Published Online June 10, 2009

Preventing dementia: role of vascular risk factors and cerebral emboli

Nitin Purandare*
Psychiatry Research Group, Room 3.319, 3rd Floor East, University Place, University of Manchester, Oxford Road, Manchester M13 9PL, UK

Introduction or background: Dementia, Alzheimers disease and vascular dementia being two main causes, is major and growing health problem. Vascular risk factors are thought to be involved in the causation of both dementias. Sources of data: A review of the literature was conducted using MedLine to identify current evidence for role of vascular risk factors as potential targets in preventing dementia. Cross-references were hand searched. Areas of agreement: The evidence from prospective epidemiological studies suggests that optimizing the control of vascular risk factors such as hypertension, high cholesterol, diabetes, smoking and heart disease may prevent dementia. However, this has been proven in randomized placebo-controlled trials (RCT) for only hypertension. Areas of controversy: Dementia is a secondary outcome in most RCTs and it is not known if there is a therapeutic time window between mid- and late-life when interventions are most effective. Also, we do not know precise mechanisms by which interventions for vascular risk factors offer brain protection. Growing points: Our research suggests that asymptomatic cerebral emboli, which are preventable, may be involved in the causation of dementia. Areas timely for developing research: There is a need for RCT targeting multiple vascular risk factors in patients at high risk of dementia such as those with mild cognitive impairment.
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Accepted: May 13, 2009 *Correspondence to: Nitin Purandare, Psychiatry Research Group, Room 3.319, 3rd Floor East, University Place, University of Manchester, Oxford Road, Manchester M13 9PL, UK. E-mail: nitin.purandare@ manchester.ac.uk

Keywords: dementia/Alzheimers disease/vascular dementia/vascular risk factors/hypertension/emboli

British Medical Bulletin 2009; 91: 4959 DOI:10.1093/bmb/ldp020

& The Author 2009. Published by Oxford University Press. All rights reserved.
For permissions, please e-mail: journals.permissions@oxfordjournals.org

N. Purandare

Introduction
Dementia affects over 24 million people in the world currently and the number with dementia is expected to increase to over 81 million by 2040.1 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 currently available cognitive enhancers for Alzheimers disease (AD) offer only a modest symptomatic improvement with some concerns about their cost-effectiveness.3 The consultation document on the National Dementia Strategy4 recognizes the important of research on prevention strategies. If the onset of dementia could be delayed by about 5 years then its prevalence could almost be halved.5 AD and vascular dementia (VaD) account for about 80% of all dementias with evidence of considerable overlap between the two and mixed dementia is common.6 The Nun study showed the additive effect of cerebrovascular and neurodegenerative pathologies in producing clinical dementia. A fewer neuropathological lesions of AD were required for the clinical manifestation of dementia in those who had infarcts in basal ganglia, thalamus or deep white matter.7 Until recently, the autopsy diagnosis of dementia subtypes was considered definitive. However, this assumption was based on the research that devised staging for one type of neuropathology [for example, senile plaques (SP) and neurofibrillary tangles (NFT)] while ignoring the other co-existent pathologies (for example, vascular disease). Gold et al. 8 in their autopsy study proposed a new system of classification which allocates the diagnosis of pure AD, pure VaD or mixed dementia depending on the severity of neurodegenerative and cerebrovascular pathology. Braak staging of NFT higher than stage II and score of greater than two on a semi-quantitative scale measuring the total burden of cortical microinfarcts and thalamic and basal ganglia lacunes are taken as cut off for dementia due to AD and VaD, respectively. 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 and VaD.

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Vascular risk factors

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

A number of cross-sectional and epidemiological studies have shown than hypertension in mid-life is a risk factor for dementia in old age. For example, Honolulu Asia aging study (HAAS) followed 3731 Japanese American men for over 14 years with autopsy data on 650 participants.9 High systolic blood pressure (BP  160 mm Hg) was associated 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 and lacunar infarcts further increased the risk of incident dementia. Interestingly, the BP drops around the time of or soon after the onset of clinical dementia and the current research is trying to find out whether this is a risk factor or risk marker for dementia. The Kungsholmen project10 followed 947 people aged  75 years every 3 years 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 was associated with an increased risk of dementia at the second follow-up (relative risk, RR 3.1). However, this finding was challenged by another prospective study of 2356 older people  65 years over 8 years. The study concluded that the association between BP and dementia depended on age at which BP was measured and not the time relative to the onset of dementia. In 65 74 years of age group, high systolic BP and borderline-high diastolic BP was associated with an increased risk of dementia while in those  75 years there was a trend towards high systolic BP being associated with low risk of developing dementia.11 There have been a number of randomized controlled trials (RCT) of antihypertensive medications with cognition and or dementia as one of the outcomes. Some of the earlier trials that used diuretics or beta-blockers were negative.12,13 SCOPE trial14 included a much older (7089 years) patient group and excluded those with stroke or myocardial infarction in previous 6 months. Candesartan [angiotensin II type 1 (AT1) receptor blocker] was not found to have any positive effect on progression of cognitive impairment over 3.7 years. However, antihypertensive medications were used in 84% of the controls. The RCTs involving angiotensin-converting enzyme (ACE) inhibitors (HOPE15 and PROGRESS16) have been mixed but encouraging. PROGRESS trial, which included both normotensive and hypertensive patients with previous history of cerebrovascular disease, found a significant reduction in stroke-related dementia in patients treated with perindopril (ACE inhibitor) as the main antihypertensive. The Syst-Eur trial included 2410 older people with isolated systolic
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hypertension (systolic BP of 160 219 and diastolic BP of , 95 mm Hg). The intervention group (n 1238) received nitrendipine (calcium channel blocker) and if required, enalapril and hydrocholrothiazide.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 the end of the trial and both groups followed for further 2 years. The long-term treatment with nitrendipine reduced incident dementia by 55% (from 7.4 to 3.3 cases per 1000 person years). Treatment of 1000 patients for 5 years could prevent 20 (95% CI: 7, 33) cases of dementia.18 The hypertension in the Very Elderly trail (HYVET)19 included patients with hypertension (systolic BP of 160 200 and diastolic BP of , 110 mm Hg, respectively) aged 80 years or older who were followed for 2 years. There was no significant reduction in incident dementia between active (indapamide with or without perindopril) and placebo arms. However, when the data were combined in a meta-analysis with other placebo-controlled trails the combined risk ratio favoured active treatment with antihypertensive HR of 0.87 (95% CI: 0.76, 1.00).

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Other vascular risk factors

A number of case control and epidemiological studies have reported hypercholesterolemia as a risk factor for dementia, including AD. For example, a prospective study from Finland with 21 years follow-up found raised cholesterol in mid-life (  6.5 mmol/l) to more than double the risk of dementia, including AD, independently of other risk factors such as hypertension and ApoE4.20 A meta-analysis of seven observational studies indicated risk reduction in cognitive impairment to be significant for only statins (OR 0.43) and not other lipid lowering agents.21 The beneficial effect may be restricted to older people below age of 80 years22 and to those statins that inhibit alpha and beta secretase.23 However, not all epidemiological studies show an association between statin use and subsequent dementia24 and the results of intervention trials, where cognition and dementia are secondary outcomes, have been disappointing.25,26 Elevated total homocysteine (tHcy) is associated with increased risk of heart disease, stroke, silent brain infarcts and dementia.27 29 In older people, higher concentrations of tHcy are associated with poor performance on neuropsychological tests with the odds of cognitive decline 2.8-fold (P , 0.05) higher in subjects with tHcy levels above 15 mmol/l compared with those with levels below 10 mmol/l.30 A large epidemiological study in Framingham, USA, involving 1092 older
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residents in the community (mean age 76 years, median follow-up 8 years) reported that the risk of AD nearly doubled (relative risk, RR 1.8; confidence intervals, CI 1.32.5) with one standard deviation increase in tHcy levels at baseline.31 Although elevated tHcy has been shown to be associated with cognitive impairment in AD, the effect of reducing homocysteine levels on cognition and global functioning has not been adequately investigated. In a small prospective study involving 33 patients, Nilsson et al. 32 reported an improvement in cognitive function after 2 months of cobalamine (B12) and folate treatment in individuals with mild-to-moderate dementia who had elevated tHcy. Patients with severe dementia and those who had normal tHcy did not however show clinical improvement. Diabetes is thought to be a risk factor for AD and VaD, especially VaD.33 36 Coronary heart disease is associated with increased amounts of cerebral amyloid deposits and increased risk of dementia, including AD.37,38 In addition, atrial fibrillation (even in absence of clinical stroke) was found to have significant positive association with both AD and VaD, and interestingly the association was stronger for AD with cerebrovascular disease than VaD.39 Smoking, a risk factor for stroke, is considered one of the prime targets in prevention of vascular cognitive impairment.40 The HAAS found smoking during middle age to be associated with later risk of cognitive impairment and the risk increased from those who had stopped smoking to continuous smokers when compared with those who had never smoked.41 Current smoking was shown to double the incidence of dementia in the Rotterdam study42 but the effect of smoking on the risk of developing AD needs further exploration. Some studies find smoking to increase the risk of AD43,44 while others find no association45,46 or protective effect47,48. The observed protective effect may be due to reduced survival among smokers or the positive effect of nicotine on neuronal survival. So far, there are no randomized control trials that show that treatment of diabetes, heart disease or cessation of smoking prevents incident cases of dementia, AD or VaD. The relevance of vascular risk factors to the causation of dementia receives further support from the literature that shows reduced leisuretime physical activity to be risk factor for dementia and AD.49 Physical activity or exercise may have protective effect on multiple cardiovascular risk factors. Lautenschlager et al. 50 randomized 170 middle-age to older people with subjective memory complaints but no dementia to receive education and usual care or 24 week home-based physical activity programme. The intervention group showed greater improvement in cognition at 6 months, with evidence of continued positive effect at 18 months.

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Potential role of asymptomatic cerebral emboli

Above evidence suggests that a number of vascular risk factors may contribute 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 which different risk factors eventually lead to cerebral damage. Stroke or transient ischaemic attacks (TIA) may be one such common pathway but not necessarily the only pathway. Over last 10 years, we (departments of old age psychiatry and vascular surgery at the University of Manchester) have been investigating the hypothesis that asymptomatic spontaneous cerebral emboli (SCE) may cause progressive brain damage and dementia. Such microemboli have been shown to be frequent in patients with severe carotid artery disease, valvular heart disease and stroke.51,52 In these and those undergoing heart bypass surgery, cerebral emboli predict future risk of cerebrovascular accidents and poor neurocognitive outcomes.53,54 We conducted a case control study that included 85 patients with AD (NINCDS/ADRDA criteria)55 and 85 patients with VaD (NINDS/AIREN criteria)56 with their respective age and sex-matched controls. In just 1 h of transcranial Doppler monitoring, SCE were detected in middle cerebral arteries in 32 (40%) AD and 31 (37%) VaD patients compared with 12 (15%) and 12 (14%) of their respective controls. The odds ratio for the presence of SCE was 2.70 (1.18 6.21) for AD and 5.36 (1.24 23.18) for VaD, adjusted for cardiovascular risk factors.57 In controls, the presence of SCE was associated with cardiovascular risk factors (a history of stoke or TIA, a history myocardial infarction or angina, higher diastolic BP, presence of severe carotid artery stenosis) and current treatment with antiplatelet medications. Carotid stenosis and other vascular risk factors did not explain the increased frequencies of SCE in patients with dementia in our study. The potential role of coagulation cascade, including platelet disorders, in increasing the risk of microemboli formation needs further investigation as some studies have shown abnormalities in coagulation pathways and platelet activation in AD patients.58,59 We investigated the clinical relevance of SCE by conducting a longitudinal follow-up of patients with dementia over 6 months.60 A total of 132 patients had validated SCE assessment and at least one of the outcome measure data initially and at 6 months. Patients with dementia who were SCE positive (n 47, 36%) at initial assessment showed a more rapid decline in cognitive functioning and activities of daily living over 6 months compared with SCE negative patients. These results were unaltered after adjusting for ApoE4 status and the use 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 is not known but is presumably by microischaemic changes. We did not find SCE to be associated with either infarcts or severity of white matter hyperintensities (WMH). However, one of the mechanisms of cerebral embolization (venous to arterial circulation shunt suggestive of patent foramen ovale in the heart) was associated with increased severity of deep and peri-ventricular WMH in patients with AD alone.61 Another source of SCE (unstable carotid plaques) was recently shown to be associated with increased frequency of WMH lesions in patients undergoing magnetic resonance imaging of the brain prior to carotid endarterectomy.62 However, it is likely that SCE do not lead to a structural evidence of cerebrovascular disease that is large enough to be detected by the currently available neuroimaging techniques. Alternatively, the initial vascular insult resulting from embolization of microvessels may trigger another mechanism of brain damage, such as inflammation, but leaves no evidence of the original vascular insult. In AD, cerebral microvessels have been shown to release significantly higher amounts of inflammatory mediators such as interleukin (IL)1b, IL-6 and tumour necrosis factor alpha.63 It is also proposed that the microglia in the diseased or aged brain are primed, and switch their phenotype to produce neurotoxic molecules when they respond to systemic inflammatory signals.64 Systemic infections are suggested as potential triggers for microglial activation. However, microglia is sensitive to other disturbances of brain homeostasis65 that may include SCE induced ischaemia in cerebral microcirculation.

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Directions for future research

The current literature on the control of vascular risk factors in prevention of dementia has certain limitations. Most RCTs target hypertension with a few targeting cholesterol. None of the RCTs attempt to optimize control of multiple vascular risk factors. Cognition and dementia is a secondary outcome with limited statistical power to detect significance of any true difference between intervention and placebo groups due to low frequencies of incident dementia in the selected population. There are not any prevention trials (except for atorvastatin) targeting specifically people at most risk of developing dementia. The term mild cognitive impairment (MCI) is commonly used to describe a group of patients who have some cognitive deficits but not severe enough to affect daily functioning and warrant a diagnosis of dementia.66 However, tests used to assess cognition and daily
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functions and diagnostic criteria for MCI vary. The trials targeting older people with MCI with incident dementia as the primary outcome are likely to need at least 2000 3000 participants and multiple centres. It is essential to operationalized criteria for MCI to allow comparison between studies67 and develop surrogate markers to help reduce the size of the study. There may be a therapeutic time window between mid- and late-life during which vascular risk factors increase the risk of dementia. This may explain the dissonance between the epidemiological research that identifies potential risk factor and the RCT that fails to show positive effect of the intervention in older people with MCI. Systolic BP drops around the onset of dementia and lowering BP in patients with MCI, some of whom may have already developed neurodegenerative changes, may not have beneficial effects. In addition, lower the better doctrine applied to BP and cholesterol in cardiovascular and stroke prevention trails may not hold true for cognition in people with MCI. Lastly, we need RCTs that optimize the control of multiple risk factors as co-morbidity is common in older people.

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Conclusion
Over the next few decades, dementia is going to be a major health problem worldwide. AD and VaD are two main causes with mixed dementia being common. Epidemiological evidence has highlighted a number of vascular risk factors in mid-life to be associated with dementia in late-life. RCT evidence that treatment of vascular risk factor prevents dementia exists for hypertension but not for others. RCT studies are limited in their methodology with dementia often being a secondary outcome and studies not specifically focusing on those at high risk of dementia, for example those with MCI. Future research needs to explore novel mechanisms of vascular brain damage. Asymptomatic SCE may be one such mechanism worth further exploration as interventions that inhibit emboli formation are already available. We are currently conducting a pilot study investigating two such therapies (clopidogrel and atorvastatin) in patients with dementia.

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