Quantitative magnetic resonance techniques as surrogate markers of Alzheimer's disease

Abstract

Recent advances in understanding the molecular biology of Alzheimer's disease (AD) offer the promise of useful therapeutic intervention in the foreseeable future. Hence, improved methods for early diagnosis and noninvasive surrogates of disease severity in AD have become more imperative. Various quantitative magnetic resonance (MR) techniques that measure the anatomic, biochemical, microstructural, functional, and blood-flow changes are being evaluated as possible surrogate measures of disease progression. Cross-sectional and longitudinal studies indicate that MR-based volume measurements are potential surrogates of disease progression in AD, starting from the preclinical stages. The validity of MR-based volumetry as a surrogate marker for therapeutic efficacy in AD remains to be tested in a positive disease-modifying drug trial. Recent development of amyloid imaging tracers for positron emission tomography has been a major breakthrough in the field of imaging markers for AD. Efforts to image plaques are also underway in MR imaging. As with indirect MR measures, these approaches of directly imaging the pathological substrate will need to undergo a validation process with longitudinal studies to prove their usefulness as surrogate markers in AD.

FIG. 1.

Hippocampal W score and crossover from MCI to AD. Kaplan-Meier curves of patients whose hippocampal W score at baseline is ≥0 (n = 13), 0 > W > −2.5 (n = 54), and ≤−2.5 (n = 13). Patients with a lower hippocampal W score at baseline progress to AD faster than those with higher W scores. Reproduced with permission from Neurology 52:1397–1403, 1999.

FIG. 2.

Regional structural markers for disease progression may vary with the pathologic stages of AD. This hypothetical graph represents the regional structural MR measurement change at different stages of disease progression. Regional measurements such as hippocampal atrophy rates (1) may be fastest early in the earliest pathologic stages, and may slow down later in the disease. Temporal lobe atrophy rates (2) may be fastest later during the intermediate or the MCI stage, and frontal lobe atrophy rates (3) may be fastest in clinically established AD. The choice of MR-based regional measurements should be tailored based on the severity of the disease.