Brain metabolism in tau and amyloid mouse models of Alzheimer's disease: An MRI study

Abstract

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.

Neuroimaging of Mouse Models of Alzheimer’s Disease

“…The rTg4510 transgenic mouse, an increasingly popular AD model, reported severe hippocampal and neocortical atrophy with concomitant increased ventricles [ 137 ], where females had larger volume decrements than males and both sexes were reduced significantly compared to WT [ 138 ]. Other AD mouse models, such as ApoE4 (24 months), Tau4RDeltaK and Tg4–42 mice, also exhibited significant hippocampal and whole brain volume decrements [ 139 , 140 , 141 ].…”

“…The decreased CBF in 12-month-old TgCRND8 mice was confirmed and reflected by reduced glucose metabolism without changes in cerebral blood volume [ 88 ]. Finally, the Tau4RDeltaK mouse model showed no change in CBF, which the authors ascribed to normal vascular function despite reduced global oxygen extraction fraction and cerebral metabolic rate [ 140 ].…”

Magnetic Resonance Imaging in Tauopathy Animal Models

“… Kindler et al (2021) showed a comparable cortical and hippocampal CBF between pR5 mice and wild-type mice at 10 and 18 months of age. Wei et al (2021) reported a reduced cerebral metabolic rate of oxygen while preserving CBF in Tau4RΔK (Tau) mice at 12 months of age compared with wild-type mice by using T 2 relaxation under spin tagging, phase contrast, and ASL MRI. For cerebral vascular response quantification, pulsed ASL and pseudocontinuous ASL methods have been utilized.…”

“…Wei et al (2021) reported a reduced cerebral metabolic rate of oxygen while preserving CBF in Tau4R K (Tau) mice at 12 months of age compared with wild-type mice by using T 2 relaxation under spin tagging, phase contrast, and ASL MRI.…”

Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

“…5×FAD mice [135] MRS TgF344 rats [132] J20 mice [109] APP/PS1 mice [121][122][123][124][125][126] 5×FAD mice [130] 3×Tg mice [129] APPswe mice [127,128]. APP/PS2/Tau mice [131] TASTPM mice [131,167] APP/PS1 mice [105,125,164,168,236] McGill-R-Thy1-APP rats [162] mice [250,251] APP-Au mice [252] 3×Tg mice [93,165,253] APPswe mice [244] APP/PS1KI mice [166] APP/TTA mice [254] DKI APP/PS1 mice [184] 3×Tg mice [188] qMTI APPswe mice [178] DTI TgF344 rats [183] APPswe mice [175,178,186,255] PDAPP mice [176] App NL-G-F knock-in mice [72] APP/PS1 mice [123,171,179,187,189,256] APP23 ...…”