Amyloid Dysmetabolism Relates to Reduced Glucose Uptake in White Matter Hyperintensities

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and cause of dementia and is characterized by amyloid plaques and neurofibrillary tangles. AD has traditionally been considered to primarily affect gray matter, but multiple lines of evidence also indicate white matter (WM) pathology and associated small-vessel cerebrovascular disease. WM glucose delivery and metabolism may have implications for local tissue integrity, and [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) may be helpful to assess neuroglial and axonal function in WM. Hypothesizing that affection of oligodendroglia will be associated with loss of glucose uptake, we aimed to investigate glucose metabolism in magnetic resonance imaging (MRI) white matter hyperintensities (WMHs) and normal-appearing WM in patients with and without evidence of amyloid plaques. Subjects with mild cognitive impairment or subjective cognitive decline were included and dichotomized according to pathological (Aβ+) or normal (Aβ−) concentrations of cerebrospinal fluid amyloid-β 1–42. A total of 50 subjects were included, of whom 30 subjects were classified as Aβ(+) and 20 subjects as Aβ(−). All subjects were assessed with MRI and FDG-PET. FDG-PET images were corrected for effects of partial voluming and normalized to cerebellar WM, before determining WMH FDG-uptake. Although there were no significant differences between the groups in terms of age, WMH volume, number of individual WMHs, or WMH distribution, we found significantly lower (p = 0.021) FDG-uptake in WMHs in Aβ(+) subjects (mean = 0.662, SD = 0.113) compared to Aβ(−) subjects (mean = 0.596, SD = 0.073). There were no significant group differences in the FDG-uptake in normal-appearing WM. Similar results were obtained without correction for effects of partial voluming. Our findings add to the evidence for a link between Aβ dysmetabolism and WM pathology in AD.

[18F]-Flutemetamol Uptake in Cortex and White Matter: Comparison with Cerebrospinal Fluid Biomarkers and [18F]-Fludeoxyglucose

“…Increased fibrillar Aβ has been associated with higher levels of Aβ oligomers, suggested to be more neurotoxic and promote neurodegeneration [ 56 ]. Hence, the current findings of negative associations between the 18 F-FDG uptake in WMHs and cortical 18 F-Flut retention support our previous findings [ 16 ], connecting increasing Aβ pathology to glucose hypometabolism in WMHs.…”

“…In addition, our findings support previous hypotheses of toxic effects of Aβ on synaptic function based on the strong correlations observed between cortical 18 F-Flut and 18 F-FDG uptake. Furthermore, we replicate our previous findings [ 16 ] linking amyloid dysmetabolism to glucose hypometabolism in WMHs. We also demonstrate generally higher 18 F-Flut retention across the brain in subjects classified as 18 F-Flut(+), including WM and WMHs, which may challenge the use of 18 F-Flut for WM analyses.…”

“…Accumulating evidence links CVD and AD [ 19 ], and we have previously demonstrated impaired WMH microstructural integrity in Aβ positive subjects using diffusion tensor imaging [ 17 ]. Furthermore, we recently found reduced glucose metabolism in WMHs in the presence of amyloid dysmetabolism [ 16 ]. Increased fibrillar Aβ has been associated with higher levels of Aβ oligomers, suggested to be more neurotoxic and promote neurodegeneration [ 56 ].…”

“…Applying PVE correction (PVC) enhances quantitative accuracy of 18 F-Flut PET [ 15 ], and may also avoid bias in WM analyses. PVC may optimize PET images for studies of WM function and pathology, as we recently demonstrated with [ 18 F]-fluorodeoxyglucose PET (FDG-PET) [ 16 ] (and also with diffusion tensor imaging [ 17 ]).…”

Can we predict amyloid deposition by objective cognition and regional cerebral blood flow in patients with subjective cognitive decline?

“…Kalheim et al . investigated the [ 18 F]‐fluorodeoxyglucose (FDG)‐PET signal in white matter hyperintensities of magnetic resonance imaging between Aβ‐positive and ‐negative subjects among mixed patients with MCI ( n = 43) and SCD ( n = 7) . They showed significantly lower FDG‐uptake in white matter hyperintensities in Aβ‐positive subjects compared to Aβ‐negative subjects.…”