Elsevier

Neurobiology of Aging

Volume 30, Issue 3, March 2009, Pages 337-352
Neurobiology of Aging

Review
Blood–brain barrier: Ageing and microvascular disease – systematic review and meta-analysis

https://doi.org/10.1016/j.neurobiolaging.2007.07.015Get rights and content

Abstract

Cerebral “microvascular” disease occurs in lacunar stroke, leukoaraiosis, vascular dementia and Alzheimer's disease. It may arise from or contribute to insidious damage to the blood–brain barrier (BBB). We systematically reviewed the literature for evidence that BBB permeability is altered in patients with manifestations of cerebral microvascular disease.

We found 31 BBB permeability studies (1953 individuals) of normal ageing or cerebral microvascular disease. In healthy humans, increasing age (10 comparisons, controls(C):subjects(S) = 357:336) was associated with increased BBB permeability (standardised mean difference (S.M.D.) 1.21, 95% confidence interval (CI) 0.60, 1.81, p < 0.01). BBB permeability was increased further in patients with either vascular or Alzheimer's dementia compared with age-matched controls (26 comparisons, C:S = 510:547, S.M.D. 0.81, 99% CI 0.37, 1.26, p < 0.01); in vascular compared with Alzheimer's dementia (10 comparisons, C:S = 291:165, S.M.D. 0.71, 99% CI 0.12, 1.29, p < 0.01); and with worsening leukoaraiosis (5 comparisons, C:S = 122:88, S.M.D. 0.60, 99% CI 0.30, 0.89, p < 0.01).

BBB permeability increases with normal ageing and may be an important mechanism in the initiation or worsening of cerebral microvascular disease. Further studies on the role of BBB permeability are urgently needed.

Section snippets

Background

Cerebral microvascular disease increases with advancing age and is found in common diseases of ageing such as lacunar stroke (20% of all strokes), leukoaraiosis, vascular and Alzheimer's dementia. What initiates it and leads to its histologic appearance and clinical manifestations is the subject of debate (Davis and Donnan, 2004, Ovbiagele and Saver, 2006). Microvessels are difficult to visualise in life; clinical features develop insidiously; and autopsy is often performed late so longstanding

Data sources and study selection

We searched the published literature from 1st January 1966 (MEDLINE) and 1980 (EMBASE), up to 8th August 2006, using the Ovid Web Gateway. We used exploded headings relating to Bloodbrain barrier, Permeability, and Ageing with the Boolean operator AND [Appendix 1]. We used a two-part search strategy: initially for BBB changes in normal healthy ageing; then for BBB changes in relevant cerebral microvascular diseases. We checked review paper reference lists. We validated the search strategy by

Results

We identified 8329 publications (Fig. 1). The healthy ageing-focussed search identified 2411 publications and we excluded: those of subjects < 60 only or investigating other diseases (n = 2056), reviews (n = 100), animal studies (n = 123), and post mortem or in vitro studies (n = 69): 63 studies assessed human BBB permeability in vivo. The cerebral microvascular disease-focussed search identified 5918 publications of which 1071 overlapped with the healthy ageing-focussed search. We excluded non-human

Discussion

In this systematic review, we found evidence that BBB permeability increased in normal ageing and further increased in patients with dementia (especially VD) and with increasing WMLs. No studies investigated patients presenting with discrete symptoms of lacunar stroke. Given that cerebral microvascular disease pathology was originally described in lacunar stroke, that lipohyalinosis and fibrinoid necrosis are believed to be the vascular pathology underlying a substantial proportion of lacunar

Disclosure statement

Neither Dr Farrall nor Prof Wardlaw have any actual or potential conflicts of interest, including any financial, personal or other relationships with other people or organizations within three years of beginning the work submitted, that could inappropriately influence (bias) their work.

The University of Edinburgh has no contracts relating to this research through which it or any other organization may stand to gain financially now or in the future. No other agreements of authors or the

Acknowledgements

We thank Ms Brenda Thomas, BSc, Medical Information Specialist, Division of Clinical Neurosciences, University of Edinburgh, for uncompensated advice on literature searching.

Contributions by both Dr Farrall and Prof Wardlaw include study design, search strategy development, data extraction and analysis, and manuscript drafting and editing. Dr Farrall performed both Medline & Embase searches and screened publications to limit findings to relevant human in vivo studies.

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