Neuroimaging biomarkers for clinical trials of disease-modifying therapies in Alzheimer's disease

Abstract

The pathophysiologic process leading to neurodegeneration in Alzheimer's disease (AD) is thought to begin long before clinical symptoms develop. Existing therapeutics for AD improve symptoms, but increasing efforts are being directed toward the development of therapies to impede the pathologic progression of the disease. Although these medications must ultimately demonstrate efficacy in slowing clinical decline, there is a critical need for biomarkers that will indicate whether a candidate disease-modifying therapeutic agent is actually altering the underlying degenerative process. A number of in vivo neuroimaging techniques, which can reliably and noninvasively assess aspects of neuroanatomy, chemistry, physiology, and pathology, hold promise as biomarkers. These neuroimaging measures appear to relate closely to neuropathological and clinical data, such as rate of cognitive decline and risk of future decline. As this work has matured, it has become clear that neuroimaging measures may serve a variety of potential roles in clinical trials of candidate neurotherapeutic agents for AD, depending in part on the question of interest and phase of drug development. In this article, we review data related to the range of neuroimaging biomarkers of Alzheimer's disease and consider potential applications of these techniques to clinical trials, particularly with respect to the monitoring of disease progression in trials of disease-modifying therapies.

FIG. 1.

Coronal MRI sections from individual subjects (Control, MCI, and AD), illustrating mild degree of atrophy in MCI and greater atrophy in mild AD compared with age-matched control.

FIG. 2.

¹H spectra from posterior cingulate from individual subjects (Control, MCI, and AD), illustrating increased mI peak in MCI and decreased NAA peak in AD. Figure courtesy of Kejal Kantarci, M.D. (Mayo Clinic, Rochester, MN).

FIG. 3.

FDG-PET data from an older control subject (top) and a patient with probable Alzheimer's disease (bottom), illustrating prominent temporoparietal hypometabolism. Figure courtesy of Keith Johnson, M.D. (Massachusetts General Hospital, Boston, MA).

FIG. 4.

Decreased medial temporal lobe activation can be detected during the performance of memory tasks in mild AD patients compared with nondemented older individuals, as measured by fMRI. Group statistical comparison showing regions with decreased activation in AD patients compared to age-matched normal controls.

FIG. 5.

In vivo PET-based detection of β amyloid. Increased retention of Pittsburgh compound-B (PIB) is found in frontal and temporo-parietal regions in patients with clinical AD. Figure courtesy of William E. Klunk, M.D., Ph.D. (University of Pittsburgh Medical Center, Pittsburgh, PA).