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Escalating Role of Medical Imaging in AD Clinical Trials

Studies Reveal Impact of Implementing, Standardizing, and Developing Neuroimaging Endpoints in Alzheimer's Disease Trials

Alzheimer's disease is one of the most important health challenges facing aging populations worldwide. Disease modifying therapies are desperately needed and many potential treatments are currently being tested in clinical trials. The role and impact of medical imaging in AD trials continues to grow, especially as clinicians and scientists seek to define and treat AD at the earliest stages of disease.

Neuroimaging provides an important non-invasive approach with the potential to assess disease progression in vivo. Imaging endpoints are already being applied in Alzheimer's clinical trials to evaluate drug efficacy in a quantitative way, to assess and monitor drug safety, and to select and enrich patients with disease. Furthermore, new diagnostic criteria using imaging biomarkers may provide AD diagnoses prior to the onset of neurodegeneration, opening the possibility of disease modification with early intervention.

The two major imaging modalities used in AD clinical trials are Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET). Let's take a closer look at each modality and its utility for AD trials.

Magnetic Resonance Imaging (MRI) for AD Trials

MRI is commonly used to assess brain structure in Alzheimer's patients. Volumetric T1 weighted MRI provides high resolution images with good contrast and is used to assess atrophy of the whole brain and brain structures (e.g. hippocampus and ventricles). The rate of change in brain atrophy and ventricular volumes, as quantified on MRI, serves as a biomarker of progression of AD in clinical trials and provides clinicians with a quantitative measure of drug efficacy.

More recently, MRI is being used to assess brain function. Functional MRI (fMRI) provides an in vivo means to investigate alterations in brain function related to the earliest symptoms of AD, possibly before development of significant irreversible structural damage. fMRI during resting state and cognitive paradigms (task-based) holds promise to improve early diagnostic and treatment options for AD.

MRI also plays an important role in evaluating drug safety. MRI signal changes known as 'amyloid-related imaging abnormalities' (ARIA) are known to be associated with amyloid modifying therapies and have been reported in some clinical trials aimed at lowering amyloid burden. The spectrum of ARIA includes hyperintensities thought to represent edema (ARIA-E) and hypointensities thought to represent microhemorrhages (ARIA-H). In 2011, recommendations from a working group of the Alzheimer's Association aimed at protecting patient safety was accepted by the U.S. Food and Drug Administration (FDA) and are now routinely incorporated into AD research studies.

Positron Emission Imaging (PET) for AD Trials

PET imaging is currently being used in several large phase III studies to visualize protein biomarkers of AD (amyloid, tau) and assess brain metabolic activity in response to treatments. Amyloid burden can be measured using radiotracers such as11C-PIB or 18F Florbetapir. More recently, Tau PET is being used to look for protein aggregates and protein phosphoisoforms in the brain (tau pathology) which serve as risk factors for neurodegenerative diseases like AD.

Alternatively, the glucose analog fluorodeoxyglucose (FDG) is used to monitor cerebral metabolism and brain activity for improved diagnostic accuracy and disease progression. FDG PET is not used as frequently compared to MRI or amyloid PET in large studies.

Neuroimaging featured at the Clinical Trials in Alzheimer's Disease meeting

With imaging playing a crucial role in the advancement of AD trials and therapies, it was featured heavily at the annual Clinical Trials in Alzheimer's Disease (CTAD) meeting. BioClinica is making important strides in implementing, standardizing, and developing neuroimaging endpoints for AD trials. BioClinica's neuroscience experts were on hand to present a series of posters summarizing collaborative work with Biogen and Janssen on the use of amyloid PET imaging and longitudinal volumetric changes in AD trials. Learn more about each of the studies below.

Hoffman Phantom Acquisition and Analysis Methods for Qualification of PET Centers in Multicenter Neurology Clinical Trials

Multicenter clinical trials in Alzheimer's disease often rely on amyloid PET as a quantitative biomarker for patient enrichment and as a longitudinal efficacy endpoint. The use of phantoms are crucial for reducing quantitative variability that arise from differences in acquisition settings and intrinsic imaging characteristics.

This work highlights the methods and pitfalls for PET center qualification using the anthropomorphic 3D Hoffman phantom and the techniques being developed to obtain traditional imaging metrics typical of tumor imaging.

Longitudinal volumetric changes in controls, MCI, and AD subjects from the ROSAS study compared to ADNI2

The ROSAS study is a monocentric observational study designed to identify and evaluate the clinical utility of AD biomarkers by analyzing samples from Normal Controls (NC), Mild Cognitive Impairment (MCI) and AD subjects over the course of up to 4 years.

This work describes changes over time in whole brain, lateral ventricles and hippocampal volumes for the ROSAS cohort using independent methods (Boundary Shift Integral and Tensor Based Morphometry). In addition, atrophy rates and longitudinal changes for the ROSAS cohort were monitored.

Rates of longitudinal change in brain volume in a clinical trial of anti-amyloid vaccine, ACC-001

The rate of change in brain atrophy and ventricular volumes, as quantified on MRI, has been used as a biomarker of progression of AD in clinical trials. In a recently completed phase 2 study, the effect of ACC-001, an N terminal peptide Aβ42 vaccine, in subjects with mild to moderate AD was assessed using volumetric MRI.

This work summarizes the efficacy (removal of cerebral fibrillar amyloid) and safety of ACC-001 and includes analysis of CSF Aβ, plasma Aβ, tau, p-tau, and immunogenicity in response to the vaccine.

Regionally-specific SUVR values in early-stage AD patients screened with amyloid PET

In an ongoing phase 1b multi-center clinical trial (221AD103), amyloid PET is being used as a screening tool to identify amyloid-positive participants as an enrichment strategy for clinical trials. PET imaging with florbetapir measures global cortical amyloid retention, enabling patient classification as amyloid positive or negative as well as quantifying amyloid burden.

This work investigates key areas of the brain that are most informative in yielding a positive visual read for amyloid, and how differences in regional SUVr are driven by diagnosis (prodromal vs. mild AD) and genetics (APOE ε4 status).

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