Background

Alterations in brain metabolism and mitochondrial bioenergetics are prominent features in Alzheimer’s disease (AD). However, due to limited methods to non-invasively image mitochondrial metabolism, our understanding of the interplay between AD pathology, mitochondrial bioenergetics, and genetic risk factors contributing to AD remains incomplete. We investigated whether an innovative MR method to detect metabolic fluxes in real-time, namely hyperpolarized ¹³C MR spectroscopy(HP ¹³C MRS), could detect glycolytic and oxidative (mitochondria) metabolism changes in a mouse model of tauopathy.

Methods

We used tauopathy mice expressing P301S-tau and human-APOE4 (TE4, n=23), and mice expressing human-APOE4 (E4, n=24). Mice were scanned prior to pathology onset (2 months (M)), and at advanced pathology (11–13M). HP ¹³C MRS data from the brain were collected using a 3T MR system after HP [1-¹³C]pyruvate (Pyr) injection. HP Pyr, [1-¹³C]lactate (Lac) and [¹³C]bicarbonate (Bic) levels were calculated. T₁w post-gadolinium injection and T₂w MRI data were acquired on a 9.4T scanner to assess blood-brain-barrier (BBB) integrity and neurodegeneration.

Results

Following injection, HP Pyr is converted into Lac and Bic and informs on glycolytic and oxidative (mitochondria) metabolism, respectively. HP Pyr, Lac and Bic were observed in the brains of E4 and TE4 mice. Pyr delivery and Lac production were unchanged between E4 and TE4 mice. In contrast, Bic levels, Bic/Pyr and Bic/Lac ratios were decreased in TE4 compared to E4 mice at 11-13M old, but not at 2M, demonstrating impaired oxidative metabolism in the tauopathy model at an advanced pathology stage.

T₂w MR images confirmed smaller hippocampal and increased ventricle volume in TE4 mice at 11-13M but not at 2M. T₁w MRI revealed hyperintensities indicative of BBB leakage in the hippocampus of 11-13M TE4 mice.

Conclusions

This is the first report of HP ¹³C MRS in a tauopathy model, revealing brain oxidative (mitochondria) metabolism impairment at an advanced pathology stage, aligning with mitochondrial changes reported in AD. Our findings add to the growing evidence suggesting that HP ¹³C MRS has considerable clinical potential, and may provide a new non-invasive way to examine mitochondrial alterations during AD pathogenesis and aid new treatment development.