FIGURE 2.

The key modules of the vascular wall disturbance (VWD) model of amyloid‐related imaging abnormalities with edema/effusion (ARIA‐E) and the behavior of the model at the individual level. The VWD model links several pharmacological and biological factors to the observed drug pharmacokinetics and magnitude of ARIA‐E (purple and cyan filled circles, respectively). Individual‐specific information about the dose and time of drug administration is given (yellow symbols). The “PK” module, that is, pharmacokinetics, describes the time course of drug concentration “Local Amyloid” module estimates the drug‐mediated change in local amyloid over time (green curve) under the assumption that the rate of amyloid removal is proportional to both existing local amyloid level and drug concentration in plasma. The instantaneous rate of drug‐mediated amyloid removal corresponds to the steepness of the amyloid curve at any given time point. The modeled amyloid is not the positron emission tomography amyloid measured in the clinical trial, but rather a hypothetical measure for either the local vascular amyloid or the local parenchymal amyloid load, whose removal may trigger a cascade of events resulting in ARIA‐E in one or more regions of the brain. The “VWD” module estimates temporal changes in the “vascular wall disturbance” variable (red curve), which is a hypothetical measure of susceptibility to fluid leakage into the brain due to disrupted vascular integrity and/or perivascular inflammation. The increase in vascular wall disturbance is driven by drug‐mediated amyloid removal and counteracted by an intrinsic repair process of the vascular wall. The “BGTS” (Barkhof's Grand Total Scale) module relates the vascular wall disturbance level to the ARIA‐E score (BGTS) in a non‐linear (sigmoidal) fashion, as shown in the right‐hand side graph. The sigmoidal relationship was derived from the overall data and assumed to be the same for each patient. Individual dosing can be adjusted based on the value of BGTS. The observed BGTS is given by the cyan filled circles and the model fit by the cyan curve