Gene E Alexander

PMID: 18337400;Abstract:

Humanstructural neuroimaging studies have supported the preferential effects of healthy aging on frontal cortex, but reductions in other brain regions have also been observed. We investigated the regional network pattern of gray matter using magnetic resonance imaging (MRI) in young adult and old rhesus macaques (RMs) to evaluate age effects throughout the brain in a nonhuman primate model of healthy aging in which the full complement of Alzheimer's disease (AD) pathology does not occur. Volumetric T1 MRI scans were spatially normalized and segmented for gray matter using statistical parametric mapping (SPM2) voxel-based morphometry. Multivariate network analysis using the scaled subprofile model identified a linear combination of two gray matter patterns that distinguished the young from old RMs. The combined pattern included reductions in bilateral dorsolateral and ventrolateral prefrontal and orbitofrontal and superior temporal sulcal regions with areas of relative preservation in vicinities of the cerebellum, globus pallidus, visual cortex, and parietal cortex in old compared with young RMs. Higher expression of this age-related gray matter pattern was associated with poorer performance in working memory. In the RM model of healthy aging, the major regionally distributed effects of advanced age on the brain involve reductions in prefrontal regions and in the vicinity of the superior temporal sulcus. The age-related differences in gray matter reflect the effects of healthy aging that cannot be attributed to AD pathology, providing support for the targeted effects of aging on the integrity of frontal lobe regions and selective temporal lobe areas and their associated cognitive functions. Copyright © 2008 Society for Neuroscience.

Abstract:

Background:We introduced a hypometabolic convergence index (HCI) to characterize in a single measurement the extent to which a person's fluorodeoxyglucose positron emission tomogram (FDG PET) corresponds to that in Alzheimer's disease (AD). Apolipoprotein E ε4 (APOE ε4) gene dose is associated with three levels of risk for late-onset AD. We explored the association between gene dose and HCI in cognitively normal ε4 homozygotes, heterozygotes, and non-carriers.Methods:An algorithm was used to characterize and compare AD-related HCIs in cognitively normal individuals, including 36 ε4 homozygotes, 46 heterozygotes, and 78 non-carriers.Results:These three groups differed significantly in their HCIs (ANOVA, p = 0.004), and there was a significant association between HCIs and gene dose (linear trend, p = 0.001).Conclusions:The HCI is associated with three levels of genetic risk for late-onset AD. This supports the possibility of using a single FDG PET measurement to help in the preclinical detection and tracking of AD. © 2013 Schraml et al.

PMID: 11248079;PMCID: PMC30654;Abstract:

Cross-sectional positron emission tomography (PET) studies find that cognitively normal carriers of the apolipoprotein E (APOE) ε4 allele, a common Alzheimer's susceptibility gene, have abnormally low measurements of the cerebral metabolic rate for glucose (CMRgl) in the same regions as patients with Alzheimer's dementia. In this article, we characterize longitudinal CMRgl declines in cognitively normal ε4 heterozygotes, estimate the power of PET to test the efficacy of treatments to attenuate these declines in 2 years, and consider how this paradigm could be used to efficiently test the potential of candidate therapies for the prevention of Alzheimer's disease. We studied 10 cognitively normal ε4 heterozygotes and 15 ε4 noncarriers 50-63 years of age with a reported family history of Alzheimer's dementia before and after an interval of approximately 2 years. The ε4 heterozygotes had significant CMRgl declines in the vicinity of temporal, posterior cingulate, and prefrontal cortex, basal forebrain, parahippocampal gyrus, and thalamus, and these declines were significantly greater than those in the ε4 noncarriers. In testing candidate primary prevention therapies, we estimate that between 50 and 115 cognitively normal ε4 heterozygotes are needed per active and placebo treatment group to detect a 25% attenuation in these CMRgl declines with 80% power and P = 0.005 in 2 years. Assuming these CMRgl declines are related to the predisposition to Alzheimer's dementia, this study provides a paradigm for testing the potential of treatments to prevent the disorder without having to study thousands of research subjects or wait many years to determine whether or when treated individuals develop symptoms.

Abstract:

A large body of evidence from neuropathological studies in Alzheimer's disease (AD) on postmortem brains has demonstrated impairment of specific neurotransmitter systems, especially of the cholinergic system. These studies, however, reflect end stages of the disease and permit only limited inference of the temporal sequence and cognitive and behavioral effects of deficits in neurotransmission. Since 1979, positron emission tomography (PET) has evolved into a powerful tool to visualize neuroreceptor binding in the living human brain and to quantify neuroreceptor density and ligand-receptor binding kinetics. Assessment of binding characteristics and receptor availability is essentially based on compartment models or saturation kinetic analysis derived from autoradiographic studies. This article describes the mathematical assumptions underlying these models and the biochemical characteristics that have to be met by a ligand to allow mapping of specific binding in PET. From this methodological basis, we review the present state of in vivo neuroreceptor imaging in AD. The majority of studies have focused on the cholinergic system, showing a decrease of nicotinic binding sites in frontal and temporal cortex in AD that was partially reversible through administration of central cholinergic drugs. As will be shown, interpretation of these results is severely limited by methodological difficulties. Recent studies have further demonstrated alterations of serotonin and opioid receptor availability in AD. We conclude with a discussion of the requirements that should be met by future studies on neurotransmission alterations in AD and outline possible future perspectives for these studies with respect to differential diagnosis and selective assessment of drug action and efficacy.

PMID: 1416806;Abstract:

A higher prevalence of dementia in individuals with fewer years of education has suggested that education may protect against Alzheimer's disease (AD). We tested whether individuals with more years of education have a more advanced AD before it is clinically evident. As a measure of pathophysiological severity, we quantified regional cerebral blood flow (rCBF), by the ¹³³Xenon inhalation technique; a specific pattern of flow reduction in the parietotemporal cortex corresponds to AD pathology. In 3 groups of patients with probable AD, matched for clinical measures of dementia severity but with varying levels of education, whole-cortex mean flows were comparable. However, the parietotemporal perfusion deficit was significantly greater in the group with the highest level of education, indicating that AD was more advanced in this group. We conclude that education or its covariates or both may provide a reserve that compensates for the neuropathological changes of AD and delays the onset of its clinical manifestations.