The neuropathology of vascular dementia

The Neuropathology of Vascular Dementia Gustavo C. Román and Oscar Benavente Ischemic infarction is the main lesion underlying vascular dementia (VaD) but cases also occur after brain hemorrhage, as well as with hypoperfusive brain ischemia. Ischemic strokes include large-vessel cortico-subcortical strokes and lacunes resulting from smallvessel disease. Arteriolosclerosis and fibrinoid necrosis are the most common forms of small-vessel disease in the elderly. Although it was originally proposed that vascular dementia could result from repeated strokes with loss of >100 mL of brain tissue loss (multi-infarct dementia), it is currently held that the location of the stroke is probably more relevant to cognitive loss and dementia. In fact, a single, strategically located stroke may interrupt cortico-subcortical circuits important for memory and cognition. Hypoperfusive lesions include border-zone cortico-subcortical infarcts, temporal lobe sclerosis, and periventricular incomplete ischemic leukoencephalopathy. The latter two lesions are commonly seen in the elderly as a result of narrowing and tortuosity of medullary arterioles irrigating these distal territories, plus cardiac pump failure. Binswanger disease is characterized by extensive periventricular ischemic leukoencephalopathy that spares the arcuate U-fibers, and presence of lacunar strokes. CADASIL is a genetic form of vascular dementia characterized by a cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. CADASIL is due to a mutation of the Notch3 gene in chromosome 19. Intracerebral hemorrhages in strategic locations may produce vascular dementia. Lesions in the basal forebrain that damage cholinergic nuclei, such as those resulting from a ruptured aneurysm of the anterior communicating artery, may produce vascular dementia. Some patients with subarachnoid hemorrhage develop normal-pressure hydrocephalus. Cerebral amyloid angiopathy (congophilic angiopathy) may cause lobar hemorrhages and dementia. Vascular lesions, in particular, microinfarcts, are frequently found in patients with a clinical diagnosis of Alzheimer disease. These mixed forms of dementia are likely to become the most common form of dementia in the elderly. Semin Cerebrovasc Dis Stroke 4:87–96 © 2004 Elsevier Inc. All rights reserved. KEYWORDS: vascular dementia, stroke, lacunes, Binswanger disease, CADASIL, leukoencephalopathy, amyloid angiopathy

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ascular dementia (VaD) is the second most common cause of dementia in the elderly and an important contributor to degenerative dementias, in particular, Alzheimer disease (AD). VaD is the result of brain injury produced by cerebrovascular disease, either hemorrhagic or ischemic, or by hypoperfusive lesions resulting from cardiac disease or circulatory failure. Table 1 summarizes the main neuropathological types of vascular brain injury that cause VaD.1

Division of Neurology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA. Address reprint requests to: Dr. Gustavo Román, University of Texas Health Science Center, San Antonio, Texas 78229, USA. E-mail: ROMANG@ UTHSCSA.EDU

1528-9931/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.scds.2004.10.002

Cerebrovascular Disease Atherosclerosis The main cause of cerebrovascular disease (CVD) is atherosclerosis, an inflammatory disease with cholesterol deposits producing obstructive lesions of large- and medium-sized elastic and muscular arteries.2 Markers of inflammation such as C-reactive protein, cytokines, and adhesion molecules are strong predictors of atherosclerosis. The main vascular risk factors include elevated low-density lipoproteins (LDL), cigarette smoking, hypertension, diabetes mellitus, increased plasma homocysteine, and infection. Endothelial dysfunction appears to be an early step leading to atherosclerosis by increasing adhesiveness of circulating leukocytes and platelets, and by activating procoagulants and 87

88 Table 1 Neuropathological Lesions Capable of Producing Vascular Dementia* 1. Multiinfarct dementia Multiple large complete infarcts, cortico–subcortical in location, usually with perifocal incomplete infarction involving the white matter. 2. Strategic infarct dementia A single brain infarct, often lacunar in size, damages functionally critical areas of the brain (angular gyrus, thalamus, basal forebrain, posterior cerebral artery, and anterior cerebral artery territories). 3. Small-vessel disease with dementia Subcortical Binswanger disease CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) Lacunar dementia or lacunar state (état lacunaire) Multiple lacunes with extensive perifocal incomplete infarctions Cortical and Subcortical Hypertensive and arteriolosclerotic angiopathy Amyloid angiopathies (including British dementia) Collagen-vascular disease with dementia 4. Ischemic-hypoxic dementia (hypoperfusive) Diffuse anoxic-ischemic encephalopathy Restricted injury due to selective vulnerability: ie, mesial temporal lobe sclerosis Incomplete white-matter infarction Border-zone infarction 5. Hemorrhagic dementia Traumatic subdural hematoma Subarachnoid hemorrhage Cerebral hematoma Venous thrombosis 6. Other mechanisms *Modified from A. Brun.1

growth factors. Inflammatory responses stimulate migration and proliferation of smooth muscle cells resulting in dilation or “remodeling” of the vessel wall. Atherosclerotic plaques in large vessel disclose, in addition to the damage of the intima and subintima, abundant cholesterol deposits with associated inflammatory changes. Atherosclerosis of the cerebral circulation results in thrombotic occlusion of large vessels, artery-to-artery thromboembolism, and large cortical-subcortical infarcts. In the brain, atherosclerosis also affects small vessels particularly by the development of plaques of microatheroma (Fig. 1) and subintimal foam cell accumulation at the proximal end of perforating arteries (200 to 800 ␮m in diameter), affecting predominantly the basilar artery and the middle cerebral artery. These lesions typically produce lacunar strokes or small, deep infarcts in basal ganglia and pons.

Arteriolosclerosis One of the frequent changes of aging in cerebral arterioles is arteriolosclerosis.3 On light microscopy (Fig. 2), this lesion shows a typical onion-skin concentric proliferation and degeneration of smooth muscle cells in small arterioles, affect-

G.C. Román and O. Benavente ing the tunica media and internal elastic lamina; there is as well a concentric lamellar deposition of collagen fibers and presence of a fibrohyaline substance in the subadventitia, with minimal changes in the intima. Electron microscopy shows proliferation of collagen fibers, accumulation of cellular debris, and deposition of amorphous material in the subadventitia; amyloid is not present and angionecrosis is seldom seen. The arterioles become elongated, tortuous, and narrow (Fig. 3). The severity of ischemic periventricular white-matter lesions observed on magnetic resonance imaging (MRI) in the elderly is closely correlated with progressive degrees of arteriolosclerosis.4,5 Likewise, arteriolosclerosis of penetrating arterioles is associated with lacunar infarcts.

Hypertensive Arteriopathy Fisher6,7 studied the cerebral microangiopathy of arterial hypertension in the context of lacunes. The main hypertensive lesions found in lacunes are microatheromata, lipohyalinosis, and fibrinoid necrosis.3 As mentioned above, minute foci of microatheromatosis (Fig. 1) produce stenosis or occlusion of penetrating arterioles in hypertensive subjects. Lipohyalinosis (Fig. 4) is a progressive disorganization of small-artery walls, usually present in vessels ⬍200 ␮m in diameter, with subintimal deposits of a hyaline fibrinoid substance. Lipohyalinosis leads either to thrombotic occlusion of the lumen and lacunar stroke or to mural destruction with formation of microaneurysms and hypertensive cerebral hemorrhage in the basal ganglia, thalamus, pons, and cerebellum.7 Fibrinoid angionecrosis occurs with extreme hypertension producing segmental narrowing, dilation, and necrosis of the vessel wall with deposits of a brightly eosinophilic substance. Around the constricted spastic segments, the perivascular tissues and neuropil are destroyed and astrocytic edema is present.8

Cerebral Amyloid Angiopathy (CAA) This is a group of disorders characterized by deposition of amyloid in the walls of leptomeningeal and cerebral cortical blood vessels, characterized clinically by recurrent or multiple lobar hemorrhages, cognitive deterioration, and ischemic stroke. On histology (Fig. 5, left), the vessels show amyloid deposition with presence of an amorphous, eosinophilic, hyaline, extracellular substance staining pink or red with the Congo red stain (hence the name Congophilic angiopathy). Under polarized light, the Congo red stained amyloid shows a striking green birefringence (Fig. 5, right) due to binding of the dye to the ␤-pleated sheets of amyloid protein chains. The vessels also show microaneurysms and fibrinoid necrosis. CAA is associated with lobar hemorrhages and microinfarcts. The A␤ protein is deposited in Alzheimer disease associated CAA,9 as well as in the Dutch-, Flemish-, and Iowa-type familial CAA. At least eight hereditary forms of CAA have been identified including hereditary cerebral hemorrhage with amyloidosis (either Dutch- or Icelandic-type)10 and Familial British dementia,11 an autosomal dominant CAA characterized by VaD, progressive spastic paraparesis, cerebellar ataxia, Binswanger-type deep white-matter hyperintensities,

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Figure 1 Typical lesion of microatheromatosis in penetrating cerebral arteriole; notice cholesterol cristals deposited in the subintima (H & E stain) (Courtesy of Dr. Helena Chui). (Color version of figure is available online.)

and lacunar infarcts but without intracerebral hemorrhages. There is systemic deposit of an amyloid subunit (ABri) entirely different from, and unrelated to, other amyloid proteins.12

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) CADASIL is the most common genetic form of VaD with more than 500 affected families worldwide. CADASIL is due to autosomal dominant mutations of the Notch3 gene, located in chromosome 19.13,14 The vascular lesion is a unique nonamyloid nonatherosclerotic microangiopathy involving arterioles (100 to 400 ␮m in diameter) and capillaries, primarily in the brain but also in other organs. The diagnosis may be established by skin biopsy,15 confirmed by immunostaining with a Notch3 monoclonal antibody.16 The vessels show striking smooth muscle cell loss along with deposits of eosinophilic, PAS-positive material in the arterial media (Fig. 6). On electron microscopy there are deposits of a granular osmiophilic material (GOM) and accumulation of the ectodomain of the Notch3 receptor in the basal lamina of degenerated smooth muscle cells.15 The brain lesions are ischemic infarcts, mainly lacunar strokes, localized in basal ganglia, thalamus, centrum ovale, and pons, associated with extensive, confluent areas of frontal ischemic leukoencephalopathy, particularly in periventricular regions. (See review on CADASIL by Ruchoux in this issue.)

Other Forms of CVD Figure 2 Ateriolosclerosis with typical onion-skin concentric proliferation and degeneration of smooth muscle cells in small arteriole; there is concentric lamellar deposition of collagen fibers and presence of a fibrohyaline substance in the subadventitia, with minimal changes in the intima. Notice the decrease in lumen resulting from these changes. (Color version of figure is available online.)

Other causes of ischemic or hemorrhagic brain injury from CVD include cardioembolism, vasculitis, coagulation abnormalities, fibromuscular dysplasia, Moyamoya disease, vascular malformations, telangiectasias, aneurysms, and venous thrombosis. Ischemic injury from brain hypoperfusion may result from pump failure secondary to congestive heart failure, cardiac disease, cardiac arrhythmias, and circulatory disturbances.

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Figure 3 Penetrating arterioles in hypertension showing striking hardening and loss of elasticity. (Color version of figure is available online.)

Figure 4 Disorganization of the arteriolar wall with subintimal deposits of a hyaline fibrinoid substance typical of hypertensive lipohyalinosis (H & E stain). (Color version of figure is available online.)

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Figure 5 Left: Congo-red stain showing amyloid deposition as amorphous, hyaline, extracellular substance staining pinkish red in meningeal vessels (Congophilic angiopathy). Right: Under polarized light, the Congo-red stained amyloid shows a striking green birefringence. (Color version of figure is available online.)

Cerebrovascular Brain Injury (CVI) The main forms of cerebrovascular injury are ischemia and hemorrhage. Hemorrhage results from rupture of the blood

vessel wall leading to extravasation of blood into the surrounding tissue. The most common ones are hypertensive intracerebral hemorrhage, traumatic subdural hematoma, subarachnoid hemorrhage, cerebral hematoma, and cortical venous and sinus thrombosis.

Figure 6 Cerebral arteriolar lesion in CADASIL. There is smooth muscle cell loss and deposits of eosinophilic, PASpositive material in the arterial media. (Courtesy of Dr. S. Salloway). (Color version of figure is available online.)

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Figure 7 Numerous bilateral lacunes in lenticular nucleus and internal capsule resulting from reabsorption of small infarcts due to occlusion of lenticulostriate arterioles. (Color version of figure is available online.)

In hemorrhagic infarct, the features of ischemic infarction are present but, in addition, red cells in varying amounts infiltrate the necrotic tissues. These lesions usually occur as a result of reperfusion of the infarcted territory following breakup of emboli. The bleeding is petechial and limited to the infarcted cortex; the white matter does not become hemorrhagic. Hemorrhagic infarcts affecting both gray and white matter are observed in sinus and cortical vein thromboses. Ischemia occurs when tissue perfusion to supply oxygen and glucose is inadequate to support cell metabolism. This may be secondary to cardiac or circulatory system failure, or to occlusion of cerebral vessels. When perfusion pressure falls below critical levels, ischemia and infarction develop according to the duration of hypoperfusion and the energy requirements of neurons and glia (ie, neurons ⬎ oligodendrocytes ⬎ astrocytes ⬎ endothelial cells). However, experimental work has shown oligodendrocyte swelling and myelin vacuolar changes occurring before any signs of injury to neurons are noted.

Complete Infarction Arterial thrombotic or embolic occlusion in the brain causes necrosis of all tissue elements due to ischemic brain injury. This is the typical pale, anemic, or bland infarction. The main types are as follows.

Large Artery Infarct Located in the distribution of major feeding arteries or their main branches, these lesions are usually wedge-shaped, involving cortex and underlying subcortical white matter. Microscopic lesions include widespread ischemic necrosis, tissue liquefaction, leukocyte infiltration at the periphery of the lesion, and later on, macrophage invasion for removal of necrotic materials. The area of necrosis is eventually converted into a cystic structure surrounded by glial reaction and filled with debris and fluid. Lacunar Infarct Lacunar infarct is defined as a small cavity, usually less than 2 cm in diameter, resulting from reabsorption of a small infarct from occlusion of lenticulostriate (Fig. 7), thalamoperforating, and long medullary arterioles (Fig. 8). Lacunes must be distinguished from a dilated perivascular space (état criblé). Microscopically, état criblé cavities show no evidence of necrosis, macrophages, or tissue debris and have a small vessel within the lacuna. Reabsorption of minute hemorrhages may result in lacunar lesions. Dilated Perivascular Spaces (état criblé) This is a common finding in the elderly brain whereby enlarged spaces of Virchow–Robin surrounding arteries and veins are filled with cerebrospinal fluid (Fig. 9). The patho-

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93 Microinfarcts A microinfarct is a minute area of ischemic infarction, a few microns in diameter, visible only under the microscope. These lesions are not seen with the naked eye on macroscopic examination of the brain and are not visualized with current imaging techniques. Under the microscope (Fig. 10), a small area of cystic or noncystic necrosis surrounded by astrocytes is seen. Microinfarcts are considered an important contributor to VaD.19,20

Figure 8 Lacune in the centrum semiovale; these lesions result from occlusion of penetrating long medullary arterioles. (Color version of figure is available online.)

genesis of these lesions is disputed and may include increased arterial permeability, perivascular inflammatory factors, and most likely, mechanical pulsatility and tortuosity of the vessels with age.17 These dilated perivascular spaces may be particularly prominent in the anterior perforated substance located below the putamen and above the lateral portion of the anterior commissure.18

Border-Zone Infarcts These lesions occur in the terminal distribution of end-arterioles at the junction of large-vessel arterial territories, for instance, in the cortex posterior to the interparietal sulcus (“parietal watershed”) at the boundaries between anterior and middle cerebral arteries in cases of extracranial internal carotid artery occlusion; or in the center of the white matter, between the deep territories of the anterior and middle cerebral arteries; as well as in the periventricular white matter fed by long-penetrating end-arterioles. Elderly patients are more susceptible to watershed infarcts than younger subjects are. Typical watershed, boundary, or border-zone infarcts occur in relentless and prolonged hypotension or in patients with impaired collateral circulation due to severe, extensive, or multiple atheromatous stenoses of the cerebral arteries. Hippocampal Sclerosis The particular vascular supply of the hippocampus helps explain the development of a typical pattern of hippocampal

Figure 9 Typical e´tat crible´ in the elderly resulting from dilated perivascular spaces of Virchow-Robin, surrounding tortuous, calcified arterioles. (Color version of figure is available online.)

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Figure 10 Cortical microinfarct seen as a small area of cystic necrosis surrounded by astrocytes. (Courtesy of Dr. Helena Chui). (Color version of figure is available online.)

sclerosis. This is a localized form of ischemia and atrophy observed in very old demented subjects, particularly in those with cardiac disease. The hippocampal arteries arise mainly from the posterior cerebral artery and to a lesser degree from the anterior choroidal artery, a branch of the internal carotid artery. Straight arteries from the hippocampal arteries enter Ammon’s horn through the dentate gyrus and then branch out at right angles in a rake-like pattern. As a result, the CA1 sector is poorly vascularized. Hippocampal sclerosis in the elderly is characterized by selective neuronal loss in the CA1 sector of the hippocampus extending into the subiculum, without cavitation.21 Hippocampal sclerosis is a common neuropathologic finding in very old patients (⬎80 years of age) with dementia,21,22 and with cardiac disease.23 Crystal and coworkers24 postulated that hippocampal sclerosis, leukoencephalopathy, and multiple lacunes are markers of VaD in the elderly and suggested that the cause of hippocampal sclerosis in the elderly is probably systemic hypoperfusion with hypoxia-ischemia; Vinters and coworkers19 suggested that it may result from ischemia due to intrinsic cerebrovascular disease. These two hypotheses are complementary and not mutually exclusive. Hippocampal sclerosis is commonly found in the elderly, representing 12% of unselected elderly patients coming to autopsy in a community-based study,21 as well as 5% of cases of “dementia of unknown etiology” in patients dying in their 70s, 21% of those in their 80s, and nearly 50% among nonagenarians.25 Recently, it has been postulated that some cases of hippocampal sclerosis may be related to the fronto-temporal dementias due to the presence of neuronal ubiquitinpositive inclusions.26

Incomplete Infarction Depending on the perfusion threshold and duration of the hypoperfusion, selective cell loss may occur without frank infarction or cystic necrosis. There is selective loss of neurons in the penumbra surrounding acute infarcts.27 Incomplete infarction is also found in the periventricular deep white matter of patients with severe stenosis of medullary arterioles,4,5 as well as in postmortem examination in more than half of patients with AD.28,29 Incomplete white matter infarcts are associated with selective loss of oligodendrocytes, myelin, and axons (Fig. 11), as well as état criblé, resulting in pallor of myelin staining due to progressive degrees of vacuolization or spongiosis (Fig. 12) of the white matter.5 These lesions are typical of Binswanger disease (Figs. 11, 12). This selective loss of tissue elements due to ischemia is known as incomplete infarction27-29 and may occur when (1) systemic blood pressure drops below autoregulatory reserve, (2) intracranial pressure exceeds mean arterial pressure, or (3) there is severe stenosis of multiple arteries or arterioles. The threshold of ischemia appears to depend on the duration of hypoperfusion. The anatomical patterns of microcirculation explain the susceptibility of certain cerebral areas to hypoperfusion. According to Moody and coworkers,30 brain areas irrigated by short penetrating arteries can tolerate hypotension and hypoperfusion better. These resistant areas include cerebral cortex, the subcortical arcuate fibers, and the corpus callosum. In addition, the claustrum and the external and extreme capsules receive dual circulation and are resistant to hypotensive and hypoperfusive injuries. In

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contrast, the white matter in the centrum semi-ovale as well as the periventricular white matter are distal watershed territories irrigated by long penetrating medullary arteries; these are highly sensitive to hypoperfusion, particularly in the elderly. Likewise, the distal territories of the lenticulostriate arteries in the basal ganglia are affected selectively by lacunar strokes.

Neuropathologic Diagnosis of Vascular Dementia The neuropathologic diagnosis of VaD is problematic because it is difficult to determine on postmortem examination whether a cerebrovascular lesion was causal, contributory, or coincidental to the dementia. This is particularly difficult in cases where lesions of AD, or Lewy-body dementia, are also present. The presence of comorbid AD and CVD is very common, as noted in several autopsy series.31-35 Pure AD, without CVD, occurs in only 20% of postmortem studies in patients with dementia.36 Moreover, there was a significant inverse relationship between the severity of CVD and Braak stage, indicating that vascular lesions and AD lesions have synergistic effects. No consensus has been reached on the pathological diagnosis of VaD. The diagnosis is usually made in the presence of vascular lesions, often of a certain size or volume, in the absence of degenerative lesions.37-40 Joachim and coworkers41 considered strokes to have contributed to the clinical dementia if sufficiently remote or larger in size than lacune, or if the vascular lesions involved the hippocampus, amygdala, thalamus, or basal forebrain. Gold and coworkers42,43

Figure 12 Periventricular pallor of myelin staining, and vacuolization or spongiosis. Notice sparing of subcortical arcuate fibers typical of Binswanger disease. (Luxol fast blue staining). (Color version of figure is available online.)45,46

defined vascular dementia as cortical-subcortical infarcts in parietal, temporal, or frontal lobes, but subcortical infarcts by themselves were not considered sufficient for a pathologic diagnosis of VaD. Binswanger disease (subcortical arteriosclerotic encephalopathy) (Figs. 13,14) can be diagnosed in the presence of severe white matter changes with demyelination and axonal loss, plus lacunes and severe, widespread arteriolosclerosis.44 Recent cohort studies in California19 and Hawaii20 use a scoring system to capture the severity and extent of cerebrovascular brain injury.

Summary Despite significant progress in the understanding of VaD, many areas remain unclear. This is one of the few forms of dementia in the elderly where a neuropathology gold standard is missing. Correlation studies with imaging and neurochemistry may provide in the future the elements that are needed to establish with certainty a neuropathologic diagnosis of VaD.

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Figure 11 White matter lesion of incomplete infarction with loss of oligodendrocytes, myelin and axons; small cavitation is seen in the center (Luxol fast blue staining). (Color version of figure is available online.)

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