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Age-related cerebral white matter disease (leukoaraiosis): a review
  1. Basil E Grueter,
  2. Ursula G Schulz
  1. Nuffield Department of Clinical Neurosciences (Neurology Division), Stroke Prevention Research Unit, University of Oxford, Oxford, UK
  1. Correspondence to Dr Ursula G Schulz, Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences (Neurology Division), Level 6, West Wing, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK; ursula.schulz{at}clneuro.ox.ac.uk

Abstract

With the availability of improved brain imaging techniques, the high prevalence and clinical importance of cerebral small vessel disease have been increasingly recognised in recent years. As age is one of the most important risk factors for this condition, its prevalence is set to rise further as populations age. This may lead to an increase in the clinical consequences of white matter disease, namely cognitive decline, decreased mobility and increased stroke risk. Given the impact this will have on individuals and on healthcare systems, knowledge of the risk factors for small vessel disease, its prevention and its treatment is becoming more important. Although a lot of data are now available on the epidemiology, risk factors, clinical consequences and prognosis of leukoaraiosis, some of this information is conflicting. In this review, we summarise the current literature on cerebral small vessel disease, with an emphasis on its clinical aspects.

  • Leukoaraiosis
  • white matter disease
  • small vessel disease
  • dementia
  • stroke
  • adult neurology
  • stroke medicine

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Introduction

Cerebral white matter disease, also known as cerebral small vessel disease, is frequently reported on brain imaging, predominantly in older patients. While it was for a long time regarded as an incidental finding with no therapeutic consequences, there is now increasing evidence that it is associated with cognitive decline and a higher risk of stroke and death.1 Given this clinical relevance, recent years have shown a growing interest in small vessel disease, its pathology, epidemiology, risk factors and treatment options. With its prevalence set to rise as the general population ages, a working knowledge of this condition is important for most general physicians. In this paper, we summarise current knowledge of the various aspects of small vessel disease.

Recognition of small vessel disease dates back to the late 19th century, when Binswanger and his student Alzheimer published the first articles on this topic.2 3 However, it now seems likely that the patients they described had vascular changes due to neurosyphilis, and that the original ‘Binswanger disease’ may have described a different pathology than what we currently understand by ‘small vessel disease’. It was only with the availability of modern brain imaging in the 1970s that lesions in the cerebral white matter could be identified in living patients. Ever since there has been some debate about the terminology to be used for these lesions. ‘Leukoaraiosis’ (from the Greek leuko (white) and araios (rarefaction))4 is a purely descriptive term to describe white matter lesions seen on brain scans, and not a clearly defined pathological entity. The expression ‘white matter disease’ is often used synonymously. However, even though this term is again purely descriptive and could also include inflammatory disorders or the leukodystrophies, the clinical context in these disorders is different, and usually ‘white matter disease’ implies a presumed ischaemic origin of the lesions. ‘Small vessel disease’ is another expression which is commonly used. It addresses the underlying pathology of the lesions and encompasses the presence of diffuse white matter changes as well as distinct lacunar infarcts.

Pathology and pathophysiology of leukoaraiosis

Cerebral small vessel disease is one of the most common degenerative vessel disorders in the ageing human brain, together with cerebral atherosclerosis and cerebral amyloid angiopathy.5 Its pathophysiology is still incompletely understood. Endothelial dysfunction is thought to play an important role, and to be one of the first steps in the development of small vessel ischaemia.6 However, a recent review concluded that although endothelial dysfunction may play a role in the development of small vessel disease, it is unlikely to be specific to this condition and also occurs in other types of cerebrovascular disease.7

Several factors may cause endothelial damage, for example mechanical factors such as hypertension. Damaged endothelium allows plasma proteins to leak into the vessel wall, which then swells and may subsequently develop hyaline degeneration and fibrosis. This leads to wall thickening, narrowing of the vessel lumen, reduced blood flow and finally to ischaemia in the tissues supplied by these vessels. Tissue damage caused by chronic ischaemia is one possible pathogenetic mechanism for the development of white matter lesions. In addition, endothelial damage leads to blood–brain barrier breakdown. Plasma components which normally cannot permeate through the blood–brain barrier will now enter into the interstitial space and brain parenchyma, and damage neurons and glial cells. These areas of damage may appear as white matter lesions on brain imaging and on histological slides5 8–11 (figure 1). White matter disease may therefore be a consequence of chronic ischaemia, of blood–brain barrier breakdown and leakage of potentially toxic substances into the brain, or of a combination of these two -mechanisms.5 12–16

Figure 1

Slice of a human brain (one hemisphere only) in luxol fast blue staining. This brain shows substantial loss of white matter due to severe small vessel disease. In this stain myelin appears dark and looks normal in the right upper region (A) whereas it has nearly disappeared in the left lower region (B) of this brain. The grey matter (light grey) is unaffected.

The brains of patients with leukoaraiosis frequently show other changes as well. For instance, leukoaraiosis and lacunar infarcts often coexist.4 11 17 Lacunar infarcts are due to occlusion of a small perforating vessel and are another manifestation of small vessel disease, although their pathophysiology differs from that of leukoaraiosis.18 The co-existence of these two processes is in keeping with the frequently reported higher risk of stroke in patients with leukoaraiosis. Enlarged perivascular spaces (Virchow–Robin spaces) are another frequent finding in small vessel disease and usually form around diseased vessels.5 19 On CT images these enlarged spaces may be mistaken for lacunar infarcts, but they can be clearly distinguished on MRI. Their clinical significance is uncertain. Cerebral microbleeds are small haemorrhages limited to perivascular spaces. They represent the leakage of blood components through the vessel wall rather than overt haemorrhage, and they are a frequent finding in leukoaraiosis. They are most commonly found in cerebral amyloid angiopathy, but also occur in patients with poorly controlled hypertension.5 20 21 Interest in the clinical importance of microbleeds is increasing. They may indicate an increased risk of cerebral haemorrhage, in particular in patients on anticoagulation therapy. Indeed, some clinicians regard cerebral microbleeds as a relative contraindication to anticoagulation. However, there are no clear data on the extent to which cerebral microbleeds increase the risk of haemorrhage and studies are ongoing. Finally, leukoaraiosis is also associated with brain atrophy.22–24 With increasing severity of white matter disease, there is often a corresponding decrease in white and grey matter volume and an increase in ventricular size.23 Grey matter atrophy may be due to deafferentation caused by loss of cortical–subcortical connections and the ventricles may enlarge due to loss of subcortical white matter.24

Imaging

The clinical symptoms and signs associated with the presence of white matter disease are relatively non-specific. While the constellation of memory deficits and gait disturbance in an elderly person with hypertension predicts white matter disease with reasonable accuracy, leukoaraiosis is a radiological diagnosis obtained with brain imaging using either CT or MRI.

White matter changes appear as low attenuation areas on CT and as areas with high signal on T2-weighted or FLAIR MRI. MRI is more sensitive than CT in the detection of small lesions, while larger lesions are detected equally well with either imaging method25 (figure 2). Gradient-echo sequences (GRE) or, providing even more sensitivity, susceptibility weighted imaging (SWI) on MRI shows the presence of cerebral microbleeds, which cannot be distinguished from ischaemic small vessel disease on CT, and which are a feature of hypertensive small vessel disease and, more commonly, of cerebral amyloid angiopathy (figure 3). Lesions can be located periventricularly, in the deep white matter or both. Typically, the disease spares the tangentially travelling white matter fibres at the junction of the grey and white matter, known as U-fibres.12

Figure 2

CT and T2-weighted MRI showing leukoaraiosis at different stages of severity.

Figure 3

Patient with amyloid angiopathy. T2-weighted images (A–C) show diffuse white matter changes and a left cerebellar haemorrhage. Gradient echo images (D–F) emphasize the cerebellar haemorrhage (D) and show several microhaemorrhages in the periventricular white matter (E) and the left occipital lobe (F).

Disease progression tends to follow a general pattern. Periventricular lesions initially form at the top of the horns of the lateral ventricles (capping), but with progressing disease severity extend around the ventricles. Deep white matter lesions generally occur in the frontal lobes first, and subsequently affect the parieto-occipital lobes and, more rarely, the brain stem and the basal ganglia. They only very rarely affect the temporal lobes—an important distinguishing feature from CADASIL, an autosomal dominant small vessel arteriopathy in which the temporal lobes are frequently affected (figure 4).26 27 In mild small vessel disease, lesions are distinct from each other, but with increasing disease severity they become confluent and eventually diffusely involve an entire region.4 25

Figure 4

Axial T2-weighted (A, B) and coronal FLAIR (C) MRI of a patient with CADASIL. The arrows show white matter changes involving the anterior temporal lobes. This is an almost pathognomonic feature of CADASIL, and a rare finding in age-related white matter changes.

Grading the severity of white matter disease can be very subjective and observer dependent. To increase objectivity, different rating scales, which vary in complexity and ease of use, have been developed.25 28 29 They are helpful in research studies of white matter disease, in that they should increase reproducibility and observer agreement regarding the assessment of white matter disease, and thus facilitate comparison between patients and between different studies. However, in clinical practice their use is often too time-consuming, and white matter disease is usually simply graded as ‘absent’, ‘mild’, ‘moderate’ or ‘severe’.

Prevalence

The reported prevalence of leukoaraiosis differs widely between studies. Rates vary from 5.3%30 to more than 95%.31–33 This large variability can be explained by methodological differences between studies, for example different ways to assess imaging, and differences in the presence of risk factors and comorbidities between study populations.

With such different estimates of the prevalence of white matter disease, it is difficult to assess if its prevalence has changed over time. However, the data we have available do not show any clear temporal changes in the prevalence of small vessel disease.33–36 This is perhaps surprising as better quality and more sensitive brain imaging might have led to a higher rate of identification, and ageing populations may have led to a real increase in the prevalence of leukoaraiosis. However, today there is more awareness of risk factors, and certainly the control of hypertension has improved.37 38 Therefore, any apparent increase in the prevalence of leukoaraiosis due to better imaging quality may have been offset by a real decrease due to improved blood pressure control. Furthermore, brain imaging has only been widely available since the 1980s, and high quality data on the prevalence of small vessel disease have been available for even less time. Three decades may simply be too short a time to show clear changes in the prevalence of leukoaraiosis.

Risk factors

Risk factors for leukoaraiosis have been extensively investigated and study findings have been conflicting, possibly due to differences in study methodology. Some of the risk factors are non-modifiable, some are acquired and treatable, and some may simply reflect confounding by hypertension, which is the strongest modifiable risk factor for leukoaraiosis. We discuss the most widely studied risk factors below.

Age

Increasing age is probably the most important risk factor for developing leukoaraiosis,15 16 36 39 40 the reason leukoaraiosis is often also referred to as ‘age-related white matter disease’. Although leukoaraiosis is a pathological phenomenon, it may to a certain extent be part of the normal ageing process. However, it is not clear at what age white matter disease starts to develop, and precise data on the extent of disease that can be regarded as ‘normal’ at a certain age do not exist. Most studies suggest that at least some white matter lesions can be expected after the age of 50–65 years.12 17 30 41 There is no doubt that leukoaraiosis is a very common finding in elderly people and that it becomes more prevalent and more severe with increasing age.16 39

Gender

Studies of the association between gender and the prevalence of leukoaraiosis have shown conflicting results. While some found a trend towards a higher prevalence of leukoaraiosis in women,22 42 others found men to be at higher risk.36 These results may at least partly be explained by differences in the characteristics of the study populations, and by confounding by other factors. For example, the study that found men to be at higher risk was carried out in Japanese subjects, whereas the other two studies examined populations in the USA. Furthermore, there may have been differences in age or the prevalence of hypertension between men and women, suggesting an apparent sex difference in the prevalence of white matter disease. A recent systematic review did not find any gender differences in the prevalence of cerebral white matter disease, although there was large variation between studies.43

Race

White matter disease appears to occur more frequently in Afro-Caribbean than Caucasian populations.44 This may be due to a higher prevalence of hypertension in Afro-Caribbean subjects. They may also have more severe hypertension, and blood pressure control is often poorer compared with Caucasian patients.45 Finally, differences in genetic factors between Afro-Caribbean and Caucasian populations may alter the effect that hypertension has on the development of white matter disease.

Hypertension

Hypertension is strongly associated with white matter disease and is probably the most important modifiable risk factor.12 39 40 46 Studies of white matter disease clearly indicate that hypertension plays an important role in the development of leukoaraiosis,43 with increased systolic as well as diastolic blood pressure both appearing to be relevant. There is no threshold value above which the disease starts, and the association represents a continuum. In addition to absolute values, abnormalities in diurnal blood pressure variation may also contribute to the development of white matter disease.12

Diabetes mellitus

Studies of the effect of diabetes mellitus on white matter disease have shown conflicting results. Some suggest an association between leukoaraiosis and diabetes mellitus,39 particularly with regard to periventricular lesions.47 Similarly, elevated fasting glucose was found to be associated with white matter disease.36 A recent comparison of diabetic patients with and without leukoaraiosis found significantly higher insulin levels in the patients with white matter disease.48 All of these data suggest that increased insulin resistance is a risk factor for white matter disease. However, the strength of this association is uncertain, and the pathological mechanism is unclear. Indeed, a number of studies failed to find an association between leukoaraiosis and diabetes mellitus.28 40 49

Dyslipoproteinaemia

Dyslipoproteinaemia is an important risk factor for large vessel disease. It is less certain if abnormalities in lipid metabolism are also a risk factor for small vessel disease. Some studies have shown that low levels of high-density lipoprotein cholesterol and hypertriglyceridaemia may increase the risk of developing leukoaraiosis.36 48 50 However, other authors failed to find an association between dyslipidaemia and white matter disease.39 40

Smoking

Likewise, it is unclear whether a history of current or previous smoking influences the development of white matter disease. Some studies found an association,36 42 whereas others detected no differences in the prevalence of leukoaraiosis between smokers and non-smokers.39 40

Large vessel atherosclerosis

Because the underlying disease process in leukoaraiosis is thought to be disease of the small vessels, large vessel atheroma and white matter disease may not necessarily be associated.40 While lack of an association has been reported,18 40 some studies found an association between atherosclerotic disease and leukoaraiosis.23 51 52 This may be due to two different mechanisms. First, a stenosis allows less blood to enter into the brain, which increases the risk of chronic ischaemia and may increase the risk of developing leukoaraiosis. Second, atherosclerotic disease and leukoaraiosis have some risk factors in common and may therefore occur concurrently.

Ischaemic heart disease

Ischaemic heart disease is caused by large vessel atheromatous disease. Any association with cerebral small vessel disease would likely be non-causal, and due to the sharing of common risk factors, such as hypertension. Studies differ in their findings as to whether ischaemic heart disease is associated with leukoaraiosis39 53 54 or not.40 50

Vitamin B12 and homocysteine

Several studies have reported an association between low vitamin B12 levels and white matter disease, especially with periventricular lesions.55 56 However, even though there is some evidence that low vitamin B12 levels and hyperhomocysteinaemia, which may be caused by lack of vitamin B12, are associated with leukoaraiosis,57 58 there are no data showing that treatment with vitamin B12 or lowering homocysteine levels improves white matter disease or slows its progression.

Genetic factors

There are some single gene disorders, for example cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), in which white matter lesions are a prominent feature (figure 4). However, CADASIL accounts only for a very small number of cases with leukoaraiosis26 and it appears highly unlikely that ‘age related white matter disease’ is due to a single gene defect, although genetic factors very likely play a role.59 For example, several studies have shown an association between the presence of white matter lesions and polymorphisms in a number of genes, such as ACE or apolipoprotein (a).60 Such genetic factors may not be directly linked to the presence of leukoaraiosis but may determine both an individual's tendency to develop a risk factor for leukoaraiosis, as well as their vulnerability to develop end-organ damage as a consequence of having a particular risk factor. For example, the tendency to develop hypertension is to a certain extent determined genetically, and furthermore, the tendency to develop white matter disease as a consequence of hypertension may also be influenced by genetic factors.

Risk factors: summary

Increasing age and hypertension are the only generally accepted risk factors for leukoaraiosis. The association between white matter disease and other risk factors may partly be due to confounding by hypertension, for example the higher prevalence of leukoaraiosis in Afro-Caribbean subjects, who are also more likely to be hypertensive, and by age, for example the higher prevalence of leukoaraiosis in women, who may be older than men in some studies. The association of white matter disease with other factors is less clear. This includes even those risk factors which are widely believed to increase the risk of developing white matter disease, such as diabetes mellitus. Differences in study methodology may explain some of the conflicting results. Risk factor associations may also depend on genetic factors or comorbidities and only be relevant in certain populations. This will require further study. However, a recent systematic review of the currently available data confirmed age and hypertension as the only consistent risk factors for leukoaraiosis, and found no association with any other factors.43

Clinical presentation

White matter changes often appear to remain asymptomatic until they affect a significant proportion of the brain.61 However, symptoms emerge slowly over time, and it is often not possible to determine their onset. Furthermore, the symptoms attributed to small vessel disease are fairly non-specific and may be caused by other pathological processes which are also common in old age. Not infrequently, such conditions may coexist. For example, patients may be diagnosed with a ‘mixed dementia’ due to having both Alzheimer's disease and vascular dementia. It is therefore difficult to be certain at which stage small vessel disease becomes symptomatic and which specific symptoms it causes in any one patient. Nevertheless, there is general agreement that leukoaraiosis is associated with

Of these, deteriorating cognitive function is the most widely recognised. It is associated with poor performance across a range of cognitive tests. Executive functioning, processing speed and attention are predominantly affected.1 61 63 In addition to cognitive decline, white matter disease also causes deteriorating gait and leads to an increased risk of falls.22 41 65 Given the association of leukoaraiosis with cognitive decline and poor mobility, it is not surprising that in an elderly population, patients with large white matter lesions performed considerably worse in their daily activities than controls with no significant white matter disease.67

The association of leukoaraiosis and stroke

White matter changes and stroke are closely associated. Previous stroke is associated with higher prevalence of leukoaraiosis,34 39 40 and leukoaraiosis is a risk factor for first ever and for recurrent stroke.1 43 66 68 This association can to some extent be explained by shared risk factors, such as hypertension. Furthermore, leukoaraiosis is thought to reflect chronic low-level ischaemia. Chronically ischaemic brain tissue may be more likely to develop infarction when exposed to further ischaemia. Finally, there is a particularly close association between leukoaraiosis and lacunar stoke. Both are manifestations of cerebral small vessel disease and often occur together. Some authors believe that lacunar infarction reflects acute damage, whereas leukoaraiosis represents chronic ischaemic changes. Other authors have shown that the risk factor profiles for these two conditions differ, and suggest they may represent slightly different pathologies.18

Prognosis

Leukoaraiosis is a common finding in the elderly, and it is widely accepted that its prevalence increases with age. However, apart from the association with age, surprisingly little is known about the progression and prognosis of white matter disease. Only a few longitudinal studies are available. The community-based Austrian stroke prevention study found that white matter lesions progressed in only 17.9% of study subjects over a 3-year period.69 In other studies, 27%,70 32%71 and 28%72 of the study population showed disease progression over a 2-, 3- and 5-year follow-up period, respectively, and more recently the multi-centre LADIS study reported that at least some degree of disease progression over 3 years was present in 74% of participants in a cohort of elderly patients who were independent at baseline.73 The risk factors for progression of white matter disease appear to be the same as those for initially developing the disease, that is increasing age and hypertension. Baseline lesion load may be a prognostic factor, in that patients who already have a high lesion load are more likely to develop further lesions.42 73 However, high baseline lesion load of course implies that the disease has already progressed, and may therefore be likely to continue to progress further. Overall, from the limited longitudinal data that are available, the main factors which are associated with progression of white matter disease are increasing age, hypertension and a high baseline lesion load.

Clinically, numerous studies have shown that progression of leukoaraiosis is associated with cognitive decline,22 23 25 34 42 74 although others have not.75–77 An association with the severity of white matter disease has also been reported for stroke risk56 68 and for gait disturbance.78 With increasing lesion volume, patients were more likely to experience gait deterioration and to develop falls compared to patients with less severe disease.41 78

Management

Current evidence suggests that once established, leukoaraiosis is irreversible.12 13 Any treatment therefore has to be directed at disease prevention, and at reducing the rate of disease progression.79 However, the evidence that any particular intervention slows down disease progression is still limited. Data are mostly derived from observational studies,33 79 and only very few data from randomised trials are available.80 81

Blood pressure control

Antihypertensive treatment should both delay the development of white matter disease and slow down the progression of already established lesions. This beneficial effect has been confirmed in several studies: the EVA MRI study found that compared to untreated controls, patients on antihypertensive treatment had a reduced risk of severe leukoaraiosis in a cross-sectional cohort.33 The MRI substudy of the PROGRESS trial found that treatment with a diuretic plus ACE inhibitor prevented disease progression in patients with severe lesion load at baseline.80 These studies support a positive effect of blood pressure lowering. Any concerns that blood pressure lowering may exacerbate white matter ischaemia in the presence of impaired auto-regulation have up to now not been confirmed.

Stroke prevention

Not only is leukoaraiosis associated with an increased risk of stroke, but a history of previous stroke is associated with a higher prevalence of leukoaraiosis.31 36 42 57 68 This suggests that reducing stroke risk with standard secondary stroke prevention therapy may reduce the risk of developing white matter disease, and slow down disease progression. In addition to antihypertensive treatment, further agents used in secondary stroke prevention include antiplatelet drugs and statins. Both of these may have beneficial effects on the progression of leukoaraiosis over and above reducing stroke risk in general.82 Statins may reduce progression of white matter disease by improving endothelial dysfunction and cerebral vasomotor reactivity.82 However, only few clinical data currently support this theory, with only a post hoc analysis of one study finding a trend for statins to delay progression of leukoaraiosis in subjects with a high lesion load at baseline, but not in patients with less severe disease.83 Furthermore, the PROSPER study found no benefit of pravastatin on disease progression in elderly patients at high risk of vascular events.81

Several studies have investigated the potential benefits of antiplatelet drugs on white matter disease.79 Acetylsalicylic acid (aspirin) inhibits cyclo-oxygenase, which produces superoxide radicals within vascular endothelial cells. Cyclo-oxygenase inhibition may reduce endothelial damage, which forms part of the pathological process leading to leukoaraiosis. In addition, acetylsalicylic acid also inhibits matrix metalloproteinase activity which may be responsible for ongoing white matter injury.79 Dipyridamole is another antiplatelet agent used in stroke prevention. In addition to its antiplatelet activity, it also has a vasodilatory effect and may reduce the progression of white matter disease by lowering blood pressure.84 However, there are currently no trial data showing that antiplatelet agents reduce disease progression or improve outcome in patients with white matter disease.

Thrombolysis and anticoagulation in leukoaraiosis

Several studies have shown that leukoaraiosis increases the risk of cerebral haemorrhage, in particular if cerebral microbleeds are also present.85 86 This includes the risk of spontaneous intracerebral haemorrhage as well as an increased risk for interventions which may cause haemorrhagic complications. Specifically, thrombolysis for acute ischaemic stroke carries a higher risk of causing haemorrhage in patients with leukoaraiosis.87 88 However, it should not be withheld, as its overall benefit does not appear to be reduced.87 Other studies indicate a higher haemorrhage risk from anticoagulation in patients with white matter disease,89 90 although it is still uncertain if this applies to all clinical contexts. Nevertheless, given that these patients may also be at higher risk of falls and have cognitive problems, the decision to anticoagulate should have a clear indication, anticoagulation should be closely supervised and overanticoagulation should be avoided.

Conclusion

With the availability of improved brain imaging techniques, the high prevalence and clinical relevance of cerebral small vessel disease have been increasingly recognised in recent years. As age is one of the most important risk factors for this condition, and with populations getting older, the prevalence of white matter disease and consequently, the prevalence of dementia, poor mobility and stroke are set to rise. Given the impact this will have on individuals and on healthcare systems, knowledge of the risk factors for small vessel disease, its prevention and its treatment is becoming more important. At present, the only uncontested modifiable risk factor for white matter disease is hypertension, while the relevance of other risk factors is less clear. Aggressive blood pressure management is therefore the only treatment option for white matter disease that we have currently available. However, this is predominantly directed at preventing lesion development and disease progression as leukoaraiosis cannot regress once it is established. Future studies should be directed at identifying further potentially treatable risk factors for leukoaraiosis, and at further defining and influencing the underlying disease process.

Main messages

  • The terms leukoaraiosis, cerebral white matter disease and cerebral small vessel disease are often used synonymously. They refer to the presence of white matter lesions in the brain, which are caused by chronic small vessel ischaemia, blood–brain barrier dysfunction or, most likely, a combination of these two factors.

  • White matter disease increases the risk of dementia, poor mobility, stroke and death. Its prevalence is set to increase as populations age, with potentially a large impact on healthcare systems.

  • MRI is more sensitive than CT in the detection of white matter lesions, and gradient echo or susceptibility weighted sequences help to identify microhaemorrhages which cannot be seen on CT. While visual rating scales to assess the severity of leukoaraiosis are used in studies, as yet there is no clinically established method to assess the severity of white matter disease.

  • Hypertension is the only definite modifiable risk factor for leukoaraiosis that has been identified so far. Aggressive blood pressure management therefore currently appears to be the only way to prevent the onset and progression of leukoaraiosis and its complications.

Current research questions

  • Risk factors

    • Identification of genetic factors which predispose to the development of leukoaraiosis

    • Identification of further extrinsic and potentially modifiable risk factors

  • Imaging

    • Use of new imaging strategies, for example diffusion-tensor imaging (DTI) or blood–brain barrier imaging to assess the development and progression of white matter disease

  • Management

    • Further study of the association of white matter disease with cognitive decline and the specific features of vascular cognitive impairment

    • Identification of appropriate outcome measures, for example progression on imaging or cognitive assessment scores, for treatment trials of white matter disease

    • Effect of risk factor modification and treatment on disease progression, both on imaging and on clinical outcomes, such as cognition and mobility

Key references

  • Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis: a review. Stroke 1997;28:652–9.

  • Grinberg LT, Thal DR. Vascular pathology in the aged human brain. Acta Neuropathol 2010;119:277–90.

  • O'Sullivan M. Leukoaraiosis. Pract Neurol 2008;8:26–38.

  • van Dijk EJ, Prins ND, Vrooman HA, et al. Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study. Stroke 2008;39:2712–19.

  • Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 2010;341:c3666.

Self-assessment questions (True (T)/False (F); Answers after the references)

1. Cerebral white matter disease

  1. Shows a strong, direct association with ischaemic heart disease

  2. Its pathophysiology is characterised by protein deposits in the small penetrating arteries of the brain

  3. Endothelial dysfunction is an important pathogenetic factor

  4. Is more common in Caucasian than Afro-Caribbean populations

2. Presence of leukoaraiosis

  1. Is detected more easily with MRI than with CT

  2. CT is the most sensitive method to detect cerebral microbleeds

  3. Decreases over time, if the appropriate treatment is given

  4. Is associated with an increased risk of cerebral ischaemic events

3. Risk factors for small vessel disease

  1. Are the same as those for large vessel atherosclerosis

  2. Increasing age is associated with a decreased risk of developing small vessel disease

  3. Hypercholesterolaemia is an important contributor

  4. Are not genetically determined

4. Severe leukoaraiosis is

  1. Associated with cognitive impairment

  2. Strongly associated with a history of diabetes mellitus

  3. Is prevented by giving high-dose vitamin B12

  4. More likely to progress than mild disease

5. Antihypertensive treatment

  1. Should routinely be given with anti-platelet agents and statins in the prevention of leukoaraiosis

  2. May also help to prevent leukoaraiosis in normotensive people

  3. Only stops progression of leukoaraiosis if β-blockers are used

  4. Causes regression of white matter lesions

Acknowledgments

We would like to thank Professor Margaret Esiri from the Department of Neuropathology, University of Oxford for providing the pathological image in figure 1.

Answers

  1. A (F); B (T); C (T); D (F)

  2. A (T); B (F); C (F); D (T)

  3. A (F); B (F); C (F); D (F)

  4. A (T); B (F); C (F); D (T)

  5. A (F); B (T); C (F); D (F)

References

View Abstract

Footnotes

  • Funding Dr UG Schulz is funded by an NIHR Clinician Scientist Fellowship.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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