Vascular Dementia: The Beginning of a New Era


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Vascular Dementia: The Beginning of a New Era

  1. 1. Vascular Dementia:The Beginning of a New EraOur concepts of vascular dementia (VaD) have been evolving rapidly during the past decade,and have broadened beyond the traditional understanding of VaD as being only a multi-infarct dementia (MID). It is now recognized that there are a broad range of cerebrovascularsyndromes that can produce VaD, including strategic infarcts, subcortical VaD, and amyloidangiopathy. There has been emerging interest in the state of vascular cognitive impairmentnot dementia (vascular CIND) where it may be possible to intercede in treating vascular riskfactors and stroke mechanisms before dementia becomes fully manifest. Indeed, there isevidence that treating vascular risk factors in asymptomatic individuals can lower the risk ofdeveloping dementia. Finally, the acetylcholinesterase inhibitors are emerging as a treatmentoption for the symptoms of VaD, with clinical trial evidence showing benefits on cognition,behaviour and functional Inge Loy-English, MD, FRCPC and Howard Feldman, MD, FRCPCEpidemiology clinics in Canada were diagnosed Classification andIn the Canadian Study of Health as having VaD.2 In addition to the Clinical Featuresand Aging (CSHA), vascular patients who are clearly demented The definitions of VaD have beendementia (VaD) was described as as a result of cerebrovascular dis- changing over the past few years.the second most common cause of ease, there also are those who In VaD caused by cerebrovasculardementia, affecting 1.5% of the have vascular cognitive impair- disease, early descriptions cen-population older than 65 years.1 In ment (VCI) without dementia. tered on multiple cortical and sub-a subsequent study, known as A This group makes up a further cortical infarcts. In this type ofCanadian Cohort Study of Cog- 2.6% of the population in the VaD, the onset and worsening ofnitive Impairment and Related CSHA,3 and accounts for about the cognitive state is linked tempo-Dementias (ACCORD), 8.7% of 18% of those in the ACCORD rally to an episode of stroke or aindividuals referred to dementia study considered cognitively imp- transient ischemic attack (TIA). aired but not demented.2 Current definitions of VaD des-Inge Loy-English, MD, FRCPC, The risk of VaD increases with cribe it as a heterogenous disorder,Assistant Professor, Division of age—though less steeply than in as symptoms and signs are relatedNeurology, Department of Alzheimer’s disease (AD)—and to the cortical or subcortical areaMedicine, University of Ottawa, generally is found to be more injured by the stroke. The patternOttawa, Ontario. prevalent in men than women.4 of deterioration usually is step- The prevalence of dementia fol- wise, and there are obvious focalHoward Feldman, MD, FRCPC, lowing a stroke is roughly 25%.5 neurologic deficits related to pre-Professor, Division of Neurology, The magnitude of the burden of vious strokes.Department of Medicine cerebrovascular disease and its The Hachinski Ischemic ScoreClinic for Alzheimer Disease andRelated Disorders impact on cognitive function rep- was developed to help differ-University of British Columbia, resents a huge challenge in an entiate between VaD and AD (seeVancouver, British Columbia. aging society. Table 1).6 A scale is used in which4 • The Canadian Alzheimer Disease Review • September 2003
  2. 2. various features considered char- Strategic infarcts are an in- Table 1acteristic of VaD are assigned a creasingly recognized and impor- Hachinski Ischemic Score*value of 1 or 2. A score over 7 is tant category of VCI and VaD.diagnostic of VaD/multi-infarct While in other types of VaD it is Feature Point Valuedementia (MID), a score between estimated that patients need a Abrupt onset 24 and 7 is diagnostic of mixed cumulative volumetric damage to Stepwise deterioration 1dementia and a score less than 4 is 100 cubic centimetres of brain to Fluctuating course 2diagnostic of AD or other non- produce dementia, in strategic Nocturnal confusion 1vascular causes of dementia. infarct dementia, the required vol- Relative preservation of personality 1 Figure 1 presents examples of ume may be only one tenth that Depression 1vascular disorders that are associ- amount.7 Examples of strategic Somatic complaints 1ated with both VCI and VaD: lesions include thalamic, hip- Emotional incontinence 1 MID. The concept of MID pocampal and dominant angular History or presence of(Figure 1A) has gradually been gyrus lesions (Figure 1C). The hypertension 1expanded to include dementia clinical cognitive impairment History of stroke 2 Evidence of associatedassociated with a larger variety of depends entirely on the location of atherosclerosis 1cerebrovascular disorders. the strategic lesions. In the exam- Focal neurologic symptoms 2 Subcortical VaD includes the ple of bilateral thalamic infarcts, Focal neurologic signs 2terms Binswanger’s disease and there may be a dense amnestic syn- * A score of >7 is suggestive of VaD; a score“état lacunaire,” and is primarily drome associated with bilateral of <4 is suggestive of AD or another non-characterized by an insidious on- upgaze palsies. A severe dominant vascular dementia; a score of 4-7 suggests mixed dementia.set in over 50% of patients, rarely angular gyrus lesion can produce Adapted from: Rosen WG, et al. Ann Neurolwith a clear stepwise progression. the classic Gerstmann’s syndrome 1980; 7:486-8.While having focal neurologic of right-left disorientation, fingerfeatures on examination (e.g., sub- agnosia, dyscalculia and agraphia. It is worth emphasizing that anytle unilateral or bilateral weakness, It is important to recognize the of the above subtypes of VCI/VaDBabinski signs, sensory deficits, phenotype of the single strategic- can coexist with AD, producing adysarthria), patients often will not area lesion, to facilitate early diag- mixed dementia. Mixed dementiahave a clear history of a TIA or nosis and treatment. of this type has been reported tostroke. Patients also may have an Global cortical hypoperfusion account for 18.7% of all dementiasatypical gait (e.g., “marche-a- post cardiac arrest is another sub- diagnosed in the ACCORD study.2petit-pas”), resulting from frontal- type of VaD (Figure 1D).subcortical damage. Cognitively, Hemorrhagic disorders (Fig- Diagnostic Criteriathere is prominent frontal dysfunc- ure 1E) also are subtypes of VaD There are three sets of diagnostiction with difficulty in executive (e.g., cerebral amyloid angiopa- criteria currently being used infunctions, including planning, seq- thy, or following subarachnoid research settings for VaD: 1) theuencing and organization. The hemorrhage). fourth revision of the Diagnosticmemory impairment in VCI and CADASIL. There also are rare and Statistical Manual of MentalVaD often is mild, especially com- hereditary causes of multiple Disorders (DSM-IV); 2) the tenthpared to AD, with more impaired strokes leading to dementia. The revision of the International Stat-retrieval and better preserved recently described entity of istical Classification of Diseasesrecognition memory. Computed Cerebral Autosomal Dominant and Related Health Problemstomography (CT) scans and, more Arteriopathy with Subcortical In- (ICD-10); and 3) the NINDS-effectively, magnetic resonance farcts and Leukoencephalopathy AIREN criteria (NINDS = Nation-imaging (MRI) show extensive (CADASIL) is becoming increas- al Institute of Neurological Dis-ischemic lesions and lacunar in- ingly recognized as a cause of orders and Stroke; AIREN = Asso-farcts in the deep and superficial otherwise unexplained subcortical ciation Internationale pour lawhite matter and grey matter bilat- VaD in young and middle-aged Recherche et l’Enseignement enerally (Figure 1B) . patients (Figure 1F). Neurosciences).8-10 Although they The Canadian Alzheimer Disease Review • September 2003 • 5
  3. 3. Figure 1 Types of VaD A) Multiple infarcts (MID) B) Subcortical C) Single strategic infarct D) Hypoperfusion E) Hemorrhagic F) CADASILare not applied rigorously in clini- factor for stroke and VaD, however tension in the elderly is safe andcal practice, it is worth considering the effects of treating hypertension effective in reducing morbidity andsome of the points of diagnostic on preventing dementia have been mortality. Angiotensin-convertingemphasis (Table 2). The NINDS- elucidated only more recently. The enzyme (ACE) inhibitors and calci-AIREN criteria, which are the most Systolic Hypertension in Europe um channel blockers (especiallywidely used in recent clinical trials, (Syst-Eur) trial investigated the nicardipine and nitrendipine) haverequire a temporal relationship effects of treatment of systolic the best supportive evidence withwith the onset of dementia occur- hypertension in mid-life.11 This respect to preventing VCI associat-ring within three months of a rec- double-blind, placebo-controlled, ed with hypertension. There is lessognized clinical stroke. They also randomized controlled trial (RCT) evidence to support the use ofspecify that there be neuroimaging compared the ability of nitrendi- diuretics and beta-blockers in thisconfirmation of ischemic lesions to pine, +/- enalapril and +/- hydro- regard.make the diagnosis. chlorothiazide, with that of placebo b) Diabetes mellitus. The to control systolic blood pressure to association between diabetesTreatment below 150 mmHg. Results dem- mellitus and stroke also is wellThe fundamental approach to the onstrated a 55% reduction in the known, with recent recognitiontreatment of VCI and VaD is cen- incidence of dementia (95% CI, of an association between dia-tered on the prevention of further 24%-73%) and a 42% reduction in betes and incident cognitiveischemic cerebrovascular disease. stroke (95% CI, 17%-60%) with impairment. A recent CochraneMore recently, however, evidence active treatment.12 There also were review14 concluded that there washas emerged supporting the use of fewer cases of VaD and AD in the upwards of a two-fold increase inacetylcholinesterase inhibitors in active treatment group. the risk of cognitive impairmentthe treatment of VaD. In a recent article analyzing all in diabetics compared to the gen- Vascular risk factors: the studies of the effects of treating eral population. Although the a) Hypertension. Hypertension hypertension on VCI,13 the authors evidence remains uncertain withhas long been known to be a risk concluded that decreasing hyper- respect to diabetes treatment6 • The Canadian Alzheimer Disease Review • September 2003
  4. 4. Table 2 Diagnostic Criteria for Probable VaD DSM-IV ICD-10 NINDS-AIREN Ischemic stroke and Yes Yes Yes hemorrhagic stroke Stepwise deterioration Yes No Yes (or temporal relationship required between stroke and dementia) Unequal distribution of No Yes No cognitive defects Focal neurologic signs Yes (or radiographic Yes Yes evidence of significant cerebrovascular disease) Focal neurologic symptoms Yes No No Etiologic relation of stroke Yes Yes Yes to the disturbance in cognition Temporal relation between No No Yes stroke and dementia onset Structural neuroimaging Yes (or clinical evidence No Yes: multiple large vessel required of significant cerebrovascular strokes or multiple lacunes or disease) extensive white-matter lesions or a single, strategically placed lesionreducing the incidence of demen- ients were allocated to receive sim- Treatment with antiplatelettia, there is evidence that treating vastatin or placebo. The risks of agents. There has only been a sin-hyperglycemia has a positive stroke, MI and death all were sig- gle RCT evaluating the effects ofeffect on cognitive function, at nificantly decreased in the active antiplatelet agents in dementia.21least in the short term.15,16 This treatment group, however there was In this three-year, single-blindadds to the clear benefits of treat- no significant benefit of simvastatin study, 70 patients with MID wereing blood sugars tenaciously to on five-year cognitive outcomes. randomized to either treatmentprevent the spectrum of diabetic d) Homocysteine. Homocys- with acetylsalicylic acid (ASA)complications. teine is a recently identified risk 325 mg or an untreated control c) Stroke. The use of 3- factor for cerebrovascular disease group. There were significanthydroxy-3-methylglutaryl-coen- and dementia. It is known from improvements in cerebral perfu-zyme A (HMG-CoA) reductase previous studies that there is an sion values and cognitive perfor-inhibitors (i.e., statins) has emer- independent linear relationship mance scores for the patientsged as a common practice in the between the risk of TIA, stroke and treated with ASA compared to thesecondary prevention of stroke. increasing homocysteine levels.20 untreated patients. This study hasThere have been two recent meta- The treatment for lowering plasma not been replicated and there haveanalyses evaluating the effect of homocysteine levels is felt to be been no studies on the role ofstatins primarily on the risk of well tolerated: daily supplement- other antiplatelet agents (e.g., tic-stroke in patients with coronary ation with vitamin B6 (25 mg), vit- lopidine, clopidogrel, dipyradi-artery disease.17,18 These analyses amin B12 (250 mg to 500 mg) and mole/ASA combinations) or war-showed a reduction in stroke rate folic acid (2 mg to 3 mg). While farin in VCI or VaD.of approximately 25% to 30% there have been no studies to date Symptomatic treatment forusing pooled data. looking specifically at the out- VaD. The recognition of cholin- The recently published Heart comes of lowering homocysteine ergic deficits in VaD and VCIProtection Study19 investigated the levels in VCI or VaD, there are cur- has led to the recent treatment tri-effects of simvastatin on vascular rently ongoing studies looking at als with acetylcholinesterase in-outcomes, including stroke, myo- the role of homocysteine in both hibitors. In one double-blind,cardial infarction (MI) and death. In reducing the risk of stroke and as a placebo-controlled study, donepe-this double-blind RCT, 20,536 pat- treatment for AD. zil was investigated for safety and The Canadian Alzheimer Disease Review • September 2003 • 7
  5. 5. efficacy in probable VaD, as def- the placebo group on the CIBIC- trying to prevent ongoing or inc-ined by the NINDS-AIREN crite- plus and the ADAS-Cog. reasing ischemic injury. The useria.22 There was benefit in the There have been no published of acetylcholinesterase inhibitors5 mg and 10 mg donepezil groups RCTs evaluating the efficacy of in the symptomatic treatment ofcompared to placebo on the Clin- rivastigmine in VaD or mixed VaD is emerging as a treatmentician’s Interview-based Impres- AD-VaD. intervention supported by level Ision of Change (CIBIC-plus; a evidence from recent assessment measure) and Conclusionson the cognitive subscale of the VCI and VaD are a heterogenous AcknowledgementsAlzheimer’s Disease Assessment group of disorders that are becom- The authors gratefully acknowl-Scale (ADAS-Cog; a psychomet- ing better understood with the ad- edge Dr. Doug Graeb and Prof-ric assessment). vent of better diagnostic criteria essor Philip Scheltens for con- Galantamine also has been and neuroimaging. The phenotyp- tributing the CTs and MRIs usedevaluated in a double-blind RCT ic identification of subtypes of in Figure 1. The capable assis-that included probable VaD and VCI and VaD may allow more tar- tance of Mr. Jacob Grand in themixed AD-VaD.23 The group treat- geted therapy in the future. At pre- development of this manuscripted with galantamine did signifi- sent, diligent control of vascular also is acknowledged withcantly better at six months than risk factors clearly is important in appreciation.References: of diseases and related health problems. control on cognitive functions in the1. Lindsay J, Hebert R, Rockwood K. The Based on recommendations of the 10th elderly patient with diabetes. J CSHA: risk factors for vascular demen- Revision Conference, 1989 and adopted Gerontol 1993; 48:M117-21. tia. Stroke 1997; 28:526-30. by the 43rd World Health Assembly, 17. Bucher HC, Griffith LE, Guyatt GH.2. Feldman H, Levy AR, Hsiung GY, et al. 1992-1994. WHO, Geneva, 1992. Effect of HMG-CoA reductase A Canadian Cohort Study of Cognitive 10. Roman GC, Tatemichi TK, Erkinjuntti inhibitors on stroke. 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