Antiphospholipid antibodies, brain infarcts, and cognitive and motor decline in aging (ABICMA): design of a community-based, longitudinal, clinical-pathological study

Abstract

The overall goal of the Antiphospholipid Antibodies, Brain Infarcts, and Cognitive and Motor Decline in Aging study is to test the hypothesis that antiphospholipid antibodies (aPL) are associated with an increased risk of pathologically proven brain infarcts and are related to cognitive and motor decline in aging. Putative biologic mechanisms underlying the association of aPL with infarcts and the relation of aPL with clinical outcomes of cognitive and motor impairment, including vascular and other processes, will be examined. The design of this longitudinal, clinical-pathologic study involves quantifying four aPL assays, and relating these to brain infarcts, and to cognitive and motor decline. Vascular mechanisms assessed using antemortem magnetic resonance neuroimaging and postmortem neuropathology, as well as nonvascular mechanisms of inflammation and blood-brain barrier permeability alterations will be examined as plausible mediators of the relation of aPL to cognitive and motor impairment. We will take advantage of antemortem biological specimens (longitudinally collected sera and plasma from which aPL, annexins, C-reactive protein, and matrix metalloproteinases will be quantified), and clinical, neuroimaging, and postmortem neuropathologic data from about 800 elderly, community-dwelling women and men who have agreed to brain autopsy at the time of death, participating in one of two ongoing studies of aging: the Religious Orders Study and the Memory and Aging Project.

Figure 1

Overall model relating aPL to outcomes of cognitive and motor decline* *The relation of aPL to cognitive and motor function is mediated by cerebrovascular disease (top middle box) and other factors (bottom middle box)

Figure 2

Specimen and data transfer

Figure 3

Ante-mortem brain MRI scan demonstrating cerebrovascular disease in vivo* *T1-weighted MP-RAGE (A) and T2-weighted FLAIR (B) images of two slices of a MAP participant, demonstrating examples of infarcts (white arrow) and white matter hyperintensities (gray arrows).

Figure 4

Postmortem neuropathology demonstrating cerebrovascular disease* *Left: chronic infarct in precentral gyrus and adjacent white matter, with central cavitation; right: microscopic confirmation of same infarct (H&E, ×20).

Figure 5

Overall study design for ABICMA* *ABICMA: Antiphospholipid antibodies, Brain Infarcts, and Cognitive and Motor decline in Aging study

Figure 6

Multistep hypothesis for aPL-mediated infarct involving annexin resistance* *Top: Intact cerebral vasculature is thromboresistant. β2GPI circulates in the circular conformation. Middle: Vascular injury in the absence of aPL antibodies: phosphatidyl-serine becomes exposed, with capacity to stimulate thrombotic response, and is available for binding to competing moieties (β2GPI, annexin A5, and coagulation factors). A5, which is expressed inside the endothelium and circulating in the microenvironment over it, has the highest affinity because of its’ two dimensional crystallization and multivalency. A5 “outcompetes” the other moieties and covers the injured surface, restoring thromboresistance. Bottom: Vascular injury in the presence of aPL antibodies: binding of β2GPI requires conformational change that snaps it open and exposes the domain 1 epitope. This leads to formation of high affinity immune complexes that “outcompetes” A5 for binding and leaves insufficient space for formation of ordered crystals of A5. Gaps in coverage of phosphatidyl-serine become occupied by coagulation factors that stimulate thrombosis.