There has been a transformation in the part played by neuroimaging in Alzheimer disease (AD) research and practice in the last decades. Diagnostically, imaging has moved from a minor exclusionary role to a central position. In research, imaging is helping address many of the scientific questions outlined in Selkow et al. (2011)
: providing insights into the effects of AD and its temporal and spatial evolution. Furthermore, imaging is an established tool in drug discovery, increasingly required in therapeutic trials as part of inclusion criteria, as a safety marker, and as an outcome measure.
Concomitantly the potential of brain imaging has expanded rapidly with new modalities and novel ways of acquiring images and of analysing them. This article cannot be comprehensive. Instead, it addresses broad categories of structural, functional, and molecular imaging in AD. The specific modalities included are magnetic resonance imaging (MRI; both structural and functional) and positron emission tomography (PET; for assessment of both cerebral metabolism and amyloid). These modalities have different strengths and limitations and as a result have different and often complementary roles and scope.
Imaging in the Diagnosis and Prognosis of AD
The uncertainty inherent in a clinical diagnosis of AD has driven a search for diagnostic imaging markers. A definitive diagnosis still requires histopathological confirmation and the inaccessibility of the brain means imaging has a key role as a “window on the brain.” Historically, imaging—first computed tomography (CT) and then MRI—was used only to exclude potentially surgically treatable causes of cognitive decline. Now its position in diagnosis also includes providing positive support for a clinical diagnosis of AD in symptomatic individuals by identifying characteristic patterns (signatures) of structural and functional cerebral alterations. We can now also visualize the specific molecular pathology of the disease—amyloid deposits—with amyloid imaging. Alongside this increasing specificity for AD, imaging also contributes to differential diagnosis in practice by identifying alternative and/or contributory pathologies. Imaging is central to identifying vascular and non-AD degenerative pathologies and has helped in the recognition of the prevalence of mixed pathology in dementia.
In the setting of mild cognitive impairment (MCI) (Petersen 2004
), the determination of underlying pathology carries immediate prognostic importance. Only a fraction of patients with MCI progress to clinical AD over 5–10 years (Petersen et al. 1999
; Ritchie et al. 2001
; Visser et al. 2006
) and a recent meta-analysis concluded that most people with MCI will not progress to dementia even after 10 years of follow-up (Mitchell and Shiri-Feshki 2009
). Two community-based studies have shown over one-third of patients diagnosed with MCI at baseline may eventually return to normal cognition (Larrieu et al. 2002
; Ganguli et al. 2004
). Obviously, it would be of great value to be able to predict which MCI subjects were destined to progress to a clinical diagnosis of AD. This is true even in the absence of disease-modifying treatments, but will be especially critical when disease-modifying treatments become available.
Looking to the future, imaging has helped establish that there is a long preclinical and presymptomatic period where the pathological effects of AD are detectable. Although more data are needed, imaging is starting to provide prognostic information at this early preclinical stage. The need for an earlier and more certain diagnosis will only increase as disease-modifying therapies are identified. This will be particularly true if, as expected, these therapies work best (or only) when initiated at the preclinical stage.
Understanding the Biology of AD
Importantly, imaging has a major role to play in improving our understanding of this disease (or diseases). Uniquely, imaging is able to delineate in life the location within the brain of the effects of AD. Together with this topographical information imaging can quantify multiple different aspects of AD pathology and assess how they relate to each other and how they change over time. The clinical correlations of these changes and their relationships to other biomarkers and to prognosis can be studied. Ultimately the role of imaging in improving our understanding of the biology of AD underpins all its applications and is a theme that runs through the following sections of this article.