CURRENT CLINICAL NEUROLOGY - PART 2 potx

Neuropathologic Substrates of ViD 23 23 From: Current Clinical Neurology Vascular Dementia: Cerebrovascular Mechanisms and Clinical Management Edited by: R. H. Paul, R. Cohen, B. R. Ott, and S. Salloway © Humana Press Inc., Totowa, NJ 3 The Neuropathologic Substrates of Vascular-Ischemic Dementia Kurt A. Jellinger 1. INTRODUCTION 1.1. Historical Background and Synonyms Although Alzheimer’s disease (AD) has become widely accepted as the most common cause of dementia in advanced age (1), the role of cerebrovascular disease (CVD) and ischemic brain lesions in cognitive decline remains controversial and confusing (2–5). Until the 1950 and 1960s, dementia in elderly subjects was usually labeled “atherosclerotic dementia,” although in 1919, Mingazzini (6) stated that this was the result of cerebral infarctions, similar to the concept stressed by Fisher (7). Tomlinson et al. (8) described the relationship between the volume of infarcted tissue and cognitive impairment, suggesting that destruction of large volumes of cortex may be necessarily followed by dementia, whereas subtle cerebrovascular lesions (CVLs) may or may not contribute to dementia, probably depending on their location. Hachinsky et al. (9) criticized the term “arteriosclerotic dementia” as both inaccurate and misleading and coined the term “multi-infarct dementia” (MID). Because MID constitutes only a small subdivision of all dementias of vascular etiology, the terms “vascular dementia” (VaD) (4,10–13), “cerebrovascular dementia” (14), “dementia associated with stroke” (15), or, more recently, “ischemic-vascular dementia” (16,17) “vascular-ischemic dementia” or “vascular cognitive impairment” (ViD) (18) were chosen. Although considerable progress has been made in understanding ViD, many questions remain, particularly regarding what pathologic lesion produces cognitive impairment and by what mecha- nisms. Many authors consider ViD to be a multifactorial disorder or an ill-defined entity (19), and causal relationships between CVD and dementia are difficult to prove. Even though some authors (20,21) provided strong reasons for the use of “vascular cognitive impairment,” the term ViD will be used in this chapter. It refers to cognitive dysfunction caused by cerebral lesions secondary to a spectrum of vascular/ischemic pathology. 1.2. Neuropathologic Classification In contrast to recently refined morphologic criteria for the diagnosis of AD and other degenerative dementias (22,23), no validated neuropathologic criteria have been established for ViD. The California’s Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC) (24) did not suggest specific details for the postmortem VaD diagnosis but indicated that histopathologic examination of the brain with clinical evidence of dementia was necessary to confirm the presence of multiple infarcts. The National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN) criteria emphasized the hetero- 24 Jellinger geneity of the VaD syndrome and its pathologic subtypes (25). For a diagnosis of “definite” VaD, criteria required that the clinical probability be completed by histopathologic evidence of CVD and absence of AD-type lesions exceeding those expected for age and other conditions causing dementia. Other investigators have emphasized the importance of clinicopathologic correlations (2,11,24,26) and the inverse relation between Braak stage and cerebrovascular pathology (27,28) or have used variable criteria (26,29–32). Notwithstanding, controversies concerning the validity and liability of diagnostic criteria for ViD continue (29). Fundamental pathological lesions in ViD consist of atherosclerosis with or without thrombosis/ thromboembolism of extracerebral and intracerebral arteries, intracerebral microangiopathies—arte- riosclerotic, hyalinotic, inflammatory, and amyloid-related—often combined with systemic factors that may produce small and large infarcts and several forms of white matter degeneration. The extent and location of cerebrovascular lesions (CVLs) and destroyed tissues, which differ considerably from case to case, multiplicity, and bilateral occurrence, are the most important factors underlying cogni- tive impairment (3–5,10–20,26,33). One of the most controversial and incompletely understood issues is the degree to which vascular pathology contributes to dementia. Complicating the postmortem ViD diagnosis are other pathologic entities coexisting with vascular lesions that could lead to cognitive decline. Many of these can be found at postmortem examination, particularly in multimorbid elderly subjects. However, it should be emphasized that the presence of CVLs at autopsy does not prove that they cause cognitive decline (4,12–14,33), underscoring that thorough clinicopathologic correlation is essential to establish a defi- nite diagnosis. Although several class I and II studies that compared clinical diagnosis and neuropathologic find- ings in reference cohorts, which are similar to population-based studies, reported low sensitivity and specificity for the currently used clinical diagnostic ViD criteria (12,29,34–39) with variable interrater reliability (12,40–42). According to recent clinicopathologic studies, The Mayo Clinic criteria (tem- poral relationship between stroke and dementia or worsening or bilateral infarctions in specified locations) had 75% sensitivity and 81% specificity for pure VaD (26). Because the criteria chosen to diagnose VaD will influence estimates on its incidence and prevalence, as well as its recognition and treatment, new research criteria (e.g., for subcortical VaD) have been proposed (14,29,43,44), and the need for prospective clinicopathologic correlation studies has been emphasized (45,46). These criteria can only be established at autopsy in patients who have been thoroughly and longitudinally evaluated before death and who do not have other causes of dementia. ViD is related to a variety of pathologic lesions (4,12–14,17–20), the clinical significance of which and their relation to AD and other age-related changes of the brain (e.g., subcortical white matter lesions [WMLs]) remain contro- versial (10–18,29,34,47–50). However, we are not aware of any validation study of the neuropatho- logic ViD criteria. 1.3. Questionnaire for Vascular Lesions in Routine Pathological Examination Based on a proposal by Pantoni and others (13,51), a group of international neuroscientists is currently preparing a questionnaire for a standardized examination of CVLs in routine neuropathol- ogy programs. On April 4, 2003, this questionnaire (see Table 1) has been sent to several investiga- tors throughout the world to prepare a position paper. It is intended to standardize the neuropathologic examination of CVLs and may present a basis for further establishment of standardized morphologic ViD criteria. 1.4. Prevalence and Epidemiology There is considerable lack of agreement about ViD epidemiology and prevalence. Given the diffi- culties in diagnosing the disorder (10,12–20,24,26,34,46), epidemiologic studies must be interpreted cautiously. Although ViD previously was considered the second most common type of dementia after AD (11,52–56) and is the second leading cause of death worldwide (57), in the Western world it Neuropathologic Substrates of ViD 25 follows AD (60–70%), dementia with Lewy bodies (DLB) (10–25%), and other non-Alzheimer’s dementias (8–10%) at place 3 or 4 (17,58). A review of clinical studies showed a frequency of ViD ranging from 4.5% to 39% (59), but in most Western memory clinic-based series, it is diagnosed in no more than 8–10% (14). Evaluation of 11 pooled European population-based clinical studies of persons over 65 yr of age revealed an age-standardized prevalence of 6.4% for all causes of dementia, 4.4% for AD, and 1.6% for ViD (60); ViD accounted for 15.8% of all dementia cases. In Canadian clinical studies of de- mented individuals, 12.1% had ViD and 12.8% mixed AD/ViD (61), with an incidence of 6–12 cases per 1000 persons over 70 yr of age (62). In the Finnish “Kuopio 75+ study,” ViD accounted for 23% vs 22% for DLB, 47% for AD, and 8% for other dementias in people aged 75 yr or older (58). Even though studies from Japan revealed that the prevalence of ViD was more than double that of AD (63–67), in other reports, AD was two times more frequent than ViD (68). Roman (57) recently suggested that ViD may be the most underdiagnosed and underestimated form of dementia in the elderly, because most individuals with dementia after a stroke probably are not included in the data cited (69). This is important because “silent” cerebral infarcts increase with advancing age and are considered a major contributor to the increasing incidence of dementia (70,71). Dementia is common after stroke, occurring in 25 to 30% of patients (15), and cerebral infarctions are associated with a twofold increase in odds of dementia (72). Therefore, a review of pathologic studies on the prevalence of ViD is difficult, because most studies may contain referral bias because they are weighted with patients from clinical centers, where AD predominates (e.g., in the Consortium to Establish a Registry for Alzheimer’s Disease [CERAD] group) (73,74). The divergence in estimates of prevalence (26,60,70) and incidence of ViD (67,75) suggests that the concept of ViD needs further investigation and validation. A review of autopsy studies of patients with dementia from 1962 to 1995 revealed an overall mean risk of 17.3% (4), whereas others classified 15–19% as pure VaD (76) or showed an even wider range from 0 to 85.2%, with a mean of 17.9%, but reasonable values, based on comparable diagnostic criteria, are between 2 and 11% (59). Reports since 1988 have an overall lower preva- lence (mean of 12 studies since 1989 was10.8%) (see Table 2). Although several recent studies have reported prevalence rates of 2–9%, others suggest that in very old subjects (85 yr plus), ViD may be more frequent than AD (77). In contrast, among 1929 autopsies of subjects with dementia collected by 10 US centers participating in the CERAD neuropathology program, autopsy revealed CVLs without morphologic features of AD or other disorders in only six cases (0.03%) (73). The Nun study revealed only three pure ViD cases among 118 old-age subjects with dementia (2.5%) at autopsy (78). For comparison, in recent autopsy series of subjects with dementia from Japanese geriatric hospi- tals, the incidence rates for AD, ViD, and mixed and other dementias were 34, 35, 11, and 20%, respectively, in one series (95) and 47, 22, 6, and 26%, respectively, in the other series (96). A recent community-based population study in England in 209 autopsies of elderly subjects, of whom 48% had dementia, showed CVLs in 78% and AD-pathology in 70%. The proportion of multiple vascular pathology was higher in the group with dementia (46 vs 33%), indicating that most patients had mixed disease (97). In a personal consecutive autopsy series of 1000 aged individuals with dementia in Vienna, Austria, ViD was seen in 8.5% but in only 2.8% of 600 patients with the clinical diagnosis of probable AD. Alzheimer-type pathology was present in 83.5 and 91.7%, respectively, but “pure” AD in only 40 and 47%, respectively, whereas the other brains showed different coexisting patholo- gies (Lewy bodies, CVDs, etc.); 4.5 to 7% had dementia disorders of other etiologies (neurodegenerations, prion diseases, tumors, etc.) (17,18). The prevalence of CVLs in a large series of autopsy-proven AD cases was significantly higher than in age-matched controls (48.1 vs 32.6%, p < 0.01), with minor to moderate CVLs (lacunes and cerebral amyloid angiopathy [CAA] with and without vascular lesions) in 31.9 vs 27.1%. Severe vascular pathology (old and recent infarcts or hemorrhages) in AD was also significantly higher than in controls (16.0 vs 5.5%; p < 0.01) (98). 26 Jellinger Table 1 Questionnaire for Vascular Lesions in Routine Pathological Examination Continued on next page Neuropathologic Substrates of ViD 27 Continued on next page 28 Jellinger Continued on next page Neuropathologic Substrates of ViD 29 30 Jellinger 2. MAJOR CEREBROVASCULAR LESIONS ASSOCIATED WITH ViD The major CVD subtypes in VaD have been summarized by Romano in the previous chapter and by others (2,4,10,11,13,16–18,33,69,99). Although causal relationships between certain CVLs and dementia evade strict classifications (2,15,18,29,49) and no classification of brain lesions causing cognitive impairment is ideal, the major CVLs associated with cognitive impairment are summarized in Tables 3 and 4. 2.1. Classical Multiinfarct Encephalopathy (MIE)/Large Vessel Disease Single or multiple infarctions involving the areas of major cerebral arteries commonly result from atherosclerosis affecting intracranial or extracranial blood vessels, giving rise to local throm- boembolism or hypoperfusion. These infarcts may be large, involving much of a cerebral hemi- sphere, or may be multiple small lesions in the cortex and/or adjacent white matter, mainly in the medial cerebral artery (MCA) territories and less frequently in other supply areas, involving the left or both hemispheres (10,11,56,72,99). Stroke patients with dementia had infarcts in the left that were eight times larger than those in the right hemisphere, with a strong correlation between demen- tia and infarctions in the left posterior cerebral artery (PCA), anterior cerebral artery (ACA), and Table 2 Autopsy Series Showing Prevalence of ViD (Compliment to ref. 4) Year Location Authors No. of cases ViD % 1962 England Corsellis (79) 167 46 27 1970 England Tomlinson et al. (8) 50 9 18 1972 United States Birkett (80) 24 14 58 1975 Switzerland Todorov et al. (81) 776 132 22 1977 Sweden Sourander et al. (82) 258 72 28 1982 Belgium De Reuck et al. (83) 312 21 6.7 1985 Finland Mölsä et al. (84) 58 11 19 1986 Switzerland Ulrich et al. (32) 54 9 17 1987 Sweden Alafuzoff et al. (85) 74 13 17.6 1987 Canada Wade et al. (86) 65 6 9 1988 United States Joachim et al. (87) 150 3 2 1988 Finland Erkinjuntti et al. (30) 27 23 85.2 1989 United States Boller et al. (88) 54 4 7 1990 Spain Jellinger et al. (31) 675 106 16 1990 Austria Del Ser et al. (89) 40 28 70 1994 Sweden Brun (90) 175 59 34 1995 Norway Ince et al. (91) 69 4 5 1995 United States Markesbery (4) 557 13 2 1997 United States (CERAD) Hulette et al. (73) 1929 6 0.03 1997 Canada Bowler et al. (92) 122 4/5 a 3/4 a 1998 Different countries (1962–1995) Markesbery (4) ? ? 11.3 1999 United States (Nun study) Snowdon and Markesbery (93) 118 3 1.3 1999 United States Nolan et al. (94) 87 0 0 1999 Japan Seno et al. (95) 122 42 35 2001 Japan Akatsu et al. (96) 270 60 22 2003 Rochester, MN, US Knopman et al. (26) 89 12 13 2003 Austria Jellinger (dementias/probable AD) 1000/600 85/17 8.5/2.8 a Reexamination. Abbr: ViD, vascular-ischemic dementia; CERAD, Consortium to Establish a Registry for Alzheimer’s Disease; AD, Alzheimer’s disease. Neuropathologic Substrates of ViD 31 parietal areas (100). In addition, cardiac disorders, such as atrial fibrillation and myocardial infarc- tion (MI), provide a source for cerebral emboli, whereas most other causes, such as hematological conditions, inflammatory angiopathies, Sneddon’s disease (101), and familial CVD (e.g., cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL] or cerebral amyloid angiopathy [CAA]), usually cause multiple subcortical and/or cortical vascular lesions (see Chapter 6). Table 4 Dementia Associated With Cerebrovascular Disease A. Multifocal/diffuse disease 1. Multiple atherosclerotic/watershed infarcts (large artery/border zone territories) 2. Anti-PL-related ischemia 3. “Granular atrophy” of cortex (multifocal cortical microinfarcts) 4. Multiple lacunar infarcts (resulting from microvascular disease or microatheroma) 5. Binswanger subcortical leukoencephalopathy (BSLE) [? linked to #4] 6. CADASIL 7. Angiitis (PCNSA, granulomatous angiitis; some cases linked to CAA) 8. Cerebral amyloid angiopathy (CAA) plus/minus infarcts, hemorrhages (AD variant?)—Familial forms, including Dutch, Icelandic, British 9. Miscellaneous angiopathies (FMD, Moyamoya) 10. Cortical laminar necrosis (post-cardiac arrest, hypotension) 11. Extreme dilatation/enlargement of brain parenchymal perivascular spaces B. Focal disease/strategically placed infarcts 1. Mesial temporal (including hippocampal) infarcts/ischemia/sclerosis 2. Caudate and thalamic infarcts (especially DM nucleus, bilateral damage) 3. Fronto-cingulate infarcts (ACA territory) 4. Angular gyrus infarct (dominant cerebral hemisphere) Abbr: ACA, anterior cerebral artery; Anti-PL, anti-phospholipid; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; DM, dorsomedial; FMD, fibromuscular dysplasia; PCNSA, primary angiitis/arteritis of the central nervous system. From ref. 16. Table 3 Major Morphological Types of Vascular Dementia 1. Classical multiinfarct encephalopathy (MIE) Multiple large (sub/territorial) infarcts in cortex and white matter/basal ganglia in territories of large cerebral arteries, MCA, MCA plus PCA; involving left or both hemispheres 2. Strategic infarct dementia (SID) Small or medium-sized infarcts/ischemic scars in functionally important brain regions: thalamus; hippocampus (PCA), basal forebrain angular gyrus (ACA), bilaterally or domi- nant hemispheres 3. Microangiopathic (small vessel infarct) dementia (SMVA) a. Subcortical arteriosclerotic leukoencephalopathy Binswanger (SAE) Multiple small infarcts in basal ganglia plus white matter with preservation of cortex b. Multilacunar state Multiple microinfarcts (scars up to 1.5 cm Ø); basal ganglia, hemispheral white matter, pontine basis Multiple cortico-subcortical microinfarctions (mixed encephalopathies) c. Granular cortical atrophy Multiple small scars within border zones ACA MCA in one/both hemispheres 4. Subcortical microvascular leukoencephalopathy (acquired/genetically determined) 5. Gliosis or hippocampal sclerosis 6. Inflammatory angiopathy and other mechanisms Abbr: MCA, middle cerebral artery; PCA, posterior cerebral artery; ACA, anterior cerebral artery. Modified from refs. 2,25,55. 32 Jellinger 2.2. Microangiopathic Small Vessel Infarct Lesions The most prominent features of small vessel infarct lesions (SMVAs) are lacunar infarcts that Pierre Marie (102) already described as small miliary softenings, from 0.5 to 1.5 cm or less in diam- eter, or small cavitations that may have more than one pathologic substrate, the most significant representing small infarcts and, less frequently, healed or reabsorbed tiny hemorrhages (2,103). Their most common sites are the periventricular white matter around the lateral ventricles, basal ganglia, thalamus, internal capsule, pons, and cerebellar white matter (104,105). A neuropathologic classification that remains useful (106,107) distinguishes lacunes as follows: Type I lacunes as irregular cavities containing lipid-laden macrophages and blood vessels surrounded by a rim of gliotic, rarified brain. They represent small foci of ischemic necrosis resulting from narrowing or occlusion of short penetrating arteries branching directly from larger cerebral arteries. This type of lacune is the most significant and has been reported in 6–11% of selected brain autopsy series (103,108). A variant type—incomplete lacunar infarct—characterized by loss of only selectively vulnerable cellular elements without cavitation, suggests a common underlying cause (i.e., arterial obstruction) but perhaps of shorter duration or lesser severity (109), or it may represent the sequelae of edema or edema-related gliosis (110). Type II lacunes are smaller in size and distribution and contain numerous hemosiderin-laden macrophages, representing old, small hemorrhages or old hem- orrhagic microinfarcts resulting from fibrinoid vascular necrosis, but are rare (111,112). Type III lacunes are dilatations of perivascular spaces surrounded by a single layer of epithelial-like cells and by compressed or mildly gliotic brain, often with corpora amylacea. They usually contain one or more segments of a normal artery and have been ascribed variously to small vessel wall perme- ability, interstitial fluid drainage disorders (113,114), cerebral atrophy, mechanical stress from pul- sating arterioles (115), perivascular inflammation, or other nonspecific factors. Roman (116) found lacunar infarcts in 36% of the patients studied, whereas a recent Japanese ViD study reported multiple lacunar infarcts in 42% of the patients studied, representing the most frequent type of CVLs (66). In a personal study of 750 autopsy-proved AD brains and 562 age-matched con- trols, lacunar lesions were found in 32 vs 27% (98). The majority of lacunes, as found by the meticulous work of Fisher (103,104), are caused by intracranial atherosclerosis, “lipohyalinosis,” or segmental fibrinoid necrosis affecting small arteries, with subsequent occlusion of single deep perforating vessels, whereas in one-fifth of patients, no thrombosis can be found. However, most perforating branches have multiple stenoses and poststenotic dilatations, suggesting that hemodynamic events might also play a role in the pathogenesis of lacunar state (117). These lesions are usually caused by hypertension, diabetes mellitus, etc. Other mecha- nisms are cerebral microembolism of vascular or cardiac origin, such as atrial fibrillation (2,14,69), CADASIL, or inflammatory angiopathies. The type of vascular lesions underlying lacunes and their causes have been recently reviewed (111,112,118). According to the predominant location of SMVA, the following types of ViD can be distinguished. 2.2.1. Strategic Infarct Dementia (SID) Infarcts or ischemic scars, often involving isolated strategically important brain regions, despite relatively small losses of cerebral parenchyma, may cause mental deterioration, culminating in dementia. Such strategic areas include the following: (2,4,10,16,18). 1. Watershed Infarcts: Watershed infarcts in circulatory border zones between the deep or superficial branches of ACA, MCA, and PCA may result from hypotension with “misery perfusion” or showers of microemboli, causing laminar necrosis between small superficial branches of the ACA and ACM or in bilateral hippocampal or thalamic softening (2,4,10,16–18). These infarcts usually occur in patients with extracranial carotid stenosis or occlusion and are often associated with decrease in blood pressure (119). 2. Angular Gyrus: Angular gyrus are present in the supply area of the ACA of the dominant hemisphere or bilaterally (120). 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(95) 122 42 35 20 01 Japan Akatsu et al. (96) 27 0 60 22 20 03 Rochester, MN, US Knopman et al. (26 ) 89 12 13 20 03 Austria Jellinger (dementias/probable AD) 1000/600 85/17 8.5 /2. 8 a Reexamination. Abbr:. United States Birkett (80) 24 14 58 1975 Switzerland Todorov et al. (81) 776 1 32 22 1977 Sweden Sourander et al. ( 82) 25 8 72 28 19 82 Belgium De Reuck et al. (83) 3 12 21 6.7 1985 Finland Mölsä. 1978 22 3 10.0 Ishii et al., 1984 22 4 11.7 Tomonaga, 1985 (lobar hemorrhages) 21 1 20 .0 Nadeau, 1989, quoted by >60 yr 17 15.0 >70 yr ca. 20 .0 Vonsattel et al., 1991 21 8 20 .0 Feldman, 1994 22 5