Featured ArticleAmyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer’s Association Research Roundtable Workgroup
Introduction
Over the past decade since amyloid-modifying therapeutic agents have entered Alzheimer’s disease (AD) clinical trials, the occurrence of magnetic resonance imaging (MRI) abnormalities has required careful consideration by academic investigators, pharmaceutical companies, and regulatory authorities. MRI signal changes, thought to represent “vasogenic edema” (VE) and cerebral microhemorrhage (mH), were first observed in trials of a monoclonal antibody against amyloid-β (Aβ) [1], [2], [3], and have since been associated with other amyloid-modifying therapies [4]. In response to guidance issued by the U.S. Food and Drug Administration (FDA) to various sponsors on the conduct of clinical trials of amyloid-modifying agents for the treatment of AD, the Alzheimer’s Association Research Roundtable convened a Workgroup in July 2010.
The Workgroup was composed of academic and industry representatives identified on the basis of their expertise and interest in this area, and was tasked with the objective of providing expert advice regarding the FDA’s concerns related to MRI abnormalities, including signal changes thought to represent VE and mH and the relationship of these MR abnormalities to experimental treatment with amyloid-modifying therapies. Because VE and mH are typically detected on different MRI sequences, and seem to represent a spectrum of image abnormalities that may share some common underlying pathophysiological mechanisms, both in the natural history of AD and in the setting of amyloid-modifying therapeutic approaches, the Workgroup suggests referring to this spectrum as amyloid-related imaging abnormalities (ARIA). Despite the likelihood of shared underlying mechanisms, there may be instances in which it is useful to describe specific phenomena, thus the Workgroup further refined the terminology: ARIA-edema/effusions (ARIA-E) refers to the MR signal alterations thought to represent VE and related extravasated fluid phenomena. ARIA-hemosiderin deposition (ARIA-H) refers to the MR signal alterations attributable to mH and hemosiderosis.
The Workgroup reviewed the relevant publicly available information, including natural history studies and spontaneous occurrence of these imaging abnormalities in aging and AD populations, the occurrence of ARIA in occurrence in the setting of trials of amyloid-lowering agents for AD, similar clinical conditions from which parallels might be drawn, and existing animal models that may elucidate the underlying mechanisms. The Workgroup sought to develop specific recommendations regarding the conduct of AD clinical trials in the setting of ARIA, including inclusion/exclusion criteria, safety monitoring, and potential areas of research that might help increase our understanding of these events.
Section snippets
The phenomenon formerly known as “VE”: ARIA-E alterations
Although early animal work had reported evidence of mH with antiamyloid immunotherapy [5], an unexpected type of MRI signal alteration was first observed in the single-dose ascending phase I trial of a monoclonal antibody against Aβ. Three of 10 patients in only the highest dose group (5 mg/kg) developed transient signal abnormalities on T2-weighted/fluid attenuation inversion recovery (FLAIR) sequences, approximately 4 to 6 weeks after a single dose of bapineuzumab [1]. Additional cases were
Characteristics of ARIA-E observed in amyloid-modifying therapeutic trials
ARIA-E most commonly manifests as increased MR signal intensity on FLAIR or other T2-weighted sequences in the parenchyma and/or leptomeninges in the parietal, occipital, and frontal lobes, but has also been observed in the cerebellum and brainstem [3]. It is not yet clear whether the edema begins in gray matter in some cases, as associated gyral swelling is sometimes apparent, with edema tracking into the underlying white matter, or whether there may be separate processes that affect gray and
Issues of ascertainment
Patients identified with CAA-related ARIA or PRES typically present with symptoms, whereas the majority of treatment-associated ARIA-E cases reported in previously published studies have been asymptomatic and identified on “per-protocol” safety MRIs. A small number of ARIA-E cases in the bapineuzumab trials were detected on off-protocol MRI, prompted by change in clinical status or symptoms. These symptomatic cases generally occurred within 4 to 8 weeks after infusion, suggesting that ARIA-E is
Clinical course associated with ARIA-E
There are currently very limited publicly available data regarding the clinical course associated with ARIA-E occurring in the setting of clinical trials of amyloid-modifying therapies. Therefore, the Workgroup reviewed the data from bapineuzumab trials, but it is unknown whether ARIA seen in other amyloid-modifying therapies will have a similar clinical course. In the phase I bapineuzumab study, two of three ARIA cases were asymptomatic at time of detection on per-protocol MRI. In retrospect,
Risk factors for ARIA-E
The pathophysiological mechanisms underlying VE remain to be elucidated; however, the bapineuzumab phase II data have provided some insight into the risk factors associated with the appearance of ARIA-E [3]. The most significant risk factor was dose of bapineuzumab, with 11 of 12 cases occurring in the 1- or 2-mg/kg dose groups. The phase III bapineuzumab noncarrier study terminated the highest dose arm because of the number of ARIA-E cases observed in this dose cohort.
The presence of APOE ɛ4
ARIA-H: MRI findings thought to represent hemosiderin deposits and mHs
Even the first reports of the ARIA cases raised the possibility of a relationship between FLAIR abnormalities, thought to represent ARIA-E, and the appearance of alterations on long echo time, gradient refocused echo (T2∗-GRE) sequences, thought to represent hemosiderin deposits, including mHs and superficial siderosis [1]. mH typically manifests as a focal, round, very low-intensity (relative to adjacent brain tissue) lesion in the brain parenchyma, detected on an appropriately weighted (T2 or
Technical issues of image acquisition for ARIA-H
The conspicuity of mH and superficial siderosis can be enhanced or diminished by specific attributes of the image acquisition. MRI sequences that enhance signal loss because of microgradients in tissue are generally used for detection of mH and superficial siderosis. Two general approaches have been used, T2∗-weighted GRE sequences and SWI.
Ascertainment
To our knowledge, reliable automated algorithms do not exist for identification of mH or superficial siderosis from medical images. Ascertainment by visual reading of scans by trained experts is the only way, but counting is not as exact as desired because it is dependent on several things: the level of training of a reader; where a particular reader falls on the receiver-operating characteristic curve (i.e., is he/she an undercaller or an overcaller); features of image acquisition discussed
Etiology and clinical significance of mH
mHs are generally attributed to one of two etiologies: small-vessel angiopathy and CAA. In the stroke literature, mHs, attributed to small-vessel angiopathy, increase in prevalence with age and vascular risk factors, especially hypertension [23]. mH also occurs in patients who undergo cardiac bypass surgery and is attributed to microemboli [24]. In AD, mH and superficial siderosis are attributed to blood leakage from CAA vessels [25]. CAA is known to weaken the vessel wall, increasing the risk
Association of ARIA with pre-existing white matter disease or other abnormalities
The cross-sectional association between mH and other MRI markers of small-vessel disease has been repeatedly reported. For example, one cross-sectional study of mild-moderate probable AD subjects, compared with normal control subjects, reported that patients with mH had higher white matter disease scores using a standardized rating scale (the age-related white matter changes score) [48], particularly in the frontal and parietal-occipital regions [31]. Also, the number of mHs correlated
Association between components of ARIA
There are very limited data available to date regarding the relationship between mH and/or hemosiderosis detected on FLAIR images (ARIA-H) and “VE” and/or sulcal effusions/exudates detected on GRE/T2∗ images (ARIA-E). Preliminary analyses of the phase II bapineuzumab trial initially noted baseline mH as a risk factor for developing ARIA-E (baseline mH, 6/17 [35%] vs. no baseline mH, 6/107 [6%]) [3]. This finding may be confounded by the overlapping risk due to APOE ɛ4 carrier status, because
Common pathophysiological processes underlying ARIA
The limited findings reported to date suggest several potential pathophysiological mechanisms that might underlie and tie together the various components of ARIA. The relationship to dose level in the bapineuzumab studies suggests that ARIA may be related to increased clearance of parenchymal plaque with transient increase in vascular amyloid. This hypothesis is supported by the published autopsy results from the AN-1792 (active immunization) trial [52], [53]. It remains unclear whether rapid
Histopathological correlates of ARIA
To date, no neuropathologic descriptions of ARIA-E have been reported, perhaps because of the transient nature of ARIA-E. Our working understanding of the pathology and pathophysiology underlying this condition is therefore based on extrapolation from conditions with similar clinical and neuroimaging features.
As described previously, ARIA shares some features with PRES disorders, which are also characterized by subacute clinical symptoms and reversible T2 hyperintensities [61], [62].
Insights from animal models
Given the paucity of human histopathological data in ARIA, the Workgroup also explored relevant reports from animal models of AD and CAA, particularly those exposed to amyloid-modifying therapies. It is now roughly 15 years since the first successful transgenic mouse models of AD were developed; over the ensuing interval, there have been additional models generated, yet there remain a relatively small number of models that are widely used by investigators [76], [77], [78], [79], [80], [81], [82]
mHs in animal models of treatment of AD/CAA
In addition to being useful models of AD for experimental analysis of disease mechanism and pathogenesis, these transgenic mice provide a fruitful testing arena for potential therapeutic interventions to slow, reverse, or prevent the pathologic changes of AD. Again, it is necessary to emphasize that these models were engineered to develop elevated brain Aβ levels that progress to plaque formation. Additionally, the models have gradually been enhanced to accelerate the process because a major
Difficulty in modeling ARIA-E in transgenic animals
Other aspects of ARIA, in particular, the phenomenon known as “VE,” have not been reported in animal models; however, it is unclear whether systematic MR surveillance with sequences sensitive to ARIA-E has been performed longitudinally in a large number of animal models treated with amyloid-modifying therapies.
As mentioned previously, cerebral edema is the increase in water content of the extravascular but intraparenchymal compartment of the brain. It includes water that is present in the
Challenges to development of an animal model for ARIA
Could one develop a standardized animal model of ARIA, ideally a model that would exhibit all components of ARIA observed in patients with AD? There are certain barriers to be considered: for ARIA-E, there is uncertainty about whether it exists in animal models at all. For example, there are no publications describing this, and unpublished studies of which the Workgroup is aware have been regularly negative. The absence of ARIA-E in mice might reflect a difference in animal model and human
Monitoring for ARIA in clinical trials
The Workgroup concluded that there is very limited information thus far regarding ARIA in the natural setting or publicly available information from ongoing clinical trial programs to make conclusive recommendations for clinical trial policies. In particular, there are limited data regarding the relationship between ARIA-H and ARIA-E. Additional information regarding whether the presence of baseline ARIA-H acts as a potential risk factor for ARIA-E, and whether in turn ARIA-E acts as a risk
Recommendations for further research into the mechanisms underlying ARIA
In parallel with close monitoring of patients in ongoing clinical trials of amyloid-modifying treatments, further research is clearly needed to elucidate the mechanisms underlying the phenomena observed in ARIA. In particular, it would be valuable to use animal models to determine whether amyloid-lowering therapies indeed are associated with increased vascular permeability, perhaps through fluorescent labeling of plasma proteins of different sizes. Additional understanding of the genetic and
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R.A.S., C.R.J., H.H.F., and R.J.S. contributed equally to the Workgroup manuscript.
Disclosures: Dr. R.A.S. has served as a site investigator for Avid, Bristol-Myers Squibb, Elan, Janssen, Pfizer, and Wyeth, and as a consultant to Avid (unpaid), Bayer, Bristol-Myers Squibb, Elan, Eisai, Janssen, Pfizer, Roche, and Wyeth. Dr. C.R.J. Jr. serves as a consultant for Janssen, Lilly, GE, Johnson and Johnson, Eisai, and Elan, and is an investigator in clinical trials sponsored by Pfizer, Allon, and Baxter, Inc. Dr. S.E.B. has received contract research funds to the Cognitive Neurology and Stroke Research Units from Roche, GlaxoSmithKline, Novartis Pharmaceuticals, Myriad Pharmaceuticals, Pfizer, Sanofi-Aventis, Boehringer Ingelheim, Novo Nordisk, and AstraZeneca. In addition, she has received speaker’s honoraria for CME from Janssen-Ortho, Novartis Pharmaceutical, Lundbeck, Pfizer, Eisai, and Myriad Pharmaceuticals, and honoraria for ad hoc consulting from Pfizer, Janssen-Ortho, Novartis Pharmaceuticals, Lundbeck, Myriad Pharmaceuticals, GlaxoSmithKline, Schering-Plough, Elan, Wyeth Pharmaceuticals, Bristol-Myers Squibb, and Eisai. Dr. S.M.G. serves as a consultant for Hoffman-La Roche, Janssen Alzheimer Immunotherapy, and Bristol-Myers Squibb Company, and has received honoraria from Medtronic and Pfizer. Dr. B.T.H. has consulted with several pharmaceutical and biotechnology companies: EMD Serrano, Janssen, Takeda, BMS, Neurophage, Pfizer, Quanterix, foldrx, Elan, and Link. Dr. P.S. serves as a consultant to Roche AG, Novartis AG, Genentech, Danone Research, Lundbeck, GE Healthcare, and Avid. Drs. M.M.B. and R.J.S. are employed by Pfizer. Dr. R.S.B. is a full-time employee of Pfizer and owns stock in the company. Dr. H.R.B. is employed by Johnson and Johnson. Dr. M.G. has consulted for Janssen Alzheimer Immunotherapy, Johnson and Johnson, Elan Pharmaceuticals, and Avid Radiopharmaceuticals. Dr. E.R.S. is a full-time employee and stockholder at Eli Lilly. Dr. H.H.F. is a full-time employee and holds stock with Bristol-Myers Squibb. Drs. M.C.C. and W.T. are employees of the Alzheimer’s Association and report no conflicts.