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Neurobiol Aging. Author manuscript; available in PMC 2016 October 01. Published in final edited form as: Neurobiol Aging. 2015 October ; 36(10): 2702–2708. doi:10.1016/j.neurobiolaging.2015.06.028.

Cerebral amyloid angiopathy and its co-occurrence with Alzheimer’s disease and other cerebrovascular neuropathologic changes Willa D. Brenowitza, Peter T. Nelsonb,c, Lilah M. Bessera, Katherine B. Hellera, and Walter A. Kukulla

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aNational

Alzheimer’s Coordinating Center, Department of Epidemiology, University of Washington, USA bDepartment

of Pathology, Division of Neuropathology, University of Kentucky, USA

cSanders-Brown

Center on Aging, University of Kentucky, USA

Abstract

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We examined the relationship between cerebral amyloid angiopathy (CAA), Alzheimer’s disease neuropathologic changes (ADNC), other vascular brain pathologies, and cognition in a large multi-center autopsy sample. Data was obtained from the National Alzheimer’s Coordinating Center on autopsied subjects (N=3,976) who died between 2005 and 2012. Descriptive statistics and multivariable regression models estimated the associations between CAA and other pathologies, and between CAA severity and cognitive test scores proximal to death. CAA tended to co-occur with ADNC but a substantial minority of cases were discrepant. CAA was absent in 22% (n= 520) of subjects with frequent neuritic plaques but present in 20.9% (n=91) of subjects with no neuritic plaques. In subjects with no/sparse neuritic plaques, non-hemorrhagic brain infarcts were more common in those with CAA pathology than without (P= 0.007). In subjects without the APOE ε4 allele, CAA severity was associated with lower cognition proximal to death, factoring in other pathologies. The presence of CAA in non-AD patients may indicate a distinct cerebrovascular condition.

Keywords

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Cerebral amyloid angiopathy; Alzheimer’s disease neuropathologic change; cerebrovascular disease; neuropathology; cognition

Corresponding Author: Willa Brenowitz, MPH; University of Washington; National Alzheimer’s Coordinating Center; 4311 11th Ave NE #300; Seattle WA 98105; Phone: (206) 616-5647; Fax: (206) 616-5927; [email protected] Conflict of interest: The authors declare no conflicts of interest. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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1. INTRODUCTION Cerebral amyloid angiopathy (CAA) is a common neuropathological finding among older adults, especially among those who meet neuropathologic criteria for Alzheimer’s disease (AD) (Smith and Greenberg, 2009; Vinters, 1987). CAA is characterized by Aβ deposits in blood vessel walls (Vinters, 1987). CAA is considered an important cause of lobar intracerebral hemorrhages and some evidence suggests that CAA has a broader impact on cerebrovascular function (Attems et al., 2008; Smith et al., 2008; Soontornniyomkij et al., 2010). Additionally, CAA is linked to the maladaptive inflammatory response to anti-Aβ immunotherapy in AD clinical trials (Eng et al., 2004; Nicoll et al., 2003). As this brain condition combines Alzheimer’s-type (Aβ) and cerebrovascular changes, it is important to understand the relationship between CAA and other brain pathologies.

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Many studies have documented associations between CAA and AD neuropathologic change (ADNC), defined by the National Institute on Aging and Alzheimer’s Association (NIAAA) criteria as comprising Aβ plaques, neuritic amyloid plaques, and neurofibrillary tangles (Hyman et al., 2012; Montine et al., 2012); however CAA may occur in the absence of ADNC (Attems et al., 2005; Ellis et al., 1996; Fernando and Ince, 2004; Kövari et al., 2012; Pfeifer et al., 2002; Thal et al., 2003; Xuereb et al., 2000; Yamada, 2002). An estimated 78– 98% of individuals with ADNC also have CAA (Jellinger, 2002), but only about 25% of patients with ADNC also have severe CAA (Ellis et al., 1996). CAA has also been linked to other vascular pathologies, in particular cerebral hemorrhages and infarcts (Smith and Greenberg, 2009). Amyloid deposition likely weakens the cerebral vessel walls facilitating rupture leading to hemorrhages (Vinters, 1987). CAA may also lead to ischemia; studies have found increased prevalence of cerebral infarcts and microinfarcts as well as subcortical white matter lesions in cases of severe CAA (Holland et al., 2008; Kimberly et al., 2009; Ringman et al., 2014; Soontornniyomkij et al., 2010). The presence of CAA in patients with AD may have a greater clinical impact than AD alone (Jellinger, 2002; Thal et al., 2003). Severe CAA has also been associated with cognitive decline independent of AD (Arvanitakis et al., 2011; Keage et al., 2009). However, the association between CAA and cognition may disappear after adjustment for ADNC (Thal et al., 2003; Nelson et al., 2010). More data are required from large datasets to better characterize the relationship between CAA, ADNC, other vascular brain pathologies, and cognition.

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APOE ε4 allele status, a strong risk factor for AD (Corder et al., 1993), is also associated with increased frequency of CAA (Attems et al., 2008, 2005; Nelson et al., 2013; Pfeifer et al., 2002; Ringman et al., 2014; Tanskanen et al., 2005; Thal et al., 2003). Patients with at least one APOE ε4 allele are more likely to have severe CAA (Attems et al., 2005; Thal et al., 2003) as well as a subtype of CAA with amyloid deposits in capillaries in addition to larger blood vessels (Grinberg and Thal, 2010; Thal et al., 2002). History of stroke and hypercholesterolemia has been associated with severe CAA in AD but only among those without any APOE ε4 alleles (Ringman et al., 2014). In another study, CAA and small vessel disease were positively correlated but only among in those with APOE ε4 allele (Esiri

Neurobiol Aging. Author manuscript; available in PMC 2016 October 01.

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et al., 2015). Since there are ongoing clinical approaches that use APOE ε4 carrier status in selection criteria, it would be desirable to understand according to APOE genotype. This study focused on CAA pathology and used data from a large multi-center database maintained by the National Alzheimer’s Coordinating Center (NACC). The NACC database comprises individuals who were evaluated by one of the Alzheimer’s Disease Centers (ADCs) funded by National Institute on Aging. The primary objectives of this study were to describe 1.) co-occurrence of CAA with ADNC, particularly neuritic plaques, in autopsied older adults; 2) clinical and pathologic features of participants with and without cooccurring CAA and neuritic plaques; and 3) the association between CAA severity and cognition adjusting for ADNC and other pathologies. This research may help identify subtypes of CAA in patients with and without AD.

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2. METHODS 2.1. Data Source and Study Sample

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Data for this analysis was obtained from NACC’s Minimum Data Set (MDS), Uniform Data Set (UDS), and Neuropathology Data Set (Beekly et al., 2004; Morris et al., 2006; Beekly et al., 2007). NACC data sets consist of information on subjects who were previously evaluated at one of 34 past and present ADCs located throughout the U.S. Each ADC operates independently—recruiting and enrolling subjects according to their own protocols. Subjects generally responded to recruiting efforts to participate in a research study or because they were referred to the ADC due to concerns about their health, cognition, or behavior. Subjects can enroll with any level of cognition, ranging from normal to demented. The MDS includes single record diagnostic data collected retrospectively for participants evaluated from 1984 through 2005 and the UDS includes standardized clinical, neuropsychological, and diagnostic data from participants who were evaluated longitudinally after September, 2005. Data were collected by trained clinicians and interviewers and methods and rationale for the MDS and UDS have been previously published (Beekly et al., 2004; Morris et al., 2006; Beekly et al., 2007). Informed consent was obtained from all participants at the individual ADCs. ADCs had IRB approval and research using NACC data was approved by the University of Washington Human Subjects Division.

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Subjects (n=5,734) were eligible for this study if they had died and been autopsied at an ADC between January 2002 and December 2012 and were aged 65 years or older at death. Subjects (n= 1,064) with rare neurological diseases based on autopsy findings were excluded (including those with frontotemporal lobar degeneration, prion disease, brain cancer, and genetic abnormalities). Subjects (n=694) were excluded from this study if they were missing data on CAA severity, CERAD stage of neuritic plaque densities (Mirra et al., 1991), or Braak stage for neurofibrillary tangles (Braak et al., 2006). The final sample included 3,976 autopsied subjects. 2.2. Measures 2.2.1. Pathologic Features at Autopsy—Neuropathological evaluations were conducted by individual ADCs according to their own protocols. These protocols may differ Neurobiol Aging. Author manuscript; available in PMC 2016 October 01.

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between ADCs but conform to consensus guidelines. Results were entered into the NACC database using a standardized NACC form. Presence of CAA was detected using amyloid stains (e.g. Congo red, thioflavin-S, or Aβ immunostaining) as determined by each ADC’s protocol. CAA was graded semi-quantitatively as none, mild, moderate, or severe. As per NACC coding guidelines, severity was based on the neuropathologist’s “estimate of overall severity rather than an individual vessel”. For analytic purposes, CAA was also categorized as present (any severity CAA) vs. absent (no CAA) to reduce potential heterogeneity in severity scoring.

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Aβ plaque frequency was assessed by Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) stages of diffuse and neuritic plaque densities (frequent, moderate, sparse, or none) (Mirra et al., 1991). Neurofibrillary degeneration was assessed by categorical Braak staging (Stages 0, I/II, III/IV, V, VI) (Braak et al., 2006). For the purpose of plotting trend by age, ADNC was also categorized in this study by severity as: High ADNC (Braak stages V/VI + frequent neuritic plaques); Low to Intermediate ADNC (Braak stages 0-IV + frequent neuritic plaques, OR Braak stage 0-VI + moderate or sparse neuritic plaques, OR Braak stages I-VI + no neuritic plaques); or No ADNC (No neuritic plaques, no neurofibrillary tangles). The new NIA-AA criteria additionally includes Thal phases for Aβ plaques (Thal et al., 2002), however, this staging was not available for the subjects in this retrospective analysis. Thus, our operationalization of ADNC overlaps but does not correspond exactly to ADNC levels as defined by new NIA-AA criteria (Hyman et al., 2012; Montine et al., 2012). In contrasting severity of CAA and ADNC, this study focused on the co-occurrence of vascular Aβ deposits (CAA) with neuritic plaques since they may share pathogenic processes (Biffi and Greenberg, 2011; Viswanathan and Greenberg, 2011). Subjects with no/spare neuritic plaques were considered to have minimal amyloid plaques. Diffuse plaques, which are defined as “plaques with non-compact amyloid and no apparent dystrophic neurites” were additionally considered in sensitivity analyses to account for other types of amyloid plaques.

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In addition, presence of other pathologies were documented. Hemorrhages, gross infarcts (larger artery and lacunar), microinfarcts, and subcortical arteriosclerotic leukoencephalopathy were noted as present or absent if assessed. Hemorrhages included any cerebral hemorrhages, regardless of size. Large artery infarcts was defined according to NACC coding guide as an infarct of any histologic age “larger than 1 cm in diameter in the distribution of large and medium meningocerebral vessels.” Lacunes were defined as one or more “cystic/old infarcts or hemorrhages 1-cm or less in diameter that are usually grossly identified and in the distribution of small parenchymal vessels.” Microinfarcts were defined as infarcts detected microscopically and not grossly visible regardless of histologic age. The presence of any cortical microinfarcts (yes or no) was recorded. Arteriolosclerosis was recorded as none, mild, moderate, or severe. Medial temporal lobar sclerosis, including hippocampal sclerosis was also noted as present or absent if assessed. Lewy bodies were categorized as none, brainstem predominant, limbic (transitional), and neocortical (diffuse) (McKeith et al., 2005). 2.2.2. Clinical Characteristics—Demographic information assessed in both the MDS and UDS included: sex, race/ethnicity, highest level of education achieved. Health history Neurobiol Aging. Author manuscript; available in PMC 2016 October 01.

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was collected in the UDS via structure interviews; vascular risk factors included history of or currently active hypertension, hypercholesterolemia, or diabetes, as well as smoking history (yes/no, ever smoked 100 cigarettes or more. Using all available information, clinicians recorded cognitive status (normal, impaired not MCI, MCI, or dementia) at each visit and determined a clinical diagnosis indicating the suspected etiology of cognitive impairment for those with impaired cognition. Overall cognition was measured in both data sets using the Mini-Mental State Examination (MMSE) (Folstein et al., 1975). Overall cognitive and functional impairment as quantified by the Clinical Dementia Rating “sum of boxes” score (CDR-SB) (Morris, 1993) was measured in the UDS only. APOE genotype is available for only a subset of participants (n= 2,985 of 3,976). For this study, APOE ε4 allele status was categorized as none or at least one APOE ε4 allele. 2.3. Statistical analyses

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The proportion of subjects with CAA was estimated overall across ADCs, and within each ADC. Participant demographics and clinical dementia status at last visit were described according to severity of CAA. Age-related trends in the proportion of subjects with CAA and ADNC were described using fitted polynomial curves. Next we examined the correlation between neuritic plaque densities and the severity of CAA.

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Among subjects with and without co-occurring CAA and neuritic plaques, participant demographics and pathological features were first described to find correlates of cooccurrence or independence. Pearson χ2 test or fisher’s exact test (if any categories included

Cerebral amyloid angiopathy and its co-occurrence with Alzheimer's disease and other cerebrovascular neuropathologic changes.

We examined the relationship between cerebral amyloid angiopathy (CAA), Alzheimer's disease neuropathologic changes, other vascular brain pathologies,...
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