Role of structural MRI in Alzheimer's disease

Alzheimer's disease (AD) is a multifaceted disease in which cumulative pathological brain insults result in progressive cognitive decline that ultimately leads to dementia. Amyloid plaques, neurofibrillary tangles (NFTs), neurodegeneration, and inflammation are the well-established pathological hallmarks of AD. A plausible model for the development of AD posits that amyloid deposition occurs early in the process but by itself does not directly cause clinical symptoms [1,2]. Neuronal and synaptic losses appear to be key determinants of cognitive impairment in AD [3,4]. If neuronal loss leads to cerebral atrophy (as is likely), then it can be expected that cognitive decline and atrophy will be closely associated. On the basis of this evidence, it has been hypothesized that AD pathological cascade is a two-stage process in which amyloidosis and neuronal pathology (tauopathy, neuronal injury, and neurodegeneration) are largely sequential rather than simultaneous processes [1,5,6]. There is also sufficient literature to support the fact that atrophy of the brain structures or neurodegeneration is the most proximate substrate of cognitive impairment in AD [2,7-9]. This hypothesis of a sequential model was proposed by Jack and colleagues [6] on the basis of biomarker data and is adapted and illustrated in Figure 1. Owing to the close relationship between neurodegeneration and cognition (as illustrated in Figure 1), atrophy measured on structural magnetic resonance imaging (sMRI) is a powerful AD biomarker.sMRI measures brain morphometry and therefore can capture gray matter atrophy related to the loss of neurons, synapses, and dendritic de-arborization that occurs on a microscopic level in AD; white matter atrophy related to the loss of structural integrity of white matter tracts, presumably resulting from demyelination and dying back of axonal processes; and ex vacuo expansion of cerebrospinal fluid (CSF) spaces. Since there is a significant negative correlation between N