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

BMJ 2006; 332 doi: (Published 11 May 2006) Cite this as: BMJ 2006;332:1119

PFO, cerebral emboli and Alzheimer’s disease: investigative artifact or biological truth?

Purandare and colleagues suggest that spontaneous cerebral emboli
occur in Alzheimer’s disease as well as vascular dementia and may
represent a potentially preventable or treatable cause of dementia. [1]
The term “venous to arterial circulation shunt” as used by these authors
is intrinsically confusing because atrial septal defect (ASD) and
ventricular septal defect (VSD) are generally associated with a systolic
left-to-right shunt and paradoxical (right-to-left shunt-related) platelet
-thrombin embolization is not a feature of such cardiac defects.
Alzheimer’s disease is not associated with any of the known causes of
paradoxical embolism, in particular migraine or decompression sickness in
scuba divers. The link between migraine and PFO is itself tenuous and
serendipitous, a clinical truth that is becoming increasingly blurred.
[2][3][4][5][6][7] Closure of ASD itself can aggravate or precipitate
migraine attacks with aura. [3][4][7] Use of β-blockers for
prevention of migraine is widespread; β-blockers increase platelet
aggregation.[8] Migraine patients receiving β-blockers for several
years or even decades form an excellent clinical model for testing and
rejecting this hypothetical link of cerebral platelet embolism to
Alzheimer’s disease

Access to the left heart at the level of the atria in patent foramen
ovale (PFO) by air bubbles during cough or Valsalva manœuvre is a
laboratory artifact that does not reflect a common real-life situation; in
paradoxical embolism, it is a platelet-thrombin plug that embolizes – such
emboli have physical properties markedly different from air bubbles.
Otherwise clinically silent (post-mortem) PFOs may permit air bubbles to
easily cross over to the left heart due to fundamentally different
rheological factors. [4]

The conceptualized link between repeated small asymptomatic emboli
over “months or years” (more correctly, over decades) and Alzheimer’s
disease [1] disregards the selective slowly progressive age-related
neuronal loss that characterizes Alzheimer’s disease. The Amplatzer PFO-
occluding device, once implanted, might itself serve as a source of
platelet emboli to the pulmonary and systemic circulations. [3][4][6]
Clinical studies that postulate associations in the absence of a central
idea or a defensible overarching/unifying hypothesis underscore the
dissociation between statistical and biological truths; such analyses
mandate suspension of clinical disbelief. Use of statistics to modify or
erase key biological idiosyncracies (known and unknown) between patients
in controlled studies is the single most important factor for the
emergence of novel often startling associations in medicine. [9,10] Once
such data emerge, it becomes essential to rationalize them as well as the
process that generated them.


1. Purandare N, Burns A, Daly KJ, et al. Cerebral emboli as a
potential cause of Alzheimer’s disease and vascular dementia: case-control
study. BMJ 2006;332:1119-1124.

2. Gupta VK. Interatrial shunt-associated migraine: serendipity,
empiricism, hope, or hype? Stroke (in press).

3. Gupta VK. Clopidogrel and atrial shunt closure for migraine: why
is migraine aggravated immediately? Heart (13 December 2005). Available

4. Gupta VK. PFO and migraine: pearls and pitfalls in the theorizing
process. Heart (26 October 2005). Available at:

5. Gupta VK. ASD closure for migraine: is there a scientific basis?
Eur Heart J 2005; 26:1446.

6. Gupta VK. PFO / ASD closure and migraine: searching the rationale
for the procedure. J Am Coll Cardiol 2005;46:737-738.

7. Gupta VK. Closure of atrial septal defect and migraine. Headache

8. Steiner TJ, Joseph R, Clifford Rose F. Migraine is not a platelet
disorder. Headache 1985;25:434-440.

9. Gupta VK. Randomized controlled trials: the hijacking of basic
sciences by mathematical logic. BMJ Online (6 July 2004). Available at:

10. Feinstein AR. Clinical judgment revisited: the distractions of
quantitative models. Ann Intern Med 1994;120:799-805.


Competing interests:
None declared

Competing interests: No competing interests

30 May 2006
Vinod K Gupta
Dubai Police Medical Services, P.O. Box 12005, Dubai, United Arab Emirates