Vascular dementia: a diagnosis running out of timeROBERT STEWARTThe British Journal of Psychiatry 2002 180: 152-156Access ...
B R I T I S H J O U R N A L O F P S YC H I AT RY ( 2 0 0 2 ) , 1 8 0 , 1 5 2 ^ 1 5 6Vascular dementia: a diagnosis running...
VA S C U L A R D E M E N T I A                                                                                            ...
S T E WARTTTable 1 Pathways of association between vascular disease and dementia and their implications with respect to pr...
VA S C U L A R D E M E N T I A                                                                                            ...
S T E WARTJournal of Neurology, Neurosurgery and Psychiatry, 67,                                       Psychiatry 67,     ...
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Vascular dementia: a diagnosis running out of time

  1. 1. Vascular dementia: a diagnosis running out of timeROBERT STEWARTThe British Journal of Psychiatry 2002 180: 152-156Access the most recent version at doi:10.1192/bjp.180.2.152 Reprints/ To obtain reprints or permission to reproduce material from this paper, please permissions write to can respond to this article at Email alerting Receive free email alerts when new articles cite this article - sign up in the box at service the top right corner of the article or click here Downloaded on December 6, 2010 from Published by The Royal College of PsychiatristsTo subscribe to The British Journal of Psychiatry go to:
  2. 2. B R I T I S H J O U R N A L O F P S YC H I AT RY ( 2 0 0 2 ) , 1 8 0 , 1 5 2 ^ 1 5 6Vascular dementia: a diagnosis running out of time{ detectable levels of vascular disease con- tinue to be excluded, the `pure Alzheimers disease group will become progressivelyROBERT STE WART smaller, defining an increasingly select group of persons who, for whatever reason, have remained free of any vascular disease into old age. The question, of course, is what level of vascular disease may cause dementia; this cannot be answered by using criteria that assume that it is or is not a cause. A major problem with the concept of multi-infarct dementia has been thatBackground The concept of vascular Once upon a time, around the first half of diagnostic criteria tried to do the samedementia has a long history but its the last century, late-onset dementia was thing as those for Alzheimers disease: that viewed as an essentially homogeneous is, to define a `pure entity. However, whileusefulness as a diagnostic category has condition. The main underlying cause was Alzheimers disease at least has a reason-been called into question. assumed to be atherosclerosis: a patho- ably well-defined pathological basis, the logical substrate for `old age. Pioneering same is not true for dementia related toAims To evaluate vascular disease as a work around the 1960s and early 1970s cerebrovascular disease. `Vascular demen-risk factor for dementia and the interface challenged this assumption, establishing tia subsumed multi-infarct dementia as abetween cerebrovascular pathology and the importance of Alzheimer pathological term because of recognition of this hetero-Alzheimers disease. changes in the majority of cases. However, geneity, and large numbers of other sub- multiple cerebral infarctions also appeared types have subsequently been proposedMethod The literature on this topic to underlie a substantial proportion. This (Konno et al, 1997). These range from syn- al,was selectively reviewed and synthesised. led to the division of dementia into the dromes where dementia appears to have two conditions of Alzheimers disease resulted from small, discrete `strategicResults Risk factors for and multi-infarct dementia. This system multi-infarct infarctions (such as bilateral thalamiccerebrovascular disease are also risk has persisted to this day but is coming infarction or lesions of the angular gyrus), under increasing criticism, particularly from to dementia associated with more diffusefactors for dementia.However, the course those who wish to investigate vascular dis- cerebrovascular disease: ischaemic orof dementia, once it has developed, ease as a risk factor for dementia. In the haemorrhagic, cortical or subcorticalappears to be frequently determined by following sections the current status of and (Brun, 2000). More diffuse diseaseAlzheimers disease. future directions for `vascular dementia are obviously exists across a spectrum of severity considered, both as a diagnostic category and with advancing age is increasinglyConclusions As a public health and as a heading for a broad field of research. likely to be comorbid with Alzheimersmeasure, modification of vascular risk disease, raising questions as to how (or whether) the two should be distinguishedrepresents a potentially powerful means AN OUTDATED DIAGNOSTIC in a diagnostic system. An additionalto prevent dementia through delaying its SYSTEM ? SYSTEM? obstacle for research is that the term `vas-onset.However, an effect on progression cular dementia makes assumptions aboutof dementia, onceit has developed, has yet Research diagnostic criteria treat Alzhei- causation and therefore is of limited useto be established.The traditional view of mers disease as a diagnosis of exclusion when it comes to investigating potential (McKhann et al, 1984). This system may al, causes. It would not be considered particu-vascular dementia and Alzheimers disease be useful for examining issues relating to larly noteworthy if a study was to reportas distinguishable conditions is becoming this disorder as a `pure entity. However, that people who have a stroke are moresteadily less tenable. it may also miss potentially important likely to have hypertension or diabetes. influences from factors such as vascular Similarly, it would not be very surprisingDeclaration of interest R.S. is disease, which have been excluded by if they were found to have higher mortalitysupported by a ResearchTraining definition. In addition, having begun by or higher levels of depression. The problemFellowship in Clinical Epidemiology from excluding major vascular disease such as with `vascular dementia as a term is that clinical stroke or multiple cerebral infarc- comparisons with Alzheimers disease orthe WellcomeTrust. tions on computed tomographic imaging, control groups are inevitably comparisons studies that use this diagnostic system of populations with different rates of cere- now have to consider what to do with brovascular disease, and it is impossible to evidence of more subtle, subclinical disease, conclude what is related to cerebrovascular such as white-matter abnormalities seen on disease and what is related to a particular magnetic resonance imaging. Increasingly dementia syndrome. sophisticated measurements of cerebro- It is perhaps preferable to consider vascular disease in vivo raise the question vascular dementia as a series of questionsy See editorial, pp. 97^98, this issue. of where exclusion criteria should stop. If rather than a diagnosis. Does vascular152
  3. 3. VA S C U L A R D E M E N T I A CUdisease cause dementia? What type (or An increasing body of epidemiological vascular amyloid deposition and micro-types) of dementia does it cause? What evidence suggests that vascular risk factors angiopathy. Apolipoprotein E (ApoE)can we do about it? such as hypertension, diabetes and hyper- genotype may also provide a potential lipidaemia are risk factors not only for the explanation for the association. However, development of vascular dementia but also although the ApoE e4 variant is associatedDOES VASCULAR DISEASE for Alzheimers disease (Stewart, 1998). with increased vascular risk, neither lipidCAUSE DEMENTIA? Community-based research can be criticised Community-based levels nor vascular disease have been found in that neuroimaging has not been routinely neuroimaging to be mediating factors between e4 and riskSystems of dementia classification have used in diagnostic assessment, so that of Alzheimers disease (Prince et al, 2000). al,been a major obstacle for investigating this subclinical levels of cerebrovascular disease Although many feasible mechanismsquestion, as previously discussed. Another may have been missed and `mixed have been proposed for direct links betweenproblem is that age groups in which de- dementia misidentified as Alzheimers vascular and Alzheimers disease processes,mentia is most common contain, to an disease. This issue, however, should be pathological evidence so far suggests thatextent, healthy survivors with respect to more a consideration of mechanisms by they interact principally in their clinicalvascular disease. Also, people with both which vascular risk factors are associated effects. The `nun study found no directconditions together have a higher mortality with dementia rather than one of arbitrarily association between cerebrovascularand are therefore less likely to be identified defined diagnostic categories. Post-stroke disease and level of Alzheimer pathology,in both cross-sectional and prospective studies have found that dementia appears but instead found that less Alzheimerstudies. to follow an Alzheimers disease-like course pathology was `required to produce Particularly high rates of dementia are in the majority of cases (Kokmen et al, al, dementia if cerebrovascular disease wasobserved following clinical stroke, with an 1996) and that approximately 10% of also present (Snowdon et al, 1997). One al,approximately nine-fold increase in risk people with post-stroke dementia have possible explanation is that memoryover the first year followed by a smaller, had gradually deteriorating cognitive impairment secondary to hippocampaltwo-fold raised annual risk which has been function before the stroke occurred pathology in Alzheimers disease is morefound to persist at least 25 years later (Pohjasvaara et al, 1999). Since Alzheimers al, likely to manifest as clinical dementia if(Kokmen et al, 1996). Vascular risk factors al, disease has a long latency period, it can be there is also impairment of executivesuch as hypertension, diabetes and hyper- assumed that a substantial further function secondary to vascular subcorticalcholesterolaemia have also been established proportion may have had subclinical pathology. Executive function impairmentas risk factors for dementia in large disease. is an important, although frequentlyprospective studies (Stewart, 1998). Early What is becoming increasingly unmeasured, factor associated withreports that smoking might be a protective apparent is that dementia associated with memory decline, and decline in executivefactor, at least for Alzheimers disease, have vascular disease frequently resembles function alone, an important potentialnot been confirmed by more rigorously Alzheimers disease in its clinical course consequence of cerebrovascular disease,designed investigations which, if anything, and, in many cases, is not obviously has been suggested as a dementia syndromereport a raised risk of both subtypes of explained by a multiple infarction in its own right (Royall, 2000).dementia in smokers (Ott et al, 1998). An al, mechanism. One possibility is that vascularimportant issue arising from these studies processes cause a gradually progressiveconcerns the stage of cognitive decline at dementia syndrome. However, recent WHAT CAN WE DO ABOUT IT ?which these factors have an effect. Raised pathological studies have suggested thatblood pressure in mid-life is, for instance, isolated cerebrovascular disease (i.e. with Considering the length of time vasculara strong risk factor for later cognitive no Alzheimer lesions) is rarely found in disease has been accepted as a commonimpairment (Elias et al, 1993). However, al, association with dementia (Hulette et al, al, and potentially reversible risk factor forblood pressure in later life tends to be lower 1997). These findings contrast with those dementia, evidence for interventions toin association with dementia (Skoog et al, al, from the early post-mortem series, although modify this risk has been woefully scant.1996). Therefore hypertension appears to it should be borne in mind that people with As summarised in Table 1, the likelyexert its effect at an early stage in cognitive dementia in the late 1960s would be success of any intervention dependsdecline and the association may no longer expected to display much more florid and crucially on the mechanism of apparent by the time cognitive function severe cerebrovascular disease. The next Of particular interest for clinicians is thehas deteriorated sufficiently to be classified question is whether vascular disease may extent to which patients with dementiaas dementia. The same pattern has been de- directly cause or `drive Alzheimers disease may benefit from treatment of vascularscribed for raised cholesterol concentrations processes. Many potential mechanisms disease or risk factors. However, there has(Notkola et al, 1998), and has important al, exist and have been proposed for vascular been no optimally designed trial of suchpotential implications for preventive or implications induction of Alzheimers disease, including interventions. Treatment of vascular risktherapeutic intervention. amyloid deposition secondary to ischaemia factors may have an impact on cognitive or peri-infarct inflammation and microglial decline through preventing stroke ± andWHAT TYPE OF DEMENTIA activation. Abnormal protein glycation increasing evidence suggests that thereDOES IT CAUSE ? may provide a link between diabetes and may be no upper age limit for stroke Alzheimers disease. Furthermore, there is prevention (Staessen et al, 2000). In addi- al,Again, traditional diagnostic criteria have a growing appreciation of cerebrovascular tion, there would be benefit if vascularhampered investigation of this question. pathology in Alzheimers disease such as disease was accelerating the progression of 153
  4. 4. S T E WARTTTable 1 Pathways of association between vascular disease and dementia and their implications with respect to preventive or therapeutic interventions ableMechanism of association Potential benefit from modifying vascular risk status In those without dementia In those with dementiaMultiple infarcts Prevention of dementia through stroke prevention Prevention of further deteriorationVascular disease accelerating Alzheimers disease Prevention/delayed onset of dementia through Alzheimers Slowing of further deterioration progression disease decelerationVascular disease accelerating the age of onset of dementia Prevention/delayed age of onset through reducing risk of Unlikely to have any effect in the presence of Alzheimers disease other cognitive impairmentCommon underlying risk factors (e.g. genetic) for vascular No effect No effect disease and Alzheimers diseaseAlzheimer lesions. On the other hand, if suggested a 50% reduction in incident 10±20 years later. However, from a clinicalvascular disease predominantly accelerates dementia (principally Alzheimers disease) standpoint (directed towards individual-the age of onset of Alzheimers disease, occurring in those treated with a calcium rather than population-level risk) there willtreatment should be directed at Alzheimers channel blocker compared with placebo also need to be a move towards identifyingdisease rather than the vascular component (Forette et al, 1998). al, cognitive decline at a much earlier stageonce dementia has developed. This issue than dementia. In particular, with regardhas become particularly important with to vascular disease, the focus on memorythe licensing of pharmacological agents WHERE DO WE GO decline influenced by Alzheimers diseasefor use in Alzheimers disease. If stroke FROM HERE ? will need to shift towards an appreciationcontinues to be considered as an exclusion of executive function impairment (Bowlercriterion, a large number of people with Further investigation into mechanisms & Hachinski, 2000).Alzheimers disease will fail to receive underlying links between vascular and What, therefore, is vascular dementia?appropriate treatment because of comorbid Alzheimer pathological processes is likely It is certainly a convenient subject headingdisease. Whatever lies ahead for the treat- to provide important avenues for risk for a rapidly accelerating field of research.ment of dementia associated with cerebro- modification. In addition, evidence from What is less clear is whether it retains anyvascular disease, the potential for its adequately designed therapeutic and pre- usefulness as a diagnosis. Vascular demen-prevention is likely to be substantial since ventive trials, even if negative, is likely to tia implies a primary cause (cerebrovascularvascular risk factors have high prevalence provide useful information regarding disease) linked with a specific consequencerates. A modest reduction in vascular risk underlying mechanisms. What may well (a distinguishable dementia syndrome).across a population could therefore be become increasingly apparent is that However, increasing evidence suggests thatexpected to result in a large reduction in dementia is a very late stage to be consider- dementia associated with vascular diseasefuture cases of dementia, if only through ing useful intervention. One challenge is to involves a very broad spectrum of mani-delaying its clinical onset. Supporting this, develop public health strategies that can festations, from strategic infarct syndromespreliminary findings from the large Systolic affect large populations, reducing vascular to Alzheimers disease. In addition,Hypertension in Europe (Syst±Eur) trial of risk earlier in life with an aim of decreasing although vascular disease is a powerful riskantihypertensive treatment in older people the burden of dementia for that generation factor for dementia, it is questionable howTTable 2 able A life-course model for the aetiology of cognitive decline and dementiaGenetic factors Early-life factors Mid-life factors Later-life factors Physiology Pathology EnvironmentApoE In utero environment Blood pressure Cerebral perfusion Large vessel disease Comorbid diseaseOther factors Childhood environment Lipid levels Inflammation Small vessel disease Depression Education Insulin resistance Neuroendocrine environment Infarction Social support Socio-economic status Glucose intolerance Oxidative stress Ischaemia Access to health care Lifestyle factors (smoking, Excitotoxicity Amyloid deposition Cultural factors exercise, etc.) Tau phosphorylation Socio-economic status Socio-economic status Developing `premorbidcognitive function `premorbid cognitive Early cognitive decline!Detectable cognitive decline!Dementia decline Detectable decline DementiaApoE, apolipoprotein E.15 4
  5. 5. VA S C U L A R D E M E N T I A CUoften it is actually the sole cause of de-mentia in the absence of underlying vulner- CLINICAL IMPLICATIONSability or comorbid disease. Dementiaresearch has suffered, in common with & Modification of vascular risk status in mid-life is likely to be an important means ofother areas of epidemiology, from a reducing the subsequent risk of dementia for a population but evidence is lacking forsimplistic conceptual framework of risk an effect on the course of dementia, once this has developed.factor±outcome relationships. What isincreasingly evident is that there are many & The usefulness of vascular dementia as a diagnostic category is questionable since itpotential factors operating across an entire involves a high degree of subjective judgement, subsumes a large number oflife course (and possibly extending back potentially heterogeneous conditions and overlaps considerably with Alzheimersinto previous generations) which may disease.influence or mediate each others effects(Table 2). Designing appropriate studies & The current system of classifying dementia into mutually exclusive subtypes poorlyand systems of analysis to take into account reflects mixed disease in older age groups and has become an important issue sincethese multiple influences and interactions is these `diagnoses now determine eligibility for pharmacological intervention.likely to provide a major challenge forfuture research. LIMITATIONS In the meantime, what is to be donewith vascular dementia? A recent editorial & The review of the literature is selective and limited.has suggested that, rather than tinkering & This review looks at the relationship between vascular disease and dementia at awith existing criteria, they should be dis- population level rather than at specific discrete syndromes within vascular dementia.carded and replaced wholesale (Bowler &Hachinski, 2000). Certain syndromes can & The focus of this review is on the relationship between cerebrovascular disease andbe reasonably considered as diagnoses, for Alzheimers disease as two overlapping disorders and does not take into accountexample dementia due to strategic infarcts other comorbid pathology.or genetic disorders such as CADASIL(cerebral autosomal dominant arteriopathywith subcortical infarcts and leuco-encephalopathy). However, for the major-ity of vascular dementia syndromes arising ROBERT STEWART, MRCPsych, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, later life, although these may manifest Tel: +44 (0)20 7848 0240; fax: +44 (0)20 7701 0167; e-mail: r.stewart@as `pure disorders, it is questionablewhether valid distinctions can truly be (First received 15 March 2000, final revision 26 April 2001, accepted 27 April 2001)drawn between sub-categories or betweenvascular dementia and Alzheimers disease.The result is that clinical research diag-nostic criteria for vascular dementia involve REFERENCES based study in Rochester, Minnesota (1960^1984).a high degree of subjective judgement Neurology, 19, 154^159. Neurology 19, ,(Skoog & Aevarsson, 2000), leading in- Bowler, J.V. & Hachinski,V. (2000) Criteria for Konno, S., Meyer, J. S., Terayama,Y., et al (1997)evitably to poor agreement between raters vascular dementia: replacing dogma with data. 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