We evaluate a fully automatic technique for labeling hippocampal subfields and cortical subregions in the medial temporal lobe (MTL) in in vivo 3 Tesla MRI. The method performs segmentation on a T2-weighted MRI scan with 0.4 × 0.4 × 2.0 mm3 resolution, partial brain coverage, and oblique orientation. Hippocampal subfields, entorhinal cortex, and perirhinal cortex are labeled using a pipeline that combines multi-atlas label fusion and learning-based error correction. In contrast to earlier work on automatic subfield segmentation in T2-weighted MRI (Yushkevich et al., 2010), our approach requires no manual initialization, labels hippocampal subfields over a greater anterior-posterior extent, and labels the perirhinal cortex, which is further subdivided into Brodmann areas 35 and 36. The accuracy of the automatic segmentation relative to manual segmentation is measured using cross-validation in 29 subjects from a study of amnestic Mild Cognitive Impairment (aMCI), and is highest for the dentate gyrus (Dice coefficient is 0.823), CA1 (0.803), perirhinal cortex (0.797) and entorhinal cortex (0.786) labels. A larger cohort of 83 subjects is used to examine the effects of aMCI in the hippocampal region using both subfield volume and regional subfield thickness maps. Most significant differences between aMCI and healthy aging are observed bilaterally in the CA1 subfield and in the left Brodmann area 35. Thickness analysis results are consistent with volumetry, but provide additional regional specificity and suggest non-uniformity in the effects of aMCI on hippocampal subfields and MTL cortical subregions.

There is great interest in the development of cognitive markers that differentiate “normal” age-associated cognitive change from that of Alzheimer's disease (AD) in its prodromal (i.e., mild cognitive impairment; MCI) or even preclinical stages. Dual process models posit that recognition memory is supported by the dissociable processes of recollection and familiarity. Familiarity-based memory has generally been considered to be spared during normal aging, but it remains controversial whether this type of memory is impaired in early AD. Here, we describe findings of estimates of recollection and familiarity in young adults (YA), cognitively normal older adults (CN), and patients with amnestic-MCI (a-MCI). These measures in the CN and a-MCI patients were then related to a structural imaging biomarker of AD that has previously been demonstrated to be sensitive to preclinical and prodromal AD, the Cortical Signature of AD (ADsig). Consistent with much work in the literature, recollection, but not familiarity, was impaired in CN versus YA. Replicating our prior findings, a-MCI patients displayed impairment in both familiarity and recollection. Finally, the familiarity measure was correlated with the ADsig biomarker across the CN and a-MCI group, as well as within the CN adults alone. No other standard psychometric measure was as highly associated with the ADsig, suggesting that familiarity may be a sensitive biomarker of AD-specific brain changes in preclinical and prodromal AD and that it may offer a qualitatively distinct measure of early AD memory impairment relative to normal age-associated change.

Two neuroanatomically dissociable, large-scale cortical memory networks, referred to as the anterior and posterior MTL (medial temporal lobe) networks have recently been described (Kahn et al 2008; Libby et al 2012) in young adults using resting-state BOLD-fMRI-based functional connectivity (fc-BOLD). They have been hypothesized to subserve distinct mnemonic, as well as non-memory cognitive functions, and are thought to be associated with differential vulnerability in neurological disorders (Ranganath & Ritchey 2012). In this paper, we demonstrate the existence of these functional networks in an older adult population, and in a cohort of patients diagnosed with amnestic mild cognitive impairment (MCI). Anatomical subregions of interest (ROI) in the MTL were defined using high-resolution T2-weighted MRI and used as seeds for defining the putative networks using fc-BOLD. While the literature has suggested that the posterior MTL network is particularly vulnerable to early Alzheimer’s Disease, we show that both networks are affected in MCI, to varying degrees, compared to the control group. Further, cortical thickness in the brain regions defined by these networks was reduced in MCI.

Episodic memory loss is the hallmark cognitive dysfunction associated with Alzheimer’s disease (AD). Amnestic mild cognitive impairment (a-MCI) frequently represents a transitional stage between normal aging and early AD. A better understanding of the qualitative features of memory loss in a-MCI may have important implications for predicting those most likely to harbor AD-related pathology and for disease monitoring. Dual process models of memory argue that recognition memory is subserved by the dissociable processes of recollection and familiarity. Work studying recognition memory in a-MCI from this perspective has been controversial, particularly with regard to the integrity of familiarity. Event-related potentials (ERPs) offer an alternative means for assessing these functions without the associated assumptions of behavioral estimation methods. ERPs were recorded while a-MCI patients and cognitively normal (CN) age-matched adults performed a recognition memory task. When retrieval success was measured (hits versus correct rejections) in which performance was matched by group, a-MCI patients displayed similar neural correlates to that of the CN group, including modulation of the FN400 and the late positive complex (LPC) which are thought to index familiarity and recollection, respectively. Alternatively, when the integrity of these components was measured based on retrieval attempts (studied versus unstudied items), a-MCI patients displayed a reduced FN400 and LPC. Furthermore, modulation of the FN400 correlated with a behavioral estimate of familiarity and the LPC with a behavioral estimate of recollection obtained in a separate experiment in the same individuals, consistent with the proposed mappings of these indices. These results support a global decline of recognition memory in a-MCI, which suggests that the memory loss of prodromal AD may be qualitatively distinct from normal aging.