Understanding the pathology of vascular cognitive impairment

Journal of the Neurological Sciences 229 – 230 (2005) 57 – 63 www.elsevier.com/locate/jns

Understanding the pathology of vascular cognitive impairment Kurt A. Jellinger* Institute of Clinical Neurobiology, Kenyongasse 18, A-1070 Vienna, Austria Available online 8 December 2004

Abstract The prevalence, morphology and pathogenesis of vascular dementia (VaD), recently termed vascular cognitive impairment (VCI), and of mixed dementia (Alzheimer disease+vascular encephalopathy) are a matter of discussion and no validated neuropathologic criteria for these disorders are currently available. In Western memory clinic-based series, VaD/CVI is suggested in 8–10% of cognitively impaired elderly; its prevalence in autopsy series ranges from 0.03% to 58% (mean 5–15%). Fairly unusual as an isolated nosological entity, CVI appears to correlate with focal, multifocal or diffuse cortical and/or subcortical microinfarcts and lacunes often affecting strategically important brain areas (thalamus, frontobasal, limbic system), hemispheric white matter and, less often, large brain areas. They result from systemic, cardiac or local large or small vessel disease. The lesion pattern in bpureQ VCI with predominant multiple small (subcortical) lesions related to microangiopathies differs from that in bmixed dementiaQ (AD+VaD), more often associated with large infarcts, suggesting different pathogenesis. In very old subjects, selective hippocampal sclerosis may be accompanied by multiple other vascular pathologies. Minor cerebrovascular lesions (CVL), except for severe amyloid angiopathy, appear not essential for cognitive decline in full-blown AD, while both mild AD-type pathology and small vessel disease may interact synergistically in bunmaskingQ or promoting dementia. AD pathology is significantly less severe in the presence of cerebrovascular lesions. Further studies are needed to validate diagnostic criteria for VCI and to clarify the impact of vascular lesions on cognitive impairment. D 2004 Elsevier B.V. All rights reserved. Keywords: Vascular cognitive impairment; Vascular dementia; Mixed type dementia; Cerebral infarcts; Small vessel disease; Subcortical vascular lesions

1. Introduction The role of cerebrovascular disease (CVD) and ischemic brain damage for cognitive decline remains controversial. Dementia related to vascular disorders was first described as barteriosclerotic dementiaQ [1] and was later replaced by other terms (Table 1). While not all patients with vascular cognitive impairment (VCI) develop dementia according to standard diagnostic criteria, such patients are at risk of dementia and at least half of them progress to dementia [3]. Morphologic substrates of cognitive impairment resulting from cerebrovascular lesions (CVL) remain confusing, since they constitute a multifactorial disorder related to a wide variety of lesions and causes. Even when cerebrovas-

cular pathology (CVP) appears to be the main underlying process, the effect of damaged brain parenchyma is variable and, therefore, the clinical, radiological and pathological appearances may be heterogeneous. Complicating the diagnosis of VCI are other coexisting pathologic entities in the aging brain. In contrast to recently refined morphological criteria for Alzheimer disease (AD) and other degenerative dementias [11,12], no generally accepted and validated neuropathological criteria for VCI have been established up to date, and no definite morphological substrates have been included in the currently used clinical diagnostic criteria for VCI, e.g. DSM-IV, SCADDTC [13] and NINDS-AIREN [14].

2. Prevalence and incidence patterns * Tel.: +43 1 5266534; fax: +43 1 5238634. E-mail address: [email protected]. 0022-510X/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2004.11.029

Given the difficulty in diagnosing VCI, considerable methodological and geographical differences, it remains

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K.A. Jellinger / Journal of the Neurological Sciences 229 – 230 (2005) 57–63

Table 1 Cognitive dysfunctions caused by cerebral lesions due to vascular/ischemic pathology Synonyms Arteriosclerotic dementia [1]—binaccurate and misleadingQ [2] Multi-infarct dementia [2]—only subtype Dementia associated with stroke [3] Vascular dementia [4,5] Cerebrovascular dementia [6] Ischemic–vascular dementia [7] Vascular–ischemic dementia [8,9] Vascular cognitive impairment [10]

difficult to draw conclusions about its frequency and distribution. Evaluation of 11 pooled European population-based studies of subjects of over age 65 revealed an age-standardized prevalence of 6.4% for all dementias, 4.4% for AD and 2.6% for vascular dementia (VaD) [15]. The incidence varies between 6 and 15/year/1000 persons aged 70 years and older and increases with advancing age [16]. In other clinical studies, VaD ranged from 12% to 23% compared to 47% for AD and 22% for dementia with Lewy bodies (DLB) [17]. bSilentQ, clinically asymptomatic cerebral infarcts increasing with advancing age are considered major contributors to cognitive impairment after stroke occurring in 25–30% of patients [18], associated with a twofold odd of dementia [19]. A review of autopsy studies of demented patients revealed an overall mean risk of 17.3% for bpureQ VaD [5] or suggested even a wider range from 0% to 85% [8]. Other reports showed a prevalence of 2–9%, while both in the CERAD and the Nun study, pure VaD without other pathological features was seen in only 0.03% and 2.5%, respectively [20,21]. In recent autopsy series of demented Japanese subjects, the incidence rate for VaD was 2235% vs. 3442% for AD [22,23]. In a consecutive autopsy series of 1000 demented aged patients in Vienna, Austria, pure VaD was seen in 8.5% and mixed VaD/AD in 3.7% as compared to AD pathology in 83.7%. However, bpureQ AD was present in only 41%, while the other brains showed different coexistent pathologies (vascular lesions in 29%, Lewy body pathology in 12%), and 7% had dementia disorders of other etiologies (Table 2). These data suggest that both AD and mixed forms of dementias due to various pathologies show a similar frequency.

3. Major morphological substrates Pathologic changes in the brain related to VCI are multiple; they include arterial territory infarcts, distal field (watershed/borderzone) infarcts, small and medium sized lesions mainly in functionally important brain areas, lacunar infarcts and scars, white matter lesions (WMLs), incomplete ischemic injury, hippocampal lesions and sclerosis. They have been categorized as multifocal and/or diffuse disease and focal, strategically placed lesions. They are caused by

many vascular and ischemic mechanisms, but mainly include large arterial and small vessel diseases, cardiac, embolic events, hemodynamic mechanisms and cerebral ischemia of various etiology. Two major types of lesions are distinguished [9]: 1.

Multifocal (disseminated) disease: ! Classical multiinfarct encephalopathy (MIE) with large territorial or watershed infarcts involving the territories, parts or borderzones of supply areas of large cerebral arteries. ! Microinfarcts and lacunes in subcortical supply areas (basal ganglia, white matter, brainstem). ! Mixed cortico–subcortical microinfarcts. ! Cortical pseudolaminar necrosis, a pattern of neuronal loss and scar formation in cerebral cortex arising from cardiac and respiratory arrest, often associated with diffuse WMLs and cerebral atrophy. ! Cortical granular atrophy, rare sequelae of diminished local flow in the endfield territories of distal branches of cerebral arteries, mainly between anterior/medial and medial/posterior arteries, caused by carotid artery occlusive disease or cerebral microembolism. ! White matter lesions (subcortical arteriosclerotic/ leuko/encephalopathy (SAE), Binswanger’s disease or leukoaraiosis). ! Multiple postischemic lacunes in cortex, white matter and basal ganglia due to dramatic systemic blood flow failure or hypotension. 2. Focal disease Dementia is not always correlated with destruction of large amounts of tissue, but can be caused by focal

Table 2 Morphological diagnosis in consecutive Vienna autopsy series of demented aged individuals (1989–2002) 354 M/646 F, age 83.3F6.0 (range 55–103) years bPureQ AD (CERAD pos., Braak V–VI) Alzheimer type pathology (plaque, limbic type, NFT-SD) 16/19/52 AD+CVD (lacunar state, old/fresh infarcts, AH scler.) 128/41/38/16 AD+cerebral hemorrhage (amyloid angiopathy) Lewy body variant AD (25), diff. Lewy body disease (31) AD+Parkinson pathology/nigral lesion/subcortical Lewy bodies 27/20/13 MIX type dementia (AD+MIE/SAE, SID) 28/6/3 AD+other pathol. (tumors, ALS, MSA, MS, PSP, old trauma) Alzheimer pathology total VaD (MIE 28, SAE 39, SID 16, AhScl 2) Other disorders (Huntington disease, FTD, CJD, others) Nothing abnormal beyond age Other pathologies Total

n

%

334 87

33.4 8.7

223

22.3

29 56

2.9 5.6

60

6.0

37 11

3.7 1.1

837 85 70

83.7 8.5 7.0

8 163 1000

0.8 16.3 100.0

K.A. Jellinger / Journal of the Neurological Sciences 229 – 230 (2005) 57–63

symmetrical or, less often unilateral, lesions in relevant cerebral territories: ! Strategically placed infarcts involving isolated functionally important brain areas (thalamus, mesio-temporal area/hippocampus, fronto-cingular, basal forebrain, angular gyrus). ! Hippocampal damage or necrosis, ranging from selective neuron loss to frank infarction, often accompanied by multiple small infarcts/lacunes in other brain areas. They are observed in 10–25% of old subjects involved with marked memory impairment but often without frank dementia [24]. Another classification distinguishes lesions related to large and small vessel disease: 1. 2.

Classical multiinfarct encephalopathy (large vessel disease). Microangiopathic (small vessel infarct) dementia with lacunar infarcts or lacunes, strategic infarct dementia, WMLs or SAE, that is often associated with lacunes or microinfarcts in the centrum semiovale, basal ganglia and/or brainstem. Myelin degeneration has usually a patchy confluent form sparing the subcortical U-fibers; perivascular vacuolation and reduction of oligodendroglia may represent an early stage. Comparative studies showed that punctate hyperintense MRI lesions corresponding to dilated perivascular spaces are to be distinguished from extensive WMLs, due to confluent patches of myelin pallor with or without cavitation. Periventricular lesions in MRI correlated with the severity of demyelination and astrocytosis, often associated with lacunes or microinfarctions in white matter and basal ganglia [25]. VCI can also arise in the setting of CVD without obvious infarctions [26].

4. Pathogenesis The pathogenic factors involved in VCI include the volume of brain destruction, its location, and the numbers of CVLs, but Pantoni [27] emphasized the overlap between vascular and degenerative mechanisms and a lack of correlation between clinical and pathology findings. 4.1. Volume of brain destruction Tomlinson et al. [28] showed that, although patients with brain tissue losses N100 ml were demented and that volumes between 50 and 100 ml produced dementia less consistently, they observed also demented patients with smaller infarcts. Those totalling N20 ml were significantly more frequent in demented subjects than in controls and marked differences between the two groups were present at 50 ml cutoff. This suggested that relative small infarcts may or may not contribute to dementia, probably depending on their

59

location, while destruction of large parts of the cortex may be followed by dementia. Other studies in VaD revealed mean infarct volumes of 40 ml, while patients with AD or AD+VaD had infarcts of less than 10 ml [29]. There was a non-significant trend for lobar infarcts to occupy more cerebral volume in VaD than in non-demented stroke patients [7]. Location of vascular lesions is probably more important than the volume of tissue destruction. Multiple brain areas have been implicated in VCI-dominant angular gyrus, bilateral or left ACA and PCA territories, dominant caudate nucleus, anterior internal capsule interrupting corticothalamic and thalamo-cortical pathways, hippocampus, amygdala, fronto-cingulate gyrus and basal forebrain (see Refs. [30,31]). Both hippocampal infarcts and sclerosis, either alone or in combination with other vascular lesions have been related to dementia that showed significant hippocampal neuronal loss [32,33]. 4.2. Number of lesions Although a basic concept of VaD suggests that multiple small infarcts, irrespective of their volume, can lead to intellectual decline, only few studies have addressed this problem. The mean number of infarcts in VaD was 5.8–6.7 compared to 3.2 in non-demented subjects [34], but additional factors, such as other brain lesions, extent of WMLs, brain atrophy, etc. are involved in determinating cognitive decline.

5. Importance of small cerebrovascular lesions Comparing the neuropathology findings in elderly demented subjects without considerable AD pathology and non-demented controls, Esiri et al. [4] saw correlations of microvascular brain damage with dementia. Severe lacunar state, microinfarcts and cerebral amyloid angiopathy (CAA) had a greater prevalence in the dementia groups, which had less frequent macroscopic infarcts than non-demented. Without differences in severity of extracerebral atheroma, the dementia group more often revealed arteriosclerosis and hypertensive microangiopathy. Examining 19 different regions from 52 human brains, Thal et al. [35] reported that the expansion of CAA and arteriosclerosis/lipohyalinosis was associated with an increase of dementia and correlated with amyloid and neurofibrillary stages, suggesting that widespread small vessel changes are an important component of AD. Vinters et al. [7] also emphasized the correlation of dementia with widespread small ischemic lesions throughout the CNS, but many brains showed more than one type of CVLs. Most were associated with severe atherosclerosis and arteriolosclerosis, while CAA was rare. These data were confirmed in a personal autopsy study of 130 elderly subjects (age 80–92 years). Among 91 demented subjects (MMSE 10F4), 27% had large old

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K.A. Jellinger / Journal of the Neurological Sciences 229 – 230 (2005) 57–63

infarcts, 52% had multiple subcortical lacunes, 9% cortical and subcortical microinfarcts, and 4.5% hippocampal sclerosis. Of cognitively impaired subjects (MMSE ca. 20), 31% showed large cystic infarcts, 52% multiple subcortical lacunes, the rest had multiple infarcts. Of the 20 cognitively normal controls, two-thirds had cystic infarcts, 30% multiple subcortical lacunes with preserved thalamus and 1 had multiple old infarcts [8]. These data indicate that subcortical lacunes and multiple disseminated infarcts are the most common morphologic features of VCI/ VaD, while large cystic infarcts are less common.

6. Pathophysiology VaD is thought to be caused by focal or multifocal lesions involving strategic brain areas with deafferentation of frontal and limbic cortical structures with interruption of thalamo-cortical and striato-cortical pathways caused by lesions in basal ganglia, thalamus or connecting white matter. The pattern of cognitive impairment is consistent with models of disturbed cortical and subcortical neuronal pathways [36]. Complex interactions between subcortical lesions and radiologically detected changes in cortex and hippocampus in producing cognitive decline have been shown [32], while others suggested significant correlations to cortical lesions and frontal atrophy [37,38]. Frontal impairment in VaD is responsible for greater executive dysfunction in comparison with AD patients who show more severe impairment of attentional shifting and working memory [39]. Synaptophysin immunoreactivity as a measure of synapse protein density in the cortex is severely reduced in Binswanger’s disease [40]. Preclinical [41] and clinical evidence [42] indicate that cholinergic deficit, similar to that seen in AD, may be associated with VaD, suggesting that these patients may benefit from treatment with cholineresterase inhibitors, which has been confirmed by recent studies [43,44].

7. The enigma of mixed dementia Mixed type dementia (MD) is characterized by combined pathologies of both AD and VaD, but the distinction between these diseases is controversial. The CERAD classification does not consider MD [45], while in the ADDTC criteria [13], a second CVD in addition to AD must be shown to be causally related to dementia. In the NINDSAIREN criteria [14], the term AD with CVD is reserved to patients fulfilling the clinical criteria of possible AD who have also clinical and imaging signs of relevant CVD, but redefinition of the term MD has been recommended. We proposed the combination of autopsy-proven AD (using accepted criteria) with multiple lacunes or CVLs in cortex, basal ganglia and hippocampus, or at least 30–50 ml of infarcted brain volume [8,12]. However, generally

accepted and validated neuropathologic criteria for the diagnosis of MD are not available and its true frequency is not known. The prevalence rates of MD in autopsy series showed a wide range from 2% to 36% with means of 12% to 17.7% [12,46]. Since strokes are common in elderly persons, in most autopsy series of demented elderly, 20– 60% of AD brains show additional CVLs [12,47,48]. In a consecutive series of 730 autopsy-proven AD cases (mean Braak stages 5.2), the prevalence of vascular pathology was significantly higher than in 55 age-matched controls (58% vs. 32%, pb0.001). The incidence of CAA in AD was 97.9% (with severe degrees in 24%) as compared to around 30% in controls. In a population-based study in the UK (MRC-SFAS), among 209 autopsies of elderly subjects, 48% being demented, 78% had evidence of CVD and 70% AD pathology. The proportion of multiple vascular lesions was higher in the demented group (46% vs. 33%), indicating that most patients had mixed disease [48]. Whether vascular pathology is a factor contributing to the pathogenesis of AD is a matter of discussion [12], but there may be a close relationship between both pathologies. Severe CAA is associated with an increased frequency of cerebral infarction in AD, but hypertension has also an important role [49], and both human and experimental studies in transgenic mice overexpressing APP suggest that cerebrovascular effects of Ah peptide render the brain more vulnerable to ischemic injury [50,51]. Vascular lesions may have synergistic effects with AD pathology and thus may magnify the effect of mild AD pathology and result in earlier and more severe cognitive impairment [52,53]. Moreover, in patients with CVLs, the density of plaques and tangles was significantly lower than in those with histologically bpureQ AD for every given level of cognitive deficit [51]. These findings are consistent with those in the nun study, where patients with autopsy confirmed AD and CVLs had a higher prevalence of dementia than those without infarcts. The risk of being demented was 20-fold higher in subjects with AD and associated lacunar infarcts, but much lower (6-fold) and statistically non-significant when a large territorial infarct was present [21]. The experience of the CERAD group has corroborated these findings [54], and in the Optima study [4], CVD significantly worsened cognitive impairment in earliest stages of AD. On the other hand, recent studies of autopsy cases of AD with and without CVLs showed no significant differences in baseline, final, and changes in Mini-Mental scores between groups [12] and no influence of the extent of CVLs on the age of death, clinical expression and severity of AD pathology or the prevalence of hypertension and myocardial infarcts was observed [55]. However, a personal study of more than 600 autopsy cases with dementia revealed significantly higher Braak stages and lower final MMSE scores in different types of VaD than in pure AD and AD with lacunar state, small old infarcts or hippocampal sclerosis. MD showed Braak stages and cognitive impairment similar to AD, but a much more

K.A. Jellinger / Journal of the Neurological Sciences 229 – 230 (2005) 57–63 Table 3 Relation between cognitive state and vascular lesions in AD Disorder

bPureQ AD AD with lacunar state AD with old infarcts (b10 cm3) AD with hippocampal sclerosis MIX (AD+CVD)N10

n (M/F)

Age at death

33 (7/26)

Table 5 Type of cerebrovascular lesions in mixed type dementia History of stroke

5.2

1.1 (77)a 10.0

5.0

4.9 (19)

21.0b

4.8

7.0 (5)

33.0

86.1F6.7b,c 4.7

5.0 (5)

NG

400 80.3F8.9 (159/241) 133 83.2F6.2 (37/96) 37 84.6F6.7 (12/25) 16 (9/7)

Braak Final stage MMSE (mean)

82.7F5.9

4.8

7.3 (4)

61

b

95.0

NG: not given. a pb0.01 vs. other groups. b pb0.01 vs. bpureQ AD. c pb0.05 vs. bpureQ AD.

frequent history of stroke [8,12]. Few studies have examined the contribution of small concomitant infarcts with less than 10 ml volume in AD. Among 227 longitudinally followed-up autopsy cases of AD, 36 with concomitant small infarcts, significantly higher age with lower Braak stages were seen in patients with MD than in bpureQ AD [47]. These data, which were at variance to others suggesting a contribution to cognitive decline of CVLs with volumes even less than one ml [56], were confirmed by evaluating 619 demented subjects: Between cases of bpureQ AD, those with additional CVLs and MD, the age at death and Braak stages were similar, severity of dementia was slightly more severe in bpureQ AD, while the history of stroke was higher in AD with vascular lesions (Table 3). In AD with minor CVLs, the majority of lesions were lacunes in basal ganglia and/or white matter and multiple microinfarcts (Table 4), while in MD large lobar infarcts or multiple lesions were much more frequent (Table 5), suggesting different pathogenic mechanisms between both types of disorders. These data also suggest that coexistent small CVLs with a volume of less than 10 ml do not significantly influence the overall rate and progression of cognitive impairment in AD, although any

1. AD+multiple infarcts ACM bilat. ACM left ACM+ACP left ACM+ACP right Multiple bilateral Multiple left hemisphere 2. SID (strategic infarcts) Thalamus+hippocampus Thalamus bilateral 3. SAE (subcortical type) (Lacunes striatum, white matter)

Infarct and location

Lee et al. [47] (n=36)

Personal series % (n=67)

Cortical microinfarcts Lacunar infarcts: Basal ganglia Thalamus Basal ganglia+thalamus White matter Multiple infarcts (cort.+subcortical)

18

15

18 15 6 3 6

33 10 12 3 5

8 1 2 5 5 Total

37

ACM=middle central artery, ACP=posterior central artery.

concomitant pathology may influence both cognitive and non-cognitive features [52,57]. Elderly patients with subclinical or mild AD and little functional brain reserve (with frequent entorhinal tangles and moderate numbers of neuritic cortical plaques) who have critically located small CVLs, may demonstrate symptoms of intellectual decline, while in progressed or full-blown stage of AD with additional small CVLs that are frequently observed by modern neuroimaging methods, cognitive decline is mainly related to the severity and extent of AD pathology [12]. The combination of two or more pathologic processes may influence the severity of cognitive deficit unmasking preclinical dementia due to mild AD lesions, while small CVLs alone may less frequently cause dementia of their own, but rather by a synergistic effect.

8. Concluding remarks CVI is a non-frequent heterogenous group of disorders in the course of which multiple ischemic and/or vascular Table 6 Major types of cerebrovascular lesions in VCI Tissue lesions

Multifocal

Focal

Circulation disorders causes: Systemic disease

large arteries

small vessel disease

multiple territorial infarcts borderline infarcts cort. granular atrophy combined cortical–subcortical lesions

microinfarcts, lacunes in cortex or strategic regions (thalamus, caudate, hippocampus, angular, cingulate gyri)

incomplete infarcts, white matter lesions (leukoaraiosis, Binswanger) multiple hemorrhages

periventricular lesions (Binswanger type)

Atherosclerosis Thrombo-embolism Cardiac disease

Table 4 Type and location of infarcts in AD+minor CVD

29 6 8 5 3 2 4

Systemic emboli Fibrohyalinosis Amyloid angiopathy CADASIL Hypoperfusion (instable arter. pressure) Hemorrhagic

focal bleeds

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K.A. Jellinger / Journal of the Neurological Sciences 229 – 230 (2005) 57–63

brain lesions of variable etiology result in progressive cognitive impairment. The major subgroups and their causes are summarized in Table 6. The concept that VaD is determined primarily by the volume of infarcted brain has not been confirmed. Cognitive involvement appears to correlate with widespread ischemic and/or vascular lesions throughout the brain with particular involvement of functionally important areas and neuronal loops. Sporadic and genetic angiopathies or CAA may result in dementia. MD, featured by a combination of definite AD and multiple vascular lesions not being extensive enough or located in strategic areas to produce cognitive decline of their own, is a diagnostic challenge for which neither definite neuropathologic criteria nor exact epidemiologic data are available. The lesion pattern of bpureQ CVL and of AD with minor CVLs, frequently showing multiple subcortical lacunes or microinfarcts and WMLs, differs from that in MD, more often associated with larger hemispheric infarcts, suggesting different pathogenic mechanisms. Both mild AD pathology and small vesseldisease-associated subcortical lesions are common and may synergistically interact in causing cognitive decline. AD pathology may be significantly less severe in demented patients with CVLs, dementia being more severe in mild to moderate AD with additional CVLs. However, in final stages of AD, minimal CVLs have no or only little impact on the severity of dementia. Besides the issues of overlap between vascular and degenerative mechanisms, many other questions remain unanswered, and prospective clinico-pathologic studies are warranted to validate diagnostic criteria for VCI and its combination with AD in order to elucidate the impact of both pathologies and their pathomechanisms to produce cognitive impairment as a basis for more precise diagnosis, early prevention and successful management of this important problem in clinical neurosciences.

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