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British Medical Bulletin Advance Access originally published online on November 23, 2008
British Medical Bulletin 2008 88(1):131-146; doi:10.1093/bmb/ldn042
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© The Authors 2008. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

The relationship between type 2 diabetes and dementia

Mark W. J. Strachan{dagger}, Rebecca M. Reynolds{ddagger}, Brian M. Frier, Rory J. Mitchell§ and Jacqueline F. Price§

{dagger} Metabolic Unit, Western General Hospital, Edinburgh, UK
{ddagger} Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
Department of Diabetes, Royal Infirmary of Edinburgh, Edinburgh, UK
§ Department of Public Health Sciences, University of Edinburgh, Edinburgh, UK

Correspondence to: Dr M. W. J. Strachan, Metabolic Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK. E-mail: mark.strachan{at}luht.scot.nhs.uk


   Abstract
Top
 Abstract
Introduction
 Sources of data
 Areas of agreement
 Areas of controversy
 Growing points
 Areas timely for research...
 Conclusions
 References
 
Introduction: The prevalence of type 2 diabetes and dementia are set to rise inexorably over the next 30–40 years. There are now substantial data to suggest that type 2 diabetes is associated with an increased risk of dementia.

Sources of data: This is a narrative review using data from individual studies and review articles known to the authors. A Medline search was also undertaken and reference lists were reviewed to identify additional relevant studies.

Areas of agreement: Type 2 diabetes is associated with an increased risk of both Alzheimer's and Vascular dementia, although the reality is that many affected individuals have mixed forms of dementia.

Areas of controversy: The mechanisms underpinning this association remain to be clearly delineated. Type 2 diabetes is a complex disorder and so it is likely that multiple different, synergistic processes may interact to promote cognitive decrements.

Growing points: Recent data suggest that glucocorticoids excess and elevated inflammatory markers may also have a role in the aetiology of diabetes-related cognitive impairment.

Areas timely for developing research: Large-scale, prospective epidemiological studies are now required to accurately delineate the pathogenesis of cognitive impairment in people with type 2 diabetes. These are underway and randomized trials of diabetes-specific interventions are also starting to include cognitive function as an outcome measure.

Keywords: Type 2 diabetes • cognition • dementia • vascular disease • glucocorticoids


   Introduction
Top
 Abstract
 Introduction
Sources of data
 Areas of agreement
 Areas of controversy
 Growing points
 Areas timely for research...
 Conclusions
 References
 
At the start of the new millennium, ~2.8% of the global population (171 million people) was thought to have diabetes and by 2030, it is predicted that 4.4% of the world population, i.e. 366 million people, will have diabetes.1 Many reasons are offered for this anticipated rise—population growth, the shift of people from rural to urban communities in developing countries, the rising tide of obesity, physical inactivity, ease of access to energy-dense foods and better case ascertainment. However, the most important demographic change in world-wide terms is the continued increase in the proportion of the global population that is aged more than 65 years. An increase in the population aged over 65 years of 134% is expected over a period of 30 years. In this time, the number of elderly people with diabetes in developed countries will rise from ~25 million to more than 48 million (Fig. 1). These figures are sobering enough by themselves, but they presume that present levels of obesity will remain static. That seems improbable and so these projected figures may turn out to be a substantial underestimate.1


Figure 1
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  		Fig. 1 Estimated number of adults with diabetes by age-group, year and countries for the developed and developing world. Copyright © 2004 American Diabetes Association. From Diabetes Care, Vol. 27, 2004, 1047–1053. Reprinted with permission of The American Diabetes Association.

 
Of course, diabetes is not the only disorder that will increase in prevalence over this time period. Other processes that are also related to increased ageing of the population will also rise significantly, foremost of which is dementia. As any family member or carer of an affected individual will attest, dementia is a devastating disorder. It renders the individual increasingly unable to live independently, places an enormous strain on family life and resources and has a substantial economic cost to the community. The projections for the future prevalence of dementia parallel that for diabetes—the number of people with dementia in the UK will rise over the next 40 years from around 700 000 to 1.7 million.2 This may also turn out to be a significant underestimate. There are now substantial data to suggest that diabetes, and in particular type 2 diabetes, is associated with an increased risk of dementia.3–5 If this is so, the dramatic rise in the prevalence of diabetes could precipitate an even greater increase in the number of people who could develop dementia. In the present review, the data linking diabetes and dementia are discussed, along with potential aetiological mechanisms.


   Sources of data
Top
 Abstract
 Introduction
 Sources of data
Areas of agreement
 Areas of controversy
 Growing points
 Areas timely for research...
 Conclusions
 References
 
This is a narrative review using data from individual studies and review articles known to the authors. A Medline search was also undertaken and reference lists were reviewed to identify additional relevant studies.


   Areas of agreement
Top
 Abstract
 Introduction
 Sources of data
 Areas of agreement
Areas of controversy
 Growing points
 Areas timely for research...
 Conclusions
 References
 
Dementia represents a constellation of symptoms and signs, including a decline in memory, reasoning and communication skills and a gradual loss in ability to carry out activities of daily living. The commonest forms are Alzheimer's disease (AD) and vascular dementia (VaD).

In AD, characteristic neuroanatomical abnormalities are observed in the form of senile plaques and neurofibrillary tangles of hyperphos- phorylated tau protein. The senile plaques contain β-amyloid protein and it is deposition of this protein which is thought to be the initial mechanism that results in the deterioration of neuronal synapse function, composition and structure.6 Early onset AD (occurring before the age of 60 years) is rare and is caused by fully penetrant mutations in three autosomal dominant genes: Aβ-precursor protein, presenilin 1 and presenilin 2.7 Most cases of AD are late-onset and are non-familial. It is likely that predisposition to late-onset AD is mediated by highly prevalent genetic variants of low penetrance in a number of different genes. The most established of these is the Apolipoprotein E (APOE) gene. Inheritance of one copy of the APOE {epsilon}4 allele increases risk of AD by a factor of 3, whereas homozygosity is associated with a 12-fold increase in risk.8 APOE {epsilon}4 is, however, neither sufficient nor necessary for the development of AD. The advent of high-density genome-wide association studies has resulted in the identification of a whole array of novel genetic risk alleles and variants for dementia.7 Many of these associations await replication in larger representative populations, but genome-wide association studies clearly offer huge potential to further our understanding of the underlying pathophysiology of AD and identify targets for novel therapeutic agents.

Vascular dementia is a heterogeneous term for many different processes that result in dementia because of cerebral infarction, hypoperfusion or haemorrhage (Table 1).9 The most common form is a consequence of cerebral small vessel disease (subcortical ischaemic VaD) and is associated with the presence of lacunar infarcts and white matter lesions.9,10 Large vessel VaD is usually embolic in nature and the cognitive impairment may result from cerebral damage through numerous infarcts, which are widely distributed throughout the brain (multi-infarct dementia) or a single infarct in a critical area of the brain (strategic infarct dementia). VaD is strongly linked to the classic vascular risk factors: age, smoking, hypertension, dyslipidaemia and diabetes. Two recent reviews have suggested that the risk of VaD is increased by 2- to 3-fold in people with type 2 diabetes.3,4 More surprisingly, these reviews have also suggested that type 2 diabetes is associated with a 1.5- to 2.0-fold increased risk of AD.3,4


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  		Table 1 Clinico-pathological classification of VaD.

 
In clinical terms, differentiating AD from VaD is not straightforward. Typically a history of sudden-onset dementia or a step-wise deterioration in cognitive function favours a vascular aetiology, whereas in AD the decline is more gradual and memory impairment often predominates over other cognitive domains. However, there appears to be a substantial clinical overlap between these two syndromes. Magnetic resonance imaging studies have demonstrated that ‘silent’ vascular lesions are extremely common in older people9 and neuropathological investigations have shown that vascular pathology is so common that few individuals with dementia lack a mixed AD and vascular pattern.11 Thus, while the epidemiological data suggest that both VaD and AD are more common in people with diabetes, in reality most individuals will have dual pathology. Whatever the aetiology, there is no doubt that dementia per se is more common in people with diabetes.

People with diabetes have always had an increased risk of macrovascular disease (ischaemic heart disease, cerebrovascular disease and peripheral vascular disease) and microvascular complications (retinopathy, nephropathy and neuropathy), so why has dementia not been recognized previously to be a complication of diabetes? There are several likely reasons. As noted earlier, increasing numbers of people with diabetes are living to an advanced age.1 This increases the size of the diabetic population in which co-existing dementia and cognitive impairment can be identified. However, mild levels of cognitive impairment may not be evident when a person is reviewed in the context of a routine diabetes clinic, particularly when an individual patient may be reviewed by many different doctors during the course of their diabetes, and where routine screening for cognitive impairment is not performed. Moreover, as individuals become increasingly frail and cognitively impaired, they may no longer be able to attend for routine review. It is, therefore, only with the advent of large-scale community-based epidemiological studies, in which sophisticated cognitive testing has been performed, that the relationship between diabetes, cognitive impairment and dementia has become apparent.


   Areas of controversy
Top
 Abstract
 Introduction
 Sources of data
 Areas of agreement
 Areas of controversy
Growing points
 Areas timely for research...
 Conclusions
 References
 
Although it is now clear that type 2 diabetes is associated with an increased risk of cognitive impairment and dementia, the mechanisms underpinning this association remain to be clearly delineated. Type 2 diabetes is a complex disorder and so it is likely that multiple different, synergistic processes may interact to promote cognitive decrements (Table 2).


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  		Table 2 Potential risk factors for cognitive impairment in type 2 diabetes.

 
Acute hyperglycaemia

Hyperglycaemia is the hallmark of all types of diabetes and could cause cognitive decrements by several different mechanisms. Acute changes in blood glucose are known to alter regional cerebral blood flow and could also cause osmotic changes in cerebral neurones. Acute hyperglycaemia was shown to cause decrements in working memory and attention in a clamp study in people with type 2 diabetes.12 In the same study, hyperglycaemia was also associated with changes in mood, such that levels of happiness and energy fell, while levels of tension rose.12 Two recent randomized trials have also examined the role of anti-diabetic therapy in improving cognitive function in people with type 2 diabetes.13,14 Neither trial was placebo-controlled, but in one study a strong correlation was observed between cognition and the change in blood glucose concentrations over 6 months, such that subjects with the greatest decline in glucose (and thus better glycaemic control) had the greatest improvement in working memory.13 In the other study, treatment with a meglitinide medication (which specifically targets post-prandial hyperglycaemia) was associated with better cognitive performance than sulphonylurea therapy over 1 year.14

Vascular disease

The recognized association between type 2 diabetes and macro- and microvascular disease is pertinent to the pathogenesis of dementia. The former could cause cognitive impairment because of the increased incidence of embolic stroke. Moreover, as discussed earlier, cerebral microvascular disease is more common in people with diabetes, which is implied by the lacunar infarcts and white matter changes that are demonstrable in neuroimaging studies.15,16 Direct imaging of the microvasculature in vivo requires sophisticated neuroimaging techniques that do not lend themselves to large-scale epidemiological studies. However, because of their similar anatomy, physiology and embryology, changes in the retinal vasculature may reflect analogous changes in the cerebral vasculature. Fortunately, the retinal microvasculature can be observed with relative ease in vivo, using non-invasive techniques. Thus an assessment of retinal vascular abnormalities may offer important clues about the state of the small vessels of the brain. Several studies of people with diabetes (and of others who do not have diabetes) have indicated that there is an association between retinal microvascular abnormalities and cognitive function.17–19

The aetiology of cerebral microvascular disease in people with diabetes is also likely to be multifactorial. Chronic hyperglycaemia causes structural and functional abnormalities in small blood vessels, but substantive longitudinal data are not available in people with type 2 diabetes to explore the relationship between long-term glycaemic control and cognitive function. Some information has emerged in studies of people with type 1 diabetes. In the Diabetes Control and Complications Trial (DCCT) and the subsequent follow-up evaluation, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, an association was observed between higher mean glycated haemoglobin concentrations and moderate decrements in motor speed and psychomotor efficiency over an average period of 18 years.20 This suggests that relative hyperglycaemia may have a long-term detrimental effect on some measures of cognitive function.

Hypertension is also highly prevalent in people with type 2 diabetes and is associated with microangiopathy. Cross-sectional data have linked hypertension with cognitive impairment in people with type 2 diabetes,5 but a Cochrane meta-analysis concluded that anti-hypertensive therapy was not associated with a lower incidence of dementia in people who did not have a preceding history of cerebrovascular disease.21 This review included the SYST-EUR trial that had reported a 50% lower incidence of dementia in subjects who had received the calcium-channel blocker, Nitrendipine, over 2 years.22 This seems biologically implausible and the authors of the Cochrane review stated that the results of this study should be interpreted with caution. In the PROGRESS trial, therapy with Perindopril and Indapamide was associated with a lower risk of dementia (34%) and cognitive decline (45%) in people with cerebrovascular disease, but only that associated with recurrent stroke.23 There is no evidence that treatment with statins reduces the risk of dementia.24

Hyperinsulinaemia

Individuals with pre-diabetic states (e.g. impaired glucose tolerance or fasting hyperglycaemia) or early type 2 diabetes typically have elevated circulating plasma insulin concentrations because of peripheral insulin resistance, which is in turn related to central obesity. Insulin receptors are found in high concentrations within the limbic system of the brain; in epidemiological studies of non-diabetic adults, hyperinsulinaemia has been associated with poorer cognitive performance and an increased risk of AD.25–28 Moreover, people with AD may have lower concentrations of insulin in the cerebrospinal fluid than normal.29 It has, therefore, been postulated that either a functional deficiency of insulin in the hippocampus (because of insulin insensitivity) or an absolute deficiency (as observed in AD) may directly cause neuronal dysfunction.30

Recurrent hypoglycaemia

In people with type 1 diabetes, a number of cross-sectional studies have suggested that recurrent exposure to severe hypoglycaemia (retrospectively estimated) will result in modest cognitive decrements.31 However, in the DCCT/EDIC studies, no relationship was observed between the frequency of severe hypoglycaemia and cognition over the follow-up period of up to 18 years.20 Severe hypoglycaemia occurs less frequently in type 2 diabetes, but in people receiving treatment with insulin or sulphonylurea agents severe hypoglycaemia is not uncommon.32 No long-term data are available concerning the potential effects of severe hypoglycaemia on cognitive function in people with type 2 diabetes, but it is plausible that severe hypoglycaemia could have a more deleterious effect on the elderly brain that is exposed to the effects of other co-morbidities.

Other factors

There are other reasons why people with type 2 diabetes may be more at risk of developing dementia than the non-diabetic population. Depression is more common in people with type 2 diabetes and is itself associated with cognitive impairment.33 It is not clear whether the association between type 2 diabetes and depression is related to a specific biological mechanism or simply because depression is more common in people who have chronic medical disorders, in general. Whatever the mechanism, it is important that depression is considered in any individual with cognitive impairment, as it is a potentially reversible cause. People with type 2 diabetes also have to take multiple medications, including anti-diabetic, anti-hypertensive, anti-platelet and lipid lowering therapies. Some of these medications, for example, β-adrenoreceptor blockers, may have deleterious effects on cognition.34


   Growing points
Top
 Abstract
 Introduction
 Sources of data
 Areas of agreement
 Areas of controversy
 Growing points
Areas timely for research...
 Conclusions
 References
 
Glucocorticoid excess

Emerging evidence has indicated that individuals with type 2 diabetes have activation of the hypothalamic-pituitary-adrenal (HPA) axis, manifested by higher morning concentrations of plasma cortisol,35,36 an enhanced cortisol response to synthetic ACTH and elevated levels of urinary cortisol.36–38 Elevated plasma cortisol levels have been reported in people with diabetic complications including angiopathy, retinopathy, neuropathy and nephropathy39 but whether glucocorticoids contribute to cognitive impairment in diabetes is unknown. Much evidence is available to support a link between elevated plasma glucocorticoids and cognitive dysfunction. Exogenous glucocorticoid administration and elevated endogenous glucocorticoids (as occurs in Cushing's syndrome) are associated with cognitive impairment in animals and humans. More subtle alterations in HPA axis function have been linked with cognitive function with higher plasma cortisol levels at 9 a.m. being associated with poorer age-related cognitive ability in otherwise healthy individuals.40 Likewise, manipulations that reduce plasma glucocorticoid concentrations or their effects on target tissues can attenuate cognitive decline with ageing.41–43 Glucocorticoids have widespread effects within the central nervous system including direct effects on hippocampal structure and function, which influences learning and long-term memory.44–47

Although the relationships between HPA axis function and cognitive decline in type 2 diabetes have not been studied in detail, a recent small study showed that when the sensitivity of the HPA axis central feedback was impaired, this was associated with declarative memory impairments, possibly reflecting hippocampal dysfunction.48 Therapeutic manipulation of the HPA axis may be a novel approach to improve cognitive function in patients with type 2 diabetes.49 Access of cortisol to the glucocorticoid receptor is regulated by local activity of the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSDs), which catalyse the interconversion of the active steroid cortisol and its inactive metabolite cortisone. 11β-HSD1 reactivates cortisol from inactive cortisone in many sites, ensuring adequate activation of the glucocorticoid receptor. In two small, randomized, double-blind, placebo-controlled, crossover studies, administration of the 11β-HSD inhibitor, carbenoxolone, (in a dose of 100 mg three times daily) improved verbal fluency after 4 weeks in 10 healthy elderly men (aged 55–75 years) and improved verbal memory after 6 weeks in 12 people with type 2 diabetes (52–70 years).50 Larger, more detailed studies are required to confirm and explore these intriguing findings.

Inflammation

The development of macrovascular disease is now recognized to involve inflammatory processes,51 although it is still uncertain whether inflammation has a causal effect on cardiovascular disease or whether it is a consequence of atherosclerotic processes. More recently, it has been hypothesized that inflammation may also play a role in the development of dementia and/or cognitive impairment. Animal studies suggest that ‘over-production’ of cytokines in the brain is associated with neurodegeneration and cognitive deficits,52 while in humans, inflammation occurs in the brain of AD sufferers.53,54 In the Rotterdam Scan Study, plasma C-reactive protein (CRP), a marker of chronic systemic inflammation, was associated with cerebral white matter lesions and lacunar infarcts, indicative of cerebral small vessel disease.55

Epidemiological studies have indicated modest but consistent associations between the levels of circulating inflammatory mediators (including CRP, interleukin-6 and fibrinogen) and the risk of cognitive decline and dementia.56–59 In several cases, findings persist even after adjustment for co-existing cardiovascular disease, suggesting that inflammatory factors may be important mediators, over-and-above any impact on macrovascular disease. In the PROSPER study, genetic variation in the gene encoding the interleukin-1β-converting enzyme was associated both with levels of production of the inflammatory cytokine, interleukin-1β, and with cognitive function in elderly people.60 In addition, in people who had dementia and cognitive impairment, the percentage of peripheral monocytes producing tumour necrosis factor (TNF)-{alpha} and other cytokines was raised,61 consistent with previous findings that plasma TNF-{alpha} was higher than normal in people with dementia.62

Inflammatory markers are elevated in several disorders in which the risk of cognitive impairment is increased, and this includes type 2 diabetes. It has been hypothesized that this may be an effect of hyperglycaemia on macromolecules to produce advance glycation end products, which in turn increase the production of proinflammatory cytokines and other inflammatory mediators. Although the inflammatory markers in the epidemiological studies that indicate an association with dementia and/or cognitive impairment were measured in peripheral venous blood, there are several pathways through which cytokines and other inflammatory mediators can communicate directly with neurones in the brain and may therefore have an impact on cognitive ability; this includes activation of cerebral endothelial cells and/or transport across the blood–brain barrier.63,64 Indeed, in the brain, macrophage populations signal the presence of inflammation by synthesizing many of the same inflammatory cytokines as are induced peripherally. An increased level of circulating inflammatory mediators in people with diabetes may therefore help to explain their increased risk of cognitive decline. However, despite accumulating data, no definitive evidence has been produced to demonstrate a causal role for inflammatory mediators in humans. Indeed, the outcomes of trials of relatively non-specific anti-inflammatory agents have been either negative or inconclusive.65–69 One promising approach to determining whether or not inflammatory mediators have a causal role (and so save time and resources on the development of drugs and other interventions for targets of dubious importance) is the use of new techniques in genetic epidemiology based around the concepts of ‘Mendelian Randomization’.70 By determining the association between cognitive function and genes that are known to affect plasma levels of inflammatory biomarkers, it should be possible to discriminate between causal and non-causal risk factors, and so provide targets for highly specific preventative and/or therapeutic interventions. Such approaches require large, richly phenotyped cohorts and collaborative efforts across cohorts to provide sufficient power and enable replication of positive findings.


   Areas timely for research development
Top
 Abstract
 Introduction
 Sources of data
 Areas of agreement
 Areas of controversy
 Growing points
 Areas timely for research...
Conclusions
 References
 
Studies of cognitive impairment and dementia in type 2 diabetes have generally taken the form either of small cohort studies in which reasonably detailed phenotypic information about diabetes has been collected or of large-scale epidemiological studies in which very little diabetes-specific information is available. However, these studies have considerable importance because they have highlighted links between type 2 diabetes, cognitive impairment and dementia. In order to progress comprehension of the pathogenesis of diabetes-related cognitive impairment, large-scale epidemiological studies are now required of people with type 2 diabetes, in which detailed phenotyping of clinical variables is performed. This approach has been supported by the UK Medical Research Council that has funded a 5-year prospective study into the risk factors for cognitive impairment in type 2 diabetes—the Edinburgh Type 2 Diabetes Study (ET2DS).71 In this study, over 1000 people with type 2 diabetes, aged 60–75 years, were recruited randomly from the Lothian Diabetes Register in central Scotland. Subjects have undergone detailed cognitive testing and phenotyping, including assessment of the presence of microvascular and macrovascular disease, measurement of inflammatory markers, HPA axis activation and diabetes-specific clinical variables. The baseline data from this study will be reported in 2009 and a DNA bank has been established to allow the study of genetic factors which may be associated with cognitive impairment.

In addition to large-scale epidemiological studies, randomized trials of specific therapeutic and preventative interventions are also required. Multi-centre trials involving cognitive testing are time-consuming and expensive to establish and, clearly, in the future will be informed by epidemiological studies such as the ET2DS. Nowadays, investigators are increasingly examining cognitive function as an outcome measure in established randomized trials. For example, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study is investigating the impact of intensive versus standard methods of management of hyperglycaemia, hypertension and dyslipidaemia on cardiovascular outcomes in over 10 000 people with type 2 diabetes. The investigators have established a sub-study (ACCORD-MIND) in which cognitive function will be assessed at baseline, 20 months and 40 months in 2977 subjects from the main study.72 In addition, full-brain magnetic resonance imaging will be performed in 630 subjects at baseline and 40 months and this should provide valuable information about the effects of diabetes on brain structure and function.

Further research is also required to consider whether there is any merit in actively screening for cognitive impairment in people with diabetes and to determine what are the best screening tools. At the present, there are little data on the clinical impact of mild cognitive impairments in people with diabetes and this would be important information to consider before any screening programme could be recommended.


   Conclusions
Top
 Abstract
 Introduction
 Sources of data
 Areas of agreement
 Areas of controversy
 Growing points
 Areas timely for research...
 Conclusions
References
 
The prevalence of type 2 diabetes and dementia will rise substantially in the immediate future. It is clear that cognitive impairment and dementia occur more frequently in people with type 2 diabetes than in the general population. Almost certainly, multiple factors account for this link, with vascular disease being a major contributor. However, other clinical variables, such as activation of the HPA axis, inflammatory processes and genetic predisposition, are being recognized to influence the development of cognitive impairment in diabetes. Large-scale studies are now urgently required to increase our understanding of this important problem, which is imposing an increasing burden on society and presents a serious challenge to clinical management.

Conflict of interest: All authors are investigators of the ET2DS that is funded by the Medical Research Council with a sub-study being supported by Pfizer. M.W.J.S. has received consultancy fees and lecturing fees from GlaxoSmith Kline and also sits on a GSK Independent Data Monitoring Committee. M.W.J.S. has received funds to support staff members from other companies that make diabetes pharmaceuticals—namely Takeda, Pfizer and Sanofi Aventis. J.F.P. has received research funding from Bayer Healthcare. B.M.F. has received research funding, consultancy fees and honoraria for lectures from Eli Lilly, and consultancy fees from Takeda, GSK, Sanofi-Aventis, Novo Nordisk and MSD.

Accepted for publication October 28, 2008.


   References
Top
 Abstract
 Introduction
 Sources of data
 Areas of agreement
 Areas of controversy
 Growing points
 Areas timely for research...
 Conclusions
 References
 

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