APPswe/PS1dE9 mice with cortical amyloid pathology show a reduced NAA/Cr ratio without apparent brain atrophy: A MRS and MRI study

Kuhla, Angela; Rühlmann, C; Lindner, Tobias; Polei, Stefan; Hadlich, Stefan; Krause, Bernd J.; Vollmar, Brigitte; Teipel, Stefan J.

doi:10.1016/j.nicl.2017.06.009

Cited by 18 publications

(16 citation statements)

References 44 publications

(58 reference statements)

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“…NAA, as a representative metabolite of neuronal integrity, is found to be reduced in AD, indicating neuronal malfunction either due to diminished neuronal density, neuronal cell loss, or partially reversible neuronal dysfunction [ 45 ], and correlates with disease progression [ 46 ]. Further, APP/PS1 mice also show significantly decreased NAA to Cr ratio [ 28 , 45 , 47 ], which was also observed in the present study. Upon long-term CR, NAA/Cr ratios were increased, reaching the same values as those found in wt mice, indicating improved neuronal integrity.…”

Section: Discussionsupporting

confidence: 89%

“…Brain tissue was fixed in 4% phosphate-buffered formalin, embedded in paraffin and sliced in 4 µm-thin sections. The sections were put on X-tra Adhesive Precleaned Micro Slides (Leica, Wetzlar, Germany) and exposed to mouse monoclonal anti-Aβ antibody (clone 6E10; 1:1000, BioLegend, San Diego, CA, USA, as described by the authors of [ 28 ]) and goat polyclonal anti-iba1 antibody (1:1000, Abcam, Berlin, Germany). DAB chromogen Universal LSAB ® kits (System-HRP; DakoCytomation, Dako, Jena, Germany) were used for development according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

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Long-Term Caloric Restriction Attenuates β-Amyloid Neuropathology and Is Accompanied by Autophagy in APPswe/PS1delta9 Mice

et al. 2021

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Caloric restriction (CR) slows the aging process, extends lifespan, and exerts neuroprotective effects. It is widely accepted that CR attenuates β-amyloid (Aβ) neuropathology in models of Alzheimer’s disease (AD) by so-far unknown mechanisms. One promising process induced by CR is autophagy, which is known to degrade aggregated proteins such as amyloids. In addition, autophagy positively regulates glucose uptake and may improve cerebral hypometabolism—a hallmark of AD—and, consequently, neural activity. To evaluate this hypothesis, APPswe/PS1delta9 (tg) mice and their littermates (wild-type, wt) underwent CR for either 16 or 68 weeks. Whereas short-term CR for 16 weeks revealed no noteworthy changes of AD phenotype in tg mice, long-term CR for 68 weeks showed beneficial effects. Thus, cerebral glucose metabolism and neuronal integrity were markedly increased upon 68 weeks CR in tg mice, indicated by an elevated hippocampal fluorodeoxyglucose [18F] ([18F]FDG) uptake and increased N-acetylaspartate-to-creatine ratio using positron emission tomography/computer tomography (PET/CT) imaging and magnet resonance spectroscopy (MRS). Improved neuronal activity and integrity resulted in a better cognitive performance within the Morris Water Maze. Moreover, CR for 68 weeks caused a significant increase of LC3BII and p62 protein expression, showing enhanced autophagy. Additionally, a significant decrease of Aβ plaques in tg mice in the hippocampus was observed, accompanied by reduced microgliosis as indicated by significantly decreased numbers of iba1-positive cells. In summary, long-term CR revealed an overall neuroprotective effect in tg mice. Further, this study shows, for the first time, that CR-induced autophagy in tg mice accompanies the observed attenuation of Aβ pathology.

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Section: Discussionsupporting

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Long-Term Caloric Restriction Attenuates β-Amyloid Neuropathology and Is Accompanied by Autophagy in APPswe/PS1delta9 Mice

et al. 2021

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“…A recent study by Mitolo et al (2019) found that a combination of the ratio of NAA/myoinositol (ml) and the volume of parahippocampal gyrus could improve the overall accuracy of predicting the conversion to AD 2 years before the occurrence of clinical symptoms. The study by Kuhla et al (2017) has shown that based on the MRI morphology and MRS-based NAA evaluation, APPswe/PS1dE9 mice showed an increase in Aβ plaques, a loss of neurons, and an impairment of the NAA/Cr ratio, but no brain atrophy. It was found that the change of NAA as a functional marker rather than the change in volume was more obvious.…”

Section: Introductionmentioning

confidence: 99%

A Pilot Study on the Cutoff Value of Related Brain Metabolite in Chinese Elderly Patients With Mild Cognitive Impairment Using MRS

Zhao

Teng

Mai

et al. 2021

Front. Aging Neurosci.

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Objective: This cross-sectional study aimed to distinguish patients with mild cognitive impairment (MCI) from patients with normal controls (NCs) by measuring the levels of N-acetyl aspartate (NAA), total creatinine (tCr), and choline (Cho) in their hippocampus (HIP) and their posterior cingulate gyrus (PCG) by using proton magnetic resonance spectroscopy (MRS) and to predict the cutoff value on the ratios of metabolites. We further aimed to provide a reference for the diagnosis of MCI in elderly patients in China.Methods: About 69 patients who underwent a clinical diagnosis of the MCI group and 67 patients with NCs, the Mini-Mental Status Examination (MMSE) score, the Montreal Cognitive Assessment (MoCA) score, and MRS of the bilateral HIP and bilateral PCG were considered. The ratio of NAA/tCr and Cho/tCr in the bilateral HIP and bilateral PCG was calculated. The relationship between the ratios of metabolites and the scores of MMSE and MoCA was analyzed, and the possible brain metabolite cutoff point for the diagnosis of MCI was evaluated.Results: Compared with the NC group, the scores of MMSE and MoCA in the MCI group decreased significantly (p < 0.05); the ratio of NAA/tCr in the bilateral HIP and bilateral PCG and the ratio of Cho/tCr at the right HIP in the MCI group decreased significantly (p < 0.05); however, there was no significant difference in the ratio of Cho/tCr in the left HIP and bilateral PCG between the two groups (p > 0.05). The correlation coefficient between MMSE/MoCA and the ratio of NAA/tCr was 0.49–0.56 in the bilateral HIP (p < 0.01). The best cutoff value of NAA/creatine (Cr) in the left HIP and the right HIP was 1.195 and 1.19. Sensitivity, specificity, and the Youden index (YDI) in the left HIP and the right HIP were (0.725, 0.803, 0.528) and (0.754, 0.803, 0.557), respectively.Conclusion: The level of metabolites in the HIP and the PCG of patients with MCI and of those with normal subjects has a certain correlation with the score of their MMSE and MoCA. When the value of NAA/tCr in the left HIP and right HIP is <1.19, it suggests that MCI may have occurred. According to this cutoff point, elderly patients with MCI in China could be screened.

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“…MRS spectrum was derived from voxel of interest and was visualized via jMRUI. As previously described by Kuhla et al [30], spectra were analyzed with the spectroscopy package. Metabolite ratios were calculated based on the area under the corresponding fitted curves for N-Acetylaspartate (NAA 2.0 ppm) and creatine (Cr 3.0 ppm).…”

Section: Mr Spectroscopymentioning

confidence: 99%

Longitudinal [18F]FDG-PET/CT analysis of the glucose metabolism in ApoE-deficient mice

et al. 2020

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Background Strong line of evidence suggests that the increased risk to develop AD may at least be partly mediated by cholesterol metabolism. A key regulator of cholesterol transport is the Apolipoprotein E4 (ApoE4), which plays a fundamental role in neuronal maintenance and repair. Impaired function of ApoE4 may contribute to altered cerebral metabolism leading to higher susceptibility to neurodegeneration. Methods To determine a possible link between ApoE function and alterations in AD in the brain of Apolipoprotein E-deficient mice (ApoE−/−) in a longitudinal manner metabolic and neurochemical parameters were analyzed. Cortical metabolism was measured by 2-deoxy-2-[18F]fluoroglucose ([18F]FDG)-PET/CT and proton magnetic resonance spectroscopy (1H-MRS) served to record neurochemical status. Results By using [18F]FDG-PET/CT, we showed that brain metabolism declined significantly stronger with age in ApoE−/− versus wild type (wt) mice. This difference was particularly evident at the age of 41 weeks in almost each analyzed brain region. In contrast, the 1H-MRS-measured N-acetylaspartate to creatine ratio, a marker of neuronal viability, did not decline with age and did not differ between ApoE−/− and wt mice. Conclusion In summary, this longitudinal in vivo study shows for the first time that ApoE−/− mice depict cerebral hypometabolism without neurochemical alterations.

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APPswe/PS1dE9 mice with cortical amyloid pathology show a reduced NAA/Cr ratio without apparent brain atrophy: A MRS and MRI study

Cited by 18 publications

References 44 publications

Long-Term Caloric Restriction Attenuates β-Amyloid Neuropathology and Is Accompanied by Autophagy in APPswe/PS1delta9 Mice

Long-Term Caloric Restriction Attenuates β-Amyloid Neuropathology and Is Accompanied by Autophagy in APPswe/PS1delta9 Mice

A Pilot Study on the Cutoff Value of Related Brain Metabolite in Chinese Elderly Patients With Mild Cognitive Impairment Using MRS

Longitudinal [18F]FDG-PET/CT analysis of the glucose metabolism in ApoE-deficient mice

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