Hypometabolism exceeds atrophy in presymptomatic early-onset familial Alzheimer's disease

Department of Psychiatry, New York University School of Medicine, New York, New York, USA.
Journal of Nuclear Medicine (Impact Factor: 6.16). 11/2006; 47(11):1778-86.
Source: PubMed


The aim of the present study is to compare brain atrophy with hypometabolism as preclinical markers of Alzheimer's disease (AD) by studying presymptomatic individuals from families with known early-onset autosomal dominant AD (FAD) carrying mutations in the Presenilin 1 gene.
Seven asymptomatic at-risk FAD individuals (age, 35-49 y; 4 women; education >/= 12 y) and 7 matched healthy control subjects received complete clinical, neuropsychologic, MRI, and (18)F-FDG PET examinations. Regions of interest (ROIs: whole brain [WB], hippocampus [Hip], entorhinal cortex [EC], posterior cingulate cortex [PCC], inferior parietal lobule [IPL], and superior temporal gyrus (STG]) were drawn on the MRI scans of all subjects and used to measure volumes on MRI and glucose metabolism (MRglc) from the MRI-coregistered, atrophy-corrected PET scans.
Compared with controls and after correcting for head size, MRI volume reductions in FAD subjects were restricted to the IPL (18%, P < 0.02). After atrophy correction and adjusting for pons MRglc, PET MRglc reductions were found in all FAD subjects compared with controls in the WB (13%), bilaterally in the IPL (17%) and in the STG (12%), and in the left EC (21%), PCC (20%), and Hip (12%) (P values < 0.05). PET MRglc measurements were consistently less variable than MRI measures, yielding significantly larger effect sizes in separating FAD from controls.
Presymptomatic FAD individuals show widespread MRglc reductions consistent with the typical AD PET pattern in the relative absence of structural brain atrophy. These data further suggest that PET MRglc measures may serve as biomarkers for the preclinical diagnosis of AD.

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Available from: Benedetta Nacmias, Oct 09, 2015
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    • "Interestingly, in the same study, they found a strong resistance of type-1 IGF receptor (IGF-IR) to ligand activation even in brain regions where amyloid plaques are found in a very late stage of AD (Talbot et al., 2012). It remains unknown whether and how this last finding is relevant to the pathophysiology of AD and is related to the low rate of brain glucose metabolism that starts decades before the clinical onset of dementia (Reiman et al., 2004; Mosconi et al., 2006; Caselli et al., 2008). Here we provide evidence that, both in native and recombinant systems, IGF-IRs can be activated by the monomer of Aß 1−42 , the predominant form of the protein at physiological concentrations (Nag et al., 2011). "
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    ABSTRACT: ß-amyloid (Aß1-42) is produced by proteolytic cleavage of the transmembrane type-1 protein, amyloid precursor protein. Under pathological conditions, Aß1-42self-aggregates into oligomers, which cause synaptic dysfunction and neuronal loss, and are considered the culprit of Alzheimer's disease (AD). However, Aß1-42 is mainly monomeric at physiological concentrations, and the precise role of monomeric Aß1-42 in neuronal function is largely unknown. We report that the monomer of Aß1-42 activates type-1 insulin-like growth factor receptors and enhances glucose uptake in neurons and peripheral cells by promoting the translocation of the Glut3 glucose transporter from the cytosol to the plasma membrane. In neurons, activity-dependent glucose uptake was blunted after blocking endogenous Aß production, and re-established in the presence of cerebrospinal fluid Aß. APP-null neurons failed to enhance depolarization-stimulated glucose uptake unless exogenous monomeric Aß1-42 was added. These data suggest that Aß1-42 monomers were critical for maintaining neuronal glucose homeostasis. Accordingly, exogenous Aß1-42 monomers were able to rescue the low levels of glucose consumption observed in brain slices from AD mutant mice.
    Frontiers in Cellular Neuroscience 08/2015; 9:297. DOI:10.3389/fncel.2015.00297 · 4.29 Impact Factor
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    • "Nevertheless, AD research studies evaluating the diagnostic and predictive value of regional specific glucose metabolic rate and volume changes suggest the greater reliability of FDG PET over MRI in discriminating AD from subjects with intact and mild cognitive impairment (MCI) [De Santi et al., 2001; Kawachi et al., 2006; Mosconi et al., 2006]. However , De Santi et al. and Mosconi et al. indicate image postprocessing influences the outcome of discriminative analyses and subsequently, their predictive value. "
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    ABSTRACT: Functional brain imaging is a common tool in monitoring the progression of neurodegenerative and neurological disorders. Identifying functional brain imaging derived features that can accurately detect neurological disease is of primary importance to the medical community. Research in computer vision techniques to identify objects in photographs have reported high accuracies in that domain, but their direct applicability to identifying disease in functional imaging is still under investigation in the medical community. In particular, Serre et al. ([2005]: In: IEEE Conference on Computer Vision and Pattern Recognition (CVPR-05). pp 994-1000) introduced a biophysically inspired filtering method emulating visual processing in striate cortex which they applied to perform object recognition in photographs. In this work, the model described by Serre et al. [2005] is extended to three-dimensional volumetric images to perform signal detection in functional brain imaging (PET, SPECT). The filter outputs are used to train both neural network and logistic regression classifiers and tested on two distinct datasets: ADNI Alzheimer's disease 2-deoxy-D-glucose (FDG) PET and National Football League players Tc99m HMPAO SPECT. The filtering pipeline is analyzed to identify which steps are most important for classification accuracy. Our results compare favorably with other published classification results and outperform those of a blinded expert human rater, suggesting the utility of this approach. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.
    Human Brain Mapping 01/2014; 35(1). DOI:10.1002/hbm.22149 · 5.97 Impact Factor
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    • "Our DLPFC results were limited to the right hemisphere, consistent with the hemispheric encoding/retrieval asymmetry (HERA) model [Tulving et al., 1994], in which right PFC is more engaged than left during episodic memory retrieval. Our results may be influenced by blood perfusion or resting metabolism, both of which influence fMRI signal and may differ in presymptomatic FAD mutation carriers [Johnson et al., 2001; Kennedy et al., 1995; Mosconi et al., 2006; Scholl et al., 2011]. A prior study of late-onset AD risk found increased resting-state perfusion and (during memory encoding) lower fractional BOLD and perfusion in the MTL of APOE4 carriers [Fleisher et al., 2009]. "
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    ABSTRACT: Rare autosomal dominant mutations result in familial Alzheimer's disease (FAD) with a relatively consistent age of onset within families. This provides an estimate of years until disease onset (relative age) in mutation carriers. Increased AD risk has been associated with differences in functional magnetic resonance imaging (fMRI) activity during memory tasks, but most of these studies have focused on possession of apolipoprotein E allele 4 (APOE4), a risk factor, but not causative variant, of late-onset AD. Evaluation of fMRI activity in presymptomatic FAD mutation carriers versus noncarriers provides insight into preclinical changes in those who will certainly develop AD in a prescribed period of time. Adults from FAD mutation-carrying families (nine mutation carriers, eight noncarriers) underwent fMRI scanning while performing a memory task. We examined fMRI signal differences between carriers and noncarriers, and how signal related to fMRI task performance within mutation status group, controlling for relative age and education. Mutation noncarriers had greater retrieval period activity than carriers in several AD-relevant regions, including the left hippocampus. Better performing noncarriers showed greater encoding period activity including in the parahippocampal gyrus. Poorer performing carriers showed greater retrieval period signal, including in the frontal and temporal lobes, suggesting underlying pathological processes. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.
    Human Brain Mapping 12/2013; 34(12). DOI:10.1002/hbm.22141 · 5.97 Impact Factor
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