Tara L. McHugh

Older adults with cognitive complaints show brain atrophy similar to that of amnestic MCI

Objective: To examine the neural basis of cognitive complaints in healthy older adults in the absence of memory impairment and to determine whether there are medial temporal lobe (MTL) gray matter (GM) changes as reported in Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI). Methods: Participants were 40 euthymic individuals with cognitive complaints (CCs) who had normal neuropsychological test performance. The authors compared their structural brain MRI scans to those of 40 patients with amnestic MCI and 40 healthy controls (HCs) using voxel-based morphometry and hippocampal volume analysis. Results: The CC and MCI groups showed similar patterns of decreased GM relative to the HC group on whole brain analysis, with differences evident in the MTL, frontotemporal, and other neocortical regions. The degree of GM loss was associated with extent of both memory complaints and performance deficits. Manually segmented hippocampal volumes, adjusted for age and intracranial volume, were significantly reduced only in the MCI group, with the CC group showing an intermediate level. Conclusions: Cognitive complaints in older adults may indicate underlying neurodegenerative changes even when unaccompanied by deficits on formal testing. The cognitive complaint group may represent a pre–mild cognitive impairment stage and may provide an earlier therapeutic opportunity than mild cognitive impairment. MRI analysis approaches incorporating signal intensity may have greater sensitivity in early preclinical stages than volumetric methods.

Regionally specific atrophy of the corpus callosum in AD, MCI and cognitive complaints

The goal of the present study was to determine if there are global or regionally specific decreases in callosal area in early Alzheimers disease (AD) and mild cognitive impairment (MCI). In addition, this study examined the corpus callosum of healthy older adults who have subjective cognitive complaints (CC) but perform within normal limits on neuropsychological tests. We used a semi-automated procedure to examine the total and regional areas of the corpus callosum in 22 patients with early AD, 28 patients with amnestic MCI, 28 healthy older adults with cognitive complaints, and 50 demographically matched healthy controls (HC). The AD, MCI, and CC groups all showed a significant reduction of the posterior region (isthmus and splenium) relative to healthy controls. The AD group also had a significantly smaller overall callosum than the controls. The demonstration of callosal atrophy in older adults with cognitive complaints suggests that callosal changes occur very early in the dementing process, and that these earliest changes may be too subtle for detection by neuropsychological assessments, including memory tests.

Comparison of Manual and Automated Determination of Hippocampal Volumes in MCI and Early AD

MRI-based hippocampal volume analysis has been extensively employed given its potential as a biomarker for brain disorders such as Alzheimer’s disease (AD), and accurate and efficient determination of hippocampal volumes from brain images is still a challenging issue. We compared an automated method, FreeSurfer (V4), with a published manual protocol for the determination of hippocampal volumes from T1-weighted MRI scans. Our study included MRI data from 125 older adult subjects: healthy controls with no significant cognitive complaints or deficits (HC, n = 38), euthymic individuals with cognitive complaints (CC, n = 39) but intact neuropsychological performance, and patients with amnestic mild cognitive impairment (MCI, n = 37) or a clinical diagnosis of probable AD (AD, n = 11). Pearson correlations and intraclass correlation coefficients (ICCs) were calculated to evaluate the relationship between results of the manual tracing and FreeSurfer methods and to estimate their agreement. Results indicated that these two methods derived highly correlated results with strong agreement. After controlling for the age, sex and intracranial volume in statistical group analysis, both the manual tracing and FreeSurfer methods yield similar patterns: both the MCI group and the AD group showed hippocampal volume reduction compared to both the HC group and the CC group, and the HC and CC groups did not differ. These comparisons suggest that FreeSurfer has the potential to be used in automated determination of hippocampal volumes for large-scale MCI/AD-related MRI studies, where manual methods are inefficient or not feasible.

HIPPOCAMPAL VOLUME AND SHAPE ANALYSIS IN AN OLDER ADULT POPULATION

This report presents a manual segmentation protocol for the hippocampus that yields a reliable and comprehensive measure of volume, a goal that has proven difficult with prior methods. Key features of this method include alignment of the images in the long axis of the hippocampus and the use of a three-dimensional image visualization function to disambiguate anterior and posterior hippocampal boundaries. We describe procedures for hippocampal volumetry and shape analysis, provide inter- and intra-rater reliability data, and examine correlates of hippocampal volume in a sample of healthy older adults. Participants were 40 healthy older adults with no significant cognitive complaints, no evidence of mild cognitive impairment or dementia, and no other neurological or psychiatric disorder. Using a 1.5 T GE Signa scanner, three-dimensional spoiled gradient recalled acquisition in a steady state (SPGR) sequences were acquired for each participant. Images were resampled into 1 mm isotropic voxels, and realigned along the interhemispheric fissure in the axial and coronal planes, and the long axis of the hippocampus in the sagittal plane. Using the BRAINS program (Andreasen et al., 1993), the boundaries of the hippocampus were visualized in the three orthogonal views, and boundary demarcations were transferred to the coronal plane for tracing. Hippocampal volumes were calculated after adjusting for intracranial volume (ICV). Intra- and inter-rater reliabilities, measured using the intraclass correlation coefficient, exceeded .94 for both the left and right hippocampus. Total ICV-adjusted volumes were 3.48 (±0.43) cc for the left hippocampus and 3.68 (±0.42) for the right. There were no significant hippocampal volume differences between males and females (p > .05). In addition to providing a comprehensive volumetric measurement of the hippocampus, the refinements included in our tracing protocol permit analysis of changes in hippocampal shape. Shape analyses may yield novel information about structural brain changes in aging and dementia that are not reflected in volumetric measurements alone. These and other novel directions in research on hippocampal function and dysfunction will be facilitated by the use of reliable, comprehensive, and consistent segmentation and measurement methods.

Morphometric MRI study of hippocampal shape in MCI using spherical harmonics

Background: Mild cognitive impairment (MCI) is characterized by memory complaints and impairment in the absence of dementia and confers a high risk for AD. Identifying medial temporal morphological abnormalities, in circuits required for learning and memory, may be critical for early diagnosis and treatment of MCI and AD. Objective: Volumetric analysis can identify hippocampal atrophy in MCI, but does not localize the structural changes. Shape analysis has the potential to provide important information beyond volume and may localize regionally specific structural changes in the absence of volume differences. This study performed hippocampal shape analysis aiming at a global and local quantitative representation of shape changes in MCI. Methods: Participants were 40 adults with amnestic MCI (age 72.5 3.3), 40 adults with cognitive complaints (CC) but no impairment (72.6 2.6), and 42 normal controls (CN) (70.8 2.6). MRI data were a T1-weighted SPGR coronal series acquired on a GE 1.5T LX magnet. The hippocampi were segmented using BRAINS software. The left and right hippocampi were treated as a single shape configuration. The spherical harmonics (SPHARM) description was used for surface modeling, with the parameter space being aligned according to the first order ellipsoid for surface correspondence. After normalizing for the total volume, landmarks were created by uniform surface sampling (Figure 1(a,b)) and aligned by a quaternion-based algorithm. For each landmark, the local shape change was defined as the distance between an individual and the mean along the normal direction of the mean surface. Surface signals were modeled as Gaussian random fields. Heat kernel smoothing was employed to increase SNR on the hippocampal surface (Figure 1(c)) and statistical inference was performed via random fields theory. Conclusions: The results of group analyses (t-maps in Figure 2) show that statistically significant regions of shape changes only appear between CN and MCI. The CC group showed a more intermediate pattern. The structural changes in MCI were primarily located in the anterior right hippocampus and posterior left hippocampus (Figure 3). Shape analysis has the potential to inform early detection and is likely to be useful for longitudinal monitoring of response to therapeutic agents. P-121 RESTING FDG-PET IN NEUROLOGICALLY NORMAL INDIVIDUALS REPORTING DREAM ENACTMENT BEHAVIOR: PRECLINICAL DEMENTIA WITH LEWY BODIES?

IC-P1-054: Comparison of manual and automated determination of hippocampal volumes in MCI and older adults with cognitive complaints

of language and semantic memory testing. Results: As a group, patients with progressive fluent aphasia demonstrated prominent left-greater-thanright temporopolar thinning, while patients with progressive non-fluent aphasia demonstrated thinning in left-greater-than-right inferior frontoinsular cortex. Yet there were notable individual differences in anatomic abnormalities that corresponded with differences in language, cognition, and behavior. Within the group of patients with fluent aphasia, the patient with the most prominent semantic impairment had the greatest degree of thinning of the left temporopolar cortex (31%) as compared to a group of controls; this patient also had prominent abnormalities of affective and social behavior, which may relate to prominent right temporopolar thinning (29%). Within the group of patients with non-fluent aphasia, the patient with non-fluent progressive aphasia and apraxia of speech had thinning not only in left inferior frontal gyrus (19%) but also in ventral precentral gyrus (26%) and supplementary motor area (24%). Conclusions: Quantitative cortical thickness analysis of MRI data shows promise in applications to individual subjects with progressive aphasia for localizing regional cortical thinning that may underlie specific language and behavioral abnormalities. Further investigation will determine whether this approach will be helpful in more detailed subtyping of these patients, in differential diagnosis, or as an imaging biomarker for monitoring the effects of potential future therapies. Supported by NIA R01-AG29411, K23-AG22509, NCRR P41RR14075, U24-RR021382, and the MIND Institute.