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September 01, 1998; 51 (3 Suppl 3) Articles

Leukoaraiosis and vascular dementia

Jan van Gijn
First published September 1, 1998, DOI: https://doi.org/10.1212/WNL.51.3_Suppl_3.S3
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Abstract

The emergence of sensitive techniques for brain imaging has drawn attention to the occurrence of diffuse or multifocal changes affecting the cerebral white matter. The white matter changes are usually termed periventricular leukoencephalopathy, or leukoaraiosis. Microscopic studies of affected areas in the deep white matter have shown mostly demyelination, reactive gliosis, and arteriolosclerosis, proportional to the degree of radiologic changes. Yet, many other disease conditions need to be ruled out. Risk factors for ischemic leukoaraiosis include arterial hypertension, a history of stroke, and age. In the hereditary disorder CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), severe white matter changes occur in the absence of hypertension. In "ordinary" cases of leukoaraiosis, genetic factors might similarly determine the effect of risk factors on the aging brain and might explain, for example, why not all patients with severe hypertension develop leukoaraiosis. Not surprisingly, diffuse demyelination affects cognitive function. Although reduced speed of mental processes is the most characteristic sign, attention, concentration, and verbal and visual memory are also affected. Most importantly, less severe forms of cognitive impairment represent a silent and perhaps largely preventable epidemic among aged or even middle-aged subjects. They live independently, but mentally they perform on a level well below their previous capacities. Although being "a bit odd" does not lead to hospital admissions, it seriously affects quality of life of a large part of the community. Moderate grades of leukoaraiosis constitute a major public health problem and deserve the attention of the scientific community.

Leukoaraiosis originated as a radiologic notion (decreased radiodensity of cerebral white matter on CT scans, especially in the elderly).1 A common assumption is that the underlying pathologic process is ischemic demyelination and that other diseases should therefore have been excluded. With the advent of magnetic resonance imaging(MRI), the same reasoning can be applied to hyperintense lesions of the white matter, but with the difference that MRI has greater sensitivity. A plethora of studies has shown a correlation between the presence and extent of these lesions and cognitive impairment, ranging from mild slowness of thinking to full-blown subcortical dementia.2,3 Even geniuses may be affected.4

With this concept of mental impairment or even dementia resulting from chronic ischemia, neurologic semeiology has come almost full circle. In this century, at least until the 1960s, gradual deterioration of cognitive function in the aged was often attributed to arteriosclerosis (Netter's textbook on the nervous system has a drawing of a shriveled brain with fattened arteries).5 Then the pendulum swung toward the assumption that primary degenerative disease of the Alzheimer type was responsible for all instances of gradual slowing of intellect and loss of memory. According to this line of thinking, vascular causes of dementia could be inferred only through the summation of consecutive strokes, large or small(multi-infarct dementia).6 Only after increasingly sensitive neuroimaging techniques became available did the concept evolve that ischemia could actually affect mentation insidiously, without overt episodes of stroke. The differences from the older theories are that the disease process involves the white matter instead of the gray matter and that the underlying process of atherosclerosis affects not the most proximal but rather the most distal parts of the cerebral arterial tree (i.e., the arterioles).

However, before being found guilty of still another untenable simplification, I should like to point out three important qualifications.(a) Not all cases of vascular dementia are caused by diffuse changes of white matter. (b) Not all instances of mental impairment associated with chronic, progressive demyelination are caused by ischemia. (c) Not all cases of cerebral small-vessel disease with chronic demyelination are caused by hypertensive arteriolosclerosis.

Vascular dementia is not always a white matter disease. Not only multiple infarcts but also single, strategically located infarcts may cause dementia. Such instances have been recorded with infarcts in the genu of internal capsule,7,8 the thalamus,9,10 caudate nucleus,11,12 and angular gyrus.13 Because similar infarcts in other patients only rarely have caused dementia, the question is, which other factors should be invoked to explain the sudden deterioration of cognitive function? Other than idiosyncratic "wiring" of a patient's brain, the contributing factor may be a coexisting-but previously subclinical-diffuse disorder of the brain such as Alzheimer's disease (AD).14

Of course, diffuse ischemia of the brain may also result from systemic hypotension or hypoxia, most often secondary to circulatory arrest.

White matter changes are not always ischemic. Vascular dementia cannot be diagnosed on the basis of a scan. Other diseases can also lead to multifocal or diffuse demyelination in the deep regions of the brain, sometimes in patterns indistinguishable from ischemic lesions. Thetable lists the most important causes of demyelination that should be considered in the differential diagnosis.

View this table:

Table Conditions other than small-vessel disease that may cause multifocal or diffuse demyelination of the brain in adults

Alzheimer's disease. Changes in the deep white matter of the brain occur in 25 to 60% of patients with AD, according to different reports.15,16 Women may be preferentially affected.17 Even though this phenomenon is not found in the early stages of AD,18,19 it cannot be explained away simply by coexisting vascular disease or by wallerian degeneration secondary to loss of cortical neurons. In series of patients with AD, vascular risk factors did not sufficiently account for the association.16,20 Blood flow was less impaired than in lesions of similar severity in patients with vascular dementia.21,22 Moreover, in pathologic specimens, the arteriolopathy is rarely of the "hypertensive" type but consists of nonspecific hyaline thickening.23,24 Amyloid (congophilic) angiopathy can also be found, but in cortical rather than subcortical vessels.23,25-27 Finally, extravasation of serum proteins occurs in diseased white matter with vascular determinants but not with AD.28

If wallerian degeneration were the underlying cause of white matter changes in AD, the severity of the changes in each brain region could be expected to correspond with the density of cortical changes typical of AD(neurofibrillary tangles and amyloid plaques), but such a relationship was confirmed only partially in some studies of autopsy specimens26 and not at all in others.15,29 Not surprisingly, patients with AD and white matter changes exhibit more severe degrees of cognitive impairment that those without.17,30,31

To epitomize, it is by no means certain that the white matter changes in AD can be explained even by the combined effect of wallerian degeneration and coexistent vascular disease in its usual sense. Given that AD is more common than vascular dementia, even if allowance is made for differences in criteria,32,33 and that diffuse abnormalities of the white matter occur in 25 to 60% of patients, this implies that vascular dementia in the sense of diffuse leukoencephalopathy cannot be diagnosed on the basis or radiologic criteria (by present standards). First of all, the diagnosis needs to be supported by the clinical characteristics of subcortical dementia: slowness of mental processing, apathy, and loss of emotional modulation.34

Gliosis and widening of perivascular spaces. Some changes in the white matter visible on MRI scans do not even represent demyelination. Hyperintense changes adjacent to the wall of the cerebral ventricles (caps and rims) correspond to gliosis rather than to demyelination on microscopic study35 and are probably secondary to leakage through an aging ependymal wall.36,37 Similarly, widening of perivascular spaces may produce hyperintensity on T2-weighted images, but these lesions are typically punctate and should not be confused with demyelination.38-40 Dementia in such cases is exceptional and occurs only with widespread dilatation of perivascular spaces.41

Arteriolopathy associated with demyelination is not always hypertensive. A number of diseases are characterized by arteriolopathy and demyelination elination of the cerebral white matter, but with morphologic changes in the vessel wall distinct from the degenerative type of concentric hyaline wall thickening considered typical of chronic hypertension or diabetes mellitus.

Cerebral amyloid angiopathy is the most common alternative cause of demyelination of the brain. The amyloid material in the subcortical arterioles can be identified with Congo red staining and by birefringence under polarized light. Although small clusters of familial amyloid angiopathy have been found in The Netherlands and in Iceland,42,43 in the vast majority of cases the condition occurs sporadically. The vulnerability of the arteriolar wall facilitates the development of intracerebral hemorrhages, which often recur at different sites in the brain.44,45 Transient ischemic attacks (TIAs) and mild cognitive deterioration often precede the first hemorrhage,46 but the diagnosis is rarely made at that stage. Patients may even be misclassified as having AD.47

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a newly recognized hereditary disorder of cerebral arterioles, which has been mapped to chromosome 19q12 (mutation of Notch3 gene).48 Apart from the conditions named in the acronym, other conditions are also associated with the disorder, including TIAs, mood changes, dementia, migraine, and epileptic seizures.49 The changes in the arterial wall are distinct, consisting of granular, eosinophilic material. Arterioles of skin, muscle, and nerve may be similarly affected.50

Other variations of cerebral arteriopathy and leukoencephalopathy include sporadic cases with multilaminar vascular basement membranes, swelling of astrocytic foot processes, and perivascular collagen packing.51

The archetypal form of arteriolopathy associated with demyelination consists of hyaline thickening, collagenous deposits in the media and adventitia, and splitting of the elastic lamina, with negative stains for amyloid or eosinophilic material.52-55 The white matter changes may also affect the pons;56 subcortical U-fibers are typically spared. On biochemical analysis, the areas of demyelinated brain tissue exhibit extravasation of serum albumin and immunoglobulins,28,57-59 and on MR spectroscopy, an increase in choline-containing metabolites and a decreased signal corresponding to (axonal) N-acetylaspartate are observed.60-62 Not surprisingly, functional studies using xenon contrast, positron emission tomography, or single photon emission computed tomography confirm decreased blood flow and hypometabolism in subcortical regions.63-65

Determinants and prognostic implications of "hypertensive" periventricular leukoencephalopathy. Interestingly, the typically hypertensive changes of concentric hyaline wall thickening can occasionally be found in patients who are not elderly or diabetic and are normotensive.66 Conversely, not all elderly patients with severe hypertension develop white matter changes.67 These points suggest that factors other than age and hypertension are probably involved in the development of "hypertensive" arteriolopathy. In case-control studies and in cross-sectional studies of the general population, determinants included, first of all, the classic vascular risk factors according to history (hypertension, cigarette smoking, a history of stroke or heart disease, and diabetes mellitus) or examination (ankle-arm index, carotid plaques, and intimal-medial thickness on ultrasonography).68-71 However, these known vascular risk factors may explain only part of the problem.72 Fibrinogen has been identified as an additional risk factor in two independent studies.73,74 Determinants implicated in single studies, without confirmation to date, are serum levels of coagulation factor VIIc,73 levels of vitamin E,74 and forced expiratory volume in 1 s.75 Data regarding associations between apolipoprotein E polymorphisms and white matter changes are conflicting.76,77

Ischemic demyelination of white matter has prognostic implications in that it confers an increased risk of stroke and vascular death, not only in patients with TIAs or nondisabling ischemic stroke78,79 but also in the general population.80 In addition, a clinical trial of anticoagulant treatment for secondary prevention of vascular disease in patients with TIAs or nondisabling stroke found that the risk of intracerebral hemorrhage was increased sevenfold in patients whose baseline CT scan showed leukoaraiosis.81

Cognitive correlates of periventricular leukoencephalopathy. Dementia is the end stage of the cognitive changes that may result from diffuse arteriolar thickening, corresponding with complete rarefaction of the cerebral white matter (except the U-fibers).82-86 This so-called subacute arteriosclerotic encephalopathy probably represents the same condition that Binswanger described in 1894,87 but we cannot be certain of this because his original description did not include microscopic studies.88,89 To reiterate, strokes from large-artery occlusions do not necessarily accompany the development of vascular dementia.86

Even more important, virtually every study to date that has addressed the question has shown that subjects with periventricular leukoencephalopathy have some degree of cognitive impairment compared with controls matched for age and education. This applies to the elderly in the general population,73 to elderly volunteers,72,90,91 and to patients with hypertension.67,92 The degree of cognitive impairment is proportional to the degree of white matter changes,93 although the quantification of these changes is far from uniform.94,95 The nature of the cognitive impairment affects a wide range of functions and is typical of subcortical dementia: decreased speed of thinking, executive control, and recall. Longitudinal studies of any kind are still scarce, but provisional reports confirm the progressive nature of the disorder.96,97

The challenge for the future. Leukoaraiosis is a major challenge in health care because some degree of white matter change occurs in approximately one-quarter of subjects aged 65 or over in the general population.73 Even though full-blown dementia is rare, the elderly suffer a continuous and silent epidemic of insidious mental slowing and intellectual decline from ischemia, not so severe that an independent existence is endangered but often severe enough to drain much of the color from life. Apart from cognition, gait is also affected by ischemic leukoencephalopathy.

High blood pressure is neither a sufficient nor a necessary factor for the development of the hyaline arteriopathy that underlies the most common form of white matter change, with its accompanying mental deterioration, in the elderly. However, it is by far the most important factor and is eminently remediable. Hypertension causes insidious damage to small blood vessels, not only in the heart and kidneys but also in the brain. Dementia is not an all-or-nothing phenomenon: patients with ischemic damage of white matter are often considered normal in superficial contacts or perhaps a bit "old," whereas in truth they are mere shadows of their former selves. Hachinski98 has coined the term "dysmentia" to emphasize the fact that any degree of cognitive impairment decreases objective performance as well as subjective quality of life.

Very likely, aggressive treatment of hypertension and management of other risk factors (some of which probably remain to be discovered) will prevent not only strokes and heart attacks but also widespread, insidious decline of mental and physical abilities. To combat this silent epidemic, cooperative efforts are needed from neurologists, radiologists, pathologists, psychologists, and epidemiologists.

Acknowledgment

Dr. L.J. Kappelle provided helpful comments on an earlier version of this article.

Footnotes

  • Series editor: J. Donald Easton MD

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