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(Stroke. 1996;27:1269-1273.)
© 1996 American Heart Association, Inc.

Articles

From UBOs to Binswanger's Disease

Impact of Magnetic Resonance Imaging on Vascular Dementia Research

Gustavo C. Roman, MD, FACP

the Division of Neurology, University of Texas at San Antonio.

Correspondence to Gustavo C. Roman, MD, 343 W Houston St, Suite 208, San Antonio, TX 78205.

Key Words: Binswanger's disease • dementia • lacunar infarction • leukoencephalopathy • magnetic resonance imaging • small-vessel disease

	Introduction

Top Introduction Significance of White Matter... Role of Age and... Senile Dementia of the... Conclusions References

 
This issue of Stroke publishes the results of arguably the largest population-based MRI brain study on record: 3301 elderly participants in the Cardiovascular Health Study (CHS).¹ In these times of budget reduction, the CHS may become—along with the Framingham study—a lasting monument to the scientific and public health benefits of the type of mega-scale epidemiological studies that only federally funded research can achieve.

The CHS provides a true random representation of the elderly US population, including African Americans. Because of its large sample size (5588 subjects), extensive baseline and follow-up evaluations, high rate of MRI studies (59%), and methodological carefulness, this study conclusively settles important issues regarding white matter changes in the elderly. The strong association of these lesions with advancing age and hypertension was confirmed. Also associated were silent strokes (in particular lacunes, observed in a third of the population), orthostatic hypotension, smoking history and its marker lower forced expiratory volume in 1 second (FEV₁), and, somewhat unexpectedly, lower income—a probable surrogate for limited access to medical care, inadequate diet, and poor long-term blood pressure control. In contrast, diabetes, carotid artery disease, and fibrinogen values were not associated. In this analysis, white matter lesions in the elderly behaved as a continuous variable, following a continuum of lesions ranging from those barely detectable (grade 1) to extensive and confluent lesions (grade 9). Last, higher-grade lesions were clinically eloquent, as manifested by cognitive impairment and alterations of gait.

	Significance of White Matter Lesions in the Elderly

Top Introduction Significance of White Matter... Role of Age and... Senile Dementia of the... Conclusions References

 
Brain imaging by CT and MR rediscovered long-forgotten pathologies of the senile brain. These lesions include Dechambre's (1838) lacunes^{2 3} ; Durand-Fardel's (1842, 1894) etat crible^{4 5} (cribriform or sieve-like state) and atrophie interstitielle du cerveau^{6 7} (brain interstitial atrophy); Pierre Marie's⁸ (1901) etat lacunaire,^{9 10} a condition previously called by Alzheimer (1894) Die arteriosklerotische Atrophie des Gehirns or cystose Degeneration¹¹ (arteriosclerotic atrophy or cystic degeneration of the brain); and last but not least, Binswanger's (1894) encephalitis subcorticalis chronica progressiva,¹² also called subcortical arteriosclerotic (ischemic) encephalopathy.^{13 14 15 16}

The high sensitivity of the MRI to proton changes in the brain and the lack of specificity of the neuropathologic lesions in the white matter have resulted in less-than-perfect correlations between MR images and clinicopathological manifestations, hence the name "unidentified bright objects" (UBOs) used earlier for the numerous images detected by MRI in the elderly brain. A sense of discouragement in the face of this situation permeates even the most recent review on this topic.¹⁷ Nonetheless, significant progress has been achieved in identifying the nature of the common hyperintense MRI lesions in the elderly¹⁸ after obvious causes are excluded, such as inflammation, edema, metastases, stroke, and trauma as well as white matter diseases of adult and elderly patients—including multiple sclerosis, gliomatosis cerebri, AIDS encephalopathy, progressive multifocal leukoencephalopathy, Pick's disease, radiation and chemotherapy sequelae, central pontine myelinolysis, toxic and metabolic disorders, leukodystrophies and leukoencephalopathies, and others that may be identified by size, location, and the judicious use of T₁, T₂, and proton-density images including gadolinium enhancement.

Etat Crible
Most punctuate (1 to 2 mm), bilateral, white matter hyperintensities seen on MRI in the elderly probably correspond to etat crible, a dilatation of Virchow-Robin perivascular space resulting from spiraled elongation of penetrating arteries and arterioles in white matter and gray nuclei.^{19 20} Blood vessels in etat crible are thickened, ectatic, and have sclerotic walls; the perivascular tissues show reactive astrocytosis and isomorphic gliosis with glial fibers extending along degenerated axons. There is perivascular leakage of serum proteins.²¹ Increased MRI signal intensity probably results from the combination of dilated, fluid-filled perivascular spaces and astrocytic gliosis.^{18 19 20}

Etat Lacunaire
Lacunes, small cavitary lesions that result from ischemic strokes due to occlusion of penetrating cerebral arterioles, are also a common cause of multiple, punctuate-to-round, hyperintense lesions of the brain parenchyma seen on long repetition-time sequences.^{19 20 22} Lacunes predominate in basal ganglia, internal capsule, pons, thalamus, and centrum ovale.^{8 9 10 23} Fresh lacunes show liquefaction necrosis, followed by reabsorption of necrotic material by fatty macrophages. The chronic stage is an irregular cavity whose walls show dense fibrillary connective tissue and gliosis. Reabsorption of minute hemorrhages may also result in lacunes,^{10 24} leaving hemosiderin-filled macrophages in the walls and the vicinity. Rarely, lacunes may represent localized and excessive dilatation of the perivascular space.^{24 25} Less commonly, telangiectases, small hemangiomas or vascular malformations, and congenital ventricular diverticula have similar MRI appearances.²²

Binswanger's Disease
The nature of larger areas of T₂-weighted hyperintensity in the periventricular white matter of the elderly brain has been controversial. However, most studies agree that these are zones of chronic white matter ischemia due to microvascular disease, typically sparing the short, arcuate subcortical fibers in a pattern that has become associated with Binswanger's disease.^{16 18 22 26 27} Among others, neuropathologists Arne Brun, Elisabet Englund, and colleagues^{15 16 28 29 30 31 32} at the University of Lund, Sweden, performed a number of careful correlative studies on the histopathology of this white matter change and its biochemical and proton MR alterations, demonstrating that these lesions are basically areas of incomplete white matter infarction ("incomplete" in the sense that complete necrosis and cavitation are not present). These lesions are neuropathologically similar to the less severely damaged area surrounding an ischemic infarction, ie, the transitional zone between a complete brain infarct and the normal tissue.

Histopathologically, these white matter lesions consist of partial loss of myelin sheaths and oligodendroglial cells and axons, producing a decrease of the meshwork density of the white matter tissue, along with mild reactive fibrillary gliosis and presence of sparse macrophages. Biochemical tissue analysis failed to disclose evidence of edema or primary myelin abnormalities,³⁰ and there was no morphological evidence of Wallerian degeneration.³² Arteriolosclerosis was constantly present in these areas of incomplete infarction, and there was severe stenosis of the smallest vessels by nonamyloid fibrohyaline material.^{19 22 26 27 28 29 30 31 32}

Contributing to the confusion created by the high frequency of these lesions in the MRI of elderly subjects is the fact that from the neuropathologic viewpoint the lesions are identical regardless of the sampled material. The transitional area of an ischemic stroke, the periventricular white matter lesions of an otherwise normal elderly brain, the white matter of full-blown Binswanger's disease, or the deep white matter lesions from 60% of patients with Alzheimer's disease who, in addition to the typical cortical lesions, also present arteriolosclerosis: all of these lesions are characterized by incomplete white matter infarction.^{16 26 27 28 29 30 31 32}

Using MRI examination of the brain in consecutive autopsies of elderly patients, van Swieten and colleagues³³ from Utrecht, the Netherlands, also confirmed the ischemic nature of the periventricular white matter lesions in the elderly. In most brains, etat crible, ischemic demyelination, and arteriolosclerosis coexisted. There was excellent morphometric correlation between the presence and severity of the white matter lesions and the degree of arteriolosclerosis, measured as the ratio of wall thickness to external vessel diameter of white matter arterioles up to 150 µm in diameter from frontal and parietal sections. van Swieten et al concluded that arteriolosclerosis is the primary factor in the pathogenesis of the Binswanger-type diffuse periventricular white matter lesions in the elderly, most likely produced by chronic ischemia.

	Role of Age and Hypertension

Top Introduction Significance of White Matter... Role of Age and... Senile Dementia of the... Conclusions References

 
What is the role of aging and hypertension—the two most important risk factors for white matter changes in the elderly—in the pathogenesis of these lesions?

Hypertensive Arteriopathy
The microangiopathy associated with arterial hypertension has been well studied, particularly in the context of lacunar strokes.^{34 35 36} Microatheromata, lipohyalinosis, and fibrinoid necrosis characterize the arteriopathy of hypertension. Minute foci of microatheromata as small as 100 to 400 µm in diameter producing stenosis or occlusion of penetrating arteries are common in patients with advanced hypertension.³⁶ Lipohyalinosis is characterized by progressive disorganization of the normal architecture of small-artery walls, usually those less than 200 µm in diameter, with subintimal deposits of a hyaline fibrinoid substance. Lipohyalinosis leads to either thrombotic occlusion of the lumen or progressive mural destruction with formation of microaneurysms.³⁴ Fibrinoid angionecrosis is the result of extremely high blood pressure on arterioles and capillaries of the brain, retina, and kidney, producing segmental narrowing, dilatation, and necrosis of the vessel with presence of a brightly eosinophilic deposit involving the connective tissue.^{34 35} Around the constricted and spastic vessels, the perivascular tissue and the neuropil are destroyed by the severe vasoconstriction; perivascular astrocytic edema may also be present.³⁷

Senile Arteriolar Tortuosity
Relatively few studies have been devoted to the effects of advancing age on cerebral vessels,^{38 39 40 41} and even fewer have used novel techniques such as scanning electron microscopy of microvascular casts.^{42 43} Quantitative changes produced by aging include a reduction of capillary density in cortical areas^{44 45} and a progressive intimal cellular thickening of intracranial cerebral arteries.⁴¹ The alkaline phosphatase histochemical technique devised by Bell⁴⁶ has contributed significantly to the study of the cerebral microvasculature in aging and hypertension. This technique^{46 47} discriminates between small arteries, arterioles, and veins and also allows the use of microradiography on thick sections because of the black precipitate of lead sulfide formed in the reaction. In a series of studies using Bell's technique, neuroradiologist Dixon M. Moody and colleagues^{48 49 50 51} from the Bowman Gray School of Medicine in Winston-Salem, NC, have shown that the most striking vascular change in the elderly is the lengthening of the vessels, resulting in twists and coils collectively known as tortuosity.

Tortuosity is particularly prominent in the long penetrating vessels supplying the deep white matter. Using computer modeling, Moody et al⁵⁰ suggested that the increase in length resulting from tortuosity raises the threshold of minimum blood pressure required for perfusion of the periventricular white matter situated at the distal end of these vessels. Therefore, even normotensive levels of blood pressure in the elderly may result in hypoperfusion of the deep white matter. The well-known absence of "downward autoregulation" in hypertensive patients, which is usually considered to be due to arteriolosclerosis, may in fact result from this mechanism. The association of orthostatic hypotension and white matter lesions found by the CHS study¹ further corroborates the importance of these seldom-mentioned morphological alterations in the genesis of deep white matter lesions.

Senile Arteriolosclerosis
In addition to lengthening and tortuosity, the medullary arteries of elderly patients with ischemic white matter changes also suffer a reduction of the lumen due to sclerotic changes.⁵² On light microscopy, the normal architecture is replaced by a concentric lamellar arrangement of collagen fibers with deposition of a fibrohyaline substance, mainly in the subadventitia, with minimal changes in the media and the intima. Stenosis due to these arteriolar changes is most commonly seen in the distal periventricular white matter vessels. Electron microscopy shows proliferation of collagen fibers, accumulation of cell debris, and deposition of amorphous material in the subadventitia; amyloid is not present and angionecrosis is seldom seen.⁵² This sclerotic change begins late in the fourth decade and increases in frequency and degree with age, being more prominent in the frontal lobe, followed by the parietal, occipital, and temporal lobes.⁵² The further the lumen is stenosed by arteriolosclerosis, the more severe the white matter lesions become.^{33 52 53 54} The extreme illustration of the latter is Binswanger's disease, in which only the short arcuate fibers in the subcortical white matter are spared because they are irrigated by short penetrating cortical arteries.^{14 48 49}

The true nature of this form of arteriolosclerosis of penetrating medullary arteries is unknown. Hypertension appears to be capable of worsening these sclerotic lesions, but this change also occurs in normotensive elderly subjects. It should be noted that similar arteriolar lesions—unrelated to amyloid angiopathy—may occur in Alzheimer's disease as well as in CADASIL, the chromosome 19–linked form of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.⁵⁵ In CADASIL, the vessel walls are thickened and contain a granular electron-dense eosinophilic material different from amyloid but not yet characterized.⁵⁶

	Senile Dementia of the Binswanger Type

Top Introduction Significance of White Matter... Role of Age and... Senile Dementia of the... Conclusions References

 
In a review article almost a decade ago,¹⁴ I called the attention of the medical community to the growing number of patients presenting with Binswanger's disease, a subcortical form of microangiopathic vascular dementia clinically different from Alzheimer's disease that is characterized by progressive dementia with focal deficits, frontal signs, pseudobulbar palsy, gait difficulties, and urinary incontinence. However, my interest in Binswanger's disease goes further back. In 1975, as a visiting fellow in neurology at the Salpetriere Hospital in Paris under Professors J.-C. Gautier and the late R. Escourolle, I reviewed the clinical and neuropathologic records, including whole-brain celloidin sections, of 100 consecutive patients with lacunes.⁵⁷ The vast majority of lacunar strokes were asymptomatic, and the dementia that occurred in a minority of cases of etat lacunaire was unrelated to the number or situation of the lacunes.¹⁰ Eight patients with lacunes and dementia were eventually diagnosed as having Binswanger's leukoencephalopathy.⁵⁸ Later progress in brain imaging brought to the fore the importance of white matter lesions as a cause of cortical disconnection leading to vascular dementia. I concluded that lacunar dementia and dementia of the Binswanger type appeared to be the same condition.⁵⁹

Despite controversy on the eponym,¹⁷ it is now abundantly clear that senile dementia of the Binswanger type is a well-defined condition.^{14 15 16 53 54 58 59 60 61 62 63 64 65 66 67 68 69} In a recent review, Caplan's⁶⁹ criteria for the pathological, clinical, and neuroimaging diagnosis of Binswanger's disease were elegantly presented, along with practical recommendations for the clinical investigation and management of these patients.

Necropsy-proven cases of Binswanger's disease are not exceptional; even in the days before brain imaging, a frequency of about 5 cases per 100 geriatric autopsies was reported in Japan.⁷⁰ Binswanger's disease is also seen in other parts of the world: 8 cases in 10 years at the neuropathology service of the Salpetriere Hospital in Paris⁵⁸ ; 21 patients from the in-patient services of the National Hospital for Nervous Diseases, Queen Square, London⁷¹ ; 7 autopsy cases in 6 years from the Institute of Psychiatry, London⁷² ; 14 neuropathology cases from 1980 through 1987 at the University Hospital in Lund, Sweden^{15 16} ; 11 cases with 5 confirmed by pathology at Harvard University Hospitals in Boston, Mass⁷³ ; and 45 neuropathologically proven cases among autopsies of 1000 elderly persons at the Tokyo Metropolitan Geriatric Hospital, Japan.⁷⁰

The main reason for the dearth of confirmed diagnoses of Binswanger's disease is the lack of appropriate neuropathologic methodology.^{16 74} These white matter lesions are almost invisible on naked-eye examination of formalin-fixed brain sections; therefore, not surprisingly, the diagnosis is easily made at institutions that use whole-brain celloidin embedding methods for myelin stain.⁷⁵ Binswanger's-type lesions will continue to be invisible with the routine brain sampling techniques used in most neuropathology laboratories.

According to Caplan,⁶⁹ "Most neurologists now know what you are talking about when you say `Binswanger's disease.' " However, determining the true prevalence of any condition requires widespread knowledge of the disease among physicians. For instance, it is hard to believe that until the 1960s, Alzheimer's disease was considered a very rare disease. In 1959, Merritt's⁷⁶ Textbook of Neurology stated:

Both Pick's disease and Alzheimer's disease are rare. Rothschild and Kasanin found 9 cases of Alzheimer's disease in a series of 234 consecutive autopsies in a hospital for mental patients in the United States. McMenemey reported the incidence of 1.2 percent of Alzheimer's disease in 487 autopsies in a mental hospital in England. Sjogren, Sjogren and Lindgren collected 80 cases from mental hospitals in Stockholm with autopsy proof in 36 of the cases, equally divided between Pick's and Alzheimer's disease.

In contrast, 30 years later, the eighth edition of the same book⁷⁷ concluded:

One of the most common degenerative diseases of the brain is named after Alois Alzheimer, who described the major pathologic changes. . . there may be as many as 700,000 individuals severely incapacitated in the United States today and as many as 1.6 million with an earlier or milder form of this disorder.

	Conclusions

Top Introduction Significance of White Matter... Role of Age and... Senile Dementia of the... Conclusions References

 
The very elderly are particularly prone to Binswanger's disease, and aging of the population may be responsible for the recent increase in this diagnosis.⁷⁸ Vascular dementia is the most common form of dementia in people 85 years old and older,⁷⁹ probably because of the presence of Binswanger's-type lesions alone or in combination with Alzheimer's disease. The leukoencephalopathy of Binswanger's disease appears to be due to chronic ischemia in the terminal zones of the medullary arteries, determined by anatomic factors, variations in perfusion pressure, and probably by hemorrheologic factors.^{69 80} More controversial is the role of alterations of the blood-brain barrier linked to hypertensive episodes with chronic vasogenic edema. Recently, ventricular dilatation from Binswanger's-type lesions leading to normal pressure hydrocephalus has been noted,^{67 81 82} as well as the possible causal contribution of periventricular venous collagenosis.⁸³

Briefly, the CHS study¹ confirmed correlations previously noted in smaller population-based MRI studies,^{84 85} indicating that white matter lesions are common in the hypertensive elderly patient with known vascular risk factors and that high-grade lesions are manifested by cognitive decline and gait problems (perhaps as an early manifestation of Binswanger's disease). Remaining unanswered questions include the true significance of MR images considered benign, such as "dots, rims, and caps," the validity of other grading systems (simpler to use in a clinical setting), and the long-term prognosis of these lesions. For instance, progression to high-grade lesions may constitute a simple and useful marker of increased risk for cognitive impairment from a vascular cause. Follow-up studies of the CHS cohort should define the outcome of patients with these lesions and identify other risk factors that could be treated opportunely to prevent the development of vascular dementia.

	Acknowledgments

 
This editorial is dedicated to Thomas K. Tatemichi, MD, in memoriam. The author is grateful to Dr Ernesto Blanco for his careful manuscript review.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

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Top Introduction Significance of White Matter... Role of Age and... Senile Dementia of the... Conclusions References

 

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