Brain Glucose Hypometabolism and Oxidative Stress in Preclinical Alzheimer's Disease

Abstract

One of the main features of Alzheimer's disease (AD) is the severe reduction of the cerebral metabolic rate for glucose (CMRglc). In vivo imaging using positron emission tomography with 2-[ 18 F] fluoro-2-deoxy-D-glucose (FDG-PET) demonstrates consistent and progressive CMRglc reductions in AD patients, the extent and topography of which correlate with symptom severity. Increasing evidence suggests that CMRglc reductions occur at the preclinical stages of AD. CMRglc reductions were observed on FDG-PET before the onset of disease in several groups of at-risk individuals, including patients with mild cognitive impairment (MCI), often a prodrome to AD; presymptomatic individuals carrying mutations responsible for early-onset familial AD; cognitively normal elderly individuals followed for several years until they declined to MCI and eventually to AD; normal, middle-aged individuals who expressed subjective memory complaints and were carriers of the apolipoprotein E epsilon-4 allele, a strong genetic risk factor for late-onset AD. However, the causes of the early metabolic dysfunction forerunning the onset of AD are not known. An increasing body of evidence indicates a deficient or altered energy metabolism that could change the overall oxidative microenvironment for neurons during the pathogenesis and progression of AD, leading to alterations in mitochondrial enzymes and in glucose metabolism in AD brain tissue. The present paper reviews findings that implicate hypometabolism and oxidative stress as crucial players in the initiation and progression of synaptic pathology in AD.

Astrocytic transporters in Alzheimer's disease

“…While debate surrounds astrocytic metabolic supply and demand, it is clear that brain glucose metabolism is decreased in preclinical patients (96), animal models of dementia (97) and people with a diagnosis of AD (98). The molecular mechanisms behind this are poorly understood, although human AD studies highlight that astrocyte/endothelial GLUT1 (as well as neuronal GLUT3) levels are reduced in post-mortem AD brains (99,100).…”

Astrocytes in Alzheimer's Disease

“…Numerous functional imaging studies demonstrated significant and progressive decrease in glucose use from the very early stages of AD in humans. 192 The A␤ remodels astroglial metabolic phenotype in vitro by affecting glucose metabolism and increasing reactive oxygen species production in cultured astrocytes. The data on actual mechanisms of A␤-dependent changes in glucose metabolic pathways are controversial.…”

Insulin Resistance, Cognitive Impairment and Neurodegeneration: Roles of Nitrosamine Exposure, Diet and Lifestyles

“…The concept that AD could represent a metabolic disease stemmed from the findings that deficits in cerebral glucose utilization are detectable in the early stages of disease (Adolfsson, Bucht et al 1980;Fujisawa, Sasaki et al 1991;Caselli, Chen et al 2008;Mosconi, Pupi et al 2008;Mosconi, Mistur et al 2009;Langbaum, Chen et al 2010), and as AD progresses, so do the metabolic abnormalities (Hoyer and Nitsch 1989;Hoyer, Nitsch et al 1991). Although several studies provided initial clues that insulin resistance could be an important feature of AD (Frolich, Blum-Degen et al 1998;Hoyer 2002;), the human postmortem brain studies were critical for definitively establishing that both insulin resistance and insulin deficiency in the brain were consistent and fundamental abnormalities in AD (Rivera, Goldin et al 2005;Steen, Terry et al 2005).…”