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Blood–brain barrier permeability in type II diabetes
  1. J V Bowler
  1. Department of Neurology, Royal Free Hospital, London NW3 2QG
  1. Correspondence to:
 J V Bowler;
 j.bowler{at}rfc.ucl.ac.uk

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There is a direct link between diabetes, a leaky blood–brain barrier, leukoaraiosis, and cognitive impairment

Diabetes has an important and readily demonstrable association with cognitive impairment and stroke. Starr et al, in their paper on page,1 have concentrated on a more subtle pathology, that of leukoaraiosis. They have shown increased blood–brain barrier permeability in well controlled diabetic patients and in association with leukoaraiosis in both patients and controls. The authors also draw attention to the poorly recognised association between diabetes, impaired cognition, and leukoaraiosis. When leukoaraiosis was first seen on CT and later on MRI it was routinely dismissed as unimportant. However, leukoaraiosis is associated with cognitive impairment and increases the risk of dementia when seen in conjunction with other dementing illnesses, whether these be primarily degenerative such as Alzheimer’s disease, or vascular.2 Its influence is often subtle in individuals, but in populations it makes a significant contribution to cognitive impairment.

While hypertension is the most important risk factor for leukoaraiosis, diabetes is also well recognised. Importantly, impairment of glucose tolerance in mid-life correlates with later life leukoaraiosis,3 suggesting an opportunity for prevention.

There is also a direct association between diabetes and cognitive impairment of various kinds in much the same way that leukoaraiosis is associated with dementia, except that the association is weaker, as would be expected in view of the role of hypertension.4 This association is not mediated by frank infarction and is unlikely to be through acceleration of the various primary processes underlying the degenerative dementias.

What then is the mechanism? Endothelial damage and the development of lipohyalinosis and subsequent lacunar infarction play a part. However, leukoaraiosis also has a role and does not include frank infarction. The authors draw attention to “ischaemic demyelination,” but a related and much more general concept was originally proposed by Brun and Englund and termed “incomplete infarction”.5 It is characterised by demyelination, loss of axons and oligodendroglia, and mild reactive gliosis without cavitation, and is thought to be ischaemic in origin. The mechanism is not considered to be chronic low perfusion, but rather diminished perfusion reserve with episodic mild ischaemia occurring as a result of intermittent changes in cerebral perfusion pressure. Cerebral blood flow in affected areas lies within normal limits at rest. However, in areas of leukoaraiosis other changes are seen which at their mildest may consist just of local oedema.6 Extensive areas of such changes may be seen without local evidence of completed ischaemic events, leading to the suggestion of leakage of serum proteins, which are known to be toxic; it is here that increased blood–brain barrier permeability may have a direct and important action. All of these pathological changes appear the same on standard MRI sequences, resulting in the not uncommon experience of patients with extensive leukoaraiosis without clinical or cognitive deficits on the one hand, through to patients with relatively mild leukoaraiosis but with significant deficits on the other.

There is therefore a direct link between diabetes, a leaky blood–brain barrier, leukoaraiosis, cognitive impairment, and—in association with other dementing illnesses—an exacerbation of dementia. In individual cases this effect is slight, but with the increasing numbers of cognitively impaired elderly people it becomes important, not least because the process is modifiable by tight control of diabetes and by meticulous control of any coexistent hypertension with ACE inhibitors.

There is a direct link between diabetes, a leaky blood–brain barrier, leukoaraiosis, and cognitive impairment

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