**1. Introduction**

Neuroimaging has revolutionized the field of cognitive neuroscience. Early studies of brainbehavior relationships relied on a precise neurological examination as the basis for hypothesizing the site of brain damage that was responsible for a given behavioral syndrome. Episodic amnesia, for example, clearly implicated the hippocampus as the site of recent memory abilities.

Clinicopathological correlations were the earliest means of obtaining precise data on the site of damage causing a specific neurobehavioral syndrome (D'Esposito & Wills, 2000). In 1861, Paul Broca's observations of nonfluent aphasia in the setting of left inferior frontal gyrus damage cemented the belief that this brain region was critical for speech output (Broca, 1861). The advent of structural brain imaging more than 100 years after Broca's observations, first with computed tomography (CT) and later with magnetic resonance imaging (MRI), paved the way for more precise anatomical localization of the cognitive deficits that are manifest after brain injury.

Anatomical analyses of Broca's aphasia using structural neuroimaging (Naeser et al., 1989, Dronkers, 1996, Alexander et al., 1990) have more precisely determined that damage restricted to the inferior frontal gyrus causes only a transient aphasia, with recovery within weeks to months. Instead, damage to deep white matter and insular cortex causes persistent nonfluency. Noninvasive, structural neuroimaging provides the remarkable power to detail anatomical pathology in every stroke patient without re-lying upon the infrequently obtained autopsy.

Neuroimaging is a powerful tool for creative exploration of the epidemiology, diagnostic sensitivity, progression and therapeutic efficacy in many brain diseases featured by memory impairment (Apostolova & Thompson, 2008). Some consider modern functional neuroimaging methods as useful tools to establish similarities and differences between different forms of amnesias with respect to their brain correlates, while others consider them adequate for constituting groups of patients in a research perspective, but still out of reach for the practitioner (Celsis, 2000).

Neuroimaging in Dementia and Other Amnestic Disorders 5

functions such as verbal ability, word knowledge, and semantic memory remain quite

Some functional neuroimaging studies on normal aging showed the involvement of different patterns of activation in comparison with control populations, such as increased frontal activity. These differences have been interpreted as reflecting the implementation of compensatory processes (Kalpouzos et al., 2008). Some authors (Rajah & D'Esposito, 2005) argue that in normal ageing distinct PFC regions exhibit different patterns of functional change, suggesting that age-related changes in PFC function are not homogeneous in nature. Specifically, these authors hypothesize that normal ageing is related to the differentiation of cortical function in a bilateral ventral PFC and deficits in function in right dorsal and anterior PFC (Rajah & D'Esposito, 2005). As a result of these changes, functional

Factors identified for healthy cognitive (brain) aging are multifactorial, and likely incorporate biological systems as well as cognitive reserve (i.e. the capability of an individual to cope with a task in order to optimize his/her performance by the recruitment

Mild cognitive impairment (MCI), a transitional state between normal aging and dementia, carries a four- to sixfold increased risk of future diagnosis of dementia (Caixeta, 2006). As complete drug-induced reversal of AD symptoms seems unlikely, researchers are now focusing on the earliest stages of AD where a therapeutic intervention is likely to realize the greatest impact. Recently neuroimaging has received significant scientific consideration as a promising in vivo disease-tracking modality that can also provide potential surrogate

Evidence to date indicates that functional brain decline precedes structural decline in prodromal dementia, including adults with MCI (Jak et al., 2009). Therefore, functional neuroimaging techniques may offer the unique ability to detect early functional brain changes in at-risk adults and identify the neurophysiological markers that best predict

While several volumetric techniques laid the foundation of the neuroimaging research in AD and MCI, more precise computational anatomy techniques have recently become available. This new technology detects and visualizes discrete changes in cortical and hippocampal integrity and tracks the spread of AD pathology throughout the living brain. Related methods can visualize regionally specific correlations between brain atrophy and important proxy measures of disease such as neuropsychological tests, age of onset or

Given that AD neuropathology preferentially targets the medial temporal lobe (MTL) early in the course of the disease, thereby resulting in the hallmark episodic memory decline, and amnestic MCI is thought to represent prodromal AD, the majority of fMRI studies of MCI involve memory processing (particularly encoding) in amnestic samples (Jak et al., 2009). No known fMRI studies have been published focusing on other clinical subtypes of MCI. While several studies demonstrate increased blood oxygen level dependent (BOLD) response in the MTL (Dickerson et al., 2004, Hamalainen et al., 2007; Kircher et al., 2007; Sperling, 2007), others report decreased MTL activity in MCI (Johnson et al., 2006; Mandzia et al., 2009). These discrepant findings have been interpreted as reflecting bimodal functional activity

factors that may influence disease progression (Apostolova & Thompson, 2008).

of different neural networks and/or by using alternative cognitive strategies).

biomarkers for therapeutic trials (Apostolova & Thompson, 2008).

preserved even to old age (Caserta et al., 2009).

compensation in left dorsal and anterior PFC may occur.

**4. Mild cognitive impairment (MCI)** 

dementia conversion.
