TY - JOUR
T1 - Brain metabolism in tau and amyloid mouse models of Alzheimer's disease
T2 - An MRI study
AU - Wei, Zhiliang
AU - Xu, Jiadi
AU - Chen, Lin
AU - Hirschler, Lydiane
AU - Barbier, Emmanuel L.
AU - Li, Tong
AU - Wong, Philip C.
AU - Lu, Hanzhang
N1 - Publisher Copyright:
© 2021 John Wiley & Sons, Ltd.
PY - 2021/9
Y1 - 2021/9
N2 - Alzheimer's disease (AD) is the leading cause of cognitive impairment and dementia in elderly individuals. According to the current biomarker framework for “unbiased descriptive classification”, biomarkers of neurodegeneration, “N”, constitute a critical component in the tri-category “A/T/N” system. Current biomarkers of neurodegeneration suffer from potential drawbacks such as requiring invasive lumbar puncture, involving ionizing radiation, or representing a late, irreversible marker. Recent human studies have suggested that reduced brain oxygen metabolism may be a new functional marker of neurodegeneration in AD, but the heterogeneity and the presence of mixed pathology in human patients did not allow a full understanding of the role of oxygen extraction and metabolism in AD. In this report, global brain oxygen metabolism and related physiological parameters were studied in two AD mouse models with relatively pure pathology, using advanced MRI techniques including T2-relaxation-under-spin-tagging (TRUST) and phase contrast (PC) MRI. Additionally, regional cerebral blood flow (CBF) was determined with pseudocontinuous arterial spin labeling. Reduced global oxygen extraction fraction (by −18.7%, p = 0.008), unit-mass cerebral metabolic rate of oxygen (CMRO2) (by −17.4%, p = 0.04) and total CMRO2 (by −30.8%, p < 0.001) were observed in Tau4RΔK mice—referred to as the tau AD model—which manifested pronounced neurodegeneration, as measured by diminished brain volume (by −15.2%, p < 0.001). Global and regional CBF in these mice were not different from those of wild-type mice (p > 0.05), suggesting normal vascular function. By contrast, in B6;SJL-Tg [APPSWE]2576Kha (APP) mice—referred to as the amyloid AD model—no brain volume reduction, as well as relatively intact brain oxygen extraction and metabolism, were found (p > 0.05). Consistent with the imaging data, behavioral measures of walking distance were impaired in Tau4RΔK mice (p = 0.004), but not in APP mice (p = 0.88). Collectively, these findings support the hypothesis that noninvasive MRI measurement of brain oxygen metabolism may be a promising biomarker of neurodegeneration in AD.
AB - Alzheimer's disease (AD) is the leading cause of cognitive impairment and dementia in elderly individuals. According to the current biomarker framework for “unbiased descriptive classification”, biomarkers of neurodegeneration, “N”, constitute a critical component in the tri-category “A/T/N” system. Current biomarkers of neurodegeneration suffer from potential drawbacks such as requiring invasive lumbar puncture, involving ionizing radiation, or representing a late, irreversible marker. Recent human studies have suggested that reduced brain oxygen metabolism may be a new functional marker of neurodegeneration in AD, but the heterogeneity and the presence of mixed pathology in human patients did not allow a full understanding of the role of oxygen extraction and metabolism in AD. In this report, global brain oxygen metabolism and related physiological parameters were studied in two AD mouse models with relatively pure pathology, using advanced MRI techniques including T2-relaxation-under-spin-tagging (TRUST) and phase contrast (PC) MRI. Additionally, regional cerebral blood flow (CBF) was determined with pseudocontinuous arterial spin labeling. Reduced global oxygen extraction fraction (by −18.7%, p = 0.008), unit-mass cerebral metabolic rate of oxygen (CMRO2) (by −17.4%, p = 0.04) and total CMRO2 (by −30.8%, p < 0.001) were observed in Tau4RΔK mice—referred to as the tau AD model—which manifested pronounced neurodegeneration, as measured by diminished brain volume (by −15.2%, p < 0.001). Global and regional CBF in these mice were not different from those of wild-type mice (p > 0.05), suggesting normal vascular function. By contrast, in B6;SJL-Tg [APPSWE]2576Kha (APP) mice—referred to as the amyloid AD model—no brain volume reduction, as well as relatively intact brain oxygen extraction and metabolism, were found (p > 0.05). Consistent with the imaging data, behavioral measures of walking distance were impaired in Tau4RΔK mice (p = 0.004), but not in APP mice (p = 0.88). Collectively, these findings support the hypothesis that noninvasive MRI measurement of brain oxygen metabolism may be a promising biomarker of neurodegeneration in AD.
KW - Alzheimer's disease
KW - TRUST
KW - arterial spin labeling
KW - cerebral blood flow
KW - cerebral metabolic rate of oxygen
KW - oxygen extraction fraction
KW - phase contrast
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U2 - 10.1002/nbm.4568
DO - 10.1002/nbm.4568
M3 - Article
C2 - 34050996
AN - SCOPUS:85106696513
SN - 0952-3480
VL - 34
JO - NMR in biomedicine
JF - NMR in biomedicine
IS - 9
M1 - e4568
ER -