The Neuropathology of Vascular and Mixed Dementia and Vascular Cognitive Impairment

Handbook of Clinical Neurology, Vol. 89 (3rd series) Dementias C. Duyckaerts, I. Litvan, Editors # 2008 Elsevier B.V. All rights reserved

Vascular dementias Chapter 62

The neuropathology of vascular and mixed dementia and vascular cognitive impairment JEAN-JACQUES HAUW 1 *, UMBERTO DE GIROLAMI 1, 2, AND DINA ZEKRY 1, 3 1

APHP, La Salpeˆtriere Hospital; Pierre and Marie Curie University, Paris, France

2

Brigham and Women’s Hospital and Children’s Hospital; Harvard Medical School, Boston, USA, and 3

Department of Rehabilitation and Geriatrics, Thoˆnex, Switzerland

62.1. Introduction The diagnosis of vascular dementia may rely on three criteria: (a) a clinical diagnosis of dementia; (b) a clinical or neuropathologic demonstration of brain lesions caused by cerebrovascular disease that can be related to the dementia; (c) a clinical or neuropathologic study that fails to demonstrate other types of brain lesions to explain the dementia. According to this operational definition, it is apparent that the diagnosis of vascular dementia cannot be made exclusively on the basis of a neuropathologic examination; it requires joint input of clinical and pathologic data. At present, it is generally agreed that one of the requirements to establish the diagnosis of definite vascular dementia is the confirmation of cerebrovascular disease by pathologic study (Chui et al., 1992; Roman et al., 1993; Lopez et al., 2005). A further complicating factor is that a number of clinical processes may mimic dementia; accordingly, even with neuropathologic documentation of cerebrovascular disease, an erroneous diagnosis of vascular dementia might be adduced. Lastly, it may be quite difficult to discriminate between vascular lesions capable of explaining the dementia and incidental postmortem findings unrelated to it. No criteria for scoring the severity of the lesions responsible for vascular dementia or vascular cognitive impairment, and particularly for the consequences of small vessel disease, are available (Ince, 2005). We propose the following guidelines be used as an initial approach to this controversial topic: the topo-

graphic distribution within the brain of the vascular lesion is of primary importance and is the basis of the useful concept of “cerebrovascular brain injury” put forth by Chui (2005). However, there is a range of severity of brain lesions that may modulate mental dysfunction (e.g., infarction with cavitation versus myelin rarefaction). The anatomic structures believed to be related to the clinical deficits that define dementia according to the DSMIVR (namely, disturbances of memory, language, praxis, gnosis, and executive functioning) need to be systematically analyzed through case studies. Moreover, one must bear in mind that the classic concepts of dementia syndromes may be different from those that underlie vascular cognitive syndromes (Ince, 2005). The larger the lesion, the higher the probability of injury to structures implicated in the mechanism of dementia. On the other hand, small lesions involving special regions of the brain can have severe consequences for mental function: “strategic infarction”. It is useful to distinguish between acquired and hereditary forms of vascular dementia (Markesbery, 1998; Ince, 2005; Kalimo and Kalaria, 2005), but, it must be noted that hereditary diseases may become clinically manifest in adulthood, sometimes in later years, and that there may be no indication of a familial history. The early stages of mental decline that precede vascular dementia, namely vascular cognitive impairment, although conceptually important from a public health viewpoint, are very difficult to recognize clinically;

*Correspondence to: Jean-Jacques Hauw, MD, Department of Neuropathology, APHP, La Salpeˆtriere Hospital, 47 bd. de l’hoˆpital, 75013, Paris, France. E-mail: [email protected], Tel: þ33-142161881, Fax: þ33-142161899.

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indeed, there are no reported diagnostic criteria at this stage of the disease (see Bowler, 2005). Although it is most likely that very similar or identical types of vascular lesions underlie both clinical syndromes of vascular cognitive impairment and vascular dementia, the burden of lesions, the variability in the degrees of severity, and the range of topographic distribution might well be important determining factors in establishing thresholds of clinical significance. The term mixed dementia has been applied to those cases wherein there is clinical and/or neuropathologic evidence of both vascular and non-vascular diseases. This complex syndrome appears to be much more frequent than was believed at one time. Its medical relevance takes into account the considerable number of cases that satisfy the criteria (a) and (b) above, as defining parameters of vascular dementia (i.e., the presence of clinical dementia and neuropathologic evidence of relevant cerebrovascular lesions), but do not fulfill criterion (c) because there are non-vascular lesions which can explain the dementia (Delay and Brion, 1962). The systematic identification of these additional factors is now a topic under active investigation. Since both vascular disease and degenerative disorders, such as Alzheimer’s disease, occur frequently in the elderly, it is now increasingly recognized that mixed dementia is actually a rather common disease. Indeed, the Neuropathology Group of the Medical Research Council (MRC) Cognitive Function and Age Study, considering the pathologic correlates of late-onset dementia in a multi-center, community-based population in England and Wales, found multiple vascular lesions in 46% of demented cases and 33% in non-demented, in a series of 209 patients, aged 70–103. They were associated with Alzheimer-type lesions thought severe enough to induce dementia in 64% of demented cases and 33% of non-demented cases (MRC CFAS Neuropathology Group, 2001). This review will not attempt to delve deeply into this broad and controversial topic. The reader is, however, referred to several important references of historical interest and recent general reviews (Yates, 1976; Loeb, 1985; Freeman et al., 1989; Pantoni, 1995; Bowler, 1998; Markesbery, 1998; Vinters, 1998; Lammie, 2002; Roman, 2002a; Zekry et al., 2002b; Bowler, 2005; Chui, 2005; Ince, 2005; Jellinger, 2005; Kalimo and Kalaria, 2005; Lammie, 2005; Jellinger, 2007). In this chapter we will first consider the lesions involved, or possibly involved, in vascular and mixed dementia and in vascular cognitive impairment, aiming to clarify the somewhat confusing terminology. We will then address recent, generally accepted, or controversial data, elaborating only on original contributions when useful for the understanding of unsettled questions.

62.2. Principal lesions involved in vascular and mixed dementia; pathogenetic mechanisms The main causes and mechanisms of vascular dementia have been reported in a number of publications. The NINDS-AIREN International Workshop (Roman et al., 1993) identified six mechanisms for vascular dementia: multiple infarcts, strategic infarction, smallvessel disease, hypoperfusion injury, hemorrhage, other mechanisms, and multiple etiologic factors in various combinations. 62.2.1. Types of brain lesions A wide range of hemispheric lesions are responsible for vascular dementia, particularly when occurring bilaterally. 62.2.1.1. Cerebral infarcts Cerebral infarcts have long been recognized as one of the most important mechanisms of vascular dementia. Infarcts are caused by the sudden compromise of the arterial blood supply irrigating a brain region of precarious collateral flow or are secondary to the complete occlusion of a basal perforating end artery leading to a small, deep lesion (so-called lacunar infarct or lacune; Fisher, 1991). The infarct may involve a variable portion of the anatomical territory of distribution of the artery (territorial infarct), usually as a consequence of the occlusion of an intracranial artery. A second important mechanism of infarction occurs when either the distal boundaries of the vascular territory of arterial distribution or the junction between two or three territories is critically hypoperfused; these are called, respectively, boundary-zone or “watershed infarcts” (a useful term that nevertheless has its semantic detractors). Boundary-zone infarcts are due to the occlusion of distal arteries. Watershed infarcts are due to misery perfusion; they are most frequent after occlusion or stenosis of the proximal portions of feeding arteries and/or are the consequence of systemic hypotension (Castaigne et al., 1965). The histopathologic features of the tissue reactions that attend the infarcts associated with vascular dementia are not different from those seen with infarction in other clinical settings. 62.2.1.2. Other vascular lesions and lesions of uncertain significance Under this heading can be included: lacunes, microinfarcts, status cribrosus (cribriform state; “e´tat crible´”), incomplete infarction, ischemic leukoencephalopathy, laminar/pseudo-laminar necrosis and granular atrophy

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B Fig. 62.1. Lacune. (A) Macroscopic view of a thalamic lacune showing the cystic appearance of the lesion. (B) The microscopic section shows a cavitary infarct and scattered blood vessels within it. Hematoxylin-eosin.

of the cortex, intracranial hemorrhage, venous infarction, and, hippocampal sclerosis. 62.2.1.2.1. Lacunes Lacunes (from the Latin lacuna: cavity) are small (up to 1–1.5 cm in diameter), acquired cavities as seen on macroscopic examination of brain sections (Fig. 62.1). When multiple, the pattern of injury is referred to as “lacunar state” (“e´tat lacunaire”). The precise mechanism that leads to their formation has been debated from the time they were first described macroscopically in the mid-nineteenth century, through the subsequent microscopic studies in the first half of the last century and beyond (for historical reviews see, Hauw (1995) and Roman (2002b) and for more recent hypotheses see Wardlaw et al., 2003). In 1984, Poirier and Derouesne´ (1984) proposed a neuropathologic and etiologic classification of the

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different types of cavities using neuroimaging data as a starting point (small infarcts, small hemorrhages and dilatations of perivascular spaces). More recent studies have expanded and further refined the distinguishing features of different types of lacunes (Lammie, 2002). Nevertheless, there has been no world-wide consensus on the terminology that is to be used for these small cavities and other small vascular lesions of the brain, especially those occurring in the white matter, the basal ganglia and the brainstem. This general lack of agreement persists as an obstacle preventing clear comparative studies of vascular dementia. Inasmuch as the earliest reports on lacunes proposed ischemia as their probable etiology, for the sake of simplicity we have chosen to retain this historical perspective, restricting the term lacune to lacunar infarcts. These small, deep infarcts are due to the occlusion of small perforating arteries, as shown in the several meticulous studies by Fisher (1991). Lacunar infarcts in the cerebral hemispheres are, by definition, lesions that do not exceed 15 mm in diameter and occur in the territories of distribution of small perforating arteries at the base of the brain; these lesions correspond to the so-called “type 1 lacune” in the Poirier and Derouesne´ (1984) classification. The distinction between the mechanism of single, symptomatic lacunar infarcts and that of multiple lacunar infarcts in the setting of hypertension and leukoaraiosis may have epidemiological validity (Boiten et al., 1993; de Jong et al., 2002). It should also be noted that some small white matter cavitating lesions due to ischemia and occurring within the junctional territory between the deep perforating branches of large basal arteries and the distal extents of superficial branches of the middle cerebral artery (Bogousslavsky and Regli, 1992) may be mistakenly identified as lacunes (Ringelstein and Zunker, 1998). There is a considerable lack of general agreement as to whether the presence of lacunes alone can induce dementia, because, even in the present state of widely used neuroimaging studies, detailed mental status evaluations of patients are seldom available before the clinical onset of a lacunar stroke. The studies by Vinters et al. (2000) suggested that lacunes alone are seldom responsible for dementia. On the other hand, other workers have demonstrated that the likelihood of developing a dementia syndrome is higher in patients who have had a previous lacunar stroke (Norrving, 2003; Gold et al., 2005). Moreover, in clinico-imaging studies, subtle cognitive changes have been detected after a lacunar stroke (van Zandvoort et al., 2005). In the LADIS study, the contribution of lacunes to general cognitive function was independent of other risk factors for dementia (such as education, depression, vascular risk factors, or stroke) or of white matter hypodensities

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(leukoaraiosis) in nondisabled elderly subjects (van der Flier et al., 2005). In patients with subcortical lesions, cognitive changes are often associated with attentional and affective disorders, including apathy, emotional lability, and depression (Yamagata, 2004). This association is not surprising in cases where the limbic-cortical network and the basal ganglia-cortical circuits are involved, since these pathways are implicated in memory as well as attentional and emotional functions. 62.2.1.2.2. Microinfarcts Microinfarcts are microscopic areas of tissue destruction associated with a gliotic scar up to 5 mm in diameter, and affecting either the cerebral cortex or the white matter. Their pathogenesis has been related to a variety of mechanisms, including small emboli or thrombi, misery perfusion and boundary-zone or watershed infarcts. It is believed that they may contribute significantly to the progression of cognitive deficits in brain aging (Ko¨vari, 2004).

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62.2.1.2.3. Widening of perivascular spaces This is also known as status cribrosus or e´tat crible´ or cribriform state (from “cribrum” and “crible´”, Latin and French words, respectively, for “perforated surface” or “sieve”) (Fig. 62.2). Durand-Fardel (1854) described widening of perivascular spaces (“criblures”) on macroscopic examination of brain sections and distinguished it from lacunes. Since then, a large number of studies with microscopic descriptions of lesions have been published (for review of this literature see Hauw, 1995; Roman, 2002b). The often contradictory nature of the results reported in these studies may, in part, be due to the frequent coexistence of status cribrosus and lacunar infarction. Nowadays, it seems reasonable to retain the original sense of the designation e´tat crible´ as referring to a lesion characterized by widening of the perivascular spaces, irrespective of pathogenesis, i.e., whether due to alterations of blood– brain barrier function, sinuosity of the aging vessels, or overall brain atrophy of any cause. We would also underline the fact that status cribrosus is often observed in association with any pathological process that leads to a reduction in the volume of the brain (e.g., Alzheimer’s disease). In the classifications of Poirier and Derouesne´ (1984) and Lammie (2002), status cribrosus corresponds to the “type IIIa lacune”. 62.2.1.2.4. Incomplete infarction of gray and white matter; selective necrosis (De Girolami et al., 1984; Brun and Englund, 1986; Lammie, 2002; Ince, 2005) This can be associated with status cribosus or is typically seen in human or animal studies at the border

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B Fig. 62.2. Widening of the perivascular spaces (e´tat crible´/ status cribrosus). (A) Macroscopic view of e´tat crible´ of the putamen and external globus pallidus; vessels are seen within the small cavities (arrows). (B) Microscopic view of e´tat crible´ of the white matter showing enlarged perivascular spaces. Note the adjacent tissue brain tissue is normal. Bodian stain for axons combined with Luxol fast blue stain for myelin.

of infarcts and within ischemic penumbras; it is not evident on macroscopic examination of the brain. Microscopic examination shows focal rarefaction of myelinated fibers associated with a loss of neurons and/or oligodendrocytes, and a moderate astrocytic/ microglial proliferation. Incomplete infarction may border focal areas of small incipient cavitations. It can also be demonstrated to good advantage with MRI examination of fixed brain slices (Ince, 2005). The pathogenesis of this lesion has been a continuing topic of discussion. According to some authors it is due to ischemia, particularly misery perfusion; others attribute it to alterations in the permeability of the blood– brain barrier (see Ince, 2005). Incomplete infarction needs to be distinguished from the mere effects of secondary degeneration that attend the processes of injured

THE NEUROPATHOLOGY OF VASCULAR AND MIXED DEMENTIA nerve cells in neighboring lesions. Lesions corresponding to this definition have been described in Alzheimer’s disease (Brun and Englund, 1986) and related to hypotension; they are possibly more relevant in cerebrovascular disease (i.e., Binswanger disease, vascular cognitive impairment, amyloid angiopathy, CADASIL and as an incidental finding in patients with radiological evidence of leukoaraiosis). 62.2.1.2.5. Vascular leukoencephalopathy On macroscopic examination of brain sections, it is a process characterized by a reduction in volume of white matter, which assumes a gray-brown discoloration but retains good preservation of the neighboring cerebral cortex. Microscopic examination shows diffuse myelin pallor and loss of myelinated fibers, but with preservation of subcortical U fibers. Other microscopic features of the lesion include a reduction in the number of oligodendrocytes, and severe astrocytic and microglial gliosis. Vascular leukoencephalopathy is associated with small vessel disease, and is seen in the same disorders as incomplete infarction of white matter. It will be fully described later on. 62.2.1.2.6. Laminar necrosis and granular atrophy of the cortex There are a number of cortical ischemic lesions due to misery perfusion that may accompany dementia: When portions of layers of the cerebral cortex are selectively involved, with lesions having a propensity to affect the third or fifth layers, or both, the lesion is called laminar (or pseudolaminar) necrosis (Petito, 2005). In granular atrophy of the cortex, patches of cerebral gray matter affected by ischemic injury of long standing show a cobblestone, irregular pattern on external examination of the brain; cut sections demonstrate that the underlying white matter may also be involved (Yates, 1976). The lesions are frequently bilateral, and occur predominantly at the junction between two or three arterial territories of the brain (when large enough, they are identical to watershed infarcts). Focal cortical and white matter gliosis can be seen in association with other lesions. There are no known clinico-pathological correlations (Ko¨vari, 2004). Cerebral hemorrhages may be associated with dementia or cognitive impairment but this clinical association occurs far less frequently than with infarcts, with two exceptions. 1. Lobar hemorrhages linked to Abeta amyloid angiopathy (see Hauw et al., 1998; Vinters, 1998; Maat-Schieman et al., 2005): in the elderly, these hemorrhages are frequently associated with Alzheimer type lesions and may be a cause of vascular, or often mixed, dementia.

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2. Small hemorrhages in association with arterial hypertension: these hemorrhages frequently occur at the cortico-subcortical junction (“slit hemorrhages”) or in the basal ganglia. The latter are called “Type II lacunes” in the classification of Poirier and Derouesne´ (1984) and Lammie (2002). In the healing stages, these small hemorrhages are difficult to distinguish from old hemorrhagic microinfarcts. Subdural hematomas and subarachnoid hemorrhages may also be uncommon causes of dementia, especially in the setting of hydrocephalus (Starkstein et al., 2005). A venous infarct, without other associated lesions has, on occasion, been found to be the most reasonable explanation for a dementing syndrome (KrolakSalmon et al., 2002). Hippocampal sclerosis is characterized by severe neuronal loss and gliosis in the pyramidal layer of the hippocampus. It can occur as focal discrete loss of neurons, often predominating in CA1 and in the subiculum, or as severe atrophy of the entire structure. In addition, other brain regions (entorhinal cortex, temporal pole, inferior frontal isocortex, and frontal pole) may be affected. Hippocampal sclerosis is quite frequently observed in the dementias of elderly patients (Dickson et al., 1994). It has been described in vascular dementia (Vinters et al., 2000), but its mechanism is probably multifactorial (e.g., associated with hypotension, misery perfusion, anoxia, epilepsy, Alzheimer’s disease). When found in isolation, it is very frequently linked to frontotemporal dementia with ubiquinated neuronal inclusions (Beach et al., 2003; Hatanpaa et al., 2004; Lippa and Dickson, 2004). 62.2.2. Mechanisms of brain lesions 62.2.2.1. Large arteries The etiologic factors which give rise to stenosis or occlusion of the large arteries that supply the brain and are derived from the carotid-vertebral vascular tree off the aortic arch are apparently not different from those which involve other large arteries. These factors include atherosclerosis, cardiogenic embolism, and artery-to-artery embolism. Additional mechanisms of injury include those that attend hypoperfusion within ischemic lesions (Markesbery, 1998). Much less common causes of lesions of large vascular arteries include meningitis, emboli from a vascular malformation, angiitis, etc. 62.2.2.2. Small arteries and arterioles (components of the microcirculation) For references see Fisher, 1991; Markesbery, 1998; Lammie, 2002, 2005; Chui, 2005. Four main diseases that involve components of microcirculation will be considered in turn.

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62.2.2.2.1. Arterial lesions associated with hypertension and aging A large number of terms have been coined for the lesions that occur in the small arteries and arterioles exclusively with aging and arterial hypertension: small vessel disease, small vessel atherosclerosis, microatheromatosis, arteriosclerosis, arteriolosclerosis, complex small vessel disease, lipohyalinosis, fibrinoid necrosis, angionecrosis, segmental arterial disorganization, hyalinosis, hyaline arteriolosclerosis, miliary aneurysms, Charcot and Bouchard microaneurysms. This proliferation of sometimes ill-defined terminology has been responsible for many semantic problems (for review, see Chui, 2005; Ince, 2005; Lammie, 2005; Nag and Robertson, 2005). An approach to achieving consensus might be to adopt the terminology, wherever possible, now in use for the systemic circulation. Atherosclerosis of small-caliber cerebral arteries (200–800 mm in diameter) is, to a large extent, comparable to atherosclerosis seen in arteries of the same diameter in other organs. The disease can reduce blood flow to the brain by narrowing the lumen of the vessel or by vascular occlusion (thrombotic, or less often, embolic). A further mechanism of hemodynamic compromise of these small arteries is that of plaque formation in the parent artery. These lesions can be seen throughout the vasculature of the central nervous system, including the larger perforating arteries such as the lenticulostriate branches of the middle cerebral artery. Smaller cerebral vessels (small arteries, arterioles and metarterioles, 40–300 mm in diameter) are prone to another lesion akin to those seen in vessels of comparable caliber found in other organs, namely arteriolosclerosis (Figs. 62.3A and 62.4B). Arteriolosclerosis is the most descriptive and least contentious term for the commonly observed, concentric, age-related hyaline thickening affecting the walls of small arteries of the brain as well as other organs (Lammie, 2005). This process is associated with the loss of mural muscle cells (Fig. 62.3A) and in some areas (especially the basal ganglia) with deposits of various minerals (“calcification”). Arteriolosclerosis is the most frequent small vessel disease lesion in vascular dementia in the elderly. The term “lipohyalinosis” (Figs. 62.3B and 62.7C, D) was coined by Fisher (1991) to describe the arterial and arteriolar lesions that underlie lacunes. The lesion involves the small arterial tree 40–300 mm in diameter and its histological features include: (a) replacement of smooth muscle cells by fibroblasts, collagen and laminin, thereby leading to hyaline thickening and sometimes calcification of the media (as seen in arteriolosclerosis); (b) fibrinoid necrosis; (c) infrequently,

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B Fig. 62.3. Lesions of small arteries. (A) Arteriolosclerosis: concentric hyaline thickening of the wall of a small artery with loss of smooth muscle cells. Note the disappearance of muscle fiber nuclei. (B) Lipohyalinosis. Disorganization of the wall of a small artery with fibrinoid necrosis (arrow). Hematoxylin-eosin.

the presence of foamy macrophages; (d) subendothelial hyperplasia. Fibrinoid necrosis of the vessel wall, described by Fisher (1991) as a component of lipohyalinosis, is characterized by leakage of plasma proteins, including fibrin, into the arterial wall and necrosis of mural smooth muscle fibers. It is believed to be related to blood–brain barrier breakdown. Fibrinoid necrosis is rarely observed in current medical practice as it is characteristic of patients with uncontrolled acute hypertension; it is now most often seen in the setting of angiitis. These mural lesions may be associated with luminal narrowing, and seldom with expansion of the vessel wall and the development of miliary microaneurysms (Charcot-Bouchard aneurysms) (Fig. 62.4). The frequency and significance of the latter remain an unresolved controversy (Lammie, 2005). It is important to make a distinction between the lesions that affect the distal portions of the arterial tree

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(arterioles and smallest arteries), i.e., “lipohyalinosis” of Fisher (1991) or arteriolosclerosis, from those that involve its proximal portions (larger small arteries), i.e., “microatheromatosis” of Fisher (1991) because their risk factors and clinical consequences may be different (De Jong et al., 2002). Furthermore, the distinction between acute lesions, such as lipohyalinosis (i.e., lesions with fibrinoid necrosis) and arteriolosclerosis (the very common small vessel disease seen in the elderly) is mandatory for a better understanding of the pathogenesis of subcortical vascular dementia. There are no objective or validated criteria to assess the severity of small artery lesions associated with hypertension and aging. However, the current interpretation of the significance of these changes on the cognitive level is based on their severity (Ince, 2005).

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B Fig. 62.4. Miliary aneurysm (Charcot-Bouchard). (A) Drawing by Charcot of a microaneurysm (Muse´e Charcot, La Salpeˆtriere Hospital). (B) A microaneurym: note the focal enlargement of a small artery and surrounding hemosiderin pigment deposits indicating old bleeding. Hematoxylin-eosin.

62.2.2.2.2. Cerebral amyloid angiopathy or so-called congophilic angiopathy (Vinters, 1988; Hauw, 1998; Attems, 2005; Revetz, 2005) This, in contrast to arteriolosclerosis, is a vascular lesion that is specific to the central nervous system (Fig. 62.5). In this chapter, we will use the term cerebral amyloid angiopathy in preference to congophilic angiopathy, as the latter term has a more restricted meaning according to some authors (see Hauw, 1998). Amyloid angiopathy is a common finding in the brains

L

C WM

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Fig. 62.5. Amyloid angiopathy. Note the selective involvement of the vessels of the leptomeninges (L) and the cerebral cortex (C) with sparing of the underlying white matter (WM). Inserts: (A) congophilic angiopathy of the walls of a small artery; (B) dyshoric angiopathy of arterioles/capillaries (arrows). A diffuse Abeta plaque is shown (arrowhead). Abeta immunohistochemistry.

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of the elderly. In an autopsy study of the brains of centenarians who died in a geriatric hospital of a wide range of medical illnesses, 8/12 cases showed amyloid deposits in the vessel walls (Hauw, 1991), very often, if not invariably, in the context of Alzheimer’s disease. The microscopic characteristics of cerebral amyloid angiopathy include deposition of amyloid in the wall of the small, predominantly parenchymal gray matter or leptomeningeal arteries of the hemispheres. The term amyloid characterizes the deposit only in terms of the physical properties of the folded protein and not its chemical composition. Indeed, classification schemes of the different types of amyloid deposits (and related angiopathies) based on the biochemical composition of the abnormal protein are now widely accepted. The most common abnormal protein deposit is Abeta, a peptide cleaved from APP (the amyloid precursor protein), and encoded by a gene located on chromosome 21; it is found in so-called normal aging, Alzheimer’s disease, and rarely in families mostly from the Netherlands and some regions of Flanders. At least 30 mutations of the gene have been described. Other cerebral amyloid angiopathies include those due to: (1) cystatin C deposition (“Icelandic familial hereditary angiopathy”); (2) transthyretin (gelsolin) deposition; (3) the BRI 2 gene product (Revetz, 2005). The cerebral amyloid angiopathies most frequently associated with cerebral hemorrhage are Abeta and cystatin C. Different pathologic manifestations of sporadic Abeta amyloid angiopathy have been described. The deposits may involve large arteries, especially those in the leptomeninges. However, the most commonly affected vessels are: (a) small arteries, 40–120 mm wide (“congophilic angiopathy” of German and Swiss early authors), of the leptomeninges and the cerebral or cerebellar cortex; (b) the smallest arterioles, metarterioles or capillaries of the cerebral cortex (“angiopathie dyshorique,” dyshoric angiopathy), where the amyloid deposit seems to extend beyond the vessel wall into the brain parenchyma (see Hauw, 1998). A recent study throws some new light on this distinction; it describes two types of sporadic Abeta cerebral amyloid angiopathies. In type 1 cortical capillaries are involved, in contrast to type II, where they are spared. The ApoE e4 allele is over-represented in the population with type 1 angiopathy (as in Alzheimer’s disease), and the e2 allele in type 2 angiopathy (Thal, 2002). Small veins are also believed to be affected according to the classic descriptions, but they may be difficult to distinguish from damaged, thin-walled, dilated arteries. The arterial wall, which can be either thickened or atrophic, is laden with amyloid deposits which exhibit the classic tinctorial affinities and optical properties (green birefringence in polarized light

when stained with Congo red and green fluorescence when thioflavin S stain is used), and are also demonstrable by immunohistochemistry. Electron microscopy of sporadic Abeta amyloid angiopathy suggests that the amyloid fibrils first deposit on the abluminal part of the basal lamina, and are then associated with degenerative changes of the smooth muscle cells of the media, which eventually decrease in number (Revetz, 2005). This observation is consistent with the results of a prospective clinico-pathologic study which showed that the thickness of the walls of small arteries is increased in patients who have minimal clinical deficits, whereas it is decreased in severely demented patients (Zekry et al., 2003b). Various other lesions of the vessel wall (e.g., double-barrel appearance, chronic inflammation including granulomatous/ giant cell angiitis, microaneurysms) may also be seen. Furthermore, arteriolosclerosis and other age- and hypertension-associated lesions are frequently seen in affected arteries containing amyloid (see Hauw, 1998). The precise pathogenetic mechanisms of amyloid angiopathy are unknown. Hypothetical sources that have been considered include: origin from the systemic general circulation, the vascular system itself, and the brain via “drainage” into the microcirculation (Revetz, 2005). In the latter instances, it has been suggested that in sporadic Abeta angiopathy, amyloid deposits may be both produced by smooth muscle cells within the vessel wall and derived from injured neurons whose degenerative products extruded though the neuropil drain into the perivascular regions of the microcirculation (Weller, 2003; Attems, 2005). 62.2.2.2.3. Cerebral autosomic dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) CADASIL is a rare hereditary disease of blood vessels. In the majority of patients, one of several mutations of the NOTCH3 gene on chromosome 19 can be found. There is degeneration of muscle cells in the walls of the small perforating arteries with fibrosis, basophilic and PAS-positive deposits, and luminal stenosis. The extracellular domain cleaved from NOTCH3 accumulates outside the degenerating smooth muscle cells as a granular osmiophilic material seen at electron microscopy. Skin biopsy with immunohistochemistry or electron microscopy and, in some cases, analysis of the NOTCH3 gene can provide the diagnosis. 62.2.2.2.4. Other arteriopathies A number of other rare vascular disorders involving small arteries may be associated with dementia at any age. These include primary angiitis of the central

THE NEUROPATHOLOGY OF VASCULAR AND MIXED DEMENTIA nervous system, anticardiolipid antibodies, Sjo¨gren syndrome, giant cell arteritis, systemic lupus erythematosus, retinocochleocerebral vasculopathy, Sneddon syndrome, polyarteritis nodosa and Behc¸et’s disease (Bowler and Hachinski, 1998). Other systemic vasculitides, sarcoidosis, meningo-vascular syphilis, multiple small vessel and venous occlusions of various causes (e.g., disseminated intravascular coagulation or other thrombogenic disturbances), and parasitic or malignant diseases, such as intravascular lymphoma (Rollins et al., 2005), may rarely induce vascular dementia. Cerebral autosomic recessive leukoencephalopathy (CARASIL or Maeda syndrome) is a familial disease A characterized by intense arteriolar lesions with neither arterial hypertension nor specific vascular lesions (no amyloid deposit or granular osmiophilic material). No gene defect has been found (Arima, 2003; Kalimo and Kalaria, 2005). Other very rare hereditary small vessel diseases include cerebroretinal vasculopathy; hereditary endotheliopathy with retinopathy, nephropathy and stroke; and hereditary vascular retinopathy; the latter two are allelic disorders which have been mapped to the locus 3p21.1–p21.3 (see Kalimo and Kalaria, 2005).

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62.3. Dementia 62.3.1. The importance of size and topography of lesions: the “strategic areas” (see Fig. 62.6) Tomlinson et al. (1970) performed a clinico-pathologic study comparing a group of 50 demented cases with 28 controls lacking intellectual impairment. Irrespective of the location of the lesion, the threshold of brain tissue destruction likely to cause dementia was 100 ml. Two cases in the control group had infarcts larger than 50 ml, whereas the infarcts of three patients with purely vascular dementia were smaller than 100 ml. These figures may be compared with the data of Zekry et al. (2002), who demonstrated that the minimal volume of the infarcted tissue associated with dementia was 50 ml, in the absence of other lesions. There was a significant correlation between the volume of vascular lesions and the severity of cognitive impairment. It had already been shown that some small infarcts may induce dementia, provided they involve areas important for cognitive function. Cases of selective, bilateral involvement of the territory irrigated by the thalamic paramedian arteries (which does not exceed 20 ml) are a particularly illustrative example of this phenomenon (Castaigne et al., 1965, 1981). Tomlinson et al. (1970) proposed the concept of “strategic site,” including the hippocampus (limbic area) and corpus callosum. Del Ser et al. (1990) considered that lesions which involved predominantly the frontal

B Fig. 62.6. Stategic infarcts. (A) Thalamic infarcts of the paramedian territory (arrows). These involve bilaterally the hippocampo-mamillothalamic pathways and the region of the thalamic dorsomedian nuclei. (B) Watershed infarcts involving the junction between the territories of the middle, anterior and posterior cerebral arteries (arrows). These infarcts may destroy, unilaterally or bilaterally, the regions involved in various cognitive functions, multimodal associative areas, and the underlying white matter. Loyez stain for myelin.

and the occipital cortex and the basal ganglia were particularly relevant. Other susceptible areas mentioned in the literature include the cingulate gyrus and caudate nucleus, other thalamic areas, and the hypothalamus (Annoni et al., 2003; Carrera et al., 2004; Perren et al., 2005). A tabulation of the most common neuropsychological symptoms reported to be associated with brain infarcts and contributing to dementia is given in Table 62.1.

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Table 62.1 Strategic infarcts: main affected structures and clinical features with emphasis on neuropsychological dysfunction Clinical features Arterial territory

Affected structures

Unilateral

Bilateral

ACA/ACoA

Medial fronto-parietal/ orbito-frontal cortex, basal forebrain, hypothalamus

“Frontal type behavior” (disinhibition, hyperorality, inappropriate sexuality, emotional lability), mutism and other speech disturbances, depression Abulia, amnesia

Same as Unilateral with more severe troubles þ

MCA

PCA and other supply of the thalamus

Non-territorial, MCA/ACA/PCA

Cingular gyrus, caudate nucleus, fornix Corpus callosum Orbito-frontal/ Prefrontal/ central territories

“Akinetic mutism”

Callosal disconnection Same as Unilateral “Frontal type behavior” with more severe (loss of programming troubles abilities, poor abstraction and categorization, abulia), delusions (?) Precentral territory Loss of kinetic melody, motor impersistence, hemineglect Balint syndrome Posterior parietal/ Wernicke aphasia (L) angular gyrus Gerstmann syndrome (L), asomatognosia (R), visuospatial dysfunction (R) Temporo-occipital L: dyslexia, aphasia, amnesia, Cortical blindness, severe amnesia, hemispheric territory inability to name colors, agitated delirium visual agnosia; R: visual neglect, auditory neglect, constructional apraxia, disorientation in place Severe persistent Apathy, anterograd Thalamic territories: Anterior (polar/ dementia, delirium, amnesia, perseverations tuberothalamic) loss of self-psychic and superimposition of territory activation unrelated information Same as Unilateral Paramedian Decreased level of with more severe territory consciousness, cognitive impairment, disinhibition, loss and persistent troubles of self-activation, amnesia, thalamic “dementia” Infero-lateral Executive dysfunction, (thalamogeniculate) abulia, apathy, memory impairment aphasia (L) Posterior Executive dysfunction, choroidal aphasia (L) Dementia with aphasia, Cerebral convexity Aphasia (L) apraxia, apraxia, agnosia, (cortical watershed) agnosia, hemineglect, hemineglect amnesia Centrum semi-ovale Hemiparesis with sometimes (deep watershed) hemisensory defect (L: expressive speech disturbances)

ACA, anterior cerebral artery; AcoA, anterior communicating artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; Nonterritorial: watershed/borderzone infarcts; L, left; R, right. Modified from Ince 2005 (data from Buge et al., 1975; Castaigne et al., 1981; Sawada, 1998; Neau and Bogousslavski, 1998; Caplan and Bogousslavski, 1998; Carrera et al., 2004; Perren et al., 2005; Jellinger, 2007).

THE NEUROPATHOLOGY OF VASCULAR AND MIXED DEMENTIA Although a number of different neuroanatomic systems and brain regions have been implicated, a precise categorization of the relevance of most cerebral areas to the dementing process is still lacking. Functional mapping of cortical areas as described by Mesulam (1985) is a potentially useful tool to assess the relative importance of damage to different brain regions in relation to degrees of mental impairment. In a multi-variate model applied to the data of a prospective clinicopathologcal study, the volume destroyed in the limbic and heteromodal association areas, including the frontal cortex, and in the white matter, explained 50% of the variability in cognitive impairment (Zekry et al., 2003a). 62.3.2. Multi-infarct and subcortical vascular dementia Most brain lesions associated with, or responsible for, vascular dementia are due to arterial ischemia. In this regard, brain infarcts, usually occurring in both hemispheres, were the first to be recognized and this led to the emergence of the concept of multi-infarct dementia (Hachinski, 1974; Hachinski et al., 1983). Characteristically, the multi-infarct dementia syndrome consists of focal neurologic symptoms and signs associated with imaging abnormalities. The term vascular dementia is now preferred for patients with dementia secondary to brain lesions caused by other vascular disorders. In contrast to multi-infarct dementia, patients with subcortical vascular dementia have small vessel disease and lesions of deep gray structures (i.e., basal ganglia lacunes) and of the white matter (leukoencephalopathies). This pattern of injury induces a pure dementing syndrome comparable to that seen in some degenerative disorders and the patients’ imaging studies may be normal. It is often the case that brain lesions caused by different vascular pathogenetic mechanisms occur concomitantly, as they share similar risk factors. In a multivariate analysis of the contributing factors to dementia in a series of prospectively studied patients, both small vessel disease and large focal infarcts were significantly correlated to the severity of the dementia (Zekry et al., 2003b). 62.3.3. Single infarcts and dementia Although vascular dementia is usually associated with bilateral infarcts, in rare instances a single infarct may be responsible for the clinical syndrome. A case in point is the paramedian bithalamic infarct due to the occlusion of a single artery, or pedicle, arising from the first

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segment of one of the posterior cerebral arteries (Castaigne et al., 1966, 1981; Percheron, 1976). Infarcts resulting from occlusion of the main cerebral arteries are likely to contribute to dementia by affecting structures involved in fundamental cognitive functions. Table 62.1 shows the range of cognitive impairments associated with unilateral or bilateral infarcts.

62.4. Diseases Selected disease states associated with dementia will be discussed in turn. 62.4.1. Subcortical ischemic vascular dementia, or Binswanger’s disease (see Fig. 62.7) Binswanger’s disease (also called Binswanger encephalopathy or subcortical arteriosclerotic encephalopathy) was first described in 1894 (Binswanger, 1894). It is a rare disorder, and today a subject of nosologic controversy (Olszewski, 1962; Markesbery, 1998; Roman, 2000), mainly because there has been a tendency to include in this diagnostic category a wide range of white matter neuroimaging abnormalities, including the more recently described entity called leukoaraiosis (Pellissier, 1989; Caplan, 1995; Pantoni, 1997; Roman, 2000; Bowler, 2005). Macroscopically, there is mild or moderate cerebral atrophy with ventricular dilatation, reduction in brain volume, and gray-brown discoloration of the white matter, ordinarily with preservation of the cerebral cortex. Microscopic examination (Fig. 62.4) shows severe white matter pallor due to both axonal loss and myelin injury, associated with astrogliosis and some macrophage infiltration. These lesions are often both diffuse throughout the hemispheric white matter and patchy; they may predominate in the frontal or occipital lobes. The subcortical U fibers are usually spared. The white matter lesions are invariably associated with healed or recent lacunes and severe arteriolar disease (mainly arteriolosclerosis, sometimes lipid deposits, seldom fibrinoid necrosis) occurring in perforating arteries. Other findings are cortical microinfarcts and sometimes granular atrophy of the cortex, but the characteristic features of degenerative disorders (such as those seen in Alzheimer’s disease) are either entirely lacking or are attributed to chance association. The white matter lesions are thought to be due to alterations of the long perforating arteries of the white matter; the associated lacunes are caused by similar lesions of deep perforating arteries. A dysfunction of the blood–brain barrier has been implicated to play a role in the pathophysiology of Binswanger’s disease by some investigators (Tomimoto et al., 1996).

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B

C

A

D

100 µM

500 µM

200 µM

Fig. 62.7. Subcortical ischemic vascular dementia (Binswanger disease) and associated small vessel lesions. (A) Hemispheric section demonstrating leukoencephalopathy with sparing of the U fibers. Loyez stain staining myelin in black. Celloidin embedded section. (B) Arteriolosclerosis of a 100-mm-wide artery. (C and D) Various lesions of the walls of small arteries including fibrinoid necrosis (small arrow), calcification (arrow head) and cell infiltrate in healing fibrinoid necrosis (long arrow). Hematoxylin-Eosin.

Although there are no prominent lymphoid cell infiltrates, some authors have suggested that an inflammatory reaction, in combination with compromised axonal transport and mediated by chronic ischemia, may also be involved (Akigushi et al., 1997). Binswanger’s disease is usually linked to arterial hypertension, but some cases have been described in normotensive patients; it is possible that such descriptions found in the older literature correspond to other disorders (e.g., amyloid angiopathy, CADASIL, etc.).

with pathological lesions of lacunes, e´tat crible´, myelin pallor of undetermined causes, and multiple sclerosis plaques, to name a few (Verny et al., 1991). Nevertheless, there does seem to be a positive correlation between the severity of leukoaraiosis and the extent of small vessel disease (Rossi, 2004); leukoaraiosis is, therefore, the radiological expression of selected structural lesions that underlie vascular cognitive impairment in some patients.

62.4.2. Leukoaraiosis

62.4.3. Cerebral amyloid angiopathy (see Fig. 62.5)

Leukoaraiosis is a term that was coined to encompass a wide range of pathologic processes associated with imaging abnormalities of the white matter as seen on CT scans (Hachinski et al., 1987) and also on MRI (Bowler, 2005). Leukoaraiosis is now known not to be the imaging counterpart of Binswanger’s disease as defined above, nor of other pathologically/molecularly well-characterized leukoencephalopathies; the designation applies to imaging findings associated

Four different brain lesions are most commonly associated with amyloid angiopathy (for review, see Hauw, 1998; Vinters, 1998). A high prevalence of intracerebral hemorrhages is characteristic of both sporadic and familial types. They are often multiple, of varying ages, and usually lobar in location. In sporadic cases, they occur mainly in the frontotemporal areas. Deep cerebral, cerebellar, or pontine locations are rare sites of involvement. Multiple, small, nonhemorrhagic

THE NEUROPATHOLOGY OF VASCULAR AND MIXED DEMENTIA infarcts, usually of cortico/subcortical topography, are also frequent. Territorial infarcts of large arteries are generally interpreted as lesions related to associated risk factors. High densities of senile plaques, and less often of neurofibrillary tangles, are the rule, and there is usually an overlap between Alzheimer’s disease and amyloid angiopathy. The diagnosis of sporadic amyloid angiopathy thus depends on the ratio between the severity of amyloid deposits in vessels and that of Alzheimer-type lesions (especially tau-associated lesions: neuritic plaques, neuropil threads and neurofibrillary tangles). This is sometimes a difficult diagnostic issue to sort out when few arterial Abeta deposits are found in association with some Alzheimer-type lesions in the vicinity of a cerebral hemorrhage. Cerebral sporadic amyloid angiopathy may be associated with a leukoencephalopathy; the white matter changes are rarely severe, with diffuse myelin pallor seen at some distance from the cerebral hemorrhages and with sparing of the subcortical U fibers (Dubas et al. 1985). The cause of the myelin pallor is not fully understood. It has been postulated to be due to hypoperfusion of the centrum semiovale because the proximal portions of the feeding vessels that supply this deep structure, located in the subarachnoid space and the cerebral cortex, are narrowed by amyloid deposits. Whether sporadic amyloid angiopathy alone might be capable of reducing cognitive function is difficult to assess because it is usually associated with other disorders (e.g., Alzheimer-type lesions, cerebral hemorrhages, or infarcts), especially in those amyloid angiopathies that involve the smallest-caliber vessels (type I of Thal et al., 2002). It has been shown in a multivariate model that integrates other macroscopic and microscopic lesions that amyloid angiopathy of small arteries may also be implicated in the mechanism of cognitive impairment; the severity of amyloid angiopathy, per se, explained 10% of the variability of the cognitive impairment in elderly patients (Zekry et al., 2003b). Severe lesions are thus likely to lower the threshold for clinically overt dementia in neurodegenerative diseases (Attems, 2005). 62.4.4. CADASIL CADASIL has been considered in detail in Chapter 61. The neuropathologic findings of the few cases of CADASIL that have been reported (see Baudrimont et al., 1993; Kalimo et al., 2002; Arima et al., 2003; Kalimo and Kalaria, 2005) have included multiple small infarcts in the white matter or deep gray matter, a leukoencephalopathy, and the characteristic vascular lesions.

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62.5. Dementia after stroke Stroke increases a patient’s risk of dementia as compared with age- and gender-matched controls (Ivan et al., 2004). The pathology of dementia after stroke has not been studied in detail, but is likely to be that of a mixed dementia (see below). 62.5.1. Mixed dementia Numerous definitions and criteria have been proposed for the neuropathologic diagnosis of mixed dementia, indeed a controversial concept from the earliest descriptions of the entity (Delay and Brion, 1962). Tomlinson and collaborators believed that the term should encompass cases that combined Alzheimertype lesions severe enough to give rise to dementia, together with vascular lesions also severe enough to cause vascular dementia (Tomlinson et al., 1970). Constantinidis, on the contrary, thought that the association of degenerative and vascular lesions, of any severity, was sufficient. (Constantinidis, 1978). Mo¨lsa and collaborators used the name combined dementia for cases in which Alzheimer’s disease was associated with any ischemic lesion (Mo¨lsa et al., 1985). The established criteria for the diagnosis of mixed dementia by the ADDTC specify that there should be at least one ischemic cerebral lesion associated with a dementing disease, of whatever type (e.g., Alzheimer’s disease, hypothyroidism, Parkinson’s disease) (Chui et al., 1992). The NINDS-AIREN recommendation is that this category be reserved for cases fulfilling the clinical criteria of possible AD who also present clinical or brain imaging signs of relevant cerebrovascular disease; the term “mixed dementia” is not favored (Roman et al., 1993); Still, many others continue to find it useful (Markesbery, 1998; Bowler, 2005). 62.5.2. Associated lesions Any degenerative lesion associated with vascular changes may be encountered in patients with mixed dementias. In practice, the association with Alzheimer-type lesions has been the most often studied. Most authors found that combined lesions had additive effects on the cognitive decline, although a few divergent studies were published (Lee et al., 2000). Nagy and collaborators (1997) measured the severity of microscopic lesions in various pathological processes associated with Alzheimer’s disease (vascular lesions and also frontal lobe dementia, Huntington’s disease, Pick’s disease, progressive supranuclear palsy, glioma, Parkinson’s disease). They found that

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for any given level of cognitive deficit, the neocortical density of either all types of plaques, or of neuritic plaques alone, was significantly lower in cases of Alzheimer’s disease superimposed on other central nervous system disease than that observed in other cases. For vascular lesions, three groups were distinguished: 15 cases in which the vascular lesions were thought to have no effect on the patients’ cognitive deficit, one case in which these lesions were thought to make only a minor contribution, and five cases in which they were thought to make a major contribution. In the latter group, the cerebrovascular disease consisted of multiple infarcts and/or a cribriform state, accompanied by rarefaction of the surrounding tissue and astrogliosis, or white matter myelin pallor. The density of plaques and tangles was significantly lower in the isocortex of these patients than in the other two groups combined. The difference in plaque and tangle density between cases with only Alzheimer-type lesions and those who had minimal or mild vascular disease was not statistically significant, but there was a trend towards lower densities in patients with minimal vascular damage. A few prospective studies have confirmed these data. The “nun study” (Snowdon et al., 1997) showed that among 61 participants meeting the neuropathologic criteria for Alzheimer’s disease, those with brain infarcts had poorer cognitive function and a higher prevalence of dementia than those without infarcts. In the OPTIMA cohort, Esiri and collaborators (1999) presented evidence that cerebrovascular disease significantly worsened cognitive performance in the earliest stages of Alzheimer’s disease, but had no significant effect on cognitive deficit in advanced stages. These data support the view that microvascular lesions may also contribute to dementia in subjects with more extensive Alzheimer-type pathology and thus lower the threshold at which Alzheimer-type pathology becomes clinically manifest (Esiri, 2000). Zekry and collaborators (2002a) quantified the absolute volume of vascular lesions and the density of Alzheimer-type lesions in a cohort of patients prospectively studied. They showed that demented patients with fewer plaques and tangles in the temporal and frontal isocortex, but with some additional vascular lesions, were as demented as those with more plaques and tangles but without vascular lesions. In the “Religious Orders Study”, cerebral infarction contributed to the probability of developing dementia as did the Alzheimer disease component but their effects were only additive and not synergistic (Schneider et al., 2004). Lastly, the correlates of Alzheimer’s disease pathology, hippocampal neuron numbers and subcortical vascular pathology have been assessed in 79 autopsy cases from a prospective longitudinal

study. Hippocampal sclerosis was a common unsuspected neuropathological finding. Apolipoprotein E4 genotype was associated with cerebral amyloid angiopathy, but not hippocampal sclerosis or arteriosclerosis. When the Braak and Braak stage was interpolated to zero, both cerebrovascular parenchymal pathology scores and hippocampal sclerosis contributed to cognitive impairment. However, advancing stages of Alzheimer’s pathology overwhelmed the effects of other factors, to become the major determinant of dementia (Chui et al., 2006). In the same series, effects of the small vessel cerebrovascular disease on the profiles of neuropsychological impairment were variable and not especially distinct, thus raising questions about the utility of using executive impairment as a diagnostic marker for vascular dementia (Reed et al., 2007). In any event, these observations provide support for the validity of the mixed dementia concept. At present, no neuropathologic criteria are available for mixed dementia or for vascular cognitive impairment. The heterogeneous spectrum of the lesions and the fact that the clinical consequences depend on their topography, extent, basic nature and severity (ischemia or white matter pallor, for example) are factors which contribute to the lack of any systematization. The designation of a critical burden of structural damage determining a threshold of clinical cognitive impairment seems a particularly difficult task.

62.6. Conclusion Vascular dementia is a heterogeneous condition, the pathological criteria of which are still undetermined, rendering the diagnosis particularly subjective (Bowler, 2004). The neuropathologic examination is mandatory in the work-up of a case because multiple pathologies are often combined, especially in the elderly, and it appears that mixed dementia is a frequent and under-recognized disease. The diagnostic pitfalls are numerous in vascular dementia, and especially in mixed dementia and vascular cognitive impairment. The diagnosis must be clinicopathologic, but clinical and pathologic uncertainties are additive. Furthermore, the relationship between clinical and pathologic data is complex: threshold and plateau effects (for psychometric and neuropathologic data, for example) modulate the statistical links. Additive or synergistic consequences of vascular and degenerative lesions are possible, and the latter are also difficult to evaluate and to standardize (Duyckaerts et al., 1990). Without doubt, the uncertainties as to the mechanisms of vascular dementia in the elderly are more numerous than the facts. To answer some of the unsolved questions would require a greater number of prospective

THE NEUROPATHOLOGY OF VASCULAR AND MIXED DEMENTIA studies of vascular and mixed dementia, with quantitative macroscopic and microscopic examinations of regions involved in the cognitive process. Both hemispheres must be examined. A state-of-the-art clinical evaluation can only be done using the multifaceted diagnostic procedures driven by the pretest likelihood of potential pathologic factors (Rikkert, 2006). This also holds true for any neuropathologic study. Neuropathologists must also resist the temptation of assigning a pathogenetic cause to every case of dementia under study.

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