ABSTRACT

The application of neuroimaging technology to study Alzheimer’s disease (AD) has been steadily increasing over the last two decades. To date, the majority of neuroimaging contributions to understanding the pathophysiology and clinical course of AD have utilized structural magnetic resonance imaging (MRI) and positron emission tomography (PET). Influenced by pathological data, which reveal that the earliest disease manifestations are in medial temporal lobe (MTL) structures such as the hippocampus and entorhinal cortex,1

structural MRI studies have largely focused on volumetric measures of the MTL. Starting in the early 1990s, MTL volumes were shown to distinguish age-matched normal controls and AD patients, including those with very mild forms of the disease where the diagnosis of dementia was not yet conclusive.2,3 Further studies using quantitative volumetric measures have now demonstrated that MTL volumes predict progression to AD from mild states of memory impairment4-7 and correlate with impaired memory performance in AD patients,8,9 thus supporting the contention that MTL volumetric measures are both clinically and biologically relevant. The application of structural MRI has continued to advance as other measures have complemented the volumetric studies. For example, the use of diffusion-weighted (DWI) MRI, sensitive to the random motion of water in the brain, revealed an increase in the apparent diffusion coefficient (ADC) in the hippocampus of AD patients that predicts progression to AD from mild impairment.10,11

Despite considerable data on anatomical changes accompanying AD, less is known of concomitant physiological alterations. Over the last two decades, and until very recently, studies that have explored physiological changes in AD have used functional tomographic techniques, specifically PET and single photon emission computed tomography (SPECT), for molecular imaging. These techniques generate three-dimensional brain maps of radionuclide distribution reflecting biochemical and physiological processes. The first studies, in the early 1980s, revealed regional changes in both oxygen and glucose metabolism in AD patients12,13 that have been confirmed to be reductions primarily localized to the temporal, parietal, and posterior cingulate cortex.14,15 In agreement with the volumetric MRI studies of the MTL, functional tomographic techniques have been shown to have both high sensitivity and high specificity for differentiating AD patients from healthy older individuals and those with mild cognitive impairment,16,17 as well as predicting progression of the disease.18-20

In contrast to the two decades of AD research using structural MRI, PET and SPECT, it was only as recently as 1999 that functional MRI (fMRI) appeared in the scientific literature as a research tool to study AD.21