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Introduction

Dementia affects over 24 million people in the world currently and thenumber with dementia is expected to increase to over 81 million by2040.1 In the UK, there are about 700 000 people suffering from

dementia with the annual cost to the economy of 17 billion.2

Dementia is a chronic progressive condition with no cure and the cur-rently available cognitive enhancers for Alzheimers disease (AD) offeronly a modest symptomatic improvement with some concerns abouttheir cost-effectiveness.3 The consultation document on the NationalDementia Strategy4 recognizes the important of research on preventionstrategies. If the onset of dementia could be delayed by about 5 yearsthen its prevalence could almost be halved.5

AD and vascular dementia (VaD) account for about 80% of alldementias with evidence of considerable overlap between the two and

mixed dementia is common.

6

The Nun study showed the additiveeffect of cerebrovascular and neurodegenerative pathologies in produ-cing clinical dementia. A fewer neuropathological lesions of AD wererequired for the clinical manifestation of dementia in those who hadinfarcts in basal ganglia, thalamus or deep white matter.7 Untilrecently, the autopsy diagnosis of dementia subtypes was considereddefinitive. However, this assumption was based on the research thatdevised staging for one type of neuropathology [for example, senileplaques (SP) and neurofibrillary tangles (NFT)] while ignoring theother co-existent pathologies (for example, vascular disease). Goldet al.8 in their autopsy study proposed a new system of classificationwhich allocates the diagnosis of pure AD, pure VaD or mixeddementia depending on the severity of neurodegenerative and cerebro-vascular pathology. Braak staging of NFT higher than stage II andscore of greater than two on a semi-quantitative scale measuring thetotal burden of cortical microinfarcts and thalamic and basal ganglialacunes are taken as cut off for dementia due to AD and VaD, respect-ively. Mixed dementia is diagnosed when both criteria are satisfied.

This review focuses on the potential role of vascular risk factors,specifically evidence from clinical studies, in the prevention of AD andVaD.

Vascular risk factors

Hypertension, hypercholesterolemia, elevated homocysteine, diabetes,heart disease, smoking and carotid artery disease are known riskfactors for dementia, AD and VaD.

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Hypertension

A number of cross-sectional and epidemiological studies have shownthan hypertension in mid-life is a risk factor for dementia in old age.For example, Honolulu Asia aging study (HAAS) followed 3731Japanese American men for over 14 years with autopsy data on 650participants.9 High systolic blood pressure (BP 160 mm Hg) wasassociated with increased risk of dementia (hazard ratio, HR 4.8).Hypertension was also associated with lower total brain weight,increased SP count and hippocampal atrophy. A coexistence of SP andlacunar infarcts further increased the risk of incident dementia.Interestingly, the BP drops around the time of or soon after the onsetof clinical dementia and the current research is trying to find outwhether this is a risk factor or risk marker for dementia. TheKungsholmen project10 followed 947 people aged 75 years every 3years for 6 years. BP decreased significantly over 3 years prior to and

following diagnosis of dementia. In people with baseline systolic BP,160 mm Hg, a drop of 15 mm Hg over the first follow-up wasassociated with an increased risk of dementia at the second follow-up(relative risk, RR 3.1). However, this finding was challenged byanother prospective study of 2356 older people 65 years over 8years. The study concluded that the association between BP anddementia depended on age at which BP was measured and not the timerelative to the onset of dementia. In 6574 years of age group, highsystolic BP and borderline-high diastolic BP was associated with anincreased risk of dementia while in those 75 years there was a trend

towards high systolic BP being associated with low risk of developingdementia.11

There have been a number of randomized controlled trials (RCT)of antihypertensive medications with cognition and or dementia asone of the outcomes. Some of the earlier trials that used diuretics orbeta-blockers were negative.12,13 SCOPE trial14 included a mucholder (7089 years) patient group and excluded those with stroke ormyocardial infarction in previous 6 months. Candesartan [angiotensinII type 1 (AT1) receptor blocker] was not found to have any positiveeffect on progression of cognitive impairment over 3.7 years.However, antihypertensive medications were used in 84% of the con-trols. The RCTs involving angiotensin-converting enzyme (ACE)inhibitors (HOPE15 and PROGRESS16) have been mixed but encoura-ging. PROGRESS trial, which included both normotensive and hyper-tensive patients with previous history of cerebrovascular disease,found a significant reduction in stroke-related dementia in patientstreated with perindopril (ACE inhibitor) as the main antihypertensive.The Syst-Eur trial included 2410 older people with isolated systolic

Preventing dementia: vascular risk factors and cerebral emboli

British Medical Bulletin 2009;91 51

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hypertension (systolic BP of 160 219 and diastolic BP of ,95 mmHg). The intervention group (n 1238) received nitrendipine(calcium channel blocker) and if required, enalapril and hydrochol-rothiazide.17 Over 2 year follow-up, the intervention group has 50%reduced risk of incident dementia compared with the group receiving

placebo. The controls were given antihypertensive medications at theend of the trial and both groups followed for further 2 years. Thelong-term treatment with nitrendipine reduced incident dementia by55% (from 7.4 to 3.3 cases per 1000 person years). Treatment of1000 patients for 5 years could prevent 20 (95% CI: 7, 33) cases ofdementia.18 The hypertension in the Very Elderly trail (HYVET)19

included patients with hypertension (systolic BP of 160 200 anddiastolic BP of ,110 mm Hg, respectively) aged 80 years or olderwho were followed for 2 years. There was no significant reduction inincident dementia between active (indapamide with or without peri-ndopril) and placebo arms. However, when the data were combinedin a meta-analysis with other placebo-controlled trails the combinedrisk ratio favoured active treatment with antihypertensive HR of 0.87(95% CI: 0.76, 1.00).

Other vascular risk factors

A number of casecontrol and epidemiological studies have reportedhypercholesterolemia as a risk factor for dementia, including AD. Forexample, a prospective study from Finland with 21 years follow-up

found raised cholesterol in mid-life (6.5 mmol/l) to more than doublethe risk of dementia, including AD, independently of other risk factorssuch as hypertension and ApoE4.20 A meta-analysis of seven observa-tional studies indicated risk reduction in cognitive impairment to besignificant for only statins (OR 0.43) and not other lipid loweringagents.21 The beneficial effect may be restricted to older people belowage of 80 years22 and to those statins that inhibit alpha and beta secre-tase.23 However, not all epidemiological studies show an associationbetween statin use and subsequent dementia24 and the results of inter-vention trials, where cognition and dementia are secondary outcomes,

have been disappointing.25,26

Elevated total homocysteine (tHcy) is associated with increased riskof heart disease, stroke, silent brain infarcts and dementia.2729 Inolder people, higher concentrations of tHcy are associated with poorperformance on neuropsychological tests with the odds of cognitivedecline 2.8-fold (P, 0.05) higher in subjects with tHcy levels above15 mmol/l compared with those with levels below 10 mmol/l.30 A largeepidemiological study in Framingham, USA, involving 1092 older

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residents in the community (mean age 76 years, median follow-up8 years) reported that the risk of AD nearly doubled (relative risk, RR1.8; confidence intervals, CI 1.3 2.5) with one standard deviationincrease in tHcy levels at baseline.31 Although elevated tHcy has beenshown to be associated with cognitive impairment in AD, the effect of

reducing homocysteine levels on cognition and global functioning hasnot been adequately investigated. In a small prospective study involving33 patients, Nilsson et al.32 reported an improvement in cognitive func-tion after 2 months of cobalamine (B12) and folate treatment in indi-viduals with mild-to-moderate dementia who had elevated tHcy.Patients with severe dementia and those who had normal tHcy did nothowever show clinical improvement.

Diabetes is thought to be a risk factor for AD and VaD, especiallyVaD.3336 Coronary heart disease is associated with increased amountsof cerebral amyloid deposits and increased risk of dementia, includingAD.37,38 In addition, atrial fibrillation (even in absence of clinicalstroke) was found to have significant positive association with both ADand VaD, and interestingly the association was stronger for AD withcerebrovascular disease than VaD.39 Smoking, a risk factor for stroke,is considered one of the prime targets in prevention of vascular cogni-tive impairment.40 The HAAS found smoking during middle age to beassociated with later risk of cognitive impairment and the riskincreased from those who had stopped smoking to continuous smokerswhen compared with those who had never smoked.41 Current smokingwas shown to double the incidence of dementia in the Rotterdamstudy42 but the effect of smoking on the risk of developing AD needs

further exploration. Some studies find smoking to increase the risk ofAD43,44 while others find no association45,46 or protective effect47,48.The observed protective effect may be due to reduced survival amongsmokers or the positive effect of nicotine on neuronal survival. So far,there are no randomized control trials that show that treatment of dia-betes, heart disease or cessation of smoking prevents incident cases ofdementia, AD or VaD.

The relevance of vascular risk factors to the causation of dementiareceives further support from the literature that shows reduced leisure-time physical activity to be risk factor for dementia and AD.49 Physical

activity or exercise may have protective effect on multiple cardiovascu-lar risk factors. Lautenschlager et al.50 randomized 170 middle-age toolder people with subjective memory complaints but no dementia toreceive education and usual care or 24 week home-based physicalactivity programme. The intervention group showed greater improve-ment in cognition at 6 months, with evidence of continued positiveeffect at 18 months.



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Potential role of asymptomatic cerebral emboli

Above evidence suggests that a number of vascular risk factors maycontribute to the clinical syndrome of dementia in AD and VaD.However, underlying pathophysiological mechanisms need further

exploration, especially if there are any common pathways by whichdifferent risk factors eventually lead to cerebral damage. Stroke or tran-sient ischaemic attacks (TIA) may be one such common pathway butnot necessarily the only pathway. Over last 10 years, we (departmentsof old age psychiatry and vascular surgery at the University ofManchester) have been investigating the hypothesis that asymptomaticspontaneous cerebral emboli (SCE) may cause progressive braindamage and dementia. Such microemboli have been shown to be fre-quent in patients with severe carotid artery disease, valvular heartdisease and stroke.51,52 In these and those undergoing heart bypass

surgery, cerebral emboli predict future risk of cerebrovascular accidentsand poor neurocognitive outcomes.53,54 We conducted a casecontrolstudy that included 85 patients with AD (NINCDS/ADRDA criteria)55

and 85 patients with VaD (NINDS/AIREN criteria)56 with theirrespective age and sex-matched controls.

In just 1 h of transcranial Doppler monitoring, SCE were detected inmiddle cerebral arteries in 32 (40%) AD and 31 (37%) VaD patientscompared with 12 (15%) and 12 (14%) of their respective controls. Theodds ratio for the presence of SCE was 2.70 (1.186.21) for AD and5.36 (1.2423.18) for VaD, adjusted for cardiovascular risk factors.57

In controls, the presence of SCE was associated with cardiovascular riskfactors (a history of stoke or TIA, a history myocardial infarction orangina, higher diastolic BP, presence of severe carotid artery stenosis)and current treatment with antiplatelet medications. Carotid stenosisand other vascular risk factors did not explain the increased frequenciesof SCE in patients with dementia in our study. The potential role ofcoagulation cascade, including platelet disorders, in increasing the riskof microemboli formation needs further investigation as some studieshave shown abnormalities in coagulation pathways and platelet acti-vation in AD patients.58,59 We investigated the clinical relevance of SCEby conducting a longitudinal follow-up of patients with dementia over 6

months.60 A total of 132 patients had validated SCE assessment and atleast one of the outcome measure data initially and at 6 months. Patientswith dementia who were SCE positive (n 47, 36%) at initial assess-ment showed a more rapid decline in cognitive functioning and activitiesof daily living over 6 months compared with SCE negative patients.These results were unaltered after adjusting for ApoE4 status and theuse of cholinesterase inhibitors and or antiplatelet drugs.

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SCE and potential mechanisms of brain damage in dementia

The mechanism by which cerebral microemboli cause brain damage isnot known but is presumably by microischaemic changes. We did notfind SCE to be associated with either infarcts or severity of whitematter hyperintensities (WMH). However, one of the mechanisms ofcerebral embolization (venous to arterial circulation shunt suggestive ofpatent foramen ovale in the heart) was associated with increased sever-ity of deep and peri-ventricular WMH in patients with AD alone.61

Another source of SCE (unstable carotid plaques) was recently shownto be associated with increased frequency of WMH lesions in patientsundergoing magnetic resonance imaging of the brain prior to carotidendarterectomy.62 However, it is likely that SCE do not lead to a struc-tural evidence of cerebrovascular disease that is large enough to bedetected by the currently available neuroimaging techniques.Alternatively, the initial vascular insult resulting from embolization of

microvessels may trigger another mechanism of brain damage, such asinflammation, but leaves no evidence of the original vascular insult. InAD, cerebral microvessels have been shown to release significantlyhigher amounts of inflammatory mediators such as interleukin (IL)1b,IL-6 and tumour necrosis factor alpha.63 It is also proposed that themicroglia in the diseased or aged brain are primed, and switch theirphenotype to produce neurotoxic molecules when they respond to sys-temic inflammatory signals.64 Systemic infections are suggested aspotential triggers for microglial activation. However, microglia is sensi-tive to other disturbances of brain homeostasis65 that may include SCE

induced ischaemia in cerebral microcirculation.

Directions for future research

The current literature on the control of vascular risk factors inprevention of dementia has certain limitations. Most RCTs targethypertension with a few targeting cholesterol. None of the RCTsattempt to optimize control of multiple vascular risk factors. Cognitionand dementia is a secondary outcome with limited statistical power to

detect significance of any true difference between intervention andplacebo groups due to low frequencies of incident dementia in theselected population. There are not any prevention trials (except foratorvastatin) targeting specifically people at most risk of developingdementia. The term mild cognitive impairment (MCI) is commonlyused to describe a group of patients who have some cognitive deficitsbut not severe enough to affect daily functioning and warrant a diagno-sis of dementia.66 However, tests used to assess cognition and daily



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functions and diagnostic criteria for MCI vary. The trials targetingolder people with MCI with incident dementia as the primary outcomeare likely to need at least 20003000 participants and multiple centres.It is essential to operationalized criteria for MCI to allow comparisonbetween studies67 and develop surrogate markers to help reduce the

size of the study. There may be a therapeutic time window betweenmid- and late-life during which vascular risk factors increase the risk ofdementia. This may explain the dissonance between the epidemiologi-cal research that identifies potential risk factor and the RCT that failsto show positive effect of the intervention in older people with MCI.Systolic BP drops around the onset of dementia and lowering BP inpatients with MCI, some of whom may have already developed neuro-degenerative changes, may not have beneficial effects. In addition,lower the better doctrine applied to BP and cholesterol in cardiovascu-lar and stroke prevention trails may not hold true for cognition inpeople with MCI. Lastly, we need RCTs that optimize the control ofmultiple risk factors as co-morbidity is common in older people.

Conclusion

Over the next few decades, dementia is going to be a major healthproblem worldwide. AD and VaD are two main causes with mixeddementia being common. Epidemiological evidence has highlighted a

number of vascular risk factors in mid-life to be associated withdementia in late-life. RCT evidence that treatment of vascular riskfactor prevents dementia exists for hypertension but not for others.RCT studies are limited in their methodology with dementia oftenbeing a secondary outcome and studies not specifically focusing onthose at high risk of dementia, for example those with MCI. Futureresearch needs to explore novel mechanisms of vascular brain damage.Asymptomatic SCE may be one such mechanism worth furtherexploration as interventions that inhibit emboli formation are alreadyavailable. We are currently conducting a pilot study investigating twosuch therapies (clopidogrel and atorvastatin) in patients with dementia.

Funding

The studies on cerebral emboli in dementia were funded by theWellcome Trust and the Alzheimers Society, UK.

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