Reiman, al. Functional brain abnormalities in young adults at genetic risk for late-onset alzheimer's dementia. Proc. Natl. Acad. Sci. USA101, 284-289

Positron Emission Tomography Center, Banner Good Samaritan Medical Center, Phoenix, AZ 85006, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2004; 101(1):284-9. DOI: 10.1073/pnas.2635903100
Source: PubMed


Fluorodeoxyglucose positron emission tomography (PET) studies have found that patients with Alzheimer's dementia (AD) have abnormally low rates of cerebral glucose metabolism in posterior cingulate, parietal, temporal, and prefrontal cortex. We previously found that cognitively normal, late-middle-aged carriers of the apolipoprotein E epsilon4 allele, a common susceptibility gene for late-onset Alzheimer's dementia, have abnormally low rates of glucose metabolism in the same brain regions as patients with probable AD. We now consider whether epsilon4 carriers have these regional brain abnormalities as relatively young adults. Apolipoprotein E genotypes were established in normal volunteers 20-39 years of age. Clinical ratings, neuropsychological tests, magnetic resonance imaging, and PET were performed in 12 epsilon4 heterozygotes, all with the epsilon3/epsilon4 genotype, and 15 noncarriers of the epsilon4 allele, 12 of whom were individually matched for sex, age, and educational level. An automated algorithm was used to generate an aggregate surface-projection map that compared regional PET measurements in the two groups. The young adult epsilon4 carriers and noncarriers did not differ significantly in their sex, age, educational level, clinical ratings, or neuropsychological test scores. Like previously studied patients with probable AD and late-middle-aged epsilon4 carriers, the young epsilon4 carriers had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex. Carriers of a common Alzheimer's susceptibility gene have functional brain abnormalities in young adulthood, several decades before the possible onset of dementia.

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Available from: Kewei Chen, Oct 04, 2015
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    • "Brain hypometabolism is a universal change observed during Alzheimer's disease (AD) progression and recently, it has been proposed to have a major causative role in AD pathogenesis (Blass, 2001; Costantini et al., 2008). Through the use of neuroimaging techniques, impaired brain glucose metabolism has been demonstrated to occur: before atrophy in autosomal AD cases, during the progression toward non-familial AD and in individuals at high risk of AD (i.e., APOE ε4 carriers) prior to symptom manifestation (Small et al., 1995; Johnson et al., 2001; Reiman et al., 2004; Mosconi et al., 2009a,b). This reduced brain glucose metabolism has been postulated to result from impaired mitochondrial functioning (Lustbader et al., 2004; Beal, 2005; Bubber et al., 2005), with similar changes observed in a variety of transgenic mouse models of AD (von Kienlin et al., 2005; Yao et al., 2009, 2011; Nilsen et al., 2014). "
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    ABSTRACT: Glucose hypometabolism and impaired mitochondrial function in neurons have been suggested to play early and perhaps causative roles in Alzheimer's disease (AD) pathogenesis. Activity of the aspartic acid protease, beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), responsible for beta amyloid peptide generation, has recently been demonstrated to modify glucose metabolism. We therefore examined, using a human neuroblastoma (SH-SY5Y) cell line, whether increased BACE1 activity is responsible for a reduction in cellular glucose metabolism. Overexpression of active BACE1, but not a protease-dead mutant BACE1, protein in SH-SY5Y cells reduced glucose oxidation and the basal oxygen consumption rate, which was associated with a compensatory increase in glycolysis. Increased BACE1 activity had no effect on the mitochondrial electron transfer process but was found to diminish substrate delivery to the mitochondria by inhibition of key mitochondrial decarboxylation reaction enzymes. This BACE1 activity-dependent deficit in glucose oxidation was alleviated by the presence of beta hydroxybutyrate or α-lipoic acid. Consequently our data indicate that raised cellular BACE1 activity drives reduced glucose oxidation in a human neuronal cell line through impairments in the activity of specific tricarboxylic acid cycle enzymes. Because this bioenergetic deficit is recoverable by neutraceutical compounds we suggest that such agents, perhaps in conjunction with BACE1 inhibitors, may be an effective therapeutic strategy in the early-stage management or treatment of AD.
    Frontiers in Cellular Neuroscience 10/2015; DOI:10.3389/fncel.2015.00382 · 4.29 Impact Factor
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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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    • "Presumably, this increased activation occurs because the neuropathological changes associated with AD begin years or decades prior to symptom manifestation in persons at genetic risk for AD (Bateman et al., 2012; Jack et al., 2010). Indeed, alterations in taskrelated brain activity and cognitive performance have been reported in cross-sectional studies of APOE-ε4 positive individuals beginning in middle age and earlier (Evans et al., 2014; Reiman et al., 2004). "
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    ABSTRACT: Healthy aging is associated with cognitive declines typically accompanied by increased task-related brain activity in comparison to younger counterparts. The Scaffolding Theory of Aging and Cognition (STAC) (Park and Reuter-Lorenz, 2009; Reuter-Lorenz and Park, 2014) posits that compensatory brain processes are responsible for maintaining normal cognitive performance in older adults, despite accumulation of aging-related neural damage. Cross-sectional studies indicate that cognitively intact elders at genetic risk for Alzheimer's disease (AD) demonstrate patterns of increased brain activity compared to low risk elders, suggesting that compensation represents an early response to AD-associated pathology. Whether this compensatory response persists or declines with the onset of cognitive impairment can only be addressed using a longitudinal design. The current prospective, 5-year longitudinal study examined brain activation in APOE ε4 carriers (N=24) and non-carriers (N=21). All participants, ages 65-85 and cognitively intact at study entry, underwent task-activated fMRI, structural MRI, and neuropsychological assessments at baseline, 18, and 57months. fMRI activation was measured in response to a semantic memory task requiring participants to discriminate famous from non-famous names. Results indicated that the trajectory of change in brain activation while performing this semantic memory task differed between APOE ε4 carriers and non-carriers. The APOE ε4 group exhibited greater activation than the Low Risk group at baseline, but they subsequently showed a progressive decline in activation during the follow-up periods with corresponding emergence of episodic memory loss and hippocampal atrophy. In contrast, the non-carriers demonstrated a gradual increase in activation over the 5-year period. Our results are consistent with the STAC model by demonstrating that compensation varies with the severity of underlying neural damage and can be exhausted with the onset of cognitive symptoms and increased structural brain pathology. Our fMRI results could not be attributed to changes in task performance, group differences in cerebral perfusion, or regional cortical atrophy. Copyright © 2015 Elsevier Inc. All rights reserved.
    NeuroImage 02/2015; 111. DOI:10.1016/j.neuroimage.2015.02.011 · 6.36 Impact Factor
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