Lauren Mancuso

Automated volumetry and regional thickness analysis of hippocampal subfields and medial temporal cortical structures in mild cognitive impairment

We evaluate a fully automatic technique for labeling hippocampal subfields and cortical subregions in the medial temporal lobe 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 nonuniformity in the effects of aMCI on hippocampal subfields and MTL cortical subregions. Hum Brain Mapp, 36:258–287, 2015.

Increased functional connectivity within medial temporal lobe in mild cognitive impairment.

Pathology at preclinical and prodromal stages of Alzheimers disease (AD) may manifest itself as measurable functional change in neuronal networks earlier than detectable structural change. Functional connectivity as measured using resting‐state functional magnetic resonance imaging has emerged as a useful tool for studying disease effects on baseline states of neuronal networks. In this study, we use high resolution MRI to label subregions within the medial temporal lobe (MTL), a site of early pathology in AD, and report an increase in functional connectivity in amnestic mild cognitive impairment between entorhinal cortex and subregions of the MTL, with the strongest effect in the anterior hippocampus. However, our data also replicated the effects of decreased connectivity of the MTL to other nodes of the default mode network reported by other researchers. This dissociation of changes in functional connectivity within the MTL versus the MTLs connection with other neocortical structures can help enrich the characterization of early stages of disease progression in AD.

Anterior and posterior MTL networks in aging and MCI

Two neuroanatomically dissociable, large-scale cortical memory networks, referred to as the anterior and posterior medial temporal lobe (MTL) networks have recently been described in young adults using resting-state blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI)-based functional connectivity (fc-BOLD). They have been hypothesized to subserve distinct mnemonic and non-memory cognitive functions and are thought to be associated with differential vulnerability in neurological disorders. In this article, 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 (aMCI). Anatomic subregions of interest in the MTL were defined using high-resolution T2-weighted MRI and used as seeds for defining the putative networks using fc-BOLD. Although the literature has suggested that the posterior MTL network is particularly vulnerable to early Alzheimers disease, we show that both the networks are affected in MCI, to varying degrees, compared with the control group. Furthermore, cortical thickness in the brain regions defined by these networks was reduced in MCI.

Automatic Clustering and Thickness Measurement of Anatomical Variants of the Human Perirhinal Cortex

The entorhinal cortex (ERC) and the perirhinal cortex (PRC) are subregions of the medial temporal lobe (MTL) that play important roles in episodic memory representations, as well as serving as a conduit between other neocortical areas and the hippocampus. They are also the sites where neuronal damage first occurs in Alzheimers disease (AD). The ability to automatically quantify the volume and thickness of the ERC and PRC is desirable because these localized measures can potentially serve as better imaging biomarkers for AD and other neurodegenerative diseases. However, large anatomical variation in the PRC makes it a challenging area for analysis. In order to address this problem, we propose an automatic segmentation, clustering, and thickness measurement approach that explicitly accounts for anatomical variation. The approach is targeted to highly anisotropic (0.4x0.4x2.0mm3 ) T2-weighted MRI scans that are preferred by many authors for detailed imaging of the MTL, but which pose challenges for segmentation and shape analysis. After automatically labeling MTL substructures using multi-atlas segmentation, our method clusters subjects into groups based on the shape of the PRC, constructs unbiased population templates for each group, and uses the smooth surface representations obtained during template construction to extract regional thickness measurements in the space of each subject. The proposed thickness measures are evaluated in the context of discrimination between patients with Mild Cognitive Impairment (MCI) and normal controls (NC).

Multi-Template Analysis Of Human Perirhinal Cortex In Brain Mri: Explicitly Accounting For Anatomical Variability

Rational: The human perirhinal cortex (PRC) plays critical roles in episodic and semantic memory and visual perception. The PRC consists of Brodmann areas 35 and 36 (BA35, BA36). In Alzheimers disease (AD), BA35 is the first cortical site affected by neurofibrillary tangle pathology, which is closely linked to neural injury in AD. Large anatomical variability, manifested in the form of different cortical folding and branching patterns, makes it difficult to segment the PRC in MRI scans. Pathology studies have found that in ˜97% of specimens, the PRC falls into one of three discrete anatomical variants. However, current methods for PRC segmentation and morphometry in MRI are based on single‐template approaches, which may not be able to accurately model these discrete variants Methods: A multi‐template analysis pipeline that explicitly accounts for anatomical variability is used to automatically label the PRC and measure its thickness in T2‐weighted MRI scans. The pipeline uses multi‐atlas segmentation to automatically label medial temporal lobe cortices including entorhinal cortex, PRC and the parahippocampal cortex. Pairwise registration between label maps and clustering based on residual dissimilarity after registration are used to construct separate templates for the anatomical variants of the PRC. An optimal path of deformations linking these templates is used to establish correspondences between all the subjects. Experimental evaluation focuses on the ability of single‐template and multi‐template analyses to detect differences in the thickness of medial temporal lobe cortices between patients with amnestic mild cognitive impairment (aMCI, n=41) and age‐matched controls (n=44). Results: The proposed technique is able to generate templates that recover the three dominant discrete variants of PRC and establish more meaningful correspondences between subjects than a single‐template approach. The largest reduction in thickness associated with aMCI, in absolute terms, was found in left BA35 using both regional and summary thickness measures. Further, statistical maps of regional thickness difference between aMCI and controls revealed different patterns for the three anatomical variants. HIGHLIGHTSA multi‐template framework is proposed to quantify perirhinal cortex (PRC) using MRI.The framework explicitly models the 3 discrete anatomical variants of PRC.Better correspondences are established between subjects PRC anatomies.Regional and summary measures yield stronger power in discriminating aMCI.Spatial distributions of early AD pathology may vary among anatomical variants.

Short-Term Memory Depends on Dissociable Medial Temporal Lobe Regions in Amnestic Mild Cognitive Impairment

Short-term memory (STM) has generally been thought to be independent of the medial temporal lobe (MTL) in contrast to long-term memory (LTM). Prodromal Alzheimers disease (AD) is a condition in which the MTL is a major early focus of pathology and LTM is thought disproportionately affected relative to STM. However, recent studies have suggested a role for the MTL in STM, particularly hippocampus, when binding of different elements is required. Other work has suggested involvement of extrahippocampal MTL structures, particularly in STM tasks that involve item-level memory. We examined STM for individual objects, locations, and object-location conjunctions in amnestic mild cognitive impairment (MCI), often associated with prodromal AD. Relative to age-matched, cognitively normal controls, MCI patients not only displayed impairment on object-location conjunctions but were similarly impaired for non-bound objects and locations. Moreover, across all participants, these conditions displayed dissociable correlations of cortical thinning along the long axis of the MTL and associated cortical nodes of anterior and posterior MTL networks. These findings support the role of the MTL in visual STM tasks and the division of labor of MTL in support of different types of memory representations, overlapping with findings in LTM.

INVOLVEMENT OF ANTERIOR AND POSTERIOR MEDIAL TEMPORAL LOBE NETWORKS IN EARLY ALZHEIMER'S DISEASE

cognitive performance was demonstrated in demented and depressed patients after 60 months of integrated therapy (Bragin V et al., 2012). Here we present the results of our ongoing, naturalistic study, in the same outpatient setting, at 72 months of treatment.Methods: 70 Patients (43 females, 27 males, mean age of 71.4 6 5.94, education 13.00 6 2.69 with mild to moderate dementia and depression, with multiple chronic medical comorbidities (hypertension, coronary artery disease, hyperlipidemia, diabetes, arthritis etc.) underwent integrative treatment which consisted of pharmacological therapy (cholinesterase inhibitors, NMDA antagonists, antidepressants, along with their regular medication regimen) and non-pharmacological interventions. The non-pharmacological modalities included office and home-based physical and cognitive exercises aimed at the modification of regional cerebral blood flow. Diet modifications, vitamins, and nutritional supplements were incorporated as well. Cognitive testing was performed annually and included the MMSE, clock drawing test, verbal fluency tasks, and the Neurobehavioral Cognitive Status Examination (Cognistat), Ruff 2 & 7 Selective Attention and Ruff Figural Fluency tests. Descriptive and non-parametric statistical analysis (Wilcoxon signed-rank test) was performed on SPSS for Windows, version 21.0. Results: Performance on all cognitive tests remained at or improved from their baseline for a period of 72 months. The baseline MMSE was 26.8 6 7.09 and by 72 months of the treatment, MMSE was 27.66 6.50 (p> 0.05). Significant improvement (p < 0.05) was observed on Cognistat orientation, attention, construction and memory subtests. Conclusions: The integrative treatment approach postponed cognitive decline in demented and depressed patients with multiple medical co-morbidities for 72 months. Future investigations addressing integrated treatment in AD are warranted.