Mixed Alzheimer’sDisease andVascular DementiaThe diagnosis of mixed Alzheimer’s disease and vasculardementia is likely mor...
sclerosis is present.3 Other cardiovas-    clear that patients with cardiovascular   diagnosis of mixed dementia could bec...
Sweden aged 75 years and older, and           attack, stroke and dementia. The               may reflect the fact that str...
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Mixed Alzheimer's Disease and Vascular Dementia


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Mixed Alzheimer's Disease and Vascular Dementia

  1. 1. Mixed Alzheimer’sDisease andVascular DementiaThe diagnosis of mixed Alzheimer’s disease and vasculardementia is likely more common than has been appreciatedto date. The diagnosis is generally made on the basis ofclinical findings and a radiograph, but can also be made onthe basis of clinical findings alone.by Kenneth Rockwood, MD, FRCPC T he diagnosis of mixed Alzheimer’s disease (AD) and vascular dementia is likely more common dementia. Even as late as the 1970s, people held somewhat contradictory beliefs about late-life dementia. On than has been appreciated to date. the one hand, dementia, in the guise The diagnosis is generally made on of senility (a synonym for aging), was the basis of a radiograph, but can seen as an inevitable part of normal also be made on the basis of clinical aging. On the other hand, dementia findings. Treatment includes the was believed to be caused by harden- judicious management of vascular ing of the arteries. Even though arte- risk factors and therapy specifically riosclerosis was recognized as a dis- aimed at AD. ease, the two were somehow lumped together into a problem that would Changing Views on Mixed AD happen to everyone who lived long and Vascular Dementia enough. In the enthusiasm to make it “Everything old is new again” is an clear that AD was a real illness, andDr. Rockwood is a professor at epigram that applies as much to medi- one deserving a systematic approachDalhousie University and a cine as it does to other human endeav- to diagnosis, the baby—vascular riskgeriatrician at Queen Elizabeth II ours. One of the recent findings that is factors—was thrown out with theHealth Sciences Centre, Halifax, potentially the most far-reaching, and bathwater—senility.Nova Scotia. one with immediate practical impor- Several lines of evidence now tance, is the rediscovery of the link point to a link between vascular risk between vascular risk factors and factors and AD. As reviewed else- dementia. This link is not limited to the where,1,2 epidemiologic studies have so-called “multi-infarct dementia,” but shown that hypertension is a risk fac- encompasses all causes of the demen- tor for all causes of late-life cognitive tia syndrome, including AD. impairment, including AD. Among This rediscovery tells us much people with AD, cognitive impair- about the recent conceptualization of ment is worse when cerebral athero- The Canadian Alzheimer Disease Review • February 2000 • 7
  2. 2. sclerosis is present.3 Other cardiovas- clear that patients with cardiovascular diagnosis of mixed dementia could becular risk factors, including high cho- disease remain at risk for cognitive made with reasonable confidence inlesterol, diabetes mellitus and atrial impairment from both vascular and such an instance. In the CIVIC study,fibrillation, have also been shown to non-vascular causes. Although other a diagnosis of mixed dementia wasincrease the risk of AD.1,2 types of dementia (e.g., dementia not made by the coincidence of typi- Interestingly, the association with Lewy bodies, frontotemporal cal AD and vascular risk factors with-between vascular risk factors and AD dementia) can be seen in the presence out other evidence of ischemia, givenlargely faded from academic con- of cerebral ischemia, we will restrict that vascular risk factors are nowsciousness despite several neu- our use of the term “mixed dementia” understood to be risks for AD (Tableropathologic and neuroradiologic to AD and vascular dementia. 2).studies that suggested otherwise.1 In The CIVIC experience meanscase series of patients with AD, pre- Contemporary that, for individual physicians, thesumptive evidence of cerebral Diagnosis of Mixed Dementia proportion of patients diagnosed withischemia was usually found in about The study of the diagnosis of mixed mixed dementia will depend on20% to 30% of patients, although one dementia is a central part of the access to neuroimaging. Physiciansstudy (of white matter changes research of the Consortium to who strictly follow the recommenda-detected by magnetic resonance Investigate Vascular Impairment of tions of the Canadian Consensusimaging) put the estimate closer to Cognition (CIVIC). Preliminary data Conference on Dementia for referraltwo-thirds. on mixed dementia from CIVIC, a for neuroimaging are likely to diag- nose mixed dementia less often than those who have adopted more liberalSeveral lines of evidence now point to a link between criteria. The same holds true for those who adopt more liberal criteria forvascular risk factors and AD. As reviewed elsewhere,1,2 referral; the CIVIC data suggest thatepidemiologic studies have shown that hypertension is dementia specialists order CT scansa risk factor for all causes of late-life cognitive for the great majority of patients seenimpairment, including AD. in consultation. Focal findings on a neurological examination can be used to make a Against this background, it is per- multicentre, Canadian clinic-based clinical diagnosis of mixed AD andhaps not surprising that many clinical study, will be published.5 These data vascular dementia. More often,dementia scientists believe that the show that there are two ways the though, the diagnosis is based on acurrent estimates of mixed AD and diagnosis of mixed dementia is gener- history of focal symptoms (includingvascular dementia, often given as 5% ally made. Most commonly, patients transient ischemic attacks andto 15% of dementia cases,1 should be with clinically typical mild to moder- strokes), sudden onset and suddenrevised upward. Indeed, it may even ate AD have white matter changes or worsening of otherwise typical ADbe the most common form of demen- other ischemic lesions such as corti- (Table 1).tia: two recent large American neu- cal and subcortical strokes, includingropathologic studies found pure vas- so-called lacunar infarcts on comput- Contemporarycular dementia (i.e., vascular demen- ed tomography (CT) scanning. Treatment of Mixed Dementiatia without any evidence of AD) to be Patients will have clinical features of The contemporary treatment ofvery uncommon—in the range of both AD and vascular dementia less mixed dementia has two compo-about 1%.1 It is important to note that frequently (Table 1). For example, a nents: treatment of the vascular riskthese are early data and that this expe- patient with insidious onset and grad- factors and treatment of the cogni-rience is not universal; one British ual progression of cognitive impair- tive impairment.study4 found an estimate in accord ment early in the course of dementia Treatment of the vascular risk fac-with the usual estimate of 10% to may have a history of interval stroke tors begins with the treatment of high20% of all dementia cases. Although with a precipitous decline followed blood pressure. Although there hasmore work needs to be done, it is by gradual progression. A clinical been some concern that treatment for8 • The Canadian Alzheimer Disease Review • February 2000
  3. 3. Table 1 HINTS POINTING TO MIXED DEMENTIA IN A PATIENT WITH OTHERWISE TYPICAL AD From the history Consider: • sudden onset • delirium precipitating or unmasking AD • prolonged plateau • subclinical decline / slowly progressive AD variant • episodes of stepwise progression • interval medical illnesses • focal motor or sensory symptoms • other space-occupying lesions On examination Consider: • unilateral rigidity • early onset of parkinsonism • other focal / lateralizing features • other space-occupying lesions or spinal nerve root entrapment Table 2 FEATURES IN OTHERWISE TYPICAL AD THAT WOULD NOT ON THEIR OWN BE SUPPORTIVE OF A DIAGNOSIS OF MIXED DEMENTIA Feature Consider: • vascular risk factors (known also as risks for AD, not just VD) • episodes of confusion (fluctuation can be part of the AD spectrum; delirium is common in AD) • isolated focal signs (unilateral signs in isolation can arise outside the cranium; suspected brain lesions require confirmation by neuroimaging)hypertension can cause cognitive with enalapril, an angiotensin- follow-up (p = 0.05). These treatmentimpairment, the most recent data do converting enzyme inhibitor. The data are compelling but have yet to benot support this. In the SYST-EUR diuretic hydrochlorthiazide was pre- replicated. Earlier studies of systolicstudy of the treatment of systolic scribed as a third choice. Of the hypertension treatment tended not tohypertension in elderly people,6 the patients with complete cognitive data, measure cognition precisely enoughincidence of dementia in the treat- 21 of 1,180 in the placebo group were for an effect to be demonstrated.ment group was half of the placebocontrol group. In the treatment group,those with systolic hypertension The contemporary treatment of mixed dementia has(defined as a systolic pressure two components: treatment of the vascular risk factorsbetween 160 mm Hg and 219 mm Hg and treatment of the cognitive impairment.and diastolic pressure below 95 mmHg) were assigned to first-time treat-ment with nitredipine, a calcium- diagnosed with dementia, compared Two recent population-basedchannel blocker. If necessary, this with 11 of 1,238 in the treatment studies have shown conflictingcould be combined or substituted group, after a median two years results. Guo et al7 studied patients in The Canadian Alzheimer Disease Review • February 2000 • 9
  4. 4. Sweden aged 75 years and older, and attack, stroke and dementia. The may reflect the fact that stroke anddemonstrated the protective effect of benefit for elderly hypertensive vascular dementia are induced bydiuretics on cognition impairment in patients with multisystem disorders different mechanisms.hypertensive patients. In contrast, in or mild cognitive impairment is More specific treatment ofthe Canadian Study of Health and uncertain, and cognitive function in mixed dementia focuses on treat-Aging, Maxwell and colleagues 8 such patients should be monitored ment of the AD component.showed an increased risk of cogni- carefully. Aggressive lowering of Although separate mixed dementiative impairment in elderly people systolic blood pressure in such studies have yet to be conducted,who were treated with calcium- patients is generally unwise. most of the AD studies to date havechannel blockers. Taking all the data Although other vascular risk factors included patients with so-called incidental subcortical or lacunarThe benefit for elderly hypertensive patients with infarcts or minor degrees of white matter changes. Given these datamultisystem disorders or mild cognitive impairment is and the lack of treatment alterna-uncertain, and cognitive function in such patients tives, I usually opt for a trial ofshould be monitored carefully. donepezil, the only approved treat- ment for AD in Canada.into account, it appears that elderly appear to be important and their con-patients with systolic hypertension, trol is linked to a decreased inci- Conclusiongood cognitive function and other- dence of stroke, such control has yet The syndrome of mixed dementiawise stable health (i.e., those most to be shown to decrease the inci- has much to teach us, both aboutlike the SYST-EUR patients) can dence of dementia. This may be mechanisms of disease and fads oftolerate antihypertensive treatment. because larger studies with better diagnosis. Perhaps our experienceIn such patients, benefit is likely to characterization of cognitive end- over the next few years will be asinclude a reduced risk of heart points need to be conducted or it revealing as those gone by.References lesions of significance in vascular trial. Lancet 1998; 352:1347-51.1. Rockwood K: Lessons from mixed dementia. J Neurol Neurosurg 7. Guo Z, Fratiglioni L, Zhu L, et al: dementia. Int Psychogeriatr 1997; Psychiatry 1997; 63:749-53. Occurrence and progression of 9:245-9. 5. Rockwood K, MacKnight C, Wentzel C, dementia in a community population2. Skoog I: The relationship between blood et al: for the CIVIC investigators: The aged 75 years and older: Relationship pressure and dementia: a review. diagnosis of “mixed” dementia in the of antihypertensive medication use. Biomed Pharmacother 1997; 51:367-75. consortium for the investigation of Arch Neurol 1999; 56:991-6.3. Snowdon DA, Greiner L, Mortimer JA, vascular impairment of cognition 8. Maxwell CJ, Hogan DB, Ebly EM: et al: Brain infarction and the clinical (CIVIC). Ann N Y Acad Sci (in press). Calcium-channel blockers and expression of Alzheimer disease. 6. Forette F, Seux ML, Staessen JA, et al: cognitive function in elderly people: The Nun Study. JAMA 1997; 277:813-7. Prevention of dementia in randomised results from the Canadian Study of4. Esiri MM, Wilcock GK, Morris JH: double-blind placebo-controlled Systolic Health and Aging. CMAJ 1999; Neuropathological assessment of the Hypertension in Europe (SYST-EUR) 161:501-6.10 • The Canadian Alzheimer Disease Review • February 2000