Sialylation patterns in cerebral amyloid angiopathy.

We have previously reported an association between severe cerebral amyloid angiopathy (CAA) and cerebrovascular lesions in Alzheimer disease (AD), which is particularly strong for microinfarcts, hemorrhages, and multiple lesion types. Cerebral amyloid angiopathy has also been associated with the apolipoprotein E4 (APOE4) genotype, which is in turn associated with premature coronary artery disease and atherosclerosis. To test whether severe CAA would be more strongly associated with cerebrovascular lesions than would APOE4 genotype. We reviewed 306 cases of autopsy-confirmed AD (from the University of California, San Diego, brain autopsy series) to assess whether APOE genotype and other clinical risk factors were predictive of vascular lesions (VLs) in AD. Cerebral amyloid angiopathy severity was assessed using a semiquantitative scale in 4 brain regions (ie, hippocampus, midfrontal cortex, inferior parietal cortex, and superior temporal cortex) and an average score was computed for each case. We found that severe CAA was associated with an increased frequency of VLs (33% of the cases of severe CAA had VLs vs 19% of the cases of mild or absent CAA; P=.02). While the APOE4/4 genotype was associated with an increased severity of CAA, there was no significant relationship between APOE genotype and frequency of VLs. Logistic regression models showed that severe CAA, advanced age, atherosclerosis, and Hachinski Ischemia Scale score of 7 or more were all significantly associated with VLs, but the number of APOE4 alleles, history of hypertension, coronary artery disease, sex, and serum cholesterol levels had nonsignificant effects. Within strata of APOE genotype, the presence of severe CAA was associated with increased frequency of VLs (eg, within APOE4/4 homozygotes, VLs were present within 47% of the cases of severe CAA vs 9.5% of the cases of mild or absent CAA; P=.01). Severe CAA confers a greater risk of VLs in AD, even within strata of APOE genotype. Therefore, the association between severe CAA and VLs in AD is not a spurious one owing to APOE4. Overall, our cases of AD with APOE4 do not seem to be a more "vasculopathic" subtype of AD. The mechanisms by which CAA produces VLs of various types need to be further elucidated, as these are probably important in producing the common entity of "mixed" AD/vascular dementia. Arch Neurol. 2000.

The deposition of amyloid beta-protein (Abeta) in the vessel wall, i.e., cerebral amyloid angiopathy (CAA), is associated with Alzheimer's disease (AD). Two types of CAA can be differentiated by the presence or absence of capillary Abeta-deposits. In addition, as in Alzheimer's disease, risk for capillary CAA is associated with the apolipoprotein E (APOE) epsilon4-allele. Because these morphological and genetic differences between the two types of AD-related CAA exist, the question arises as to whether there exist further differences between AD cases with and without capillary CAA and, if so, whether capillary CAA can be employed to distinguish and define specific subtypes of AD. To address this question, we studied AD and control cases both with and without capillary CAA to identify the following: (1) distinguishing neuropathological features; (2) alterations in perivascular protein expression; and (3) genotype-specific associations. More widespread Abeta-plaque pathology was observed in AD cases with capillary CAA than in those without. Expression of perivascular excitatory amino acid transporter 2 (EAAT-2/GLT-1) was reduced in cortical astrocytes of AD cases with capillary CAA in contrast to those lacking capillary Abeta-deposition and controls. Genetically, AD cases with capillary CAA were strongly associated with the APOE epsilon4 allele compared to those lacking capillary CAA and to controls. To further validate the existence of distinct types of AD we analyzed polymorphisms in additional apoE- and cholesterol-related candidate genes. Our results revealed an association between AD cases without capillary CAA (i.e., AD cases with CAA but lacking capillary CAA and AD cases without CAA) and the T-allele of the alpha(2)macroglobulin receptor/low-density lipoprotein receptor-related protein-1 (LRP-1) C766T polymorphism as opposed to AD cases with capillary CAA and non-AD controls. Taken together, these results indicate that AD cases with capillary CAA differ significantly from other AD cases both genetically and morphologically, thereby pointing to a specific capillary CAA-related and APOE epsilon4-associated subtype of AD.

Blood-brain barrier (BBB) leakage may be an early step in the pathophysiology of cerebral amyloid angiopathy (CAA), possibly preceding hemorrhages. This exploratory study measured BBB leakage in vivo at the level of the leptomeningeal and small parenchymal vessels in patients with probable CAA. We hypothesized that BBB leakage from leptomeningeal and cortical small vessels would be higher in patients with CAA compared with controls and that leakage would be associated with hemorrhagic manifestations of CAA, that is, cortical superficial siderosis (cSS) and lobar cerebral microbleeds (CMBs). Patients with probable CAA without previous intracerebral hemorrhage and non-CAA patients with mild cognitive impairment from the memory clinic were recruited in this prospective observational exploratory study. Participants underwent 3T brain MRI with injection of a gadolinium-based contrast agent (Dotarem). Leakage from leptomeningeal vessels was assessed on postcontrast vs precontrast T2-fluid-attenuated inversion recovery as either focal or sulcal CSF enhancements. Dynamic contrast-enhanced scans were analyzed to quantify permeability-surface area product (PS): a measure of leakage from parenchymal small vessels. Fourteen patients with CAA (mean age 67.7 ± 9.0 years; 57% female) and 7 non-CAA patients with mild cognitive impairment (mean age 70.1 ± 6.5 years; 29% female) were recruited. Focal CSF enhancements were observed similarly often in patients with CAA (7 [50%]) and non-CAA controls (4 [57%], p = 0.98), whereas sulcal CSF enhancements were only seen in patients with CAA (5 [36%] vs 0 [0%]). In patients with CAA, focal and sulcal CSF enhancement counts were associated with higher cSS volume (B = 2.61, p = 0.003; B = 1.02, p = 0.02), but not with CMBs. PS was numerically higher in the cortex in patients with CAA (5.08 ± 4.02 × 10-4 min-1) than in non-CAA controls (1.29 ± 4.08 × 10-4 min-1, p = 0.07), but it was not associated with CMB count or cSS volume (p > 0.67). Leakage of gadolinium-based contrast agent through the BBB can be measured in vivo in CAA from the leptomeningeal vessels, and findings point to likely leakage from cortical small vessels as well. Leakage from leptomeningeal vessels was associated with cSS. Studies with follow-up data need to determine whether these measures could serve as a predictive biomarker in CAA.

Tissue transglutaminase colocalizes with extracellular matrix proteins in cerebral amyloid angiopathy

We determined the frequency of cerebral amyloid angiopathy (CAA) in 135 consecutive cases of diffuse Lewy body disease (DLBD) (N = 67), Alzheimer's disease (AD) (N = 34), and normal elderly controls (NECs) (N = 34). DLBD cases were subdivided into those with pathologic changes compatible with coexistent AD (DLBD/AD) and those without sufficient AD-type changes to warrant that diagnosis. In each case, we assessed the frequency, severity, and distribution of CAA on multiple thioflavin-S-stained sections of cerebral cortex examined with fluorescent microscopy. Based on immunocytochemistry with beta-amyloid antibodies, amyloid in all the brains was composed of beta/A4. CAA was present in the leptomeningeal vessels in 50% of the NECs and in 100% of AD cases. In DLBD without coexisting AD, the frequency of leptomeningeal CAA was 58%, whereas in DLBD/AD, the frequency was 85%. The frequency of CAA in parenchymal vessels was 38% for NECs, 97% for AD, 43% for DLBD, and 85% for DLBD/AD. There was no significant difference in the frequency or severity of CAA between NECs and DLBD, but CAA was significantly more severe, and comparable with CAA in AD, in the cases of DLBD/AD. Ten NECs had focal CAA without senile plaques (SPs), whereas all other cases with CAA had at least some SPs. Neither CAA nor SPs were present in 14 cases, including seven NECs and seven DLBD cases. We found cerebrovascular accidents in 50 cases (including nine without CAA) and leukoencephalopathy in 24 cases. These results suggest that CAA and other AD-type changes are not concomitant with DLBD but are related to coexisting AD or pathologic aging.

Cerebral amyloid angiopathy (CAA) is caused by the deposition of the amyloid β-protein (Aβ) in the wall of cerebral and leptomeningeal blood vessels and is related to Alzheimer's disease (AD). Capillary Aβ deposition is observed in a subset of CAA cases and represents a distinct type of CAA named capillary CAA or CAA type 1. This type of CAA is strongly associated with the presence of the apolipoprotein E ε4 allele. CAA type 1-associated AD cases often exhibit a more severe Aβ plaque pathology but less widespread neurofibrillary tangle (NFT) pathology. The objective of this study was to analyze whether capillary CAA and its effects on cerebral blood flow have an impact on dementia. To address this objective, we performed neuropathological evaluation of 284 autopsy cases of demented and non-demented individuals. We assessed the presence of CAA and its subtypes as well as for that of hemorrhages and infarcts. Capillary CAA and CAA severity were associated with allocortical microinfarcts, comprising the CA1 region of the hippocampus. Allocortical microinfarcts, capillary CAA and CAA severity were, thereby, associated with cognitive decline. In conclusion, allocortical microinfarcts, CAA severity, and the capillary type of CAA were associated with one another and with the development of cognitive decline. Thus, AD cases with CAA type 1 (capillary CAA) appear to develop dementia symptoms not only due to AD-related Aβ plaque and NFT pathology but also due to hippocampal microinfarcts that are associated with CAA type 1 and CAA severity, and that damage a brain region important for memory function.

Alzheimer’s disease (AD) is characterized by extracellular amyloid plaques containing amyloid-β (Aβ) peptides, intraneuronal neurofibrillary tangles, extracellular neuropil threads, and dystrophic neurites surrounding plaques composed of hyperphosphorylated tau protein (pTau). Aβ can also deposit in blood vessel walls leading to cerebral amyloid angiopathy (CAA). While amyloid plaques in AD brains are constant, CAA varies among cases. The study focuses on differences observed between rare and poorly studied patient groups with APP duplications (APPdup) and Down syndrome (DS) reported to have higher frequencies of elevated CAA levels in comparison to sporadic AD (sAD), most of APP mutations, and controls. We compared Aβ and tau pathologies in postmortem brain tissues across cases and Aβ peptides using mass spectrometry (MS). We further characterized the spatial distribution of Aβ peptides with MS-brain imaging. While intraparenchymal Aβ deposits were numerous in sAD, DS with AD (DS-AD) and AD with APP mutations, these were less abundant in APPdup. On the contrary, Aβ deposits in the blood vessels were abundant in APPdup and DS-AD while only APPdup cases displayed high Aβ deposits in capillaries. Investigation of Aβ peptide profiles showed a specific increase in Aβx-37, Aβx-38 and Aβx-40 but not Aβx-42 in APPdup cases and to a lower extent in DS-AD cases. Interestingly, N-truncated Aβ2-x peptides were particularly increased in APPdup compared to all other groups. This result was confirmed by MS-imaging of leptomeningeal and parenchymal vessels from an APPdup case, suggesting that CAA is associated with accumulation of shorter Aβ peptides truncated both at N- and C-termini in blood vessels. Altogether, this study identified striking differences in the localization and composition of Aβ deposits between AD cases, particularly APPdup and DS-AD, both carrying three genomic copies of the APP gene. Detection of specific Aβ peptides in CSF or plasma of these patients could improve the diagnosis of CAA and their inclusion in anti-amyloid immunotherapy treatments.

Purpose: The influence of cerebral amyloid angiopathy (CAA) in Alzheimer’s disease (AD) remains unexplored. The present post-mortem study investigated possible differences in the degree of hippocampal atrophy (HA) between AD patients with and without CAA using 7.0-tesla magnetic resonance imaging (MRI). Also, the incidence of the hippocampal cortical micro-infarcts (HCoMIs) and hippocampal cortical micro-bleeds (HCoMBs) is compared to those in the neocortex. Methods: The examined post-mortem brains included 30 AD-CAA cases and 20 AD without CAA cases. The samples of the hippocampus were evaluated on the most representative coronal section with T2 and T2* MRI sequences. The average degree of HA was determined in both groups. The incidences of HCoMIs and HCoMBs, along with the frequency of CoMIs and CoMBs in the neocortex were compared in both groups: AD-with CAA and AD without CAA cases. Results: No significant differences were observed in the degree of HA and the incidence of hippocampal micro-infarcts (HMIs) and hippocampal micro-bleeds (HMBs) between the AD-CAA and the AD brains in contrast to the higher incidence of these cerebrovascular lesions in the neocortex of AD-CAA brains. The incidence of CoMIs and CoMBs in the neocortex showed similarity to that in the hippocampus of AD patients without CAA. Conclusions: CAA does not influence the degree of HA and the incidence of micro-infarcts (MIs) and micro-bleeds (MBs) in the hippocampus, in contrast to the high contribution of the latter with CAA in the neocortex. The hippocampus seems to be more spared from cerebrovascular involvement than the other parts of the brain.

The relative amounts of amyloid beta-protein (A beta) in cerebral blood vessels and parenchyma vary considerably amongst patients with Alzheimer's disease (AD). Although several mechanisms have been proposed to explain this variability, the underlying genetic and environmental determinants are still unclear, as are the functional consequences. Polymorphisms in APOE, the gene for apolipoprotein E (ApoE), influence the risk of developing AD and of deposition of A beta within the brain. We examined the relationship between the APOE genotype and the relative extent of accumulation of A beta as plaques within the cerebral parenchyma and in cortical blood vessels in the form of cerebral amyloid angiopathy (CAA), in autopsy brain tissue from 125 AD cases and from 53 elderly, neurologically normal controls of which 19 had CAA without other neuropathological features of AD. In the AD cases, we also assessed whether the severity of CAA was related to the age of onset and duration of dementia, risk factors for atherosclerotic vascular disease, and histologically demonstrable cerebral infarcts or foci of haemorrhage. The APOE genotype was determined by a standard polymerase chain reaction-based method. Paraffin sections of frontal, temporal and parietal lobes were immunolabelled for A beta and the parenchymal A beta load (total A beta minus vessel-associated A beta) was quantified by computer-assisted image analysis. CAA severity was scored for cortical and leptomeningeal vessels. The relevant clinical data were obtained from the database of the South West Brain Bank. In AD, we found the severity of CAA to be strongly associated with the number of epsilon 4 alleles (P < 0.0001) but the parenchymal A beta load to be independent of APOE genotype. Cases with severe CAA had a lower parenchymal A beta load than had those with moderate CAA (P = 0.003). Neither the severity of CAA nor the parenchymal A beta load correlated with age of onset, duration of disease or age at death, and the severity of CAA also did not correlate with the presence of cerebral infarcts or foci of haemorrhage. These findings indicate that possession of the APOE epsilon 4 allele favours vascular over parenchymal accumulation of A beta in AD. This may influence the pathogenesis of neurodegeneration in epsilon 4-associated AD.

Cortical superficial siderosis is an established haemorrhagic neuroimaging marker of cerebral amyloid angiopathy. In fact, cortical superficial siderosis is emerging as a strong independent risk factor for future lobar intracerebral haemorrhage. However, the underlying neuropathological correlates and pathophysiological mechanisms of cortical superficial siderosis remain elusive. Here we use an in vivo MRI, ex vivo MRI, histopathology approach to assess the neuropathological correlates and vascular pathology underlying cortical superficial siderosis. Fourteen autopsy cases with cerebral amyloid angiopathy (mean age at death 73 years, nine males) and three controls (mean age at death 91 years, one male) were included in the study. Intact formalin-fixed cerebral hemispheres were scanned on a 3 T MRI scanner. Cortical superficial siderosis was assessed on ex vivo gradient echo and turbo spin echo MRI sequences and compared to findings on available in vivo MRI. Subsequently, 11 representative areas in four cases with available in vivo MRI scans were sampled for histopathological verification of MRI-defined cortical superficial siderosis. In addition, samples were taken from predefined standard areas of the brain, blinded to MRI findings. Serial sections were stained for haematoxylin and eosin and Perls' Prussian blue, and immunohistochemistry was performed against amyloid-β and GFAP. Cortical superficial siderosis was present on ex vivo MRI in 8/14 cases (57%) and 0/3 controls (P = 0.072). Histopathologically, cortical superficial siderosis corresponded to iron-positive haemosiderin deposits in the subarachnoid space and superficial cortical layers, indicative of chronic bleeding events originating from the leptomeningeal vessels. Increased severity of cortical superficial siderosis was associated with upregulation of reactive astrocytes. Next, cortical superficial siderosis was assessed on a total of 65 Perls'-stained sections from MRI-targeted and untargeted sampling combined in cerebral amyloid angiopathy cases. Moderate-to-severe cortical superficial siderosis was associated with concentric splitting of the vessel wall (an advanced form of cerebral amyloid angiopathy-related vascular damage) in leptomeningeal vessels (P < 0.0001), but reduced cerebral amyloid angiopathy severity in cortical vessels (P = 0.048). In terms of secondary tissue injury, moderate-to-severe cortical superficial siderosis was associated with the presence of microinfarcts (P = 0.025), though not microbleeds (P = 0.973). Collectively, these data suggest that cortical superficial siderosis on MRI corresponds to iron-positive deposits in the superficial cortical layers, representing the chronic manifestation of bleeding episodes from leptomeningeal vessels. Cortical superficial siderosis appears to be the result of predominantly advanced cerebral amyloid angiopathy of the leptomeningeal vessels and may trigger secondary ischaemic injury in affected areas.

Background/Purpose: Although cerebral amyloid angiopathy (CAA) and Alzheimer’s Disease (AD) can manifest as separate diseases it can co-exist due to shared amyloid β pathogenic mechanisms. We assessed admission rates and outcomes of ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) among hospitalized patients with a secondary diagnosis of AD and CAA. Methods: Adult patients discharged with a secondary diagnosis of CAA or AD in National Inpatient Sample (NIS) in the years 2016 and 2017 were identified. Admission rates for IS, ICH, and SAH were primary outcomes. In-hospital mortality and discharge to home were secondary outcomes. Multivariate logistic regression analysis was performed to evaluate secondary outcomes with model adjusted for demographics, medical history, hospital characteristics, and Elixhauser comorbidity index. Results: Among 60,609,519 admissions in NIS, 893,834 (1.5%) patients had a secondary diagnosis of AD [mean age 82.1 years and 62% women] and 14,850 (0.02%) patients had CAA [mean age 76.2 years and 51% women]. Combined AD+CAA was present in 1,335 (0.002%) patients. Compared to AD and controls (non AD or CAA), patients with CAA had higher admission rates for IS (11.5% CAA vs 2.8% AD vs 1.7% control, p&lt;0.0001), for ICH (29.5% CAA vs 0.4% AD vs 0.2% control, p&lt;0.0001) and for SAH (3% CAA vs 0.1% AD vs 0.1% control, p&lt;0.0001). Among patients admitted for IS, discharge to home was less likely in AD compared to controls (10.4% AD vs 36.3% control, OR=0.40; 95%CI=0.36-0.44). Among patients admitted for ICH, discharge to home was less likely in AD compared to controls (6.3% AD vs 18.5% control, OR=0.57; 95%CI=0.41-0.78) but higher in CAA (17.8% CAA vs 18.5% control, OR=1.35; 95%CI=1.11-1.63). In-hospital mortality was less likely in patients with CAA than controls among patients admitted for ICH (9.6% CAA vs 23% control, OR=0.33; 95%CI=0.26-0.41) and SAH (6.7% CAA vs 19.1% control, OR=0.27; 95%CI=0.11-0.62). Conclusion: Admissions for IS, ICH, and SAH were higher among CAA compared to AD in NIS. CAA patients had lower in-hospital mortality for ICH and SAH admissions and higher rates of home discharge for ICH admissions. AD patients were less likely to be discharged home for IS and ICH admissions.

Alzheimer's disease (AD) is characterized neuropathologically by the presence of amyloid plaques, neuritic plaques, and neurofibrillary tangles (NFTs). These lesions occur not only in demented individuals with AD but also in non-demented persons. In non-demented individuals, amyloid and neuritic plaques are usually accompanied with NFTs and are considered to represent asymptomatic or preclinical AD (pre-AD) pathology. Here, we defined and characterized neuropathological differences between clinical AD, non-demented pre-AD, and non-AD control cases. Our results show that clinical AD may be defined as cases exhibiting late stages of NFT, amyloid, and neuritic plaque pathology. This is in contrast to the neuropathological changes characteristic of pre-AD, which display early stages of these lesions. Both AD and pre-AD cases often exhibit cerebral amyloid angiopathy (CAA) and granulovacuolar degeneration (GVD), and when they do, these AD-related pathologies were at early stages in pre-AD cases and at late stages in symptomatic AD. Importantly, NFTs, GVD, and CAA were also observed in non-AD cases, i.e., in cases without amyloid plaque pathology. Moreover, soluble and dispersible, high-molecular-weight amyloid β-protein (Aβ) aggregates detected by blue-native polyacrylamide gel electrophoresis were elevated in clinical AD compared to that in pre-AD and non-AD cases. Detection of NFTs, GVD, and CAA in cases without amyloid plaques, presently classified as non-AD, is consistent with the idea that NFTs, GVD, and CAA may precede amyloid plaque pathology and may represent a pre-amyloid plaque stage of pre-AD not yet considered in the current recommendations for the neuropathological diagnosis of AD. Our finding of early stages of AD-related NFT, amyloid, and GVD pathology provides a more clear definition of pre-AD cases that is in contrast to the changes in clinical AD, which is characterized by late stages of these AD-related pathologies. The observed elevation of soluble/dispersible Aβ aggregates from pre-AD compared to that in AD cases suggests that, in addition to more widespread AD-related pathologies, soluble/dispersible Aβ aggregates in the neuropil play a role in the conversion of pre-AD to clinical AD.

Hereditary cystatin C amyloid angiopathy (HCCAA), an autosomal dominant form of cerebral amyloid angiopathy (CAA) occurring primarily in Iceland, is characterized by a variant cystatin C amyloid deposition in the walls of cerebral parenchymal and leptomeningeal vessels. Cystatin C is also found to colocalize with amyloid beta/A4 protein in cerebral vessel walls of patients with Alzheimer's disease (AD), sporadic CAA, and hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D). The abundance of cystatin C deposition in cerebral blood vessel walls suggests that cellular elements of the vessel wall itself may play a role in its deposition. Microvascular changes in the brains of HCCAA patients were investigated by single- and double-label immunohistochemistry. We found that cystatin C amyloid immunoreactivity was present not only in cerebral cortical and leptomeningeal vessels, but also in white matter parenchymal vessels. Cystatin C deposition was more prominent in the media of parenchymal vessels and in the adventitia of leptomeningeal vessels. Smooth muscle (sm) cells were few or could not be identified within vessel walls showing extensive cystatin C deposition, suggesting progressive loss of these cells as cystatin C accumulates. However, in less severely affected vessels, cystatin C was present in cells that also had the phenotype of sm, suggesting that sm cells synthesize or process cystatin C. Cystatin C immunoreactivity was in addition, detected in some neuronal cell bodies throughout the cortex in patients with HCCAA and AD-related CAA. Our results indicate that cellular components of the vessel walls may play an important role in cystatin C deposition, as they do in beta/A4 deposition in AD-related CAA. Cystatin C deposition within the vascular media and adventitia, with associated vessel wall injury as manifested by sm cell loss, represents microvascular degeneration that leads to cerebral hemorrhage.

Pathological heterogeneity of Aβ deposition in senile plaques (SP) and cerebral amyloid angiopathy (CAA) in Alzheimer's disease (AD) has been long noted. The aim of this study was to classify cases of AD according to their pattern of Aβ deposition, and to seek factors which might predict, or predispose towards, this heterogeneity. The form, distribution and severity of Aβ deposition (as SP and/or CAA) was assessed semiquantitatively in immunostained sections of frontal, temporal and occipital cortex from 134 pathologically confirmed cases of AD. Four patterns of Aβ deposition were defined. Type 1 describes cases predominantly with SP, with or without CAA within leptomeningeal vessels alone. Type 2 describes cases where, along with many SP, CAA is present in both leptomeningeal and deeper penetrating arteries. Type 3 describes cases where capillary CAA is present along with SP and arterial CAA. Type 4 describes a predominantly vascular phenotype, where Aβ deposition is much more prevalent in and around blood vessels, than as SP. As would be anticipated from the group definitions, there were significant differences in the distribution and degree of CAA across the phenotype groups, although Aβ deposition as SP did not vary. There were no significant differences between phenotype groups with regard to age of onset, age at death, disease duration and brain weight, or disease presentation. Women were over-represented in the type 1 phenotype and men in type 2. Genetically, type 3 (capillary subtype) cases were strongly associated with possession of the APOE ε4 allele. This study offers an alternative method of pathologically classifying cases of AD. Further studies may derive additional genetic, environmental or clinical factors which associate with, or may be responsible for, these varying pathological presentations of AD.

Cerebral amyloid angiopathy (CAA) is conspicuous for its association with Alzheimer disease (AD) and as a cause of lobar hemorrhages in the elderly, but its role in cerebral infarction is less clear. There is evidence that CAA may also be a risk factor for ischemic infarction in AD. To further investigate CAA as a risk factor for infarction, we studied 108 cases of recent cerebral or cerebellar infarction diagnosed in tissue samples obtained from surgical material. There were 69 males and 39 females with a mean age of 52 yr (range 1-86). The majority of biopsies were obtained from the frontal and parietal lobes. Radiological studies demonstrated a lesion confined to a vascular distribution in 12 of the 17 (71%) cases examined. Microscopic sections stained with hematoxylin and eosin revealed complete, organizing infarction in 107 cases with areas of coagulative necrosis, anoxic-ischemic neuronal injury, inflammation, macrophages, vascular proliferation, gliosis, and swollen axons. One case showed an incomplete infarct. Most cases also exhibited a minor hemorrhagic component with hemosiderin and hematoidin pigments. CAA, defined as amyloid deposition in the walls of leptomeningeal and parenchymal arteries, was found by immunohistochemical stains for beta amyloid in 14 (13%) cases of complete cerebral infarct. Cortical beta amyloid plaques were found by immunohistochemistry in 19 (17%) cases. Cerebral or cerebellar tissues containing cortex and leptomeninges obtained from 136 patients with a mean age of 52 yr (range 1-85) during surgical procedures for diagnosis of primary or metastatic neoplasms and demyelinating lesions were used as age-matched controls. In this control group, CAA was found in 5 (3.7%) and beta amyloid plaques in 19 (14%). The results indicate that CAA, but not beta amyloid plaque formation, is significantly more common in patients with ischemic cerebral infarction than in age-matched controls with nonvascular lesions (odds ratio 3.8; 95% confidence interval 1.3-10.9; p < 0.01). Our results indicate that CAA is a risk factor for ischemic cerebral infarction in the population studied.