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Research

Cerebral emboli as a potential cause of Alzheimers disease andvascular dementia: case-control studyNitin Purandare, Alistair Burns, Kevin J Daly, Jayne Hardicre, Julie Morris, Gary Macfarlane, Charles McCollum

Abstract

Objective To compare the occurrence of spontaneous cerebralemboli and venous to arterial circulation shunts in patients withAlzheimers disease or vascular dementia and controls without

dementia.Design Cross sectional case-control study.SettingSecondary care old age psychiatry services, Manchester.Participants 170 patients with dementia (85 with Alzheimersdisease, 85 with vascular dementia) and 150 age and sexmatched controls. Patients on anticoagulant treatment, patientswith severe dementia, and controls with marked cognitiveimpairment were excluded.Main outcome measures Frequencies of detection ofspontaneous cerebral emboli during one hour monitoring ofthe middle cerebral arteries with transcranial Doppler andvenous to arterial circulation shunts by a transcranial Dopplertechnique using intravenous microbubbles as an ultrasound

contrast.Results Spontaneous cerebral emboli were detected in 32(40%) of patients with Alzheimers disease and 31 (37%) ofthose with vascular dementia compared with just 12 each (15%and 14%) of their controls, giving significant odds ratiosadjusted for vascular risk factors of 2.70 (95% confidenceinterval 1.18 to 6.21) for Alzheimers disease and 5.36 (1.24 to23.18) for vascular dementia. These spontaneous cerebralemboli were not caused by carotid disease, which was equallyfrequent in dementia patients and their controls. A venous toarterial circulation shunt indicative of patent foramen ovale wasfound in 27 (32%) Alzheimers disease patients and 25 (29%)vascular dementia patients compared with 19 (22%) and 17(20%) controls, giving non-significant odds ratios of 1.57 (0.80

to 3.07) and 1.67 (0.81 to 3.41).Conclusion Spontaneous cerebral emboli were significantlyassociated with both Alzheimers disease and vascular dementia.They may represent a potentially preventable or treatable causeof dementia.

Introduction

Alzheimers disease and vascular dementia account for 80% of alldementias; evidence exists of considerable overlap between thetwo, epidemiologically, clinically, and histopathologically.1Vascu-lar risk factors such as hypertension, hypercholesterolaemia, dia-betes, and smoking are implicated in both dementias, but the

underlying pathophysiology remains uncertain.2

Both Alzheim-ers disease and vascular dementia are associated with carotidatherosclerosis, even in patients without symptoms of cerebrov-ascular disease.3

Carotid disease is one potential source of spontaneouscerebral emboli (SCE). Embolic signals will be detected on tran-scranial Doppler of the middle cerebral arteries, if monitoredover several hours, in most patients with symptomatic or severe

stenosis.

4

A large embolus may cause stroke or transient ischae-mic attack, but repeated small asymptomatic emboli over manymonths or years may cause progressive cerebral damage. Micro-emboli entering the cerebral circulation during open heart sur-gery or carotid surgery have been associated with cognitivedeficits and in particular memory loss.58

Valvular heart disease, atrial fibrillation, and paradoxicalembolisation of venous emboli into the arterial circulation areother potential sources of SCE.9 10 Atrial fibrillation has beenshown to be a risk factor for dementia,11 but the significance ofparadoxical embolisation has not been explored. Paradoxicalembolisation has recently been found to be associated with cryp-togenic stroke in young adults, postoperative confusion after hipreplacement, migraine, decompression sickness in scuba divers,

and transient global amnesia.1215 As venous emboli may enterthe arterial circulation through a patent foramen ovale, otheratrial-ventricular septal defects, or pulmonary arteriovenous fis-tulas, we prefer the term venous to arterial circulation shunt(v-aCS) to either patent foramen ovale or right to left heartshunt.

We standardised a minimally invasive transcranial Dopplertechnique to detect v-aCS and did a pilot study in patients withAlzheimers disease or vascular dementia.16 17 SCE and v-aCSwere more common in dementia patients than in communitycontrols. We therefore set up this study to explore definitively thefrequencies of SCE, carotid artery disease, and v-aCS inAlzheimers disease and vascular dementia.

Methods

This was a case-control study, in which we individually matchedpatients with Alzheimers disease or vascular dementia tocontrols of the same sex and age. All participants gave written,informed consent, and, in the case of patients with dementia,their carers were involved in the consent process.

Study subjectsPatientsWe recruited patients who satisfied the Diagnostic

and Statistical Manual of Mental Disorders, fourth edition(DSM-IV) criteria for dementia through a network of old agepsychiatrists in Greater Manchester. We used the National Insti-

tute of Neurological and Communicative Disorders and Stroke-

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Cite this article as: BMJ, doi:10.1136/bmj.38814.696493.AE (published 28 April 2006)

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Alzheimers Disease and Related Disorders Association(NINCDS-ADRDA) criteria for Alzheimers disease and theNational Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et lEnseignementen Neurosciences (NINDS-AIREN) criteria for vascular demen-tia.18 19 We used neuroimaging by computed tomography or

magnetic resonance imaging to help to allocate the diagnosis ofprobable Alzheimers disease or probable vascular dementia.

ControlsWe individually matched controls to dementiapatients by sex, age, and geographical area of residence. For eachpatient, we identified six people from the same general practicelist of the same sex and closest in age to the index patient. Wesent study information to all six potential controls, and, fromthose replying, the researcher saw the closest in age to check eli-gibility and obtain consent. If a potential control was ineligible orrefused consent, we approached the next closest in age. Controlswere never duplicated within the same dementia group, butwhen we had difficulties with general practice or individual con-sent, we examined potential controls not recruited previously foranother patient in the same or neighbouring practice andrecruited the closest match by age. For each case, the respectivecontrol was from the same general practice (62/170, 36%) orfrom a general practice in a similar socioeconomic area ofGreater Manchester (108/170, 64%).

Exclusion criteriaWe excluded patients if they had a mini-mental state examination score of less than 10 (severe dementia,unlikely to be able to participate).20 We excluded controls if theyhad a diagnosis of dementia or scored less than 24 on the mini-mental state examination (suggesting significant cognitiveimpairment or undiagnosed dementia). We excluded patientsand controls who had severe aphasia, had an inadequatetranstemporal window for transcranial Doppler insonation ofthe middle cerebral arteries, or were taking anticoagulant drugs.

Study assessmentsWe collected details on cardiovascular risk factors at interviewwith patients and their carers or with controls. We examined thepsychiatric notes to verify medical and psychiatric history forcases. An independent clinician used the above criteria todiagnose Alzheimers disease and vascular dementia. Technolo-gists in the Vascular Studies Unit at South Manchester UniversityHospital independently investigated SCE, carotid disease, andv-aCS; they were not told the diagnosis but obviously could notbe kept fully blind to dementia.

Spontaneous cerebral emboli

We detected SCE, thought to be par ticulate, by continuous tran-scranial Doppler insonation of the middle cerebral arteriesthrough the transtemporal window for one hour. This was donebefore transcranial Doppler investigation of v-aCS, to avoiddetecting air microemboli. The consensus on microembolusdetection by transcranial Doppler advises that studies shouldreport key technical parameters used in embolus detection (seeappendix on bmj.com).21 We used a Neuroguard (softwareversion 2.9, Medasonics) transcranial Doppler with a 2 MHzpulsed wave Doppler probe. The output was recorded on digitaltape for subsequent blind analysis by two trained vasculartechnologists. The same trained vascular laboratory staffobserved patients throughout each one hour session and

recorded any movement so that artefacts could be identified. Weused international consensus criteria to define emboli: Embolicsignals should be transient (lasting < 300 milliseconds), at least 3dB higher than the background blood flow signal, unidirectional,

within the Doppler spectrum, and accompanied by an audiblesnap, chirp, or moan.22

Transcranial Doppler monitoring for SCE was unilateral(middle cerebral arteries with the best signal) in 111 (65%) of 170dementia patients and 122 (72%) of 170 of their controls(P = 0.24). We found no association between the number of mid-

dle cerebral arteries monitored and detection of either v-aCS orSCE. Furthermore, adjustment for type of monitoring in thelogistic regression analyses resulted in almost identical results tothose obtained without adjustment.

Carotid artery diseaseWe used colour duplex ultrasound (ATL Ultramark 9) to imagecarotid disease and used established criteria to calculate theseverity of stenosis from the peak systolic velocity in the internalcarotid arteries.23

Detection of venous to arterial circulation shuntsWe used a standardised transcranial Doppler technique to detect

v-aCS, with insonation of the middle cerebral arteries and intra-venous injection of an emulsion of air microbubbles in saline asan ultrasound contrast medium. This is a minimally invasivetechnique that has been shown to be sensitive and specific topatent foramen ovale.2426

An 18 French cannula was inserted into an antecubital veinwith the participant lying semirecumbent. Saline (8 ml), air (1ml), and the patients own blood (0.5 ml) as an emulsificant weremixed vigorously 12 times between two 10 ml syringes througha three way tap to create a microbubble emulsion that was thenrapidly injected intravenously. Each emulsion, separated byintervals of at least one minute, was injected twice each whileresting quietly; with provocation by coughing repeatedly duringinjection and for a further five seconds; and with provocation by

a standardised Valsalva manoeuvre, blowing into a mouthpieceto maintain a pressure of 40 mm Hg immediately on injectionand released by exhaling five seconds later.

Two trained vascular technologists counted microbubbleembolic signals from the middle cerebral arteries. The studycoordinator, who was blind to case or control status, verified theresults by subsequent analysis of data tapes. The procedure wasstopped if > 50 microbubbles were detected at rest or > 80 weredetected after provocation. For participants who had unilateralmonitoring of middle cerebral arteries, we duplicated thenumber of embolic signals to equate to bilateral monitoring. Webased the criteria for significant v-aCS on our study comparingtranscranial Doppler with the diagnosis of patent foramen ovale

on transoesophageal echocardiography.16

As we use a rigorouslystandardised protocol for provocation testing, we prefer the fol-lowing definition of significant v-aCS to that of the InternationalConsensus Committee.27We defined a significant v-aCS (criteriafor patent foramen ovale) as transcranial Doppler detection of 15 embolic signals within 12 cardiac cycles of contrastinjection.16 We defined a major v-aCS as either > 50 embolicsignals at rest or > 10 at rest and > 80 after provocation bycoughing or Valsalva manoeuvre.

Power and statistical analysisWe found a v-aCS (any v-aCS) in 18 (51%) of the first 35 patientsexamined in our pilot study and used this as the basis for thepower calculations.17 As we would expect to detect a patent

foramen ovale in 22-24% of normal people,28

a sample size of 85Alzheimers disease and 85 vascular dementia case-control pairswould have over 80% power to detect differences of 25% or morebetween cases and controls, with an average odds ratio of 2.4,

Research

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determined using a McNemars test with a discordant pair rateranging between 50% and 70%. We used nQuery Advisor 5.0 toderive the power calculations and SPSS release 11.5 and Stataversion 8.0 to do statistical analyses.

We used McNemars test, paired ttest, and conditional logis-tic regression analysis to compare dementia patients with theirmatched controls for cardiovascular risk factors, the occurrenceof SCE, carotid disease, and v-aCS. We used 2 tests and two sam-ple t tests to assess the relation between SCE positivity andcardiovascular risk factors.

Results

We recruited a total of 170 patients with dementia (85 withAlzheimers disease and 85 with vascular dementia) and 150controls (tables 1 and 2). These included 22 dementia patients(17 Alzheimers disease, 5 vascular dementia) and 15 controls

reported in the pilot study.

17

Twenty controls were used for bothAlzheimers disease and vascular dementia patients. The meanage difference between cases and controls was 0.12 (SD 1.74)years.

Risk factors for cerebrovascular diseasePatients with Alzheimers disease and vascular dementia had asimilar profile of cardiovascular risk factors to their respectivecontrols (table 3), except for the more frequent history of strokeor transient ischaemic attack in vascular dementia patients com-pared with their controls (odds ratios 8.5 (95% confidence inter-val 2.0 to 36.8) for stroke and 21.5 (5.2 to 88.7) for transientischaemic attack). Both Alzheimers disease and vascular demen-tia patients also had lower body mass index than their controls.

Compared with Alzheimers disease patients, those with vasculardementia were more likely to have a history of stroke (P < 0.001),transient ischaemic attack (P < 0.001), antiplatelet drugs(P < 0.001), and hypertension (P = 0.01) and lower high densitylipoprotein cholesterol concentrations (P = 0.03). These factorsare all likely to lead a clinician to diagnose vascular dementia or,in the case of antiplatelet drugs, a consequence of that diagnosis.

Spontaneous cerebral emboliIn a single hour of transcranial Doppler monitoring, we detectedSCE in 32 (40%) Alzheimers disease and 31 (37%) vasculardementia patients compared with only 12 (15%) and 12 (14%)respectively of their controls (table 4). We detected two or moreSCE in 17 (21%) Alzheimers disease and 18 (21%) vascular

dementia patients, and in 9 (11%) and 8 (9%) of their respectivecontrols. The median number of SCE when present was 2 (inter-quartile range 1-2) for Alzheimers disease, 2 (1-3) for vasculardementia, and 1 (1-5) for controls. The odds ratio for SCE was3.22 (1.52 to 6.81) in Alzheimers disease and 4.80 (1.83 to 12.58)in vascular dementia. After exclusion of participants reported inthe pilot study, the odds ratio was 2.88 (1.29 to 6.43) forAlzheimers disease (61 case-control pairs, 26 (43%) v11 (18%),P = 0.01) and 4.00 (1.50 to 10.66) for vascular dementia (70 case-control pairs, 27 (38%) v12 (17%), P = 0.006). The odds ratios forSCE (all participants) remained similar and highly significant at2.70 (1.18 to 6.21) for Alzheimers disease and 5.36 (1.24 to23.18) for vascular dementia after adjustment for cardiovascularrisk factors.

Carotid diseaseWe detected moderate or severe ( > 50%) carotid stenosis ineither internal carotid artery in 7/82 (8%) Alzheimers diseasepatients and 20/78 (26%) vascular dementia patients comparedwith 13/82 (16%) and 26/78 (20%) of their respective controls(P = 0.14 and P = 1.0). We detected severe ( > 70%) carotid steno-sis in none of the Alzheimers disease patients, 6 (8%) vasculardementia patients, and 5 (6%) of both sets of controls (P = 0.06and P = 0.74).

Venous to arterial circulation shuntsWe detected a significant v-aCS in 27 (32%) Alzheimersdisease patients and 25 (29%) vascular dementia patientscompared with 19 (22%) and 17 (20%) of their respectivecontrols. The odds ratio was 1.57 (0.80 to 3.07) for Alzheimersdisease and 1.67 (0.81 to 3.41) for vascular dementia. Excludingparticipants reported in the pilot study gave odds ratios of 1.58(0.77 to 3.26) for Alzheimers disease (64 case-control pairs, 23(36%) v 16 (25%), P = 0.21) and 1.50 (0.72 to 3.11) for vasculardementia (72 case-control pairs, 22 (31%) v16 (22%), P = 0.28).We detected a major v-aCS in 16 (19%) Alzheimers diseasepatients and 13 (15%) vascular dementia patients compared with10 (12%) and 12 (14%) of their respective controls (P = 0.21 andP = 0.83).

SCE and cardiovascular risk factors

As expected, SCE were associated with all the majorcardiovascular risk factors in controls (table 5). We found no suchassociation in dementia patients, implying that SCE may be uni-versal in dementia. We found a greater than 70% carotid stenosisin 4 (19%) of 21 SCE positive controls compared with only 6(5%) of 124 controls who were SCE negative (P = 0.02), but thedifference was not significant in patients with dementia. SCE

Table 1 Recruitment of case-control pairs

Stage of recruitment Cases Controls

Consented 255 186

Excluded or withdrawn 49 19

Taking oral anticoagulant 2 NA

Did not satisfy Alzheimers disease or vascular

dementia criteria

4 NA

No acoustic window for transcranial Doppler 29 14

No adequate antecubital vein 1

MMSE score

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were not significantly associated with v-aCS in either patients orcontrols.

Discussion

This study shows that spontaneous cerebral emboli aresignificantly more common in patients with dementia than in

age and sex matched population controls. The frequency of SCEwas similar in Alzheimers disease and vascular dementia, whichmay explain the similarity in risk factors between these twodementias with differing final pathology.1

Frequency and sources of SCESCE may occur in carotid disease, especially in patients withsymptomatic or severe disease; with several hours of monitoring,SCE can be detected in more than half of patients with > 70%stenosis.4 29 Remarkably, the frequency of SCE during a singlehour of monitoring in patients with dementia was 37-40%, rais-ing the possibility that SCE would be detected in many morepatients if they were monitored over several hours. As we foundno significant association between carotid disease and SCE inthese dementia patients, carotid atherosclerosis seems to be anunlikely source for most SCE in dementia. None of the studyparticipants had clinically significant or uncontrolled atrial fibril-lation, and we excluded everyone taking anticoagulant drugs.Undiagnosed atrial fibrillation would not explain the presence ofemboli in almost 40% of dementia patients.

In controls, in whom SCE were less frequent, we found theexpected and statistically significant association between cardio-vascular risk factors and SCE. In dementia, SCE were muchmore common and were not associated with cardiovascular riskfactors. Many of our emboli negative patients might have hademboli detected if they were monitored for longer, and no asso-ciation with cardiovascular risk factors would exist if SCE were

universal in dementia patients. Alternatively, other mechanismssuch as inflammation could be involved in the pathophysiologyof both SCE and dementia.

Are some SCE paradoxical?We had insufficient evidence to conclude that any real differenceexisted in the frequencies of significant venous to arterialcirculation shunt (patent foramen ovale) between patients withdementia and controls. Our study was not sufficiently powered,as we based the original power calculations on a pilot study donebefore v-aCS criteria for patent foramen ovale (significant v-aCS)had been worked out.16 Percutaneous closure of patent foramenovale is used increasingly for atrial septal aneurysms with multi-ple embolic events. The risks and benefits of patent foramenovale closure are also being explored in other conditions, such asmigraine, and in divers.30

LimitationsA possible limitation of our study was that vascular technologistscould not be blinded to the case or control status of participants.

Table 3 Cardiovascular risk factors. Values are numbers (percentages) unless stated otherwise

Risk factor

Alzheimers disease Vascular dementia All dementia

Cases (n=85)Controls

(n=85) P value Cases (n=85) Controls (n=85) P value Cases (n=170) Controls (n=150) P value

Hypertension 25 (29) 31 (36) 0.29 41 (48) 34 (40) 0.31 66 (39) 57 (38) 0.88

Myocardial infarction 6 (7) 6 (7) 1.0 6 (7) 8 (9) 0.57 12 (7) 13 (9) 0.59

Angina 9 (11) 15 (18) 0.17 12 (14) 9 (11) 0.49 22 (13) 23 (15) 0.54

Stroke 1 (1) 5 (6) 0.12 18 (21) 3 (4) 0.004 19 (11) 8 (5) 0.06

Transient ischaemicattack

4 (5) 7 (8) 0.37 49 (58) 8 (9)

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This is unlikely to have biased our results, as we recordedtranscranial Doppler sessions for subsequent blind analysis. Wewere also unable to compare data on health betweenparticipants and non-participants (those who refused consent),as we would have needed consent to get this information.Although we asked about memory problems, and used anaccepted cut-off score on the mini-mental state examination toexclude controls with significant cognitive impairment,20

controls did not have further neuropsychological assessment todiagnose or exclude early dementia.

Cardiovascular risk factorsThe distribution of cardiovascular risk factors was similar indementia patients and their controls. Only a history of stroke ortransient ischaemic attack was more common in vasculardementia than in controls and Alzheimers disease patients. Thelikely explanation is that a history of cerebrovascular symptomsand infarcts on brain imaging would influence the clinician todiagnose vascular dementia rather than Alzheimers disease. Asthe diagnosis of vascular dementia would usually lead to the pre-scription of antiplatelet drugs, this factor was also associated withvascular dementia.

This study is the first to show an association between SCEand dementia. The similar frequency of emboli in both types ofdementia suggests a common cause and shared pathophysiol-ogy. We are investigating whether SCE predict future cognitivedecline in both dementia patients and controls.

ConclusionSpontaneous cerebral emboli were significantly more frequentin both Alzheimers disease and vascular dementia patients than

in sex and age matched controls. They may be a potentially pre-ventable or treatable cause of dementia.

We are grateful for the contribution made by the patients, their carers, andthe elderly people who volunteered to help as controls.

Contributors: NP participated in the study design, assessment of dementia,statistical analysis, and writing the manuscript. KJD did venous to arterialcirculation shunt testing and commented on the manuscript. JHcoordinated the study, validated transcranial Doppler monitoring for spon-taneous cerebral emboli, and commented on the manuscript. JM did thestatistical analysis and commented on the manuscript. GM participated instudy design and commented on the manuscript. AB participated in devel-

Table 5 Comparison of spontaneous cerebral emboli (SCE) positive and SCE negative participants. Values are numbers (percentages) unless stated otherwise

CharacteristicDementia* Controls

SCE positive (n=65) SCE negative (n=102) P value SCE positive (n=21) SCE negative (n=124) P value

Mean (SD) age (years) 76.7 (7.8) 76.0 (6.6) 0.53 76.5 (6.8) 76.5 (6.5) 1.0

Male sex 37 (57) 51 (50) 0.38 9 (43) 69 (56) 0.28

Mean (SD) MMSE score 21.1 (4.4) 21.9 (5.1) 0.29 28.2 (1.6) 28.6 (1.4) 0.21

Carotid disease:

>50% 10 (15) 15 (15) 0.90 8 (38) 23 (19) 0.06

>70% 3 (5) 2 (2) 0.32 4 (19) 6 (5) 0.023

Venous to arterial circulation shunt:

Significant 22 (34) 29 (28) 0.46 4 (19) 28 (23) 0.72

Major 11 (17) 18 (18) 0.90 2 (10) 16 (13) 0.66

Mean (SD) blood pressure (mm Hg):

Systolic 143.1 (26.0) 140.9 (27.8) 0.62 150.5 (24.4) 143.6 (22.9) 0.22

Diastolic 74.3 (14.3) 76.8 (13.1) 0.26 86.0 (11.9) 77.4 (14.5) 0.013

Mean (SD) lipid concentrations (mmol/l):

Cholesterol 5.42 (1.23) 5.27 (0.99) 0.39 5.32 (1.13) 5.41 (1.06) 0.73

HDL cholesterol 1.37 (0.39) 1.34 (0.40) 0.66 1.39 (0.33) 1.42 (0.49) 0.80

LDL cholesterol 3.34 (1.05) 3.14 (0.80) 0.17 3.03 (1.05) 3.20 (0.91) 0.45

Triglycerides 1.36 (0.9-1.9) 1.45 (1.0-1.9) 0.37 1.62 (1.2-2.2) 1.63 (1.1-2.3) 0.94

MI or angina: 12 (19) 18 (18) 0.86 8 (38) 22 (18) 0.03MI 4 (6) 8 (8) 0.68 3 (14) 9 (7) 0.28

Angina 9 (14) 13 (13) 0.81 6 (29) 17 (14) 0.09

Stroke or TIA: 21 (32) 36 (35) 0.69 9 (43) 9 (7)

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oping the hypothesis, the study design,assessment of dementia, and writingthe manuscript. CMcC conceived the hypothesis and participated in thestudy design and writing the manuscript. CMcC is the guarantor. JaneByrne independently validated the diagnosis of dementia. JennyShuttleworth, Sophie Holliday, and Zoe Bonner collected the data. JoanneWren (funded by the Alzheimers Society) completed data validation.

Funding: The study was funded by the Wellcome Trust. The researchers

were independent of the funding body, who played no role in the analysis orwriting of the manuscript.

Competing interests: None declared.

Ethical approval: Local research ethics committees in Manchester andStockport: South and North Manchester LREC reference SOU/98/132;Central Manchester LREC reference CEN/00/027/CA; Stockport LRECreference EE/SR/MREC2029.

1 Stewart R, Prince M, Mann A. Vascular risk factors and Alzheimers disease. Aust N Z JPsychiatry 1999;33:809-13.

2 Skoog I, Kalaria RN, Breteler MMB. Vascular factors and Alzheimer disease. AlzheimerDis Assoc Disord1999;13:S106-14.

3 Hofman A, Ott A, Breteler MM, Bots ML, Slooter AJ, van Harskamp F. Atherosclerosis,apolipoprotein E, and prevalence of dementia and Alzheimers disease in theRotterdam study.Lancet1997;349:151-4.

4 Hutchinson S, Riding G, Coull S, McCollum CN. Are spontaneous cerebral microem-boli consistent in carotid disease? Stroke2002;33:685-8.

5 Deklunder G, Roussel M,Lecroart JL, Prat A, Gautier C.Microemboli in cerebral circu-lation and alteration of cognitive abilities in patients with mechanical prosthetic heartvalves. Stroke1998:29;1821-6.

6 Fearn SJ, Pole R, Wesnes K, Faragher EB, Hooper TL, McCollum CN. Cerebral injuryduring cardiopulmonary bypass: emboli impair memory. J Thorac Cardiovasc Surg2001;121:1150-60.

7 Russell D. Cerebral microemboli and cognitive impairment. J Neurol Sci 2002;203-204:211-4.

8 Stygall J,Newman SP, Fitzgerald G, Mulligan K, Arrowsmith JE,Pugsley W, et al.Cogni-tivechange 5 yearsafter coronary artery bypass surgery.Health Psychol2003;22:579-86.

9 Sliwka U, Job FP, Wissuwa D, Diehl RR, Flachskampf FA, Hanrath P, et al. Occurrenceof transcranial Doppler high-intensity transient signals in patients with potentialcardiac sources of embolism: a prospective study. Stroke1995;26:2067-70.

10 Anzola GP. Clinical impact of patent foramen ovale diagnosis with transcranialDoppler.Eur J Ultrasound2002;16:11-20.

11 Ott A, Breteler MM, de Bruyne MC, van Harskamp F, Grobbee DE, Hofman A. Atrialfibrillation and dementia in a population-based study. Stroke1997;28:316-21.

12 Lechat P, Mas JL, Lascault G. Prevalence of patent foramen ovale in patients withstroke.N Engl J Med 1988;318:1148-52.

13 Webster MW, Chancellor AM, Smith HJ, Swift DL, Sharpe DN, Bass NM, et al. Patent

foramen ovale in young stroke patients.Lancet1988;ii:11-2.14 Riding G, Rao S, Hutchinson S, Kilic J,Lovell M,McCollum C.Cerebral emboli duringhip and knee replacement: the role of venous to arterial shunting [abstract]. Br J Surg2001;88:745.

15 Meier B, Lock JE. Contemporary management of patent foramen ovale. Circulation2003;107:5-9.

16 Sastry S, MacNab A, Daly K, Ray SG, McCollum CN. Transcranial Doppler ortransoesophageal echocardiography for the detection of venous-to-arterial circulationshunts [abstract].Heart2002;88(suppl IV):32.

17 PurandareN, WelshS, HutchinsonS, Riding G,Burns A, McCollumC. Cerebral emboliand paradoxical embolisation in dementia: a pilot study. Int J Geriatr Psychiatry2005;20:12-6.

18 McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diag-nosis of Alzheimers disease: report of the NINCDS-ADRDA Work Group under theauspices of Department of Health and Human Services Task Force on Alzheimers Dis-ease.Neurology 1984;34:939-44.

19 Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, et al.Vascular dementia: diagnostic criteria for research studies. Report of the

NINDS-AIREN International Workshop.Neurology 1993;43:250-60.20 Folstein MF, Folstein SE, McHugh PR. Mini-mental state: a practical method for grad-

ing the cognitive state of patients for the clinician.Psychiatry Res1975;12:189-98.21 Ringelstein EB, Droste DW, Babikian VL, Evans DH, Grosset DG, Kaps M, et al.

Consensus on microembolus detection by TCD.Stroke1998;29:725-9.22 Consensus Committee of the Ninth International Cerebral Hemodynamic

Symposium. Basic identification criteria of Doppler microembolic signals. Stroke1995;26:1123.

23 Sidhu PS, Allen PL. Ultrasound assessment of internal carotid artery stenosis. ClinRadiol1997;52:654-8.

24 Di Tullio M, Sacco RL, Venketasubramanian N, Sherman D, Mohr JP, Homma S. Com-parison of diagnostic techniques for the detection of a patent foramen ovale in strokepatients. Stroke1993;24:1020-4.

25 Nygren AT, Jogestrand T. Detection of patent foramen ovale by transcranial Dopplerand carotid duplex ultrasonography: a comparison with transoesophageal echocardi-ography. Clin Physiol1998;18:327-30.

26 Droste DW, Silling K, Stypmann J, Gr ude M, Kemeny V, Wichter T, et al. Contrast tran-scranial doppler ultrasound in the detection of right-to-left shunts: time window andthreshold in microbubble numbers. Stroke2000;31:1640-5.

27 Jauss M, Zanette E. Detection of right-to-left shunt with ultrasound contrast agent and

transcranial Doppler sonography. Cerebrovasc Dis2000;10:490-6.28 Hagan PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale dur-

ing the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc1984;59:17-20.

29 Stork JL, Kimura K, Levi CR, Chambers BR,Abbott AL,Donnan GA.Source of micro-embolic signals in patients with high-grade carotid stenosis. Stroke2002;33:2014-8.

30 Meier B. Closure of patent foramen ovale: technique, pitfalls, complications,and followup.Heart2005;91:444-8.

(Accepted 7 March 2006)

doi 10.1136/bmj.38814.696493.AE

Department of Psychiatry, University of Manchester, ManchesterNitin Purandare senior lecturer in old age psychiatryAlistair Burns professor of old age psychiatry

Academic Surgery Unit, University of ManchesterKevin J Daly lecturer in surgeryJayne Hardicre study coordinator

Charles McCollum professor of surgerySouth Manchester University Hospitals NHS Trust, ManchesterJulie Morris head of medical statistics

School of Epidemiology and Health Sciences, University of Manchester,Manchester M13 9PTGary Macfarlane professor of epidemiology

Correspondence to: C McCollum cnmcc@manchester.ac.uk

Research

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