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.

Figure 1

CMRglc reductions (red arrows) on FDG–PET in the parietal regions (left) and MTL (right) in the absence of atrophy on MRI in a 35-year-old woman, a PS1 carrier examined 35 years prior to the expected AD onset age.

Figure 2

Regional CMRglc reductions in AD patients (top row), individuals with MCI who declined to AD after 2 years (MCI–AD, middle row), and stable MCI patients (MCI–MCI, bottom row) compared with age-matched controls. Statistical parametric maps of reduced CMRglc are shown on a red-to-yellow color-coded scale reflecting Z scores between 2 and 6, and are displayed (from left to right) on the left lateral, left medial and posterior views of spatially standardized, volume-rendered MRI.

Figure 3

Weibull survival prediction models showing the association between hippocampal (HIP) CMRglc during normal aging and the time to decline to AD. In cognitively normal 70-year-old subjects, for HIP CMRglc ≤ 24 μmol/g/min, the predicted median time to decline is 7 years; for CMRglc = 25–28 μmol/g/min, the predicted time to decline is 9.5 years; and for CMRglc ≥ 29 μmol/g/min, the predicted time to decline is 12 years. In comparison, in cognitively normal 60-year-old subjects, HIP CMR-glc ≤ 24 μmol/g/min predicts a median time to decline of 11 years; for CMRglc = 25–28 μmol/g/min, the predicted time to decline is 13 years; and for CMRglc ≥ 29 μmol/g/min, the predicted time to decline is 18 years.