Altered Brain Energy Metabolism Related to Astrocytes in Alzheimer's Disease

Kosei Hirata; Kiwamu Matsuoka; Kenji Tagai; Hironobu Endo; Harutsugu Tatebe; Maiko Ono; Naomi Kokubo; Asaka Oyama; Hitoshi Shinotoh; Keisuke Takahata; Takayuki Obata; Masoumeh Dehghani; Jamie Near; Kazunori Kawamura; Ming-Rong Zhang; Hitoshi Shimada; Takanori Yokota; Takahiko Tokuda; Makoto Higuchi; Yuhei Takado

doi:10.1002/ana.26797

Altered Brain Energy Metabolism Related to Astrocytes in Alzheimer's Disease

Ann Neurol. 2023 Sep 13. doi: 10.1002/ana.26797. Online ahead of print.

Authors

Kosei Hirata^{1

2}, Kiwamu Matsuoka¹, Kenji Tagai¹, Hironobu Endo¹, Harutsugu Tatebe¹, Maiko Ono^{1

3}, Naomi Kokubo¹, Asaka Oyama¹, Hitoshi Shinotoh^{1

4}, Keisuke Takahata¹, Takayuki Obata⁵, Masoumeh Dehghani⁶, Jamie Near^{6

7}, Kazunori Kawamura⁸, Ming-Rong Zhang⁸, Hitoshi Shimada^{1

9}, Takanori Yokota², Takahiko Tokuda¹, Makoto Higuchi¹, Yuhei Takado^{1

3}

Affiliations

¹ Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba, Japan.
² Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Tokyo, Japan.
³ Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, Chiba, Japan.
⁴ Neurology Clinic Chiba, Chiba, Japan.
⁵ Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba, Japan.
⁶ Physical Sciences, Sunnybrook Research Institute, Toronto, Canada.
⁷ Department of Medical Biophysics, University of Toronto, Toronto, Canada.
⁸ Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba, Japan.
⁹ Center for Integrated Human Brain Science, Brain Research Institute, Niigata University, Niigata, Japan.

PMID: 37703428
DOI: 10.1002/ana.26797

Abstract

Objective: Increasing evidence suggests that reactive astrocytes are associated with Alzheimer's disease (AD). However, its underlying pathogenesis remains unknown. Given the role of astrocytes in energy metabolism, reactive astrocytes may contribute to altered brain energy metabolism. Astrocytes are primarily considered glycolytic cells, suggesting a preference for lactate production. This study aimed to examine alterations in astrocytic activities and their association with brain lactate levels in AD.

Methods: The study included 30 AD and 30 cognitively unimpaired participants. For AD participants, amyloid and tau depositions were confirmed by positron emission tomography using [¹¹ C]PiB and [¹⁸ F]florzolotau, respectively. Myo-inositol, an astroglial marker, and lactate in the posterior cingulate cortex were quantified by magnetic resonance spectroscopy. These magnetic resonance spectroscopy metabolites were compared with plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker, and amyloid and tau positron emission tomography.

Results: Myo-inositol and lactate levels were higher in AD patients than in cognitively unimpaired participants (p < 0.05). Myo-inositol levels correlated with lactate levels (r = 0.272, p = 0.047). Myo-inositol and lactate levels were positively associated with the Clinical Dementia Rating sum-of-boxes scores (p < 0.05). Significant correlations were noted between myo-inositol levels and plasma glial fibrillary acidic protein, tau phosphorylated at threonine 181 levels, and amyloid and tau positron emission tomography accumulation in the posterior cingulate cortex (p < 0.05).

Interpretation: We found high myo-inositol levels accompanied by increased lactate levels in the posterior cingulate cortex in AD patients, indicating a link between reactive astrocytes and altered brain energy metabolism. Myo-inositol and plasma glial fibrillary acidic protein may reflect similar astrocytic changes as biomarkers of AD. ANN NEUROL 2023.

Abstract

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