the elderly.
      ]. This implies that small, even clinically unrecognized lesions can culminate in cognitive decline, although large strokes are important contributors.
      Lacunar infarcts are cavitating anemic infarcts, measuring up to 10 mm in diameter, visible radiologically and upon gross examination. They are largely confined to the cerebral white matter and subcortical structures. Subcortical nuclei are most vulnerable given they are irrigated by end arteries, which are almost devoid of anastomoses. Lacunar infarcts are associated to hypertension [
      • Grinberg L.T.
      • Thal D.R.
      Vascular pathology in the aged human brain.
      ] and are shown to be associated with cognitive decline [
      • Koga H.
      • Takashima Y.
      • Murakawa R.
      • Uchino A.
      • Yuzuriha T.
      • Yao H.
      Cognitive consequences of multiple lacunes and leukoaraiosis as vascular cognitive impairment in community-dwelling elderly individuals.
      ,
      • Jellinger K.A.
      A critical evaluation of current staging of alpha-synuclein pathology in Lewy body disorders.
      ]. Although special terms are used to denote a large number of lacunes in the same region, such as etat lacunaire or status lacunaris (when seen in the gray matter) and etat crible or status cribrosus (when seen in the white matter), these terms are merely descriptive terms and do not reflect the pathogenesis [
      • Kalaria R.N.
      • Kenny R.A.
      • Ballard C.G.
      • Perry R.
      • Ince P.
      • Polvikoski T.
      Towards defining the neuropathological substrates of vascular dementia.
      ].
      In contrast to gross infarction and lacunar infarcts, microinfarcts not visible on gross or in imaging examinations. They are most commonly seen in the watershed areas of cortex and apparently do contribute to cognitive decline [
      • Kovari E.
      • Gold G.
      • Herrmann F.R.
      • Canuto A.
      • Hof P.R.
      • Bouras C.
      • et al.
      Cortical microinfarcts and demyelination affect cognition in cases at high risk for dementia.
      ].
      Cortical laminar necrosis or pseudolaminar necrosis is characterized by neuronal loss and gliosis in the neocortex caused by global hypotension or hypoxaemia [
      • Jellinger K.A.
      Understanding the pathology of vascular cognitive impairment.
      ]. It appears more commonly at arterial borderzones and is often associated with WML.
      Hippocampal sclerosis (HS) is a pathological term used to describe severe loss of neurons and reactive gliosis without pseudocystic cavitation in the CA1 sector of the hippocampus and the subiculum. It is commonly seen after global hypoxemia because the pyramidal neurons of CA1 sector are particularly vulnerable to ischemia. However, HS is also seen in epilepsy, frontotemporal lobar degeneration [
      • Probst A.
      • Taylor K.I.
      • Tolnay M.
      Hippocampal sclerosis dementia: a reappraisal.
      ], and even in normal people [
      • Labate A.
      • Gambardella A.
      • Aguglia U.
      • Condino F.
      • Ventura P.
      • Lanza P.
      • et al.
      Temporal lobe abnormalities on brain MRI in healthy volunteers: a prospective case-control study.
      ].
      White matter lesions are found in up to 65% of subjects over 65 years of age, and their frequency increases in patients with cerebrovascular disease or with cardiovascular risk. WMLs have been recognized since the work of Binswanger, as causing dementia [
      • Binswanger O.
      Die Abgrenzung der allgemeinen progressiven Paralyse.
      ]. It is of course not surprising that extensive destruction of the connectivity between neurons will result in cognitive impairment. WMLs usually comprise, in variable degrees, demyelination, axonal loss, mild reactive astrocytosis, oedema, macrophage reaction, and microangiopathy of the penetrating arteries [
      • Fazekas F.
      • Kleinert R.
      • Offenbacher H.
      • Schmidt R.
      • Kleinert G.
      • Payer F.
      • et al.
      Pathologic correlates of incidental MRI white matter signal hyperintensities.
      ]. As a rule, the subcortical U-fibers are spared. The underlying pathology of WML includes a wide range of lesions, including microangiopathy, venous collagenosis [
      • Brown W.R.
      • Moody D.M.
      • Thore C.R.
      • Anstrom J.A.
      • Challa V.R.
      Microvascular changes in the white mater in dementia.
      ], global chronic ischemia [
      • Fazekas F.
      • Kleinert R.
      • Offenbacher H.
      • Schmidt R.
      • Kleinert G.
      • Payer F.
      • et al.
      Pathologic correlates of incidental MRI white matter signal hyperintensities.
      ] and Wallerian degeneration [
      • Leys D.
      • Pruvo J.P.
      • Parent M.
      • Vermersch P.
      • Soetaert G.
      • Steinling M.
      • et al.
      Could Wallerian degeneration contribute to "leuko-araiosis" in subjects free of any vascular disorder?.
      ].
      Microbleed is the term used to describe blood extravasation into perivascular or Virchow–Robin spaces, or small intracerebral haemorrhages, less than 10 mm in diameter. Their prevalence increases with age. Usually, microbleeds are associated with CAA and hypertension. Their exact pathogenesis and cognitive effects remain to be clarified, as these may be surrogate for microvascular disease [
      • De Reuck J.
      • Auger F.
      • Cordonnier C.
      • Deramecourt V.
      • Durieux N.
      • Pasquier F.
      • et al.
      Comparison of 7.0-T T*-magnetic resonance imaging of cerebral bleeds in post-mortem brain sections of Alzheimer patients with their neuropathological correlates.
      ,
      • Tsushima Y.
      • Aoki J.
      • Endo K.
      Brain microhemorrhages detected on T2*-weighted gradient-echo MR images.
      ].

      10. Biomarkers

      Since its inception, brain imaging methods particularly CT and MRI, are being used as important tools for supporting the diagnosis of VaD [
      • O'Brien J.T.
      Role of imaging techniques in the diagnosis of dementia.
      ]. Imaging changes frequently seen in patients diagnosed with VaD include infarcts of variable size, white matter changes, hippocampal sclerosis, and hemosiderin deposits indicative of hemorrhages. However, caution must be exercised in the interpretation of vascular-related brain lesions found in imaging, since lacunes and WMLs are commonly seen in non-demented elderly individuals. Moreover, imaging lack specificity of other causes of dementia, such as AD, and thus relying on imaging alone will result in excessive diagnosis of VaD, and underestimation of mixed dementia cases [
      • Korczyn A.D.
      Mixed dementia—the most common cause of dementia.
      ,
      • Nagga K.
      • Radberg C.
      • Marcusson J.
      CT brain findings in clinical dementia investigation—underestimation of mixed dementia.
      ]. Lately, the advent of amyloid imaging is helping to identify mixed dementia cases, although this is expensive and not widely available. Cerebrospinal fluid changes on Aβ, tau and phosphorylated tau levels indicate AD in a group level [
      • Halperin I.
      • Morelli M.
      • Korczyn A.D.
      • Youdim M.B.
      • Mandel S.A.
      Biomarkers for evaluation of clinical efficacy of multipotential neuroprotective drugs for Alzheimer's and Parkinson's diseases.
      ]. On the other hand, to date, no reliable CSF biomarkers for VaD exist.

      11. Therapy

      11.1 Primary prevention

      Prevention of VaD, will, in principle, depend on the prevention of strokes through risk factor modification. Positive results have so far been demonstrated with the calcium channel blocker nitrendipine [
      • Forette F.
      • Seux M.L.
      • Staessen J.A.
      • Thijs L.
      • Babarskiene M.R.
      • Babeanu S.
      • et al.
      The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study.
      ], ACE inhibitors, and diuretics [
      • Shah K.
      • Qureshi S.U.
      • Johnson M.
      • Parikh N.
      • Schulz P.E.
      • Kunik M.E.
      Does use of antihypertensive drugs affect the incidence or progression of dementia? A systematic review.
      ]. It is still unclear whether all antihypertensive drugs have the same effect. Angiotensin II receptor blockers may be particularly effective because of their direct effects on the brain [
      • Mogi M.
      • Horiuchi M.
      Effects of angiotensin II receptor blockers on dementia.
      ]. Because of the proven efficacy of antihypertensive drugs against cardiovascular diseases, placebo-controlled trials with these drugs are unethical. Any differences between drugs could be shown only by head-to-head comparisons.
      Blood hypertension is considered to be an important cardiovascular risk. However, As opposed of previously believed, lowering blood pressure in older people may have a deleterious effect on the cognition, by causing ischemic damage to these brains, usually affected by impaired cerebral autoregulation [
      • McGuinness B.
      • Todd S.
      • Passmore P.
      • Bullock R.
      Blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia.
      ,
      • Verghese J.
      • Lipton R.B.
      • Hall C.B.
      • Kuslansky G.
      • Katz M.J.
      Low blood pressure and the risk of dementia in very old individuals.
      ].
      On the other hand, epidemiological data suggest a benefit in controlling vascular risk factors, including hypertension in midlife [
      • Monsuez J.J.
      • Gesquiere-Dando A.
      • Rivera S.
      Cardiovascular prevention of cognitive decline.
      ]. Yet, if protective actions need to extend for several decades, it may be impossible to prove its efficacy.

      11.2 Secondary prevention

      In the event of cognitive decline following a stoke, aggressive protective measures against further strokes should be initiated. Indeed, such protective measures may also benefit AD patients [
      • Deschaintre Y.
      • Richard F.
      • Leys D.
      • Pasquier F.
      Treatment of vascular risk factors is associated with slower decline in Alzheimer disease.
      ,
      • Richard E.
      • Gouw A.A.
      • Scheltens P.
      • van Gool W.A.
      Vascular care in patients with Alzheimer disease with cerebrovascular lesions slows progression of white matter lesions on MRI: the evaluation of vascular care in Alzheimer's disease (EVA) study.
      ].

      11.3 Symptomatic therapy

      No drug has so far been approved for the treatment of VaD. However, all approved anti-AD drugs have been investigated in VaD, including the cholinesterase inhibitors (ChEIs) [
      • Meyer J.S.
      • Chowdhury M.H.
      • Xu G.
      • Li Y.S.
      • Quach M.
      Donepezil treatment of vascular dementia.
      ,
      • Auchus A.P.
      • Brashear H.R.
      • Salloway S.
      • Korczyn A.D.
      • De Deyn P.P.
      • Gassmann-Mayer C.
      Galantamine treatment of vascular dementia: a randomized trial.
      ,
      • Moretti R.
      • Torre P.
      • Antonello R.M.
      • Cazzato G.
      Rivastigmine in subcortical vascular dementia: a comparison trial on efficacy and tolerability for 12 months follow-up.
      ,
      • Dichgans M.
      • Markus H.S.
      • Salloway S.
      • Verkkoniemi A.
      • Moline M.
      • Wang Q.
      • et al.
      Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL.
      ], and memantine [
      • Orgogozo J.M.
      • Rigaud A.S.
      • Stoffler A.
      • Mobius H.J.
      • Forette F.
      Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300).
      ]. While all were found to be useful in some (but not all) measures, the effect size was rather small and marked heterogeneity among studies was observed [
      • Dichgans M.
      • Markus H.S.
      • Salloway S.
      • Verkkoniemi A.
      • Moline M.
      • Wang Q.
      • et al.
      Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL.
      ,
      • Kavirajan H.
      • Schneider L.S.
      Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials.
      ]. Actually, the observed benefit could result from an effect on co-existing AD [
      • Dichgans M.
      • Markus H.S.
      • Salloway S.
      • Verkkoniemi A.
      • Moline M.
      • Wang Q.
      • et al.
      Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL.
      ], although it is recognized that vascular lesions involved the cholinergic pathways from the nucleus basalis of Meynert or the nucleus itself [
      • Kavirajan H.
      • Schneider L.S.
      Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials.
      ]. Donepezil has been tested in CADASIL [
      • Deschaintre Y.
      • Richard F.
      • Leys D.
      • Pasquier F.
      Treatment of vascular risk factors is associated with slower decline in Alzheimer disease.
      ], a rare genetic disorder causing VaD, with no benefits. In clinical practice, ChEI and memantine are usually given empirically to VaD patients and continued when symptomatic improvement is observed.
      Several other studies reported beneficial effects of cerebrolysin [
      • Muresanu D.F.
      • Alvarez X.A.
      • Moessler H.
      • Buia M.
      • Stan A.
      • Pintea D.
      • et al.
      A pilot study to evaluate the effects of cerebrolysin on cognition and qEEG in vascular dementia: cognitive improvement correlates with qEEG acceleration.
      ], citicoline [
      • Secades J.J.
      • Lorenzo J.L.
      Citicoline: pharmacological and clinical review, 2006 update.
      ] and ginkgo biloba [
      • Napryeyenko O.
      • Sonnik G.
      • Tartakovsky I.
      Efficacy and tolerability of Ginkgo biloba extract EGb 761 by type of dementia: analyses of a randomised controlled trial.
      ], but these results need confirmation. Other drugs such as anxiolytics, antidepressant drugs, sleeping pills, anticonvulsants can be prescribed to modulate for non-cognitive manifestations. Special care needs to be employed when using neuroleptic drugs because of their unfavourable effect on cardiovascular disease [
      • Ray W.A.
      • Chung C.P.
      • Murray K.T.
      • Hall K.
      • Stein C.M.
      Atypical antipsychotic drugs and the risk of sudden cardiac death.
      ,
      • Trifiro G.
      • Spina E.
      • Gambassi G.
      Use of antipsychotics in elderly patients with dementia: do atypical and conventional agents have a similar safety profile?.
      ]. Non-medicamental therapies have been suggested for improving VaD symptoms and recurrence of vascular lesions, including social interaction and intellectual stimulation, treatment of aphasia and emotional changes, and acupuncture (Table 4).
      Table 4Targets of non-pharmacological interventions to modify vascular risk factors.
      Heart failure
      Blood hyperviscosity
      Polycythaemia
      Carotid artery and intracranial arteries stenosis
      Overweight
      Physical inactivity
      Smoking
      Diet

      12. Conclusions

      Vascular brain disease can take several forms, most commonly associated with stroke. However, multiple vascular disorders occur in the aging human brain, which may induce various types of cerebral tissue lesions like hemorrhage, infarction, hippocampal sclerosis, and white matter lesions. Any of these changes can result in cognitive decline and dementia also. Recent studies suggest that parkinsonism and depression can also present a presumably vascular etiology. Pure VaD appears to be rare, but strong evidence point that vascular changes do worsen the cognition and even other brain functions when associated with other neurodegenerative changes. Considering that among the common etiologies of dementia, vascular changes are the only ones which can at present be prevented, special attention to vascular risk factors must be employed in patients with either dementia or incipient cognitive decline.

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