Abstract
BackgroundThe underlying mechanism of brain glucose hypometabolism, an invariant neurodegenerative feature that tightly correlates with cognitive impairment and disease progression of Alzheimer’s disease (AD), remains elusive.MethodsPositron emission tomography with 2-[18F]fluoro-2-deoxy-d-glucose (FDG-PET) was used to evaluate brain glucose metabolism, presented as the rate of 2-[18F]fluoro-2-deoxy-d-glucose standardized uptake value ratio (FDG SUVR) in patients with AD or control subjects and in mice with or without thiamine deficiency induced by a thiamine-deprived diet. Brain amyloid-β (Aβ) deposition in patients with clinically diagnosed AD was quantified by performing assays using 11C-Pittsburgh compound B PET. The levels of thiamine metabolites in blood samples of patients with AD and control subjects, as well as in blood and brain samples of mice, were detected by high-performance liquid chromatography with fluorescence detection.ResultsFDG SUVRs in frontal, temporal, and parietal cortices of patients with AD were closely correlated with the levels of blood thiamine diphosphate (TDP) and cognitive abilities, but not with brain Aβ deposition. Mice on a thiamine-deprived diet manifested a significant decline of FDG SUVRs in multiple brain regions as compared with those in control mice, with magnitudes highly correlating with both brain and blood TDP levels. There were no significant differences in the changes of FDG SUVRs in observed brain regions between amyloid precursor protein/presenilin-1 and wild-type mice following thiamine deficiency.ConclusionsWe demonstrate, for the first time to our knowledge, in vivo that TDP reduction strongly correlates with brain glucose hypometabolism, whereas amyloid deposition does not. Our study provides new insight into the pathogenesis and therapeutic strategy for AD.
Highlights
The underlying mechanism of brain glucose hypometabolism, an invariant neurodegenerative feature that tightly correlates with cognitive impairment and disease progression of Alzheimer’s disease (AD), remains elusive
We investigated whether the level of blood thiamine metabolites correlates with brain glucose metabolism as evaluated by positron emission tomography with 2[18F]fluoro-2-deoxy-D-glucose (FDG-PET) and cerebral amyloid deposition as assayed by PET with 11C-Pittsburgh compound B (PiB-PET) in patients with AD
thiamine diphosphate (TDP) reduction correlates significantly with brain glucose hypometabolism Blood TDP levels in patients with AD were significantly reduced as compared with levels in age- and sexmatched control subjects (P < 0.001, n = 14) (Fig. 1a)
Summary
The underlying mechanism of brain glucose hypometabolism, an invariant neurodegenerative feature that tightly correlates with cognitive impairment and disease progression of Alzheimer’s disease (AD), remains elusive. Methods: Positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (FDG-PET) was used to evaluate brain glucose metabolism, presented as the rate of 2-[18F]fluoro-2-deoxy-D-glucose standardized uptake value ratio (FDG SUVR) in patients with AD or control subjects and in mice with or without thiamine deficiency induced by a thiaminedeprived diet. Brain amyloid-β (Aβ) deposition in patients with clinically diagnosed AD was quantified by performing assays using 11C-Pittsburgh compound B PET. A better understanding of the mechanisms that drive AD clinical deterioration and definitively connect progressive cognitive deterioration to biomarkers would yield important insights into the disease’s pathogenesis. This has direct implications for new strategies for diagnosis of and therapy for the disease
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