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. 
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.
 Closure of ASD itself can aggravate or precipitate
migraine attacks with aura.  Use of β-blockers for
prevention of migraine is widespread; β-blockers increase platelet
aggregation. 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
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. 
The conceptualized link between repeated small asymptomatic emboli
over “months or years” (more correctly, over decades) and Alzheimer’s
disease  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. 
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.
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8. Steiner TJ, Joseph R, Clifford Rose F. Migraine is not a platelet
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10. Feinstein AR. Clinical judgment revisited: the distractions of
quantitative models. Ann Intern Med 1994;120:799-805.
Competing interests: No competing interests