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Cerebral emboli as a potential cause of Alzheimer's disease and vascular dementia: casecontrol study

BMJ 2006; 332 doi: https://doi.org/10.1136/bmj.38814.696493.AE (Published 11 May 2006) Cite this as: BMJ 2006;332:1119

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Reply from the authors

Thank you for the comments received so far. Jonathan Golledge
mentions evidence that NSAIDs are not effective in inhibiting the onset or
progression of dementia. We are aware of one small clinical trial [1] with
indomethacin that showed arrest of progression over a six-month period.
There is also a complementary body of epidemiological evidence [e.g.
2,3,4,5] suggesting that NSAIDs do reduce the risk of AD and other
research showing that NSAIDs decrease the highly amyloidogenic Abeta42
peptide [6]. Furthermore, it has been suggested [7] that treatment with
anti-inflmmatory agents must take place within a critical period ending
approximately two years before dementia can be diagnosed for an effect to
be seen and that this can explain many of the negative findings from
treatment trials. Another possibility is that SCE may have been occurring
repeatedly over many years making it difficult to detect the influence of
anti-platelet therapy prescribed over a relatively short term.

Regarding the diagnosis of Alzheimer’s and vascular dementia, we
followed all of the processes outlined by Dipanker Choudhury and agree
with Dr Spathis that there may be overlap between the clinical syndromes.
Indeed, our results support such an overlap and we consequently combined
these two groups in our analysis. One suggestion is to think of the
elderly population as two groups, one with and one without a history of
risk factors for cerebrovascular disease (for example, symptomatic carotid
stenosis, atrial fibrillation, MI, diabetes, intermittent claudication).
The clinician making a diagnosis of dementia is likely to allocate
vascular dementia in those with such a history. The presence of cerebral
infarcts picked up using brain imaging might simply indicate that larger
emboli are associated with the syndrome similar to VaD and smaller emboli
a syndrome similar to AD but with considerable overlap in the middle.

Aspirin is commonly taken by this age group and in our patients with
dementia, SCE were no less frequent in those taking aspirin. Most
participants were on aspirin 75mg, which may not be sufficient to reduce
cerebral emboli [8]. There is information on antiplatelet medication at
the bottom of table 5. Antiplatelet medication was not used as an
exclusion. Cardiovascular risk factors were associated with SCE in
controls and the absence of an association in patients with dementia might
indicate that SCE are universal in this group.

In response to Vinod Gupta, we would like to clarify that we are not
disregarding the neurodegenerative aetiology of AD. It is known that
cerebrovascular disease can trigger and accentuate AD pathology [9]. We
are suggesting that SCE, over a period of decades as Gupta states
(certainly all risk factors for dementia, including AD, are from midlife),
may contribute to the brain damage in both AD and VaD. In those
predisposed to AD (e.g. ApoE4 allele) SCE may be the mechanism by which
vascular risk factors trigger neurodegeneration. The technique used for
detecting PFO in our study is fully compliant with the international
consensus criteria [10] and as such we feel that Gupta’s scepticism about
the use of Trans-cranial Doppler is wrong. Similarly, it may be that
migraine is associated with dementia but the evidence for this is
currently inadequate.

Our study was the first to suggest that SCE may be a potentially
treatable cause of both Alzheimer’s disease and vascular dementia. It
alone cannot establish causation, but our findings warrant further
research on the role SCE have in both the causation and progression of
dementia.

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8. Markus HS, Droste DW, Kaps M, Larrue V, Lees KR, Siebler M, Ringelstein
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Competing interests:
None declared

Competing interests: No competing interests

09 June 2006
Charles N McCollum
Consultant Vascular Surgeon
Alistair Burns, Ewan P Perry, Kevin J Daly, Jayne Hardicre, Julie Morris, Gary Macfarlane
Wythenshawe Hospital, Wythenshawe, Manchester, M23 9LT