Posterior Cingulate Glucose Metabolism, Hippocampal Glucose Metabolism, and Hippocampal Volume in Cognitively Normal, Late-Middle-Aged Persons at 3 Levels of Genetic Risk for Alzheimer Disease

Abstract

To characterize and compare measurements of the posterior cingulate glucose metabolism, the hippocampal glucose metabolism, and hippocampal volume so as to distinguish cognitively normal, late-middleaged persons with 2, 1, or 0 copies of the apolipoprotein E (APOE) ε4 allele, reflecting 3 levels of risk for lateonset Alzheimer disease.Design: Cross-sectional comparison of measurements of cerebral glucose metabolism using 18 F-fluorodeoxyglucose positron emission tomography and measurements of brain volume using magnetic resonance imaging in cognitively normal ε4 homozygotes, ε4 heterozygotes, and noncarriers.Setting: Academic medical center.Participants: A total of 31 ε4 homozygotes, 42 ε4 heterozygotes, and 76 noncarriers, 49 to 67 years old, matched for sex, age, and educational level. Main Outcome Measures:The measurements of posterior cingulate and hippocampal glucose metabolism were characterized using automated region-of-interest algorithms and normalized for whole-brain measurements. The hippocampal volume measurements were charac-terized using a semiautomated algorithm and normalized for total intracranial volume.Results: Although there were no significant differences among the 3 groups of participants in their clinical ratings, neuropsychological test scores, hippocampal volumes (P=.60), or hippocampal glucose metabolism measurements (P = .12), there were significant group differences in their posterior cingulate glucose metabolism measurements (P =.001). The APOE ε4 gene dose was significantly associated with posterior cingulate glucose metabolism (r = 0.29, P = .0003), and this association was significantly greater than those with hippocampal volume or hippocampal glucose metabolism (PϽ.05, determined by use of pairwise Fisher z tests).Conclusions: Although our findings may depend in part on the analysis algorithms used, they suggest that a reduction in posterior cingulate glucose metabolism precedes a reduction in hippocampal volume or metabolism in cognitively normal persons at increased genetic risk for Alzheimer disease.

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…The prodromal stage encompasses the presymptomatic and mild cognitive impairment stages of AD. White line = progression of cognitive decline through the 5 stages of AD [11][12][13][14][15][16][17]. FDG-PET = fluoro-2-deoxyglucose positron emission tomography; MRI, magnetic resonance imaging adenosine triphosphate (ATP) production [9].…”

“…Decrements observed in cerebral glucose metabolism using fluoro-2-deoxyglucose positron emission tomography (FDG-PET) and brain volume using magnetic resonance imaging are early signs of bioenergetic decline in the prodromal state of AD ( Fig. 1) [16]. Observations from a clinical trial of the Dominantly Inherited Alzheimer's Network suggested several surrogate disease markers, including compromised FDG-PET signal in specific brain regions (posterior cingulate cortex and prefrontal cortex) vulnerable to development of AD pathology, that arise in patients with AD decades before cognitive symptoms [11-15, 17, 24, 44].…”

The Roles of Genetics in Aβ related Alzheimer's Diseases

“…3, using the florbetapir (18F-FDG) positron emission tomography (PET) imaging technique, it has been shown that the APOE alleles in chromosome 19 and butyrylcholinesterase (BCHE) can be regarded as Aβ peptide deposition regulator [47]. In cognitively normal AD patients, the cortex glucose metabolism rate (CMRgI) is significantly reduced for Apo-E ε4 carrier [ε4 +], especially in the front frontal lobe, parietal lobe, temporal lobe and posterior cingulate regions [48][49][50][51][52]. Apo-E ε4 dose is related with higher and earlier risk of dementia [50].…”

The link between cardiovascular risk, Alzheimer's disease, and mild cognitive impairment: support from recent functional neuroimaging studies

“…109 Glucose hypometabolism has been associated with the presence of the APOE e4 allele in non-demented older adults. [110][111][112] In the FDG-PET study by Reiman et al, 95 the sample of cognitively normal middle-aged and elderly individuals was subdivided into APOE e4 homozygous (n=24), heterozygous (n=38), and non-carriers (n=55). In some cortical regions, the relationship between hypometabolism and CVRFs had greater salience in e4 allele carriers than in non-carriers.…”

“…On the other hand, findings involving the lateral temporoparietal neocortices lost their significance when the analysis was repeated after controlling for the effects of the e4 allele, 113 indicating that metabolism in those latter regions may be influenced by APOE, as suggested by previous PET studies of non-elderly subjects. 95,114,115 Although e4-related hypometabolism has been associated with the neuropathological processes of AD, 112,116 such findings may not be necessarily pathological or specifically linked to AD. 117 For instance, APOE e4 is also a risk factor for vascular disease.…”