Vascular dementia: dead or alive?

EDITORIAL

Vascular Dementia: Dead or Alive?RAHUL RAO1* AND ROBERT HOWARD2

1Senior Registrar in Old Age Psychiatry Maudsley Hospital, Denmark Hill, London SE5 8AZ, UK2Senior Lecturer in Old Age Psychiatry, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK

SUMMARY

The term `Vascular Dementia' remains popular as a diagnostic entity, since it encompasses a variety of vascularpathologies. This is in stark contrast to many clinical classi®catory systems that weight their de®nitions stronglytowards stroke alone. A diagnosis of vascular dementia is complicated by compounding factors that reduce both thevalidity and speci®city of diagnostic systems. This review highlights some of the problems faced in epidemiological,clinical, neuropathological and radiological studies attempting to de®ne a clear-cut syndrome of dementia associatedwith cerebrovascular disease. The role of non-stroke ischaemia is also discussed. It is concluded that the term `vasculardementia' may have outlived its usefulness as a valid concept; alternative approaches are suggested. # 1998 JohnWiley & Sons, Ltd.

Int. J. Geriat. Psychiatry, 13: 277±284, 1998.

KEY WORDSÐdementia; cognitive impairment; stroke; cerebrovascular disease; diagnosis

Opinion regarding the relationship betweenthe cerebrovascular circulation and its e�ectson intellectual function has swung backwardsand forwards in a pendular fashion over the pasttwo centuries. The two aetiopathological mech-anisms debated have been those of thrombo-embolic disease and chronic ischaemia. Thedevelopment of brain imaging techniques in the1980s allowed the contribution of both pathologiesto be assessed more comprehensively. As a result,the term `vascular dementia' (VaD) emphasizesthe importance of both ischaemic and thrombo-embolic/haemorrhagic correlates. Notwithstandingthe in¯uences that have shaped the current conceptof VaD, the validity of a `pure' dementia associatedwith cerebrovascular pathology remains open todebate.

CARDIOVASCULAR RISK FACTORSAND DEMENTIA

Cerebrovascular disease is known to be associatedwith certain risk factors, often referred to as

vascular risk factors (VRFs). The relationshipbetween VRFs and cognitive impairment hascommonly been studied following stroke, as thisis the commonest manifestation of cerebrovasculardisease seen on clinical examination. The role ofVRFs associated with cerebrovascular disease inthe aetiology of cognitive impairment not accom-panied by clinical/radiological evidence of strokeis less clear (Drachman, 1993). This includes VRFsassociated with `cerebral hypoperfusion' asopposed to thromboembolism or haemorrhage(O'Brien, 1988; Frederiks, 1993). VRFs are alsoimplicated in the pathogenesis of Alzheimer'sdisease (AD) (Skoog et al., 1996; Kokmen et al.,1991; Prince et al., 1994; Mortel et al., 1993).

CLINICAL VALIDITY OFVASCULAR DEMENTIA

The commonest classifactory systems in use basetheir criteria for dementia on AD (World HealthOrganisation, 1993; American Psychiatric Associ-ation, 1994), although more recent diagnosticsystems (Chui et al., 1992) allow a number ofdi�erent areas of cognitive function to be a�ected.

CCC 0885±6230/98/050277±08$17.50 Received 18 April 1997# 1998 John Wiley & Sons, Ltd. Accepted 15 December 1997

INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, VOL. 13: 277±284 (1998)

*Correspondence to: Dr R. Rao, Consultant/Senior Lecturer inOld Age Psychiatry, Job Ward, Thomas Guy House, Guy'sHospital, London SE1 9RT, UK.

Using both diagnostic systems, criteria for thepresence of cerebrovascular disease are synony-mous with those for stroke (Hachinski, 1992).The Hachinski Ischaemic Scale (HIS) (Hachinskiet al., 1975) was developed as a method ofdistinguishing AD from `multi-infarct dementia',but the validity and reliability of this scale havebeen questioned. Firstly, it is based on the clinicalfeatures of reduced cerebral blood ¯ow, which areheavily weighted towards the clinical ®ndingsassociated with stroke. Thus, patients with cerebralhypoperfusion and clinically `silent' cerebral in-farcts would be classi®ed as having AD on the basisof the scale (Larson et al., 1989). The fact thatclinical features such as ¯uctuating course, abruptonset, stepwise progression and preservation ofpersonality are also shared with Lewy bodydementia also serves to weaken the validity of theHIS. Secondly, ambiguity in the interpretation ofcertain items has been shown to reduce interraterreliability (O'Neill et al., 1995).

Attributing causality from clinical manifesta-tions of cerebrovascular disease to dementia can beproblematic, as the temporal relationship betweenthe two may be uncertain (Lopez et al., 1994;Tatemichi et al., 1993); this is further complicatedby the presence of multiple pathologies in `mixeddementia' (Goto et al., 1981) where there isevidence for the coexistence of pathologies ofboth AD and cerebrovascular disease (Altermanand Avnon, 1992; Erkinjunnti, 1994).

CLINICOPATHOLOGICAL STUDIESOF VASCULAR DEMENTIA

Prospective clinicopathological studies examiningthe relationship between vascular risk factors anddementia have been hampered by an incompleteunderstanding of de®nitive pathological markersfor VaD as opposed to those found in normalageing (Crystal et al., 1993). The HIS uses a cuto�point of 7 to classify VaD. Using this scale,speci®cities of 70% or more have been found inthose studies designed to distinguish VaD fromAD,but these same studies have found low speci®citieswhen attempting to separate VaD from mixeddementia (Molsa et al., 1985; Chui, 1989; Wadeet al., 1987; Jellinger et al., 1990). The contributionof the HIS towards making a clinical diagnosis ofmixed dementia therefore remains problematic.Diagnoses of VaD according to NINCDS±AIRENcriteria await clinicopathological correlation.

NEUROPSYCHOLOGY ANDVASCULAR DEMENTIA

In comparison with AD, the neuropsychologicalassessment of VaD has been subject to compara-tively fewer studies (La Rue, 1992). A number ofstudies have shown that there is no pro®le ofgeneralized intellectual dysfunction (Erkinjunntiet al., 1986; Olafsson et al., 1989; Gandolfo et al.,1986; Mazzuchi et al., 1987), or impairment ofmemory (Carlesimo et al., 1994; Fischer et al.,1988a; Padovani et al., 1995), language (Lowensteinet al., 1991; Fischer et al., 1988b) or visuospatialfunction (Almkvist et al., 1993; Almkvist, 1994)that is speci®c to VaD. This is perhaps notsurprising, given the heterogeneity in pathophysio-logical processes involved in VaD (eg multiplecortical infarcts, strategic infarcts, lacunar infarctsand ischaemic white matter lesions), as well as thesize and number of such lesions.

The concept of `subcortical dementia' (Rogers,1986) speci®cally associated with deep small vesseldisease (Marie, 1901) has gained momentumduring the past 50 years. Among a broad rangeof clinical features that characterize subcorticaldementia and serve to distinguish it from AD,frontal lobe dysfunction is listed as one suchfeature. However, no speci®c pattern of frontalde®cit has been consistently demonstrated inVaD (Caplan and Schoene, 1978; Babikian et al.,1990; Wolfe et al., 1990; Villardita, 1993). Closerinspection studies ®nding frontal lobe impairmentto be commoner in VaD reveal methodological¯aws such as selection bias. Moreover, somestudies exclude patients with stroke-related demen-tia, which would result in other vascular lesions(such as lacunar infarcts) becoming more prevalent(Kertesz and Clysedale, 1994). Impaired frontallobe function is also observed in early AD (Miller,1984; Pendleton et al., 1982; Storandt et al., 1984).

NEUROIMAGING AND VASCULARDEMENTIA

Neuroimaging has revolutionized the detectionof lesions associated with vascular pathology(Erkinjunnti et al., 1988). Current imagingmethods have advanced from structural imaging(such as the use of computerized tomography (CT)and magnetic resonance imaging (MRI)) to func-tional imaging of cerebral blood ¯ow and regional

# 1998 John Wiley & Sons, Ltd. INT. J. GERIAT. PSYCHIATRY, VOL. 13: 277±284 (1998)

278 R. RAO AND R. HOWARD

metabolism using transcranial Doppler, radio-labelled xenon, single-photon emission computer-ized tomography (SPECT) and positron emissiontomography (PET). The two main areas of interestin VaD are the detection of cortical infarctsinvolving major cerebral arteries and lesionsre¯ecting small vessel disease. The evidence for anassociation between dementia and the presence ofstrategic cortical infarcts appears consistent,particularly those located in the medial temporallobe, medial frontal lobe and the dominant angulargyrus (Ott and Saver, 1993; Alexander and Freed-man, 1984; Benson et al., 1990). When dementia isaccompanied by multiple cortical infarcts, theproblem of attributing causality becomes morecomplex. However, in cases of VaD where suchmultiple infarcts are present, temporoparietallesions show a more consistent association withdementia (Erkinjunnti et al., 1987; Liu et al., 1992;Tatemichi et al., 1990; Gorelick et al., 1992).

The association between VaD and deep smallartery disease a�ecting subcortical structures ismore contentious. In the case of single lacunarinfarcts, there is some limited evidence for strategicinfarcts in certain thalamic regions to be associatedwith VaD (Bougousslavasky et al., 1988; Castaigneet al., 1981; Gra�-Radford et al., 1985; Tatemichiet al., 1992). Infarcts in the head of the caudate(Caplan et al., 1990) and putamen (Pullicino et al.,1994) have similarly been associated with VaD.Dementia associated with lacunar rather thancortical infarcts has been hotly disputed by someresearchers (Tatemichi et al., 1994) and has been asource of ongoing debate for more than 30 years(Fisher, 1965). The lack of replicable data showinga clear association between lacunar infarctionand dementia leaves this debate open (Loeb et al.,1992).

White matter disease seen on structural neuro-imaging has attracted a considerable degree ofinterest since the more widespread use of MRI(Awad et al., 1986a,b). The most consistentassociations have been with hypertension (Bolleret al., 1977; Brott et al., 1986; Schmidt et al., 1990)and stroke (Gerrard and Weisberg, 1986; Sullivanet al., 1990; Zimmerman et al., 1988; Hijdra et al.,1990). These ®ndings are confounded by the sharprise in the presence of white matter lesions with age(Bradley et al., 1984; Hunt et al., 1989; Fazekas,1989; Diaz et al., 1991). Another ®nding that mayreduce the speci®city of VaD based on structuralimaging is that of white matter lesions in AD(Skoog et al., 1993), which some investigators have

found to be commoner than in healthy age-matched controls (Rezek et al., 1987; Lechneret al., 1991). It should be noted that white matterlesions are not necessarily synonymous withischaemic changes, and pathological processessuch as spongiosis (Munoz et al., 1993) and eÂtatcribleÂ (widening of the extravascular spaces)(van Sweiten et al., 1991) are known to have anassociation with cerebrovascular disease.

Functional imaging has allowed a better under-standing of metabolic and haemodynamic corre-lates of cognitive function, but has (as mentionedabove) also questioned the di�erentiation of VaDfrom AD on the basis of vascular pathology. Of thefunctional imaging techniques mentioned earlier,the commonly employed methods in studyingcerebrovascular disease are cerebral blood ¯ow,oxygen utilization and glucose consumption.

Using functional imaging, the diversity in lesionlocation has hampered the search for focal patternsof low cerebral blood ¯ow. However, neitherbaseline perfusion (Duara et al., 1989) nor a patchyfocal pattern of cortical perfusion (Hamada et al.,1993) have been useful in di�erentiating VaDfrom AD. Studies of brain glucose metabolismusing PET have been similarly inconclusive(Schapiro et al., 1993; Mielke et al., 1994). Adi�erent approach has been to measure haemo-dynamic abnormalities as a measure of vascularreserve; in this respect, a higher pulsatility index(a measure of vascular resistance) has been foundin VaD than in AD (Biedert et al., 1993). A similarprinciple involving cerebrovascular `reactivity'(vasodilation) after hypercapnic challenge hasproduced similar results (Kuwabara et al., 1992).In common with other areas of study, interpretingthe results of functional imaging research sharesthe potential biases inherent in any study design,which include both technical considerationsrelated to the type of imaging and epidemiologicalconsiderations such as matching groups for age,education, VRFs and severity of cognitive impair-ment. Certainly, the most important limitation is inpatient numbers, owing to the considerable costinvolved in using methods such as PET andSPECT.

NON-STROKE CEREBROVASCULARISCHAEMIA AND DEMENTIA

There is growing interest in the role of cerebro-vascular hypoperfusion in the pathogenesis of


VASCULAR DEMENTIA 279

cognitive impairment, although this still remains acontentious issue. It has been proposed that acute/chronic ischaemia (in the absence of arrestedcardiac function or stroke) may be associatedwith the development of cognitive impairment.The putative correlates of such ischaemic episodesare diverse and include heart failure (Raiha et al.,1993), atrial ®brillation (DePedis et al., 1987),carotid artery stenosis (Wodarz, 1980) and hyper-tension. Hypertension is the most widely studiedvascular risk factor in relation to chronic (non-stroke) cerebral ischaemia. Both cross-sectionaland longitudinal epidemiological studies haveshown hypertensive subjects to perform less wellthan their case-matched normotensive counter-parts on speci®c neuropsychological tests(Waldstein et al., 1991; Elias et al., 1993; Wilkieand Eisdorfer, 1971; Sands and Meredith, 1992).

The group most widely studied in exploring thee�ects of acute/transient ischaemic on cognitivefunction is patients with symptomatic transientischaemic attacks (TIAs) related to thromboem-bolic cardiac disease or carotid stenosis. In the caseof the latter, cognitive function has commonly beenexamined in patients prior to carotid endart-erectomy or intracranial/extracranial (ICA/ECA)bypass operations. Very few of these studies havebeen restricted to TIAs in the absence of completedstroke. One study restricted to this subgroup foundevidence of intellectual impairment preoperatively(Nielson et al., 1985). However, this study failed toinclude a control group. Preoperative studies ofcarotid endarterectomy patients compared to con-trol groups have not been conclusive (Kelly et al.,1980; Casey et al., 1989; Sinatra et al., 1984; Vanden Burgh, 1985; Taghavey and Hamer, 1995).

The mechanism by which cerebral hypoper-fusion is related to cognitive impairment in humansis largely speculative, as neuropathological studieshave been con®ned to animal models of ischaemia.Such studies have demonstrated disruption ofcentral cholinergic function following bilateralocclusion of the internal carotid arteries (Kondoet al., 1996; Tanaka et al., 1996). It is known thatwatershed areas in the cerebral cortex and deepwhite matter are most sensitive to hypoxia, butbecause the cortex has a lower threshold forischaemia and a higher metabolic demand, severetransient ischaemia commonly results in infarc-tion in cortical areas more readily than in deepwhite matter. Thus, the study of patients withtransient ischaemic attacks may not be useful inthis respect.

VASCULAR DEMENTIA: A VALIDDIAGNOSTIC ENTITY?

The existence of a clear-cut syndrome of globalcognitive impairment associated with speci®c riskfactors for cardiovascular disease and characteristicfeatures on clinical examination and on neuro-imaging that can distinguish it reliably from otherdementias (particularly AD) remains dubious. Theway forward in examining the relationship betweencerebrovascular disease and cognition requires thetraditional boundaries previously applied to VaDto be transcended. This would require the adoptionof a dimensional approach to cognitive testing, aswell as correlating domains of cognitive functionwith in vivo functional neuroimaging. The develop-ment of cognitive impairment following stroke doesnot appear to be in dispute; as such, investigatingthe relationship between VRFs and cognitiveimpairment may be best examined by excludingpatients with evidence of stroke.

Both the above issues surrounding conceptrede®nition are encompassed by the term `vascularcognitive impairment' (VCI) (Hachinski andBowler, 1993). The core elements of this conceptinvolve the dimensional nature of cognitiveimpairment as well as the search for patterns ofneuropsychological de®cit and neuroimagingabnormalities associated with particular VRFs(Devasenapathy and Hachinski, 1997). Given thatthe progression of cerebrovascular disease ispotentially treatable, VCI also encompasses theconcept of studying patients with known VRFs andno evidence of cognitive impairment/abnormalitieson neuroimaging (so-called `brain-at-risk' patients)(Hachinski, 1994) through to those with focal andglobal neuropsychological de®cit. The transitionfrom VaD to vascular cognitive impairment is notsimply a matter of degree, but a means ofexamining the range of cognitive impairmentacross individual domains of cognitive function inrelation to cerebrovascular pathology, therebyproviding a more valid methodology to a newconcept that has been clouded by the historicalmisconception of de®ning cognitive impairmentbased on AD.

The millennium will undoubtedly bring with itthe development of a radical rede®nition of thecurrent concept of VaD, which is now outdated.This will also require close collaboration betweendi�erent disciplines if a new concept of `vascularcognitive impairment' is to be achieved. As VaDnow appears to have outlived its usefulness as a



valid concept, it would seem timely for it to be laidto rest.

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