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(Stroke. 1997;28:652-659.)
© 1997 American Heart Association, Inc.

Articles

Pathogenesis of Leukoaraiosis

A Review

Leonardo Pantoni, MD; Julio H. Garcia, MD

From the Department of Pathology (Neuropathology), Henry Ford Hospital, Detroit, Mich (L.P., J.H.G.); the Department of Neurological and Psychiatric Sciences, University of Florence (Italy) (L.P.); and the Department of Pathology (Neuropathology), Case Western Reserve University, Cleveland, Ohio (J.H.G.).

Correspondence to Julio H. Garcia, MD, Department of Pathology (Neuropathology), Henry Ford Hospital/K-6, 2799 W Grand Blvd, Detroit, MI 48202.

	Abstract

Top Abstract Introduction Pathogenesis of Leukoaraiosis:... Pathogenesis of Leukoaraiosis:... Conclusion Future Developments References

 
Background Changes in the cerebral hemispheric white matter, detectable with increasing frequency by modern neuroimaging methods, are associated with aging and conceivably may contribute to the development of specific cognitive deficits. The pathogenesis of these cerebral white matter abnormalities (sometimes described as leukoaraiosis) is unknown. This review evaluates the available evidence in support of the hypothesis that the etiology of leukoaraiosis is related to a specific type of cerebral ischemia and highlights mechanisms by which ischemic injury to the brain may induce selected structural alterations limited to the cerebral white matter.

Summary of Review The review is based on the critical analysis of over 100 publications (most appearing in the last decade) dealing with the anatomy and physiology of the arterial circulation to the cerebral white matter and with the pathogenesis of leukoaraiosis.

Conclusions A significant number of clues support the hypothesis that some types of leukoaraiosis may be the result of ischemic injury to the brain. Structural changes affecting the small intraparenchymal cerebral arteries and arterioles that are associated with aging and with stroke risk factors, altered cerebral blood flow autoregulation, and the conditions created by the unique arterial blood supply of the hemispheric white matter each seem to contribute to the development of leukoaraiosis. To the best of our ability to interpret current information, the type of ischemic injury that is most likely responsible for these white matter changes involves transient repeated events characterized by moderate drops in regional cerebral blood flow that induce an incomplete form of infarction. This hypothesis could be tested in appropriate experimental models.

Key Words: cerebral ischemia • small-vessel disease • leukoaraiosis • leukoencephalopathy • white matter

	Introduction

Top Abstract Introduction Pathogenesis of Leukoaraiosis:... Pathogenesis of Leukoaraiosis:... Conclusion Future Developments References

 
Abnormalities involving the cerebral WM, in particular the centrum ovale, are a subject of great current interest. Partly this is because modern neuroimaging methods detect subcortical WM changes with increasing frequency in persons older than 60 years¹ and also because these abnormalities may be associated with specific neurobehavioral deficits, including dementing syndromes.^{1 2 3 4 5} The descriptive term "leukoaraiosis,"⁶ frequently applied to these neuroimaging abnormalities of the WM, refers to bilateral and either patchy or diffuse areas of hypodensity on CT or hyperintensity on T2-weighted MRI. However, the lesions detected by these two techniques are not completely superimposable as to number, site, and extension. The pathogenesis of WM abnormalities detectable by each of these methods is different, especially because MR detects tiny WM alterations that are of doubtful significance. Because it is impractical to delve separately into the pathogenesis of each set of abnormalities, in this review we discuss CT- and MR-detectable changes jointly, and we emphasize only the more severe types of LA. The terminology used by various authors, the probable clinical significance, and some pathological correlates of these WM changes were recently reviewed.⁷ Here we analyze selected publications dealing with the presumed pathogenesis of LA. In particular, we reassess evidence suggesting an ischemic origin for LA. We also analyze an alternative but not mutually exclusive hypothesis that explains cerebral WM abnormalities on the basis of disturbances in the circulation of the CSF and changes in the permeability of the BBB to macromolecules. Understanding the pathogenesis of LA is essential before preventive measures and therapeutic interventions can be attempted.

	Pathogenesis of Leukoaraiosis: Possible Role of Ischemia

Top Abstract Introduction Pathogenesis of Leukoaraiosis:... Pathogenesis of Leukoaraiosis:... Conclusion Future Developments References

 
Clues suggesting an ischemic pathogenesis for LA derive from analysis of anatomic, physiopathologic, and clinicopathologic data. Recent observations on experimental models of ischemic injury lend support to this hypothesis.

Selective injury to the hemispheric WM has been noted in a limited number of human conditions characterized by hypoxia/ischemia to the brain.^{8 9} These leukoencephalopathies are associated with prolonged depression of oxygenation and impaired circulation, and in some instances the brain injury becomes clinically manifest after a latent period of several days.⁹ Carbon monoxide poisoning is a representative form of anoxic leukoencephalopathy (Grinker's myelinopathy), although in this condition, direct carbon monoxide toxicity could contribute to the brain lesion.¹⁰ The histological changes of the WM in cases of hypoxic/ischemic injury range from coagulative necrosis and cavitation⁹ to nonspecific tissue changes such as sponginess, patchy demyelination, and astrocytic proliferation.¹⁰ Such changes are comparable with the lesions observed in patients with LA.¹¹ We hypothesize that the nature and the extent of damage to the WM depends on the severity, expressed in terms of regional CBF values, and duration of ischemia. According to this hypothesis, the degree of ischemic injury in patients with LA would be sufficient to injure only selected WM constituents, such as oligodendrocytes and axons. The reasons why some ischemic injuries selectively affect the WM are unknown, but the unique pattern of blood supply to the WM could be both a predisposing and a localizing factor.

Blood Supply of the Cerebral White Matter
The cerebral hemispheric WM receives most of its blood supply through long penetrating arteries originating from the pial network located on the surface of the brain. These penetrating arteries arise at right angles from the subarachnoid vessels, run through the cortical layers perpendicular to the brain surface, and enter the WM along the course of myelinated fibers.¹² Each of these vessels measures from 20 to 50 mm in length depending on their tortuosity.¹³ At their origin, the average diameter of these carrying vessels or rami medullares is 100 to 200 µm; such caliber remains unchanged until each vessel ends at some distance from the walls of the lateral ventricles. Carrying vessels do not arborize but give off perpendicularly oriented short branches (distributing vessels) that irrigate the WM; each of the distributing vessels from a single penetrating artery provides the blood supply to a cylindrically shaped metabolic unit.¹⁴

A region of the WM immediately adjacent to the walls of the lateral ventricles receives its blood supply from ventriculofugal vessels arising from subependymal arteries; these branches originate either from the choroidal arteries or from terminal branches of the rami striati.¹⁴ These ventriculofugal vessels supplying portions of the basal ganglia, the internal capsule, and part of the thalamus arise from arteries situated at the base of the brain.¹⁵ The ventriculofugal vessels, measuring about 15 mm in length, run toward the penetrating centripetal vessels coming from the pial surface (carrying vessels or rami medullares). Anastomoses between the vessels originating at the surface and those branching off the subependymal system are either scarce¹⁶ or absent.¹⁷

This pattern of vascularization suggested to de Reuck¹⁷ that the periventricular WM harbors an arterial border zone (or watershed) that is particularly susceptible to being injured as a result of systemic or focal decreases in CBF. Arteriolosclerosis might be the substrate for the decreases in blood flow observed in the WM of aged and hypertensive patients. An additional factor that may impair the WM irrigation among the elderly is the tortuosity and elongation of these vessels that accompany aging.^{18 19} The existence of a periventricular arterial border zone has been challenged by those who hold the view that the ventriculofugal vessels described by van den Bergh¹⁵ and de Reuck¹⁷ are veins rather than arteries.^{13 20 21} If such an interpretation is correct, the periventricular WM might be considered a "distal irrigation field" or an area prone to become seriously ischemic under conditions of moderate blood flow deficit; this is attributed to the scarcity of anastomoses that interconnect branches of the long medullary penetrating carrying vessels or rami medullares.^{12 16} Moreover, the arrangement of each metabolic unit is such that, although anastomoses do exist at the precapillary level, one distributing vessel irrigates only one metabolic unit.¹⁴

A strip of cerebral WM (3 to 4 mm in width) located immediately beneath the cerebral cortex (the so-called U-fibers) is irrigated not only by the long penetrating vessels but also by shorter vessels that straddle both the WM and the adjacent cortex.^{13 14} This distinctive arterial supply might account for the fact that the U-fibers are consistently spared in cases of subcortical leukoencephalopathy of presumed ischemic origin.

Clinical and Pathological Features of Leukoaraiosis
The strong epidemiological association that exists between LA and several cerebrovascular diseases suggests that ischemia may be a contributing factor. Notwithstanding the fact that some studies failed to demonstrate an association between WM abnormalities and cerebrovascular risk factors,⁷ LA is usually seen more frequently in patients with history of strokes and in individuals with cognitive deterioration of presumed vascular origin.^{22 23 24 25 26 27} Also, persons with severe LA are at increased risk to develop stroke and myocardial infarction.²⁸ The most common risk factor for LA is aging^{7 27} ; arterial hypertension, diabetes mellitus, and cardiac diseases are additional risk factors frequently associated with LA.^{29 30 31} Aging, chronic hypertension, and diabetes share a common substrate in the type of alterations that these conditions induce on the small penetrating arteries and arterioles of the WM. Such changes include replacement of the smooth muscle cells by fibro-hyaline material with thickening of the wall and narrowing of the vascular lumen (arteriolosclerosis).^{32 33 34} Arteriolosclerosis, almost always detected within areas of LA,^{35 36 37} may be one of the reasons the blood supply to the WM is altered, and this vascular alteration may lead to either localized ischemic areas of necrosis and cavitation (ie, lacunes) or diffuse rarefaction (ie, LA).

Blood Pressure Dysregulation
Evidence of elevated blood pressure does not exist in all symptomatic patients with LA.^{38 39 40 41} Yet, complex alterations in blood pressure regulation might contribute to the pathogenesis of LA. Compared with matched control subjects, persons with LA have both higher blood pressure values and a different circadian rhythm that is characterized by either a lack of the nocturnal physiological drops in blood pressure^{42 43} or wide daily fluctuations.^{44 45} Moreover, the observation that a subgroup of symptomatic patients with LA suffer frequent hypotensive crises^{45 46} is consistent with the demonstration of impaired cerebral autoregulation in hypertensive patients who have severe periventricular LA.^{47 48}

Within a well-defined range of blood pressure values (mean arterial pressure of 60 to 150 mm Hg), CBF is maintained constant (average of 55 and 20 mL·100 g^-1·min^-1 in the gray matter and WM, respectively) despite changes in systemic arterial blood pressure. Different from other organs,⁴⁹ the cervical segment of the carotid arteries and the large intracranial arteries also play a role in the regulation of vascular resistance in the cerebral circulation.⁵⁰ Notwithstanding the contribution of the large-caliber vessels, the physiological responses of the small cerebral vessels are essential for autoregulation, and their response to blood pressure changes is caliber dependent. In the cat, vascular responses to variations in mean arterial blood pressure between 110 and 160 mm Hg affect mainly pial vessels >200 µm. Arterioles with an average caliber of <100 µm dilate only at blood pressures <90 mm Hg; at <70 mm Hg, the degree of dilation in these small arterioles exceeds that of the larger vessels.⁵¹

If human intraparenchymal vessels are controlled by similar mechanisms, then in hypertensive patients with arteriolosclerotic vessels a drop in blood pressure of the type that occurs during cardiac dysrhythmias or as a result of impaired autoregulation could lead to a decrease in blood flow attributable to the inability of sclerotic vessels to dilate.⁵² Autoregulatory limits are shifted upward in hypertensive patients⁵³ ; thus, a rapid reduction of blood pressure, within physiological limits, might markedly reduce CBF in the WM of patients with chronic hypertension. Consequently, the cerebral WM of hypertensive patients could become ischemic at blood pressure levels considered normal for normotensive subjects.⁵⁴ Moreover, autoregulatory responses in the WM vessels of experimental animals are less effective than they are in the vessels of the gray matter; therefore, at low blood pressure values, the decreases in blood flow are more pronounced in the WM than in the gray matter.^{55 56}

Cerebral Blood Flow Studies in Leukoaraiosis
Support for the hypothetical ischemic origin of LA could be derived from studies based on estimates of the CBF. Several authors report whole brain or gray matter alterations in the CBF of patients with LA,^{57 58 59 60 61 62 63 64 65} but few studies have compared regional CBF values in brain areas with and without LA. In one study, CBF values were depressed in areas of LA when compared with normal white matter areas.⁶⁶ Similar results were obtained using single-photon emission CT⁶⁷ or xenon CT,^{68 69} although the latter technique does not allow a sharp separation between gray matter and WM.⁷⁰

Decreased regional CBF together with an increased oxygen extraction fraction has yet to be shown in areas with LA; this leaves unresolved the question of whether the decreased blood flow is the cause of LA or the consequence of the reduced metabolism in WM that became atrophic by other causes.^{66 70 71 72} Decreased blood flow in the frontal and parietal but not in the occipital WM was demonstrated in nondemented subjects with LA, suggesting that the pathogenesis of LA varies depending on its topographic location in the brain.⁷² Other studies have failed to demonstrate CBF alterations in patients who have patchy WM abnormalities⁷³ ; this might be because the pathogenesis of small WM lesions is different from that responsible for the more diffuse WM changes.

Hereditary Leukoencephalopathy of Probable Vascular Origin
CADASIL is a condition characterized by multiple subcortical infarcts, leukoencephalopathy, and an autosomal dominant pattern of inheritance.⁷⁴ Among patients with CADASIL, small arteries (in the brain, skin, and peripheral nerve) show granular osmiophilic deposits in the tunica media; the lumen in these vessels is narrowed secondary to the deposits of this electron-dense material,⁷⁵ and the normal autoregulatory responses may be impaired because of the structural changes in smooth muscle cells. These changes can result in WM damage.

Experimental Studies of Brain Ischemia
Histopathological studies of either rat or gerbil brains exposed to various types of ischemic injury suggest that both oligodendrocytes and myelinated axons are highly vulnerable to ischemia⁷⁶ and that chronic cerebral hypoperfusion produces progressive "rarefaction"^{77 78 79} and glial activation⁸⁰ in the WM. Permanent middle cerebral artery occlusion of up to 24 hours in duration in Wistar rats caused oligodendrocytes in the subcortical cerebral WM to significantly swell as early as 30 minutes after the occlusion of the artery.⁷⁶ In this model, 3 hours after the arterial occlusion, oligodendrocytes display histological changes characteristic of irreversible injury, such as pyknosis and plasma membrane rupture. The contemporaneous vacuolization of the WM that develops in these animals corresponds to (1) spaces formed by the separation of the inner myelin layer sheaths from the axolemma, (2) enlarged extracellular spaces, and (3) swelling of the astrocyte processes.⁷⁶ All of these changes in the WM precede the appearance of irreversible neuronal injury (ie, eosinophilia), thus suggesting that the early WM damage is independent of injury to the neuronal perikaryon. Studies based on either bilateral narrowing of the carotid artery in gerbils^{77 78} or bilateral carotid occlusion in rats^{79 80} consistently demonstrate two types of changes in the WM: reactive astrogliosis and nonspecific rarefaction of the WM. Significantly, increased extracellular fluid accumulation and astrogliosis are two of the main pathological features noted in areas where CT and MRI show LA in humans.⁷

	Pathogenesis of Leukoaraiosis: Alternative Hypotheses

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Hypotheses alternative to ischemia have been proposed to explain the origin of LA. We suggest that these mechanisms may be interrelated to the ischemic origin of LA.

Leukoaraiosis and Disturbances in Cerebrospinal Fluid Circulation
Patients with normal pressure hydrocephalus have a high prevalence of alterations in the WM that are detectable by either CT or MRI.⁸¹ Experimental hydrocephalus in dogs causes changes in the WM that can be reversed by shunting.⁸² On the basis of these observations, the authors hypothesized that disturbances in CSF circulation may play a role in the pathogenesis of LA, particularly the extensive periventricular lesions. The question of whether normal pressure hydrocephalus causes LA or vice versa is unresolved; this is because subjects with extensive LA often have enlarged lateral ventricles,²⁹ an abnormality that may be the result of ex-vacuo dilatation. Román⁸³ suggested two mechanisms for the development of LA in patients with normal pressure hydrocephalus. (1) The increased accumulation of CSF in the ventricles raises interstitial pressure in the periventricular parenchyma and causes ischemia to the WM. In fact, while the mean CSF pressure may be normal, the pulse pressure can be markedly increased in normal pressure hydrocephalus.⁸⁴ The hypothesis that increased ventricular pressure causes ischemic changes in the WM is supported by observations showing that among patients with normal pressure hydrocephalus, blood flow in the WM returns to normal values after shunting procedures that lower the intraventricular pressure; this is accompanied by parallel clinical improvement and reduction in the severity of LA.⁸⁵ (2) The second mechanism could involve alterations in the ependymal lining. Leakage of CSF into the adjacent brain parenchyma may be the result of structural alterations in the ependymal cells. Age-related changes affecting the penetrating vessels and altering the BBB could hinder the reabsorption of this excessive interstitial fluid.^{86 87} Abnormalities in the BBB, in the form of increased concentration of CSF proteins, have been described in a group of patients with LA.⁸⁸

The chronic effects of arterial hypertension, a condition that is more prevalent in normal pressure hydrocephalus patients than in control subjects, are a third factor that may cause rarefaction of WM in patients with normal pressure hydrocephalus.^{89 90} The arteriopathic changes of hypertension may contribute to the occurrence of multiple microinfarcts (lacunes) in the periventricular WM, leading to loss of tissue and consequent expansion of the lateral ventricles.⁸⁹

White Matter Changes and Cerebral Edema
WM changes similar to those of LA (pallor of the WM sparing the U-fibers, accompanied by reactive astrogliosis and small-vessel thickening) have been described in conditions in which brain edema might have preceded the appearance of LA.⁹¹ This suggests that transient cerebral edema might be an added cause of WM changes. The increased interstitial fluid concentration in the WM of patients with LA, which gives rise to CT hypodensities, may be a consequence of arterial hypertension and the subsequent alterations in the BBB. The BBB may be leaky, and the capillary permeability to proteins may be increased in patients with systemic hypertension.^{92 93} In addition to the effects of sustained hypertension, hypertensive bouts of short duration could cause fluid transudation and protein leakage.

Impaired venous return in the deep WM compartment is another possible cause of interstitial WM edema.⁹⁴ This idea has received increasing attention after the demonstration of structural alterations in the periventricular venules of patients with LA.⁹⁵ Changes in these veins, characterized by deposition of collagen fibers in the vessel wall, may be responsible for narrowing the venular lumen. This may disrupt the BBB at the venular level and may increase the perfusion pressure on the arterial side of the capillary bed.

Leukoaraiosis in Alzheimer's Disease
A considerable proportion of patients with AD have radiologically and structurally detectable WM changes, although they are usually less severe than in patients with cerebrovascular disease.⁹⁶ The hypothesis that LA in patients with AD might simply reflect wallerian changes secondary to cortical loss of neurons^{97 98} seems unlikely. The histological markers of wallerian changes, such as abundant lipid-laden macrophages, are missing in most areas of LA, and the discrepancy between the severity of changes in adjacent cortical and WM areas also militates against this hypothesis.⁹⁶ That wallerian changes may be undetectable at autopsy appears unlikely, since this process is a long-lasting phenomenon.⁹⁹ Moreover, it is difficult to understand why many AD patients with severe cortical atrophy and "loss" of neurons lack demonstrable WM changes at autopsy.⁹⁶ Data derived from MR spectroscopy confirm that decreases in myelin phospholipids exist in areas of LA, in the absence of changes in the concentration of N-acetyl-aspartate, a marker for neuronal perikarya.¹⁰⁰ This reinforces the hypothesis that the changes in the WM can occur independently of the alterations involving the gray matter.

LA among patients with AD may have an ischemic origin secondary to structural changes in the small blood vessels, as suggested by the observation that amyloid angiopathy (a small blood vessel disease) is present in almost 90% of AD patients.¹⁰¹ The hypothesis that amyloid angiopathy in AD patients may be causally linked to LA is supported by the observation that subcortical leukoencephalopathy was demonstrated in patients with cerebral amyloid angiopathy who lacked changes characteristic of AD.^{102 103 104} Leukoencephalopathy also exists in presymptomatic carriers of the amyloid precursor protein gene codon 693 mutation, which is responsible for hereditary cerebral hemorrhage with amyloidosis (Dutch type).¹⁰⁵ Furthermore, the extent and frequency of changes affecting the tunica media and tunica adventitia of the WM vessels is higher among AD patients than in age-matched control subjects^{32 96 106} ; these vascular changes might be a heretofore overlooked cause of LA in AD patients.

Extensive damage to the WM among AD patients could be a consequence of changes in the permeability of the BBB to proteins and the accumulation of fluid in the extracellular space. This leakiness might be the result of structural alterations, such as thickening of the basal lamina and pericapillary gliosis affecting the precapillary arterioles.^{107 108}

	Conclusion

Top Abstract Introduction Pathogenesis of Leukoaraiosis:... Pathogenesis of Leukoaraiosis:... Conclusion Future Developments References

 
The causes of LA are incompletely understood. In part this is because the neurological and histological abnormalities associated with LA are nonspecific.^{7 109} Both hypodensity on CT and hyperintensity on MRI reflect an increase of brain water content that can be accounted for by several conditions¹¹⁰ ; therefore, more than one mechanism could be responsible for LA. Notwithstanding the heterogeneity of radiological-pathological correlates, the most consistent histological substrate of LA is a diffuse pallor of the WM attributed to rarefaction of the myelin sheaths.^{11 36 111 112} The studies reviewed herein suggest that in a large group of patients, this type of myelin alteration may be related to ischemic injury (Table). Appraisal of alternative hypotheses such as those involving alterations in the CSF circulation and disturbances in the BBB also suggests a possible connection with ischemia. A unifying theory to explain diffuse WM changes of the type seen in LA has been proposed.¹¹³ Aging, arterial hypertension, and diabetes mellitus each produce structural alterations in the wall of small blood vessels, and the consequent narrowing or occlusion of the arteriolar lumen may cause small infarcts in the WM. This event may be accompanied by a breakdown of the BBB, with consequent leakage of macromolecules and ensuing activation of astrocytes. Activated and swollen astrocytes, typically seen in areas of LA, may contribute to the alterations commonly detected by CT and MRI.^{110 111}

View this table: [in this window] [in a new window]   Table 1. Clues Pointing to an Ischemic Origin of Leukoaraiosis

The myelin rarefaction typical of LA has been interpreted as the expression of incomplete infarct or the result of an ischemic event not severe enough to cause pannecrosis.⁹⁶ According to this suggestion, under yet-to-be-described conditions, ischemic injury may affect selected components of the WM while sparing many others. This hypothesis is supported by the observation that lesions similar to those of LA are detectable in the marginal zones of brain infarcts where the degree of ischemia is less severe than in the center.⁹⁶ However, direct demonstration for the ischemic origin of LA is lacking. Ipsilateral WM changes in patients undergoing therapeutic occlusion of the internal carotid artery became demonstrable by MRI shortly after arterial occlusion.¹¹⁴ These patients had been pretreated with anticoagulants, and the postoperative angiograms had shown patent large arteries; thus, secondary thromboembolic occlusion of the large collateral vessels seemed an unlikely cause of the WM changes. Instead, the authors hypothesized that in these patients a failure in the regulatory function of the intraparenchymal small blood vessels could have been responsible for the WM changes.¹¹⁴

These and similar observations strongly suggest that microvascular disturbances may have a central role in the pathogenesis of LA. The structural changes of arteriolosclerosis, those seen in CADASIL patients, and perhaps those of cerebral amyloid angiopathy may lead to deficits in the mechanisms regulating the blood flow to the WM.

In patients with small-vessel alterations, the cerebral WM may suffer brief and repeated episodes of hypoperfusion that eventually result in rarefaction, reactive gliosis, and edema; injury to the BBB permeability may contribute to the escape of macromolecules and the development of changes typical of LA.

	Future Developments

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Defining the structural changes of WM in an experimental model of moderate brain ischemia would be extremely valuable to clarify some of the unresolved issues regarding leukoencephalopathy and ischemia. In a study based on short-term occlusion (<3 hours) of the middle cerebral artery in Wistar rats, oligodendrocytes and axons were extremely sensitive to the effects of this type of ischemia, and pallor (rarefaction) of the subcortical WM was recognized in the involved territory before neuronal necrosis appeared.⁷⁶ Modifying the severity of the ischemic injury in this or similar models may provide the means with which specific hypotheses can be tested: eg, can selective injury to the WM, in the absence of injury to neuronal perikarya, be induced by moderate ischemia?

	Selected Abbreviations and Acronyms

 

AD = Alzheimer's disease BBB = blood-brain barrier CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CBF = cerebral blood flow CSF = cerebrospinal fluid LA = leukoaraiosis WM = white matter

	Acknowledgments

 
Partial financial support for this study was provided by US Public Health Service grant NS 31631. We thank Nancy Vesey and Maureen Malek (Detroit) for excellent secretarial support.

	Footnotes

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

Received September 3, 1996; revision received November 7, 1996; accepted November 27, 1996.

	References

Top Abstract Introduction Pathogenesis of Leukoaraiosis:... Pathogenesis of Leukoaraiosis:... Conclusion Future Developments References

 
1. Breteler MMB, van Swieten JC, Bots ML, Grobbee DE, Claus JJ, van den Hout JHW, van Harskamp F, Tanghe HLJ, de Jong PTVM, van Gijn J, Hofman A. Cerebral white matter lesions, vascular risk factors, and cognitive function in a population-based study: the Rotterdam Study. Neurology. 1994;44:1246-1252. [Abstract/Free Full Text]

2. Junquè C, Pujol J, Vendrell P, Bruna O, Jodar M, Ribas JC, Vinas J, Capdevila A, Marti-Vilalta JL. Leuko-araiosis on magnetic resonance imaging and speed of mental processing. Arch Neurol. 1990;47:151-156. [Abstract/Free Full Text]

3. Liu CK, Miller BL, Cummings JL, Mehringer CM, Goldberg MA, Howng SL, Benson DF. A quantitative MRI study of vascular dementia. Neurology. 1992;42:138-143. [Abstract/Free Full Text]

4. Schmidt R, Fazekas F, Offenbacher H, Dusek T, Zach E, Reinhart B, Grieshofer P, Freidl W, Eber B, Schumacher M, Koch M, Lechner H. Neuropsychological correlates of MRI white matter hyperintensities: a study of 150 normal volunteers. Neurology. 1993;43:2490-2494. [Abstract/Free Full Text]

5. Ylikoski R, Ylikoski A, Erkinjuntti T, Sulkava R, Raininko R, Tilvis R. White matter changes in healthy elderly persons correlate with attention and speed of mental processing. Arch Neurol. 1993;50:818-824. [Abstract/Free Full Text]

6. Hachinski VC, Potter P, Merskey H. Leuko-araiosis. Arch Neurol. 1987;44:21-23. [Abstract/Free Full Text]

7. Pantoni L, Garcia JH. The significance of cerebral white matter abnormalities 100 years after Binswanger's report: a review. Stroke. 1995;26:1293-1301. [Abstract/Free Full Text]

8. Brucher JM. Leukoencephalopathy in anoxic-ischemic processes. In: Koetsier JC, ed. Handbook of Clinical Neurology, Vol 3 (47): Demyelinating Diseases. Amsterdam, Netherlands: Elsevier Science Publishers BV; 1985:525-549.

9. Ginsberg MD, Hedley-Whyte ET, Richardson EP. Hypoxic-ischemic leukoencephalopathy in man. Arch Neurol. 1976;33:5-14. [Abstract/Free Full Text]

10. Schwedenberg TH. Leukoencephalopathy following carbon monoxide asphyxia. J Neuropathol Exp Neurol. 1959;18:597-608. [Medline] [Order article via Infotrieve]

11. Inzitari D, Mascalchi M, Giordano GP, Marini P, Sità D, Abbamondi AL. Histopathological correlates of leuko-araiosis in patients with ischemic stroke. Eur Neurol. 1989;29(suppl 2):23-26.

12. van den Bergh R, van der Eecken H. Anatomy and embryology of cerebral circulation. Prog Brain Res. 1968;30:1-26.

13. Moody DM, Bell MA, Challa VR. Features of the cerebral vascular pattern that predict vulnerability to perfusion or oxygenation deficiency: an anatomic study. AJNR Am J Neuroradiol. 1990;11:431-439. [Abstract]

14. Rowbotham GF, Little E. Circulation of the cerebral hemispheres. Br J Surg. 1965;52:8-21. [Medline] [Order article via Infotrieve]

15. van den Bergh R. Centrifugal elements in the vascular pattern of the deep intracerebral blood supply. Angiologica. 1969;20:88-98.

16. Ravens JR. Anastomoses in the vascular bed of the human cerebrum. In: Cervós-Navarro J, ed. Pathology of Cerebral Microcirculation. Berlin, Germany: Walter de Gruyter; 1974:26-38.

17. de Reuck J. The human periventricular arterial blood supply and the anatomy of cerebral infarctions. Eur Neurol. 1971;5:321-334. [Medline] [Order article via Infotrieve]

18. Moody DM, Santamore WP, Bell MA. Does the tortuosity in cerebral arterioles impair down-autoregulation in hypertensive and elderly normotensive? A hypothesis and computer model. Clin Neurosurg. 1990;37:372-387.

19. Spangler KM, Challa VR, Moody DM, Bell MA. Arteriolar tortuosity of the white matter in aging and hypertension: a microradiographic study. J Neuropathol Exp Neurol. 1994;53:22-26. [Medline] [Order article via Infotrieve]

20. Nelson MD Jr, Gonzales-Gomez I, Gilles FH. The search for human telencephalic ventriculofugal arteries. AJNR Am J Neuroradiol. 1991;12:215-222. [Abstract]

21. Mayer PL, Kier EL. The controversy of the periventricular white matter circulation: a review of the anatomic literature. AJNR Am J Neuroradiol. 1991;12:223-228. [Medline] [Order article via Infotrieve]

22. Awad IA, Spetzler RF, Hodak JA, Awad CA, Carey R. Incidental subcortical lesions identified on magnetic resonance imaging in the elderly, I: correlation with age and cerebrovascular risk factors. Stroke. 1986;17:1084-1089. [Abstract/Free Full Text]

23. Inzitari D, Diaz F, Fox A, Hachinski VC, Steingart A, Lau C, Donald A, Wade J, Mulic H, Merskey H. Vascular risk factors and leuko-araiosis. Arch Neurol. 1987;44:42-47. [Abstract/Free Full Text]

24. Inzitari D, Giordano GP, Ancona AL, Pracucci G, Mascalchi M, Amaducci L. Leukoaraiosis, intracerebral hemorrhage, and arterial hypertension. Stroke. 1990;21:1419-1423. [Abstract/Free Full Text]

25. Cadelo M, Inzitari D, Pracucci G, Mascalchi M. Predictors of leukoaraiosis in elderly neurological patients. Cerebrovasc Dis. 1991;1:345-351.

26. Streifler JY, Eliasziw M, Benavente OR, Hachinski VC, Fox AJ, Barnett HJM, for the North American Symptomatic Carotid Endarterectomy Trial. Lack of relationship between leukoaraiosis and carotid artery disease. Arch Neurol. 1995;52:21-24. [Abstract/Free Full Text]

27. Longstreth WT Jr, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA, Enright PL, O'Leary D, Fried L, for the Cardiovascular Health Study Collaborative Research Group. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people: the Cardiovascular Health Study. Stroke. 1996;27:1274-1282. [Abstract/Free Full Text]

28. Inzitari D, Di Carlo AS, Mascalchi M, Pracucci G, Amaducci L. The cardiovascular outcome of patient with motor impairment and extensive leuko-araiosis. Arch Neurol. 1995;52:687-691. [Abstract/Free Full Text]

29. Breteler MMB, van Amerongen NM, van Swieten JC, Claus JJ, Grobbee DE, van Gijn J, Hofman A, van Harskamp F. Cognitive correlates of ventricular enlargement and cerebral white matter lesions on magnetic resonance imaging: the Rotterdam Study. Stroke. 1994;25:1109-1115. [Abstract]

30. Erkinjuntti T, Gao F, Lee DH, Eliasziw M, Merskey H, Hachinski VC. Lack of difference in brain hyperintensities between patients with early Alzheimer's disease and control subjects. Arch Neurol. 1994;51:260-268. [Abstract/Free Full Text]

31. Ljindgren A, Roijer A, Rudling O, Norrving B, Larsson E-M, Eskilsson J, Wallin L, Olsson B, Johansson BB. Cerebral lesions on magnetic resonance imaging, heart disease, and vascular risk factors in subjects without stroke. Stroke. 1994;25:929-934. [Abstract]

32. Furuta A, Ishii N, Nishihara Y, Horie A. Medullary arteries in aging and dementia. Stroke. 1991;22:442-446. [Abstract/Free Full Text]

33. Ostrow PT, Miller LL. Pathology of small artery disease. Adv Neurol. 1993;62:93-123. [Medline] [Order article via Infotrieve]

34. Alex M, Baron EK, Goldenberg S, Blumenthal HT. An autopsy study of cerebrovascular accident in diabetes mellitus. Circulation. 1962;25:663-673. [Abstract/Free Full Text]

35. Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, Payer F, Radner H, Lechner H. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology. 1993;43:1683-1689. [Abstract/Free Full Text]

36. Leifer D, Buonanno FS, Richardson EP Jr. Clinicopathologic correlations of cranial magnetic resonance imaging of periventricular white matter. Neurology. 1990;40:911-918. [Abstract/Free Full Text]

37. van Swieten JC, van den Hout JHW, van Ketel BA, Hijdra A, Wokke JHJ, van Gijn J. Periventricular lesions in the white matter on magnetic resonance imaging in the elderly: a morphometric correlation with arteriolosclerosis and dilated perivascular spaces. Brain. 1991;114:761-774. [Abstract/Free Full Text]

38. Iijima M, Ishino H, Seno H, Inagaki T, Haruki S. An autopsy case of Binswanger's disease without hypertension and associated with cerebral infarction in the terminal stage. Jpn J Psychiatr Neurol. 1993;47:901-907. [Medline] [Order article via Infotrieve]

39. Loizou LA, Jefferson JM, Smith WT. Subcortical arteriosclerotic encephalopathy (Binswanger's type) and cortical infarcts in a young normotensive patient. J Neurol Neurosurg Psychiatry. 1982;45:409-417. [Abstract/Free Full Text]

40. Ma K-C, Lundberg PO, Lilja A, Olsson Y. Binswanger's disease in the absence of chronic arterial hypertension: a case report with clinical, radiological and immunohistochemical observations on intracerebral blood vessels. Acta Neuropathol (Berl). 1992;83:434-439. [Medline] [Order article via Infotrieve]

41. Räihä I, Tarvonen S, Kurki T, Rajala T, Sourander L. Relationship between vascular factors and white matter low attenuation of the brain. Acta Neurol Scand. 1993;87:286-289. [Medline] [Order article via Infotrieve]

42. Shimada K, Kawamoto A, Matsubayashi K, Nishinaga M, Kimura S, Ozawa T. Diurnal blood pressure variations and silent cerebrovascular damage in elderly patients with hypertension. J Hypertens. 1992;10:875-878. [Medline] [Order article via Infotrieve]

43. Tohgi H, Chiba K, Kimura M. Twenty-four-hour variation of blood pressure in vascular dementia of the Binswanger type. Stroke. 1991;22:603-608. [Abstract/Free Full Text]

44. Ginnanneschi A, Marinoni M, Inzitari D, Amaducci L. Blood pressure monitoring in patients with leukoaraiosis. Neurology. 1992;42(suppl 3):273. Abstract.

45. McQuinn BA, O'Leary DH. White matter lucencies on computed tomography, subacute arteriosclerotic encephalopathy (Binswanger's disease), and blood pressure. Stroke. 1987;18:900-905. [Abstract/Free Full Text]

46. Harrison MJG, Marshall J. Hypoperfusion in the aetiology of subcortical arteriosclerotic encephalopathy (Binswanger type). J Neurol Neurosurg Psychiatry. 1984;47:754.

47. Marinoni M, Ginanneschi A, Ancona AL, Modesti PA, Piccininni M, Inzitari D. Orthostatic transcranial Doppler variations in patients with leukoaraiosis. Neurology. 1991;41(suppl 1):123. Abstract.

48. Matsushita K, Kuriyama Y, Nagatsuka K, Nakamura M, Sawada T, Omae T. Periventricular white matter lucency and cerebral blood flow autoregulation in hypertensive patients. Hypertension. 1994;23:565-568. [Abstract/Free Full Text]

49. Faraci FM, Heistad DD. Regulation of large cerebral arteries and cerebral microvascular pressure. Circ Res. 1990;66:8-17. [Abstract/Free Full Text]

50. Stromberg DD, Fox JR. Pressures in the pial arterial microcirculation of the cat during changes in systemic arterial blood pressure. Circ Res. 1972;31:229-239. [Abstract/Free Full Text]

51. Kontos HA, Wei EP, Navari RM, Levasseur JE, Rosenblum WI, Patterson JL Jr. Responses of cerebral arteries and arterioles to acute hypotension and hypertension. Am J Physiol. 1978;234:H371-H383. [Abstract/Free Full Text]

52. Heistad DD, Mayhan WG, Coyle P, Baumbach GL. Impaired dilatation of cerebral arterioles in chronic hypertension. Blood Vessels. 1990;27:258-262. [Medline] [Order article via Infotrieve]

53. Strandgaard S. Autoregulation of cerebral blood flow in hypertensive patients: the modifying influence of prolonged antihypertensive treatment on the tolerance to acute, drug-induced hypotension. Circulation. 1976;53:720-727. [Abstract/Free Full Text]

54. Miller JD, Bell BA. Cerebral blood flow variations with perfusion pressure and metabolism. In: Wood JH, ed. Cerebral Blood Flow: Physiologic and Clinical Aspects. New York, NY: McGraw-Hill Book Co; 1987:119-129.

55. Symon L, Pasztor E, Dorsch NWC, Branston NM. Physiological responses of local areas of the cerebral circulation in experimental primates determined by the method of hydrogen clearance. Stroke. 1973;4:632-642. [Abstract/Free Full Text]

56. Young RSK, Hernandez MJ, Yagel SK. Selective reduction of blood flow to white matter during hypotension in newborn dogs: a possible mechanism of periventricular leukomalacia. Ann Neurol. 1982;12:445-448. [Medline] [Order article via Infotrieve]

57. Fazekas F, Niederkorn K, Schmidt R, Offenbacher H, Horner S, Bertha G, Lechner H. White matter signal abnormalities in normal individuals: correlation with carotid ultrasonography, cerebral blood flow measurements, and cerebrovascular risk factors. Stroke. 1988;19:1285-1288. [Abstract/Free Full Text]

58. Fazekas F, Alavi A, Chawluk JB, Zimmerman RA, Hackney D, Bilaniuk L, Rosen M, Alves WM, Hurtig HI, Jamieson DG, Kushner MJ, Reivich M. Comparison of CT, MR, and PET in Alzheimer's dementia and normal aging. J Nucl Med. 1989;30:1607-1615. [Abstract/Free Full Text]

59. Herholz H, Heidel W, Rackl A, Neubauer I, Steinbrich W, Pietrzyk U, Erasmi-Körber H, Heiss W-D. Regional cerebral blood flow in patients with leuko-araiosis and atherosclerotic carotid artery disease. Arch Neurol. 1990;47:392-396. [Abstract/Free Full Text]

60. Isaka Y, Okamoto M, Ashida K, Imaizumi M. Decreased cerebrovascular dilatatory capacity in subjects with asymptomatic periventricular hyperintensities. Stroke. 1994;25:375-381. [Abstract]

61. Kawabata K, Tachibana H, Sugita M, Fukuchi M. A comparative I-123 IMP SPECT study in Binswanger's disease and Alzheimer's disease. Clin Nucl Med. 1993;18:329-336. [Medline] [Order article via Infotrieve]

62. Kawamura J, Meyer JS, Terayama Y, Weathers S. Leukoaraiosis correlates with cerebral hypoperfusion in vascular dementia. Stroke. 1991;22:609-614. [Abstract/Free Full Text]

63. Kobari M, Meyer JS, Ichijo M, Oravez WT. Leukoaraiosis: correlation of MR and CT findings with blood flow, atrophy, and cognition. AJNR Am J Neuroradiol. 1990;11:273-281. [Abstract]

64. Loizou LA, Kendall BE, Marshall J. Subcortical arteriosclerotic encephalopathy: a clinical and radiological investigation. J Neurol Neurosurg Psychiatry. 1981;44:294-304. [Abstract/Free Full Text]

65. Sultzer DL, Mahler ME, Cummings JL, Van Gorp WG, Hinkin CH, Brown C. Cortical abnormalities associated with subcortical lesions in vascular dementia: clinical and positron emission tomographic findings. Arch Neurol. 1995;52:773-780. [Abstract/Free Full Text]

66. Meguro K, Hatazawa J, Yamaguchi T, Itoh M, Matsuzawa T, Ono S, Miyazawa H, Hishinuma T, Yanai K, Sekita Y, Yamada K. Cerebral circulation and oxygen metabolism associated with subclinical periventricular hyperintensity as shown by magnetic resonance imaging. Ann Neurol. 1990;28:378-383. [Medline] [Order article via Infotrieve]

67. De Cristofaro MT, Mascalchi M, Pupi A, Nencini P, Formiconi AR, Inzitari D, Dal Pozzo G, Meldolesi U. Subcortical arteriosclerotic encephalopathy: single photon emission computed tomography-magnetic resonance imaging correlation. Am J Physiol Imaging. 1990;5:68-70. [Medline] [Order article via Infotrieve]

68. Fazekas F. Magnetic resonance signal abnormalities in asymptomatic individuals: their incidence and functional correlates. Eur Neurol. 1989;29:164-168. [Medline] [Order article via Infotrieve]

69. Kawamura J, Meyer JS, Terayama Y, Weathers S. Leuko-araiosis and cerebral hypoperfusion compared in elderly normals and Alzheimer's dementia. J Am Geriatr Soc. 1992;40:375-380. [Medline] [Order article via Infotrieve]

70. Yao H, Sadoshima S, Kuwabara Y, Ichiya Y, Fujishima M. Cerebral blood flow and oxygen metabolism in patients with vascular dementia of the Binswanger type. Stroke. 1990;21:1694-1699. [Abstract/Free Full Text]

71. Yao H, Sadoshima S, Ibayashi S, Kuwabara Y, Ichiya Y, Fujishima M. Leukoaraiosis and dementia in hypertensive patients. Stroke. 1992;23:1673-1677. [Abstract/Free Full Text]

72. de Reuck J, Decoo D, Strijckmans K, Lemahieu I. Does the severity of leukoaraiosis contribute to senile dementia? A comparative computerized and positron emission tomographic study. Eur Neurol. 1992;32:199-205. [Medline] [Order article via Infotrieve]

73. Yamauchi H, Fukuyama H, Harada K, Yamaguchi S, Miyoshi T, Doi T, Kimura J, Iwasaki Y, Asato R, Yonekura Y. White matter hyperintensities may correspond to areas of increased blood volume: correlative MR and PET observations. J Comput Assist Tomogr. 1990;14:905-908. [Medline] [Order article via Infotrieve]

74. Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H, Mas J-L, Cabanis E-A, Baudrimont M, Maciazek J, Bach M-A, Bousser M-G. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps on chromosome 19q12. Nat Genet. 1993;3:256-259. [Medline] [Order article via Infotrieve]

75. Baudrimont M, Dubas F, Joutel A, Tournier-Lasserve E, Bousser M-G. Autosomal dominant leukoencephalopathy and subcortical ischemic stroke: a clinicopathological study. Stroke. 1993;24:122-125. [Abstract/Free Full Text]

76. Pantoni L, Garcia JH, Gutierrez JA. Cerebral white matter is highly vulnerable to ischemia. Stroke. 1996;27:1641-1647. [Abstract/Free Full Text]

77. Hattori H, Takeda M, Kudo T, Nishimura T, Hashimoto S. Cumulative white matter changes in the gerbil under chronic cerebral hypoperfusion. Acta Neuropathol (Berl). 1992;84:437-442. [Medline] [Order article via Infotrieve]

78. Kudo T, Takeda M, Tanimukai S, Nishimura T. Neuropathologic changes in the gerbil brain after chronic hypoperfusion. Stroke. 1993;24:259-265. [Abstract/Free Full Text]

79. Ni J-W, Matsumoto K, Li H-B, Murakami Y, Watanabe H. Neuronal damage and decrease of central acetylcholine level following permanent occlusion of bilateral common carotid arteries in rat. Brain Res. 1995;673:290-296. [Medline] [Order article via Infotrieve]

80. Wakita H, Tomimoto H, Akiguchi I, Kimura J. Glial activation and white matter changes in the rat brain induced by chronic cerebral hypoperfusion: an immunohistochemical study. Acta Neuropathol (Berl). 1994;87:484-492. [Medline] [Order article via Infotrieve]

81. Bradley WG Jr, Whittemore AR, Watanabe AS, Davis SJ, Teresi LM, Homyak M. Association of deep white matter infarction with chronic communicating hydrocephalus: implications regarding the possible origin of normal-pressure hydrocephalus. AJNR Am J Neuroradiol. 1991;12:31-39. [Abstract]

82. Murata T, Handa H, Mori K, Nakano Y. The significance of periventricular lucency on computed tomography: experimental study with canine hydrocephalus. Neuroradiology. 1981;20:221-227. [Medline] [Order article via Infotrieve]

83. Román GC. White matter lesions and normal-pressure hydrocephalus: Binswanger's disease or Hakim syndrome? AJNR Am J Neuroradiol. 1991;12:40-41.[Medline] [Order article via Infotrieve]

84. Di Rocco C, Petterossi VC, Caldarelli M, Mancinelli R, Vellardi F. Communicating hydrocephalus induced by mechanically increased amplitude of the intraventricular cerebrospinal fluid pressure: experimental studies. Exp Neurol. 1978;59:40-52. [Medline] [Order article via Infotrieve]

85. Kimura M, Tanaka A, Yoshinaga S. Significance of periventricular hemodynamics in normal pressure hydrocephalus. Neurosurgery. 1992;30:701-705. [Medline] [Order article via Infotrieve]

86. Stewart PA, Magliocco M, Hayakawa K, Farrel CL, Del Maestro RF, Girvin J, Kaufmann JCE, Vinters HV, Gilbert J. A quantitative analysis of blood-brain barrier ultrastructure in the aging human. Microvasc Res. 1987;33:270-282. [Medline] [Order article via Infotrieve]

87. Stewart PA, Hayakawa K, Akers MA, Vinters HV. A morphometric study of the blood-brain barrier in Alzheimer's disease. Lab Invest. 1992;67:734-742. [Medline] [Order article via Infotrieve]

88. Pantoni L, Inzitari D, Pracucci G, Lolli F, Giordano G, Bracco L, Amaducci L. Cerebrospinal fluid proteins in patients with leucoaraiosis: possible abnormalities in blood-brain barrier function. J Neurol Sci. 1993;115:125-131. [Medline] [Order article via Infotrieve]

89. Earnest MP, Fahn S, Karp JH, Rowland LP. Normal pressure hydrocephalus and hypertensive cerebrovascular disease. Arch Neurol. 1974;31:262-266. [Abstract/Free Full Text]

90. Graff-Radford NR, Godersky JC. Idiopathic normal pressure hydrocephalus and systemic hypertension. Neurology. 1987;37:868-871. [Abstract/Free Full Text]

91. Feigin I, Popoff N. Neuropathological changes late in cerebral edema: the relationship to trauma, hypertensive disease and Binswanger's encephalopathy. J Neuropathol Exp Neurol. 1963;22:500-511. [Medline] [Order article via Infotrieve]

92. Kobayashi H, Magnoni MS, Govoni S, Izumi F, Wada A, Trabucchi M. Neuronal control of brain microvessel function. Experientia. 1985;41:427-434. [Medline] [Order article via Infotrieve]

93. Nag S. Cerebral changes in chronic hypertension: combined permeability and immunohistochemical studies. Acta Neuropathol (Berl). 1984;62:178-184. [Medline] [Order article via Infotrieve]

94. Stochdorph O, Meessen H. Die arteriosklerotische und die hypertonische Hirnerkrankung. Handbuch d spez path Anat u Histol. 1957;13/1B:1465-1510.

95. Moody DM, Brown WR, Challa VR, Anderson RL. Periventricular venous collagenosis: association with leukoaraiosis. Radiology. 1995;194:469-476. [Abstract/Free Full Text]

96. Brun A, Englund E. A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann Neurol. 1986;19:253-262. [Medline] [Order article via Infotrieve]

97. Leys D, Pruvo JP, Parent M, Vermersch P, Soetaert G, Steinling M, Delacourte A, Défossez A, Rapoport A, Clarisse J, Petit H. Could Wallerian degeneration contribute to "leuko-araiosis" in subjects free of any vascular disorders? J Neurol Neurosurg Psychiatry. 1991;54:46-50. [Abstract/Free Full Text]

98. Meyer JS, Takashima S, Terayama Y, Obara K, Muramatsu K, Weathers S. CT changes associated with normal aging of the human brain. J Neurol Sci. 1994;123:200-208. [Medline] [Order article via Infotrieve]

99. Daniel PM, Strich SJ. Histological observations on Wallerian degeneration in the spinal cord of the baboon, Papio papio. Acta Neuropathol (Berl). 1969;12:314-328. [Medline] [Order article via Infotrieve]

100. Constans JM, Meyerhoff DJ, Norman D, Fein G, Weiner MW. 1H and 31P magnetic resonance spectroscopic imaging of white matter signal hyperintensities areas in elderly subjects. Neuroradiology. 1995;37:615-623. [Medline] [Order article via Infotrieve]

101. Mandybur TI. The incidence of cerebral amyloid angiopathy in Alzheimer's disease. Neurology. 1975;25:120-126. [Abstract/Free Full Text]

102. Gray F, Dubas F, Roullet E, Escourolle R. Leukoencephalopathy in diffuse hemorrhagic cerebral amyloid angiopathy. Ann Neurol. 1985;18:54-59. [Medline] [Order article via Infotrieve]

103. Heffner RR, Porro RS, Olson ME, Earle KM. A demyelinating disorder associated with cerebrovascular amyloid angiopathy. Arch Neurol. 1976;33:501-506. [Abstract/Free Full Text]

104. Tabaton M, Caponnetto C, Mancardi G, Loeb C. Amyloid beta protein deposition in brains from elderly subjects with leukoaraiosis. J Neurol Sci. 1991;106:123-127. [Medline] [Order article via Infotrieve]

105. Bornebroek M, Haan J, van Buchem MA, Lanser JBK, deVries-vd Weerd MACS, Zoeteweij M, Roos RAC. White matter lesions and cognitive deterioration in presymptomatic carriers of amyloid precursor protein gene codon 693 mutation. Arch Neurol. 1996;53:43-48. [Abstract/Free Full Text]

106. Scheltens P, Barkhof F, Leys D, Wolters EC, Ravid R, Kamphorst W. Histopathological correlates of white matter changes on MRI in Alzheimer's disease and normal aging. Neurology. 1995;45:883-888. [Abstract/Free Full Text]

107. Vinters HV, Secor DL, Read SL, Frazee JG, Tomiyasu U, Stanley TM, Ferreiro JA, Akers M-A. Microvasculature in brain biopsy specimens from patients with Alzheimer's disease: an immunohistochemical and ultrastructural study. Ultrastruct Pathol. 1994;18:333-348. [Medline] [Order article via Infotrieve]

108. Buée L, Hof PR, Bouras C, Delacourte A, Perl DP, Morrison JH, Fillit HM. Pathological alterations of the cerebral microvasculature in Alzheimer's disease and related dementing disorders. Acta Neuropathol (Berl). 1994;87:469-480.[Medline] [Order article via Infotrieve]

109. Chimowitz MI, Estes ML, Furlan AJ, Awad IA. Further observations on the pathology of subcortical lesions identified on magnetic resonance imaging. Arch Neurol. 1992;49:747-752. [Abstract/Free Full Text]

110. Ormerod IEC, Roberts RC, du Boulay EP, McDonald WI, Callanan MM, Halliday AM, Johnson G, Kendall BE, Logsdail SJ, MacManus DG, Moseley IF, Ron MA, Rudge P, Zilkha KJ. NMR in multiple sclerosis and cerebral vascular disease. Lancet. 1984;2:1334-1335.

111. Muñoz DG, Hastak SM, Harper B, Lee D, Hachinski VC. Pathologic correlates of increased signals of the centrum semiovale on magnetic resonance imaging. Arch Neurol. 1993;50:492-497. [Abstract/Free Full Text]

112. Révész T, Hawkins CP, du Boulay EPGH, Barnard RO, McDonald WI. Pathological findings correlated with magnetic resonance imaging in subcortical arteriosclerotic encephalopathy (Binswanger's disease). J Neurol Neurosurg Psychiatry. 1989;52:1337-1344. [Abstract/Free Full Text]

113. Balòh RW, Vinters HV. White matter lesions and disequilibrium in older people, II: clinicopathologic correlation. Arch Neurol. 1995;52:975-981. [Abstract/Free Full Text]

114. Awad IA, Masaryk T, Magdinec M. Pathogenesis of subcortical hyperintense lesions on magnetic resonance imaging of the brain: observation in patients undergoing controlled therapeutic internal carotid artery occlusion. Stroke. 1993;24:1339-1346.[Abstract/Free Full Text]

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				P. E. Gates, W. D. Strain, and A. C. Shore Human endothelial function and microvascular ageing Exp Physiol, March 1, 2009; 94(3): 311 - 316. [Abstract] [Full Text] [PDF]

				S. Black, F. Gao, and J. Bilbao Understanding White Matter Disease: Imaging-Pathological Correlations in Vascular Cognitive Impairment Stroke, March 1, 2009; 40(3_suppl_1): S48 - S52. [Abstract] [Full Text] [PDF]

				L. Saba, R. Sanfilippo, L. Pascalis, R. Montisci, and G. Mallarini Carotid Artery Abnormalities and Leukoaraiosis in Elderly Patients: Evaluation with MDCT Am. J. Roentgenol., February 1, 2009; 192(2): W63 - W70. [Abstract] [Full Text] [PDF]

				L. H. Coker, P. E. Hogan, N. R. Bryan, L. H. Kuller, K. L. Margolis, K. Bettermann, R. B. Wallace, Z. Lao, R. Freeman, M. L. Stefanick, et al. Postmenopausal hormone therapy and subclinical cerebrovascular disease: The WHIMS-MRI Study Neurology, January 13, 2009; 72(2): 125 - 134. [Abstract] [Full Text] [PDF]

				G. J. Francis, J. A. Martinez, W. Q. Liu, K. Xu, A. Ayer, J. Fine, U. I. Tuor, G. Glazner, L. R. Hanson, W. H. Frey II, et al. Intranasal insulin prevents cognitive decline, cerebral atrophy and white matter changes in murine type I diabetic encephalopathy Brain, December 1, 2008; 131(12): 3311 - 3334. [Abstract] [Full Text] [PDF]

				G. F. Mitchell Effects of central arterial aging on the structure and function of the peripheral vasculature: implications for end-organ damage J Appl Physiol, November 1, 2008; 105(5): 1652 - 1660. [Abstract] [Full Text] [PDF]

				E. J. van Dijk, N. D. Prins, H. A. Vrooman, A. Hofman, P. J. Koudstaal, and M. M.B. Breteler Progression of Cerebral Small Vessel Disease in Relation to Risk Factors and Cognitive Consequences: Rotterdam Scan Study Stroke, October 1, 2008; 39(10): 2712 - 2719. [Abstract] [Full Text] [PDF]

				J. K. Virtanen, D. S. Siscovick, W. T. Longstreth Jr, L. H. Kuller, and D. Mozaffarian Fish consumption and risk of subclinical brain abnormalities on MRI in older adults Neurology, August 5, 2008; 71(6): 439 - 446. [Abstract] [Full Text] [PDF]

				M van Oijen, E Y L Cheung, C E M Geluk, A Hofman, P J Koudstaal, M M B Breteler, and M P de Maat Haplotypes of the fibrinogen gene and cerebral small vessel disease: the Rotterdam scan study J. Neurol. Neurosurg. Psychiatry, July 1, 2008; 79(7): 799 - 803. [Abstract] [Full Text] [PDF]

				N. Altaf, P. S. Morgan, A. Moody, S. T. MacSweeney, J. R. Gladman, and D. P. Auer Brain White Matter Hyperintensities Are Associated with Carotid Intraplaque Hemorrhage Radiology, July 1, 2008; 248(1): 202 - 209. [Abstract] [Full Text] [PDF]

				M. Fornage, Y. A. Chiang, E. S. O'Meara, B. M. Psaty, A. P. Reiner, D. S. Siscovick, R. P. Tracy, and W.T. Longstreth Jr Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain: The Cardiovascular Health Study Stroke, July 1, 2008; 39(7): 1952 - 1959. [Abstract] [Full Text] [PDF]

				D. M. Mandell, J. S. Han, J. Poublanc, A. P. Crawley, A. Kassner, J. A. Fisher, and D. J. Mikulis Selective Reduction of Blood Flow to White Matter During Hypercapnia Corresponds With Leukoaraiosis Stroke, July 1, 2008; 39(7): 1993 - 1998. [Abstract] [Full Text] [PDF]

				R. Pettersen, Y. Haig, P. H. Nakstad, and T. B. Wyller Subtypes of urinary incontinence after stroke: relation to size and location of cerebrovascular damage Age Ageing, May 1, 2008; 37(3): 324 - 327. [Full Text] [PDF]

				C. M. Holland, E. E. Smith, I. Csapo, M. E. Gurol, D. A. Brylka, R. J. Killiany, D. Blacker, M. S. Albert, C. R.G. Guttmann, and S. M. Greenberg Spatial Distribution of White-Matter Hyperintensities in Alzheimer Disease, Cerebral Amyloid Angiopathy, and Healthy Aging Stroke, April 1, 2008; 39(4): 1127 - 1133. [Abstract] [Full Text] [PDF]

				M. L. Baker, P. J. Hand, J. J. Wang, and T. Y. Wong Retinal Signs and Stroke: Revisiting the Link Between the Eye and Brain Stroke, April 1, 2008; 39(4): 1371 - 1379. [Abstract] [Full Text] [PDF]

				L. H.G. Henskens, R. J. van Oostenbrugge, A. A. Kroon, P. W. de Leeuw, and J. Lodder Brain Microbleeds Are Associated With Ambulatory Blood Pressure Levels in a Hypertensive Population Hypertension, January 1, 2008; 51(1): 62 - 68. [Abstract] [Full Text] [PDF]

				L BRONGE and L-O WAHLUND White matter changes in dementia: does radiology matter? Br. J. Radiol., December 1, 2007; 80(Special_Issue_2): S115 - S120. [Abstract] [Full Text] [PDF]

				M. F. O'Rourke Arterial aging: pathophysiological principles Vascular Medicine, November 1, 2007; 12(4): 329 - 341. [Abstract] [PDF]

				A.C.G.M. van Es, W.M. van der Flier, F. Admiraal Behloul, H. Olofsen, E.L.E.M. Bollen, H.A.M. Middelkoop, A.W.E. Weverling-Rijnsburger, J. van der Grond, R.G.J. Westendorp, and M.A. van Buchem Lobar Distribution of Changes in Gray Matter and White Matter in Memory Clinic Patients: Detected Using Magnetization Transfer Imaging AJNR Am. J. Neuroradiol., November 1, 2007; 28(10): 1938 - 1942. [Abstract] [Full Text] [PDF]

				S. Debette, S. Bombois, A. Bruandet, X. Delbeuck, S. Lepoittevin, C. Delmaire, D. Leys, and F. Pasquier Subcortical Hyperintensities Are Associated With Cognitive Decline in Patients With Mild Cognitive Impairment Stroke, November 1, 2007; 38(11): 2924 - 2930. [Abstract] [Full Text] [PDF]

				D. J. Schretlen, A. B. Inscore, T. D. Vannorsdall, M. Kraut, G. D. Pearlson, B. Gordon, and H. A. Jinnah Serum uric acid and brain ischemia in normal elderly adults Neurology, October 2, 2007; 69(14): 1418 - 1423. [Abstract] [Full Text] [PDF]

				M.-C. Corti, G. Baggio, L. Sartori, G. Barbato, E. Manzato, E. Musacchio, L. Ferrucci, G. Cardinali, D. Donato, L. J. Launer, et al. White Matter Lesions and the Risk of Incident Hip Fracture in Older Persons: Results From the Progetto Veneto Anziani Study Arch Intern Med, September 10, 2007; 167(16): 1745 - 1751. [Abstract] [Full Text] [PDF]

				B. Minguez, A. Rovira, J. Alonso, and J. Cordoba Decrease in the Volume of White Matter Lesions with Improvement of Hepatic Encephalopathy AJNR Am. J. Neuroradiol., September 1, 2007; 28(8): 1499 - 1500. [Abstract] [Full Text] [PDF]

				C. Rosano, H. J. Aizenstein, S. Studenski, and A. B. Newman A Regions-of-Interest Volumetric Analysis of Mobility Limitations in Community-Dwelling Older Adults J. Gerontol. A Biol. Sci. Med. Sci., September 1, 2007; 62(9): 1048 - 1055. [Abstract] [Full Text] [PDF]

				J Albrecht, P R Dellani, M J Muller, I Schermuly, M Beck, P Stoeter, A Gerhard, and A Fellgiebel Voxel based analyses of diffusion tensor imaging in Fabry disease J. Neurol. Neurosurg. Psychiatry, September 1, 2007; 78(9): 964 - 969. [Abstract] [Full Text] [PDF]

				M. F. O'Rourke and J. Hashimoto Mechanical Factors in Arterial Aging: A Clinical Perspective J. Am. Coll. Cardiol., July 3, 2007; 50(1): 1 - 13. [Abstract] [Full Text] [PDF]

				Y. Peng, S. Xu, G. Chen, L. Wang, Y. Feng, and X. Wang l-3-n-Butylphthalide Improves Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 902 - 910. [Abstract] [Full Text] [PDF]

				W. B. White The Riskiest Time for the Brain: Could the Nighttime Be the Right Time for Intervention? Hypertension, June 1, 2007; 49(6): 1215 - 1216. [Full Text] [PDF]

				C.-C. Wu and Y.-H. Young Association Between Leukoaraiosis and Saccadic Oscillation Arch Otolaryngol Head Neck Surg, March 1, 2007; 133(3): 245 - 249. [Abstract] [Full Text] [PDF]

				J. Ishikawa, Y. Tamura, S. Hoshide, K. Eguchi, S. Ishikawa, K. Shimada, and K. Kario Low-Grade Inflammation Is a Risk Factor for Clinical Stroke Events in Addition to Silent Cerebral Infarcts in Japanese Older Hypertensives: The Jichi Medical School ABPM Study, Wave 1 Stroke, March 1, 2007; 38(3): 911 - 917. [Abstract] [Full Text] [PDF]

				C. Opherk, N. Peters, M. Holtmannspotter, A. Gschwendtner, B. Muller-Myhsok, and M. Dichgans Heritability of MRI Lesion Volume in CADASIL: Evidence for Genetic Modifiers Stroke, November 1, 2006; 37(11): 2684 - 2689. [Abstract] [Full Text] [PDF]

				A. Spilt, R. Goekoop, R.G.J. Westendorp, G.J. Blauw, A.J.M. de Craen, and M.A. van Buchem Not all age-related white matter hyperintensities are the same: a magnetization transfer imaging study. AJNR Am. J. Neuroradiol., October 1, 2006; 27(9): 1964 - 1968. [Abstract] [Full Text] [PDF]

				T. Neumann-Haefelin, S. Hoelig, J. Berkefeld, J. Fiehler, A. Gass, M. Humpich, A. Kastrup, T. Kucinski, O. Lecei, D. S. Liebeskind, et al. Leukoaraiosis Is a Risk Factor for Symptomatic Intracerebral Hemorrhage After Thrombolysis for Acute Stroke Stroke, October 1, 2006; 37(10): 2463 - 2466. [Abstract] [Full Text] [PDF]

				Y. W. Chen, M. E. Gurol, J. Rosand, A. Viswanathan, S. M. Rakich, T. R. Groover, S. M. Greenberg, and E. E. Smith Progression of white matter lesions and hemorrhages in cerebral amyloid angiopathy. Neurology, July 11, 2006; 67(1): 83 - 87. [Abstract] [Full Text] [PDF]

				X. Guo, L. Pantoni, M. Simoni, D. Gustafson, C. Bengtsson, B. Palmertz, and I. Skoog Midlife Respiratory Function Related to White Matter Lesions and Lacunar Infarcts in Late Life: The Prospective Population Study of Women in Gothenburg, Sweden Stroke, July 1, 2006; 37(7): 1658 - 1662. [Abstract] [Full Text] [PDF]

				D. G. Munoz Leukoaraiosis and Ischemia: Beyond the Myth Stroke, June 1, 2006; 37(6): 1348 - 1349. [Full Text] [PDF]

				M. S. Fernando, J. E. Simpson, F. Matthews, C. Brayne, C. E. Lewis, R. Barber, R. N. Kalaria, G. Forster, F. Esteves, S. B. Wharton, et al. White Matter Lesions in an Unselected Cohort of the Elderly: Molecular Pathology Suggests Origin From Chronic Hypoperfusion Injury * Annex - Supplemental Online-Only Content Stroke, June 1, 2006; 37(6): 1391 - 1398. [Abstract] [Full Text] [PDF]

				H. Naka, E. Nomura, T. Takahashi, S. Wakabayashi, Y. Mimori, H. Kajikawa, T. Kohriyama, and M. Matsumoto Combinations of the presence or absence of cerebral microbleeds and advanced white matter hyperintensity as predictors of subsequent stroke types. AJNR Am. J. Neuroradiol., April 1, 2006; 27(4): 830 - 835. [Abstract] [Full Text] [PDF]

				T. den Heijer, P. E. Sijens, N. D. Prins, A. Hofman, P. J. Koudstaal, M. Oudkerk, and M.M.B. Breteler MR spectroscopy of brain white matter in the prediction of dementia Neurology, February 28, 2006; 66(4): 540 - 544. [Abstract] [Full Text] [PDF]

				J.-M. Lee and H. S. Markus Does the white matter matter in Alzheimer disease and cerebral amyloid angiopathy? Neurology, January 10, 2006; 66(1): 6 - 7. [Full Text] [PDF]

				M. K. Ikram, F. J. De Jong, E. J. Van Dijk, N. D. Prins, A. Hofman, M. M. B. Breteler, and P. T. V. M. De Jong Retinal vessel diameters and cerebral small vessel disease: the Rotterdam Scan Study Brain, January 1, 2006; 129(1): 182 - 188. [Abstract] [Full Text] [PDF]

				W M van der Flier, E C W van Straaten, F Barkhof, J M Ferro, L Pantoni, A M Basile, D Inzitari, T Erkinjuntti, L O Wahlund, E Rostrup, et al. Medial temporal lobe atrophy and white matter hyperintensities are associated with mild cognitive deficits in non-disabled elderly people: the LADIS study J. Neurol. Neurosurg. Psychiatry, November 1, 2005; 76(11): 1497 - 1500. [Abstract] [Full Text] [PDF]

				W. M. van der Flier, E. C.W. van Straaten, F. Barkhof, A. Verdelho, S. Madureira, L. Pantoni, D. Inzitari, T. Erkinjuntti, M. Crisby, G. Waldemar, et al. Small Vessel Disease and General Cognitive Function in Nondisabled Elderly: The LADIS Study Stroke, October 1, 2005; 36(10): 2116 - 2120. [Abstract] [Full Text] [PDF]

				N. D. Prins, E. J. van Dijk, T. den Heijer, S. E. Vermeer, J. Jolles, P. J. Koudstaal, A. Hofman, and M. M. B. Breteler Cerebral small-vessel disease and decline in information processing speed, executive function and memory Brain, September 1, 2005; 128(9): 2034 - 2041. [Abstract] [Full Text] [PDF]

				L. H.G. Henskens, A. A. Kroon, M. P.J. van Boxtel, P. A.M. Hofman, and P. W. de Leeuw Associations of the Angiotensin II Type 1 Receptor A1166C and the Endothelial NO Synthase G894T Gene Polymorphisms With Silent Subcortical White Matter Lesions in Essential Hypertension Stroke, September 1, 2005; 36(9): 1869 - 1873. [Abstract] [Full Text] [PDF]

				M. D. Napoli and F. Papa C-Reactive Protein and Cerebral Small-Vessel Disease: An Opportunity to Reassess Small-Vessel Disease Physiopathology? Circulation, August 9, 2005; 112(6): 781 - 785. [Full Text] [PDF]

				E. J. van Dijk, N. D. Prins, S. E. Vermeer, H. A. Vrooman, A. Hofman, P. J. Koudstaal, and M. M.B. Breteler C-Reactive Protein and Cerebral Small-Vessel Disease: The Rotterdam Scan Study Circulation, August 9, 2005; 112(6): 900 - 905. [Abstract] [Full Text] [PDF]

				D. J. Vinkers, M. L. Stek, R. C. van der Mast, A.J.M. de Craen, S. Le Cessie, J. Jolles, R. G.J. Westendorp, and J. Gussekloo Generalized atherosclerosis, cognitive decline, and depressive symptoms in old age Neurology, July 12, 2005; 65(1): 107 - 112. [Abstract] [Full Text] [PDF]

				M. Torn, W. L. E. M. Bollen, F. J. M. van der Meer, E. E. van der Wall, and F. R. Rosendaal Risks of Oral Anticoagulant Therapy With Increasing Age Arch Intern Med, July 11, 2005; 165(13): 1527 - 1532. [Abstract] [Full Text] [PDF]

				S. Soljanlahti, T. Autti, K. Lauerma, R. Raininko, P. Keto, H. Turtola, and A. F. Vuorio Familial Hypercholesterolemia Patients Treated With Statins at No Increased Risk for Intracranial Vascular Lesions Despite Increased Cholesterol Burden and Extracranial Atherosclerosis Stroke, July 1, 2005; 36(7): 1572 - 1574. [Abstract] [Full Text] [PDF]

				H. S. Markus, B. Hunt, K. Palmer, C. Enzinger, H. Schmidt, and R. Schmidt Markers of Endothelial and Hemostatic Activation and Progression of Cerebral White Matter Hyperintensities: Longitudinal Results of the Austrian Stroke Prevention Study Stroke, July 1, 2005; 36(7): 1410 - 1414. [Abstract] [Full Text] [PDF]

				T. H. Mosley Jr, D. S. Knopman, D. J. Catellier, N. Bryan, R. G. Hutchinson, C. A. Grothues, A. R. Folsom, L. S. Cooper, G. L. Burke, D. Liao, et al. Cerebral MRI findings and cognitive functioning: The Atherosclerosis Risk in Communities Study Neurology, June 28, 2005; 64(12): 2056 - 2062. [Abstract] [Full Text] [PDF]

				M. D. Hill and J. D. Bisognano Leukoaraiosis: The brain under pressure: Target for treatment? Neurology, June 14, 2005; 64(11): 1832 - 1833. [Full Text] [PDF]

				I. B. Goldstein, G. Bartzokis, D. Guthrie, and D. Shapiro Ambulatory blood pressure and the brain: A 5-year follow-up Neurology, June 14, 2005; 64(11): 1846 - 1852. [Abstract] [Full Text] [PDF]

				J H Fu, C Z Lu, Z Hong, Q Dong, Y Luo, and K S Wong Extent of white matter lesions is related to acute subcortical infarcts and predicts further stroke risk in patients with first ever ischaemic stroke J. Neurol. Neurosurg. Psychiatry, June 1, 2005; 76(6): 793 - 796. [Abstract] [Full Text] [PDF]

				M. Ouhlous, H. Z. Flach, T. T. de Weert, J. M. Hendriks, M. R. H. M. van Sambeek, D. W. J. Dippel, P. M. T. Pattynama, and A. van der Lugt Carotid Plaque Composition and Cerebral Infarction: MR Imaging Study AJNR Am. J. Neuroradiol., May 1, 2005; 26(5): 1044 - 1049. [Abstract] [Full Text] [PDF]

				M. A. Ritter, D. W. Droste, K. Hegedus, R. Szepesi, D. G. Nabavi, L. Csiba, and E. B. Ringelstein Role of cerebral amyloid angiopathy in intracerebral hemorrhage in hypertensive patients Neurology, April 12, 2005; 64(7): 1233 - 1237. [Abstract] [Full Text] [PDF]

				S. T. Turner, M. Fornage, C. R. Jack Jr, T. H. Mosley, S. L. R. Kardia, E. Boerwinkle, and M. de Andrade Genomic Susceptibility Loci for Brain Atrophy in Hypertensive Sibships From the GENOA Study Hypertension, April 1, 2005; 45(4): 793 - 798. [Abstract] [Full Text] [PDF]

				P S Sachdev, W Wen, H Christensen, and A F Jorm White matter hyperintensities are related to physical disability and poor motor function J. Neurol. Neurosurg. Psychiatry, March 1, 2005; 76(3): 362 - 367. [Abstract] [Full Text] [PDF]

				M. Alchanatis, N. Deligiorgis, N. Zias, A. Amfilochiou, E. Gotsis, A. Karakatsani, and A. Papadimitriou Frontal brain lobe impairment in obstructive sleep apnoea: a proton MR spectroscopy study Eur. Respir. J., December 1, 2004; 24(6): 980 - 986. [Abstract] [Full Text] [PDF]

				D. M. Moody, C. R. Thore, J. A. Anstrom, V. R. Challa, C. D. Langefeld, and W. R. Brown Quantification of Afferent Vessels Shows Reduced Brain Vascular Density in Subjects with Leukoaraiosis Radiology, December 1, 2004; 233(3): 883 - 890. [Abstract] [Full Text] [PDF]

				E. E. Smith, M. E. Gurol, J. A. Eng, C. R. Engel, T. N. Nguyen, J. Rosand, and S. M. Greenberg White matter lesions, cognition, and recurrent hemorrhage in lobar intracerebral hemorrhage Neurology, November 9, 2004; 63(9): 1606 - 1612. [Abstract] [Full Text] [PDF]

				M. Shibata, R. Ohtani, M. Ihara, and H. Tomimoto White Matter Lesions and Glial Activation in a Novel Mouse Model of Chronic Cerebral Hypoperfusion Stroke, November 1, 2004; 35(11): 2598 - 2603. [Abstract] [Full Text] [PDF]

				E. J. van Dijk, M. M.B. Breteler, R. Schmidt, K. Berger, L.-G. Nilsson, M. Oudkerk, A. Pajak, S. Sans, M. de Ridder, C. Dufouil, et al. The Association Between Blood Pressure, Hypertension, and Cerebral White Matter Lesions: Cardiovascular Determinants of Dementia Study Hypertension, November 1, 2004; 44(5): 625 - 630. [Abstract] [Full Text] [PDF]

				J. van der Grond, A. F. van Raamt, Y. van der Graaf, W. P.T.M. Mali, and R. H.C. Bisschops A fetal circle of Willis is associated with a decreased deep white matter lesion load Neurology, October 26, 2004; 63(8): 1452 - 1456. [Abstract] [Full Text] [PDF]

				T. den Heijer, S. E Vermeer, E. J van Dijk, N. D Prins, P. J Koudstaal, C. M van Duijn, A. Hofman, and M. M. Breteler Alcohol intake in relation to brain magnetic resonance imaging findings in older persons without dementia Am. J. Clinical Nutrition, October 1, 2004; 80(4): 992 - 997. [Abstract] [Full Text] [PDF]

				N. D. Prins, E. J. van Dijk, T. den Heijer, S. E. Vermeer, P. J. Koudstaal, M. Oudkerk, A. Hofman, and M. M. B. Breteler Cerebral White Matter Lesions and the Risk of Dementia Arch Neurol, October 1, 2004; 61(10): 1531 - 1534. [Abstract] [Full Text] [PDF]

				D. J. Werring, D. W. Frazer, L. J. Coward, N. A. Losseff, H. Watt, L. Cipolotti, M. M. Brown, and H. R. Jager Cognitive dysfunction in patients with cerebral microbleeds on T2*-weighted gradient-echo MRI Brain, October 1, 2004; 127(10): 2265 - 2275. [Abstract] [Full Text] [PDF]

				S Artero, H Tiemeier, N D Prins, R Sabatier, M M B Breteler, and K Ritchie Neuroanatomical localisation and clinical correlates of white matter lesions in the elderly J. Neurol. Neurosurg. Psychiatry, September 1, 2004; 75(9): 1304 - 1308. [Abstract] [Full Text] [PDF]

				P. Sachdev, R. Parslow, C. Salonikas, O. Lux, W. Wen, R. Kumar, D. Naidoo, H. Christensen, and A. Jorm Homocysteine and the Brain in Midadult Life: Evidence for an Increased Risk of Leukoaraiosis in Men Arch Neurol, September 1, 2004; 61(9): 1369 - 1376. [Abstract] [Full Text] [PDF]

				H. Shibata, T. Nabika, H. Moriyama, J. Masuda, and S. Kobayashi Correlation of NO Metabolites and 8-Iso-Prostaglandin F2a With Periventricular Hyperintensity Severity Arterioscler Thromb Vasc Biol, September 1, 2004; 24(9): 1659 - 1663. [Abstract] [Full Text] [PDF]

				H.-K. Kuo and L. A. Lipsitz Cerebral White Matter Changes and Geriatric Syndromes: Is There a Link? J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2004; 59(8): M818 - M826. [Abstract] [Full Text] [PDF]

				L. H. Kuller, W.T. Longstreth Jr, A. M. Arnold, C. Bernick, R. Nick Bryan, N. J. Beauchamp Jr, and for the Cardiovascular Health Study Collaborative White Matter Hyperintensity on Cranial Magnetic Resonance Imaging: A Predictor of Stroke Stroke, August 1, 2004; 35(8): 1821 - 1825. [Abstract] [Full Text] [PDF]

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