Topographical distribution of cerebral amyloid angiopathy and its effect on cognitive decline are influenced by Alzheimer disease pathology

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Abstract

Cerebral amyloid angiopathy (CAA) is defined by β-amyloid peptide (Aβ) depositions in cerebral vessels and is associated with Alzheimer disease (AD). It has been suggested that severe CAA is an independent risk factor for cognitive decline. 171 autopsy brains underwent standardized neuropathological assessment, the patients age ranged from 54 to 104 years (mean age: 83.9 years, +/− 9.2, 59.6% female, 56.1% clinically demented). Using immunohistochemistry, the severity of Aβ depositions in vessels was assessed semiquantitatively in the frontal, frontobasal, hippocampal, and occipital region, respectively. CAA was present in 117 cases (68.4%), with the occipital region being affected significantly stronger than other regions. The overall incidence of CAA was significantly higher in cases with high grade neuritic AD pathology (ADP) compared to those with low grade or no ADP. The severity of CAA significantly increased with increasing ADP, with CAA in the occipital region increasing significantly stronger than that in other regions. The association of CAA and clinical dementia failed to remain statistically significant when adjusting for concomitant ADP. However, in cases devoid of any ADP CAA was significantly associated with the presence of clinical dementia. These results indicate a strong association of AD with CAA, but do not unequivocally support reports suggesting CAA to be an independent risk factor for cognitive decline, except for a subgroup of demented patients lacking any ADP.

Introduction

Cerebral amyloid angiopathy (CAA) is defined as deposition of a congophilic material i.e. β-amyloid peptide (Aβ) in meningeal and cortical (parenchymal) arteries, arterioles, capillaries, and veins [1], [2], [3], [4], [5], [6], [7], [8], [9]. Familial CAA refers to CAA occurring in a variety of familial disorders associated with mutations of the amyloid precursor protein [9], [10], [11], [12], [13], [14]. However, CAA much more frequently occurs as a sporadic, non familial disease. In the present paper the term CAA refers to sporadic CAA, which is a common finding in the brains of elderly demented and non-demented individuals and which is associated with Alzheimer disease (AD) as its prevalence varies from 70% to 100% in AD [1], [4], [6], [8], [15], [16], [17], [18], [19], [20], [21], [22], [23]. Independent of AD, both incidence and severity of CAA increase with age [1], [6], [9], [14], [17], [24], [25], [26], [27]. Severe CAA is associated with cerebral hemorrhages, infarctions, and white matter lesions [1], [2], [6], [9], [14], [26], [28], [29], [30], [31], [32] (for review on CAA see [26], [33]).

The origin of Aβ in CAA remains unclear. Basically, three different mechanisms have been proposed (see [26]): derivation of Aβ from blood and/or cerebrospinal fluid [9], [34], [35], production of Aβ by smooth muscle cells within vessel walls and/or pericytes [9], [36], [37], [38], [39], [40], and derivation of Aβ from the neuropil in the course of its perivascular drainage [2], [7], [41], [42], [43], [44], [45].

CAA seems to be most prominent in occipital, frontal, and temporal lobes, followed by parietal lobe and white matter, whereas basal ganglia and thalamus are usually spared [1], [3], [4], [9], [19], [42], [43], [45], [46]. Its occurrence in the cerebellum ranges from absent to frequent [16], [42].

Despite its association with AD, CAA has been shown recently to be an independent risk factor for cognitive decline [3], [27], [32], [47], [48].

However, data on both topographical distribution of CAA and its impact on cognitive decline are rare [19], [20], [46], [49], [50]. The aim of the present study was to further evaluate the influence of neuritic AD pathology (ADP; e.g., CERAD scores [51], Braak stages [52], NIA-Reagan Institute Criteria [53]) on the association between CAA and clinical dementia and on severity and topographical distribution of CAA, respectively.

Section snippets

Materials and methods

We examined 171 human brains obtained at autopsy in the pathological department of a large hospital in Vienna, Austria. The patients' age ranged from 54 to 104 years (mean: 83.9 years, SD:+/− 9.18), 102 were female (59.6%) and 96 were clinically demented (56.1%). Dementia was assessed retrospectively from hospital charts according to ICD-10 criteria or MMSE < 20.

Tissue was fixed in 8% aqueous solution of formaldehyde; blocks were taken from frontal, frontobasal, temporal, and occipital cortices,

Results

Our cohort consisted of 66 (38.6%) brains with high grade (CERAD B, C; Braak stages 5,6; NIA-RI Criteria high probability), 25 (14.6%) with medium grade (CERAD A, B; Braak stages 3, 4; NIA-RI Criteria medium probability), 42 (24.6%) with low grade (CERAD negative, A; Braak stages 1, 2; NIA-RI Criteria low probability), and 38 (22.2%) without ADP (CERAD negative; Braak stages 0, 1; NIA-RI Criteria negative), respectively. High grade ADP was seen in 16% of clinically non-demented patients and in

Discussion

CAA was present in 68.4% of the whole study cohort and in 86.4% of cases with neuropathology indicative for definite AD (i.e., NIA-RI Criteria high probability). These data are in accordance with CAA prevalence rates of 80% to almost 100% [1], [26], [40], [54] in AD, but are somewhat higher than the 10% to 40% prevalence rates reported in the general elderly population [1], [3], [4], [17], [27], [44].

CAA was both most frequent and most severe in the occipital lobe, followed by frontal,

Acknowledgements

The authors are grateful to Nutricia Corp. for providing financial support for M. Quass and thanks to Mrs. Veronika Rappelsberger and Mrs. Barbara Weidinger for their excellent laboratory work. Part of the study was supported by the Society for Support of Research in Experimental Neurology, Vienna, Austria.

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