In vivo mapping of incremental cortical atrophy from incipient to overt Alzheimer’s disease

Progressive brain atrophy is believed to be the Alzheimer’s disease (AD) marker with the greatest evidence for validity. Mapping the topography of cortical atrophy throughout the stages of severity may allow the neural networks affected to be identified. Twenty healthy elderly persons (OH, MMSE 29.1 ± 1.0), 11 patients with incipient AD (iAD, 26.5 ± 2.0), 15 with mild AD (miAD, 23.5 ± 2.2), and 15 with moderate AD (moAD, 16.5 ± 2.0) underwent 3D magnetic resonance. Cortical pattern matching analysis was performed and maps of percent differences in gray matter distribution were computed between the following groups: iAD versus OH, miAD versus iAD, and moAD versus miAD. Compared to OH, iAD patients exhibited a mean cortical gray matter loss of 9–20% in areas encompassing the polysynaptic hippocampal pathway (posterior cingulate/retrosplenial and medial temporal cortex) and subgenual/orbitofrontal cortices, and a less widespread loss of 5–11% in other neocortical areas. Compared to iAD, miAD featured widespread mean gray matter loss of 14–19% in areas encompassing the direct hippocampal pathway (temporal pole, temporoparietal association cortex, and dorsal prefrontal cortex), sensorimotor, and visual cortex, with a less marked loss (7–9%) in the polysynaptic pathway areas. Compared to miAD, only atrophy in the primary sensorimotor cortex was still relatively marked in moAD, with a mean gray matter loss of 10–11%; the loss in other regions was generally below 10%. These findings suggest that the polysynaptic hippocampal pathway is affected in iAD, the direct pathway and sensorimotor and visual networks are affected in moAD, and the sensorimotor network is affected in moAD. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Functional abnormalities of the medial temporal lobe memory system in mild cognitive impairment and Alzheimer's disease: insights from functional MRI studies

Functional MRI (fMRI) studies of mild cognitive impairment (MCI) and Alzheimer's disease (AD) have begun to reveal abnormalities in memory circuit function in humans suffering from memory disorders. Since the medial temporal lobe (MTL) memory system is a site of very early pathology in AD, a number of studies, reviewed here, have focused on this region of the brain. By the time individuals are diagnosed clinically with AD dementia, the substantial memory impairments appear to be associated with not only MTL atrophy but also hypoactivation during memory task performance. Prior to dementia, when individuals are beginning to manifest signs and symptoms of memory impairment, the hippocampal formation and other components of the MTL memory system exhibit substantial functional abnormalities during memory task performance. It appears that, early in the course of MCI when memory deficits and hippocampal atrophy are less prominent, there may be hyperactivation of MTL circuits, possibly representing inefficient compensatory activity. Later in the course of MCI, when considerable memory deficits are present, MTL regions are no longer able to activate during attempted learning, as is the case in AD dementia. Recent fMRI data in MCI and AD are beginning to reveal relationships between abnormalities of functional activity in the MTL memory system and in functionally connected brain regions, such as the precuneus. As this work continues to mature, it will likely contribute to our understanding of fundamental memory processes in the human brain and how these are perturbed in memory disorders. We hope these insights will translate into the incorporation of measures of task-related brain function into diagnostic assessment or therapeutic monitoring, such as for use in clinical trials.     

Distinct laterality alterations distinguish mild cognitive impairment and Alzheimer's disease from healthy aging: Statistical parametric mapping with high resolution MRI

Laterality of human brain varies under healthy aging and diseased conditions. The alterations in hemispheric asymmetry may embed distinct biomarkers linked to the disease dynamics. Statistical parametric mapping based on high‐resolution magnetic resonance imaging (MRI) and image processing techniques have allowed automated characterization of morphological features across the entire brain. In this study, 149 subjects grouped in healthy young, healthy elderly, mild cognitive impairment (MCI), and Alzheimer's disease (AD) were investigated using multivariate analysis for regional cerebral laterality indexed by surface area, curvature index, cortical thickness, and subjacent white matter volume measured on high‐resolution MR images. Asymmetry alteration of MCI and AD were characterized by marked region‐specific reduction, while healthy elderly featured a distinct laterality shift in the limbic system in addition to regional asymmetry loss. Lack of the laterality shift in limbic system and early loss of asymmetry in entorhinal cortex may be biomarkers to identify preclinical AD among other dementia. Multivariate analysis of hemispheric asymmetry may provide information helpful for monitoring the disease progress and improving the management of MCI and AD. Hum Brain Mapp 34:3400–3410, 2013. © 2012 Wiley Periodicals, Inc.     

In vivo imaging of region and cell type specific neocortical neurodegeneration in Alzheimer's disease. Perspectives of MRI derived corpus callosum measurement for mapping disease progression and effects of therapy. Evidence from studies with MRI,EEG and PET

Summary. Neuropathological studies in Alzheimer's disease (AD) indicate specific loss of layer III and V large pyramidal neurons in association cortex. These neurons give rise to long cortico-cortical connections, projecting through the corpus callosum, in an anterior-posterior topology. Based on these findings we hypothesized that regional corpus callosum atrophy may be a potential in vivo marker for neocortical neuronal loss in AD. To evaluate this hypothesis, we developed a method to measure cross-sectional area of the corpus callosum and of five corpus callosum subregions on midsagittal magnetic resonance imaging scans (MRI). In a subsequent series of six experimental studies using MRI, ¹⁸FDG-PET and EEG, we investigated the relation of white matter hyperintensities (WMH) to corpus callosum size and correlated regional pattern of corpus callosum atrophy with regional cortical metabolic decline as well as intracortical coherencies. Mean total corpus callosum area was reduced significantly in AD patients compared to healthy age-matched controls, with the greatest changes in the rostrum and the splenium and relative sparing of the truncus. The regional pattern of corpus callosum atrophy was independent of WMH load and correlated significantly with pattern of regional metabolic decline measured with ¹⁸FDG-PET, the degree of cognitive impairment and regional decline of bilateral intracortical-coherency in EEG in AD patients. We further found that hippocampus atrophy, as a marker of early allocortical degeneration, was more pronounced than total corpus callosum atrophy in mild stages of AD. Regional corpus callosum atrophy in mild disease, however, suggested early neocortical degeneration in AD. In a longitudinal study, AD patients showed significantly greater rates of corpus callosum atrophy than controls. Rates of atrophy correlated with progression of clinical dementia severity in AD. Our results indicate that regional corpus callosum atrophy in AD patients represents the loss of callosal efferent neurons in corresponding regions of the neocortex. As these neurons are a subset of cortico-cortical projecting neurons, region-specific corpus callosum atrophy may serve as a marker of progressive neocortical disconnection in AD. In combination with measurement of hippocampal atrophy, assessment of corpus callosum atrophy over time in individual patients is useful to evaluate effects on brain structure of currently developed drugs, thought to slow or modify AD progression. Received November 26, 2001; accepted January 8, 2002