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First published online November 12, 2007
British Journal of Radiology (2008) 81, 30-34
© 2008 British Institute of Radiology
doi: 10.1259/bjr/90498392
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Full paper

Paradoxical embolisation and cerebral white matter lesions in dementia

N Purandare, MRCPsych1, R C Oude Voshaar, MD, PhD1,2, C McCollum, MD, FRCS3, A Jackson, PhD, FRCP4 and A Burns, FRCP, FRCPsych1

1 University of Manchester, Division of Psychiatry, Education and Research Centre, Wythenshawe Hospital, Wythenshawe, Manchester M23 9LT, UK, 2 Radboud University Nijmegen Medical Centre, Department of Psychiatry (961), PO Box 9101, 6500 HB, Nijmegen, the Netherlands, 3 Vascular Studies Unit, Academic Surgery Unit, University of Manchester, South Manchester University Hospital, Wythenshawe, Manchester M23 9LT, 4 Imaging Science & Biomedical Engineering, University of Manchester, Manchester M13 9PT, UK

Correspondence: Prof Alan Jackson, Division of Imaging Science, The Medical School, University of Manchester, Oxford Rd, Manchester M13 9PT, UK. E-mail: alan.jackson{at}manchester.ac.uk


   Abstract
Top
 Abstract
Introduction
 Methods and materials
 Results
 Discussion
 Conclusions
 References
 
The study aimed to examine the relationship between spontaneous cerebral emboli (SCE), patent foramen ovale (PFO) and white matter hyperintensities (WMH) on cerebral MRI in patients with Alzheimer's disease (AD) and vascular dementia (VaD). SCE were identified by transcranial Doppler of the middle cerebral artery for 1 h. A "significant" v-aCS (venous-to-arterial circulation shunt indicative of PFO; ≥15 embolic signals within 12 cardiac cycles) was detected by intravenous injection of "air in saline" ultrasound contrast. Deep white matter hyperintensities (DWMH) and periventricular hyperintensities (PVH) were assessed using Schelten's scale. After correction for cardiovascular risk factors, both DWMH and PVH were significantly associated with the presence of a PFO in AD (β = 0.31, p = 0.02 for DWMH, odds ratio 8.7, p = 0.011 for PVH) but not in VaD. No consistent relationship was found between SCE and WMH in AD. In VaD, the severity of DWMH was negatively correlated with SCE (β = –0.55; p = 0.001). In conclusion, the presence of a significant venous-to-arterial shunt is associated with more severe DWMH in AD, and may play a part in the aetiology of the disorder. In addition, there is a significant negative correlation between SCE and DWMH in VaD, which supports the hypothesis that VaD may be the result of ischaemic injury, predominantly reflecting embolic aetiology.


   Introduction
Top
 Abstract
 Introduction
Methods and materials
 Results
 Discussion
 Conclusions
 References
 
In older individuals, white matter hyperintensities (WMH) are frequently found on T2 weighted MRI of the brain. WMH, especially deep WMH (DWMH), are associated with a more rapid cognitive decline in both patients with dementia and older people without dementia [1–3]. DWMH are associated with older age and cardiovascular risk factors, particularly hypertension [4], which suggests small-vessel disease as a major pathogenic mechanism for their development. However, some studies examining DWMH specifically exclude patients with cerebral infarctions, whereas others have found an association between WMH and cerebral infarctions, suggesting that arterial emboli may also play a role in their formation [2, 4]. In this respect, asymptomatic cerebral microemboli might be of particular importance, as they have been associated with brain damage in a number of neurological conditions [5]. The recent description of a link between unstable carotid plaques, a known risk factor for cerebral emboli, and WMH also suggests the possibility of a causative link between microemboli and DWMH [6].

Potential sources of asymptomatic spontaneous cerebral emboli (SCE) include (unstable) carotid disease, valvular heart disease, atrial fibrillation and paradoxical embolisation of venous emboli into the arterial circulation [5, 7]. Recently, we showed that SCE (measured by continuous transcranial Doppler (TCD) of the middle cerebral artery (MCA)) and venous-to-arterial circulation shunt (v-aCS) (indicative of patent foramen ovale (PFO)) are more common in both Alzheimer's disease (AD) and vascular dementia (VaD) [8, 9]. This suggests that paradoxical embolisation (associated with cryptogenic stroke in young adults), migraine, cluster headache, obstructive sleep apnoea and decompression sickness in scuba divers [10–14] may also play a role in the aetiology of dementia disorders.

In this study, we have tested the hypothesis that SCE and v-aCS will be associated with more severe DWMH in both VaD and AD, independent of other cardiovascular risk factors.


   Methods and materials
Top
 Abstract
 Introduction
 Methods and materials
Results
 Discussion
 Conclusions
 References
 
Patients
Patients with AD (National Institute of Neurological and Communication Disorders and Stroke (NINCDS) and Alzheimer's Disease and Related Disorders Association (ADRDA) criteria) [15] and VaD (National Institute of Neurological Disorders and Stroke (NINDS) and Association Internationale pour la Recherché et l'Enseignement en Neurosciences (AIREN) criteria) [16] who agreed to undergo MRI were included in the current study. Patients with dementia were recruited from secondary care old-age psychiatry clinics in Greater Manchester (UK). The use of anticoagulants and severe dementia (Mini-Mental State Examination (MMSE) score of <10) were the main exclusion criteria [17]. The local research ethical committees approved the study, and written informed consent was obtained from all patients and their carers.

Detection of cerebral emboli
The detailed methodology for the detection of SCE has been described previously [9]. Briefly, SCE were detected by TCD monitoring of the MCAs via trans-temporal windows for 1 h [18]. The output was recorded on digital tape for subsequent blind analysis by a vascular technologist. Patients were observed during each session for any movement, so that artefacts could be identified. Emboli were defined using the international consensus criteria: "embolic signals should be transient (lasting <300 ms), at least 3 dB higher than the background blood flow signal, unidirectional, within the Doppler spectrum, and accompanied by an audible snap, chirp, or moan" [19]. In the majority of patients, TCD monitoring of the MCA was unilateral (AD 29/57 (51%); VaD 36/51 (71%)). There was no association between the type of monitoring and detection of SCE.

Venous-to-arterial circulation shunt
Following monitoring for SCE, a standardized TCD technique was used to detect v-aCS. The MCA was insonated during intravenous injection of an emulsion of air microbubbles in saline as an ultrasound contrast medium [20–22]. The ultrasound contrast was injected on six occasions: (a) twice while resting quietly; (b) twice following provocation by coughing repeatedly during injection and for a further 5 s; and (c) twice following provocation by a standardized Valsalva manoeuvre immediately after the injection (blowing into a tube to maintain a pressure of 40 mmHg for 5 s). A "significant" v-aCS (indicative of PFO) was defined as TCD detection of ≥15 embolic signals within 12 cardiac cycles of contrast injection [23].

Cardiovascular risk factors
Carotid artery disease was assessed by measuring the peak systolic velocity in the internal carotid arteries (colour ultrasound, ATL 'Ultramark 9'; ATL Ultrasound Ltd, WA). Information about cardiovascular risk factors was collected by interviewing patients and carers and by checking current medications and psychiatry case records. Blood pressure was measured manually after a 5 min rest.

Neuroimaging
Imaging was conducted using a 1.5 Tesla Philips Gyro-scan scanner (Philips Medical Systems, Best, the Netherlands) using a standard birdcage head coil. Following localization images, the protocol included axial fluid attenuated inversion recovery (FLAIR; repetition time/echo time (TR/TE) 11000/140, inversion time (TI) 2600, field of view 230 mm2, matrix 2562, slice thickness 3.0 mm) and axial T1 weighted inversion recovery (TR/TE 6850/18, TI 300, field of view 230 mm2; matrix 2562; slice thickness 3.0 mm). Images for both sequences were geometrically matched so that slice locations were directly comparable. Images were acquired in a plane perpendicular to the lower borders of the genu and splenium of the corpus callosum, and covered the entire head from the vertex to the foramen magnum.

WMH were assessed on a PC workstation using EFilm viewstation software (EFilm Medical Ltd, Toronto, Canada). The assessment was performed on matched T1 weighted inversion recovery and T2 weighted FLAIR images using the Scheltens scale, which has four subscales: cortical DWMH (0–24); periventricular hyperintensities (PVH) (0–6); basal ganglia changes (0–30); and infratentorial changes (0–24) [24]. All ratings were conducted by an experienced neuroradiologist (A.J.) who was blind to diagnosis. Inter- and intra-observer variation for this scale had previously been established in a heterogeneous sample of normal subjects and subjects with AD, frontotemporal dementia and VaD [25]. These trials indicated weighted Cohen {kappa} values ranging from 0.52 to 0.89 (good to excellent) for all components of the scale.

Statistical analyses
Demographic, cardiovascular and MRI data from patients with AD and VaD were compared using Student's t-, Mann–Whitney U- and {chi}2-tests. Subsequently, patients with and without SCE or a significant v-aCS were compared within the AD group and VaD groups. The main outcome variables were PVH and DWMH. As the mean score for PVH was not normally distributed within the two groups, this score was dichotomized at the median score in the multivariate analyses. The total score for the DWMH was normally distributed. For each group, logistic regression analyses with PVH and cerebral infarctions (yes/no) as the dependent variables, and linear regression analyses with DWMH as the dependent variable, were performed to assess their relationship with SCE and v-aCS. Multivariate models were corrected for the most important potential confounders, i.e. age, cognitive functioning (MMSE score), hypertension (defined as receiving treatment for hypertension, diastolic blood pressure >95 mmHg, systolic blood pressure >160 mmHg), carotid disease (>50% stenosis) and presence of MRI-proven cerebral infarcts.


   Results
Top
 Abstract
 Introduction
 Methods and materials
 Results
Discussion
 Conclusions
 References
 
Subjects
Of the original study cohort, 62/170 (36%) dementia patients refused MRI. Excluded patients were similar to included patients with respect to gender and the presence of either SCE or a "significant" v-aCS (all p-values were >0.31), but were significantly older (mean ±standard deviation (STD) age: 78.2±6.1 years, p = 0.011) and had a significantly lower mean MMSE score (20.5±5.5, p = 0.028).

57 patients with AD and 51 patients with VaD were included in the current analyses (see Table 1Go for comparisons between AD and VaD). The mean (±STD) age of participants (n = 108) was 75.3±7.4 years, and 49/108 were female. The mean (STD) MMSE score was 22.3±4.3 points. SCE were detected in 43/106 (41%) of the included patients and a "significant" v-aCS in 36/108 (33%). AD and VaD patients had similar MMSE scores and similar frequencies of female gender, SCE and v-aCS (all p-values were >0.41), although AD patients were significantly younger than VaD patients (p = 0.043).


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  		Table 1. Patient characteristics

 
MRI findings and type of dementia
As expected, the severity of WMH and cerebral infarcts differed significantly between AD and VaD patients (Table 2Go). The mean (±STD) score for DWMH was 5.9±5.8 for AD and 9.3±6.4 for VaD (p = 0.004). The mean (±STD) score for PVH was 3.5±2.0 for AD and 4.3±2.1 for VaD (p = 0.036). Furthermore, VaD patients had a significantly higher prevalence of cerebral infarctions (p<0.001), carotid disease (stenosis >50%, p = 0.020; stenosis >70%, p = 0.047) and a history of hypertension (p = 0.025) compared with patients with AD.


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  		Table 2. Relationship between SCE and WMH

 
Relationship between SCE and MRI findings
No significant associations were found between SCE and either DWMH or PVH in AD (Table 3Go). In VaD, the presence of SCE was univariately associated with less severe DWMH; a posteriori tests of anatomical distribution demonstrated significant differences in the occipital and the temporal region (Table 3Go). Linear regression analyses yielded a standardized regression coefficient (β) between the presence of SCE and DWMH of –0.37 (p = 0.005) after correction for age, MMSE score, hypertension, carotid disease and cerebral infarcts. This association remained significant after exclusion of patients with cerebral infarcts (β = –0.55; p = 0.001). PVH score was not related to SCE in VaD. No relationship between SCE and cerebral infarcts was found in either AD or VaD.


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  		Table 3. Relationship between a"significant" v-aCS and WMH

 
Relationship between a "significant" v-aCS and MRI findings
In AD patients, a "significant" v-aCS was associated with more severe DWMH (p = 0.005) and PVH (p = 0.038) (Table 3Go). Patients with a "significant" v-aCS had more severe DWMH in all subregions (frontal, p = 0.013; parietal, p = 0.020; temporal, p = 0.034; occipital, p = 0.019). The linear regression analyses yielded an unadjusted β value of 0.37 (p = 0.005) between the presence of a "significant" v-aCS and the severity of DWMH, which changed to 0.36 (p = 0.006) after adjustment for age, MMSE score, hypertension, carotid disease and cerebral infarcts. After exclusion of cases with cerebral infarcts, this association remained significant (β = 0.31, p = 0.030). A univariate odds ratio (95% confidence interval (CI)) of 3.9 (1.2–12.5) (p = 0.021) for having severe PVH was found for AD patients having a "significant" v-aCS, which increased to 8.7 (1.6–46.7) (p = 0.011) in the fully adjusted model. The association between a "significant" v-aCS and PVH severity remained unchanged when we excluded AD patients with cerebral infarcts from the analyses.

We found no relationship between the presence of a "significant" v-aCS and DWMH or PVH in VaD; nor did we find a relationship between a "significant" v-aCS and cerebral infarctions in either AD or VaD.


   Discussion
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
Conclusions
 References
 
In this study, we explored the relationship of DWMH and PVH with SCE and v-aCS in patients with AD and VaD. DWMH and PVH in VaD patients were more severe than in those with AD, and were associated with higher vascular risk factors. Interestingly, there was also a robust negative correlation between the incidence of SCE and the severity of DWMH. In AD patients, there was no relationship between SCE and DWMH, but the presence of a "significant" v-aCS (suggestive of PFO) was associated with a significant increase in both DWMH and PVH. This relationship was independent of age, cognitive functioning, blood pressure and cerebral infarcts, and was similar in all areas of the brain.

The presence of a v-aCS in relation to brain lesions has been examined previously only in decompression sickness, where the pathophysiological mechanism is thought to be venous gas bubbles entering the arterial system. Gerriets et al [26] found no relationship between right-to-left shunt and brain lesions, whereas Knauth et al [14] found that scuba divers with a PFO of high haemodynamic relevance showed multiple brain lesions on T2 weighted brain MRI scans. Similarly, Steiner et al [27] found the size of a PFO to be related to increased numbers of embolic infarcts in patients with ischaemic stroke.

The finding of a negative correlation between SCE and DWMH in patients with VaD is surprising. It is currently believed that VaD results from widespread ischaemic insults. These most commonly result from microvascular angiopathy (MVA), but other aetiological factors such as embolic disease (principally from peripheral atheromatous disease) may also contribute. The negative correlation between SCE and DWMH could suggest that embolic disease is capable of independently causing significant cognitive impact in patients in whom MVA is either minimal or absent, whereas in patients with MVA as a predominant aetiological factor the presence of DWMH acts as a direct indicator of the severity of disease. This is in keeping with the common observation that embolic multi-infarct disease is associated with dementia. If substantiated, this observation would suggest that the presence of SCE could form a basis for the recognition of two subtypes of VaD characterized by predominantly embolic or predominantly atheromatous aetiological mechanisms. This would have significant impact on the management of patients with early VaD, and deserves further consideration in a larger scale study. Ideally, the relationship between SCE and biomarkers specific to MVA or systemic atheromatous disease should also be compared in a larger study.

Our previous observation of the relationship between "significant" v-aCS and AD is consistent with the critically attained threshold of cerebral hypoperfusion (CATCH) hypothesis. This states that the development of AD is triggered when the CATCH is exceeded in people predisposed to AD [28]. The hypothesis explains why a wide variety of vascular risk factors are associated with AD. Our current results show that WMH (both DWMH and PVH) in patients with AD are also associated with a "significant" v-aCS. These findings suggest that ischaemic insult related to v-aCS may be sufficient to trigger the onset of symptomatic AD. We hypothesize that the presence of the relatively minor embolic load associated with v-aCS is sufficient to trigger these ischaemic events, but is insufficient to cause significant ischaemic brain injury. This would explain the lack of any relationship between v-aCS and lesion load in VaD.


   Conclusions
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
 Conclusions
References
 
In summary, we have demonstrated a significant correlation between the presence of a "significant" v-aCS and the severity of DWMH and PVH in patients with AD, which may reflect an important aetiological pathway in the pathogenesis of AD. In addition, we have demonstrated a significant negative correlation between SCE and DWMH in VaD, which supports the hypothesis that VaD is the result of ischaemic injury, reflecting predominantly either MVA or SCE.

Grant support: The Wellcome Trust, UK


   Acknowledgments
 
The authors would like to thank Jane Byrne for her independent assessments to confirm the diagnosis of dementia, Kevin Daly for performing the v-aCS assessments and Jayne Hardicre for performing the SCE measurements.

Received for publication March 15, 2007. Accepted for publication April 5, 2007.


   References
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
 Conclusions
 References
 

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S MILLS, J CAIN, N PURANDARE, and A JACKSON
Biomarkers of cerebrovascular disease in dementia
Br. J. Radiol., December 1, 2007; 80(Special_Issue_2): S128 - S145.
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