Apathy is present after stroke in approximately 35% of patients based on a recent meta-analysis¹ and impacts stroke outcomes on multiple levels. It directly lowers patient interaction with family and friends, thereby worsening quality of life. Moreover, multiple studies have found that apathy is associated with worse disability and slower recovery, and generally does not improve even up to a year later^2-4. It is hypothesized that this is a behavioral representation of injury to the arousal regulation system. Recent studies have observed more conservative behavior on a gambling task in patients with apathy, and abnormal blood flow in the brain regions involved in reward processing⁵.

In this study, abnormal brain metabolism in post-stroke patients with apathy was investigated with simultaneous MRI and PET measurement. Quantitative BOLD (qBOLD) approach⁶, combined with brain perfusion measurement by pCASL-3D GRASE, provides a non-invasive measurement on cerebral metabolic rate of oxygen (CMRO₂)⁷. The MRI-derived CMRO₂ values will be correlated with metabolic rate of glucose (CMR_Glu) values measured from quantitative ¹⁸F-FDG PET. Our working hypothesis is that post-stroke apathy will lead to dysfunction in the medial prefrontal cortex by FDG-PET (reduced glucose metabolism) and MRI (reduced oxidative metabolism).

Five post-stroke patients with diagnosed apathy were recruited for this IRB-approved study. Simultaneous PET/MR quantification of brain metabolism was performed on Siemens 3T Biograph mMR with a 16-channel head RF coil. MRI parameters for 2D qBOLD were: FOV of 256x256 mm²; voxel size of 2x2x4 mm³; 5 interleaved 4 mm slices with 100% spacing; TR of 1000 ms; 4 repetitions with total acquisition time of ~8 minutes. Navigator echoes were inserted to correct B0 drifting during the scan. Pseudo-continuous ASL (pCASL) with background suppression and segmented echo-shifting 3D-GRASE acquisition was implemented⁸. The labeling time was 1600ms with a post-labeling delay of 1400ms. Other parameters for ASL sequence were: voxel size of 3x3x3 mm³; matrix of 64×48×28; 3PAR× 2PE segmentation; echo spacing of 700µs; echo train duration of 21 ms; 120^◦ refocusing RF; TR of 4 sec; total acquisition time of ~7 min (16 label/control pairs). Standard dynamic quantitative ¹⁸F-FDG-PET protocol ran simultaneously with the MRI. Two IV catheters were inserted into the subject’s upper limbs. One was used to inject no more than 5 mCi of FDG when the patient was on the PET/MR scanner table. The other was used to obtain venous blood samples to measure glucose levels at 45 mins after injection. Total PET acquisition time was 60 min.

The MR qBOLD data was processed individually before the estimated maps were averaged to calculate oxygen extraction fraction (OEF). CBF maps were calculated using the standard approach. CMRO2 was subsequently calculated as the product of CBF and OEF. Figures 1 and 2 show the CMRO2 and 18F-FDG-PET maps along with the corresponding T1w image from 2 representative subjects.

In general, oxygen and glucose metabolism show good overall agreement. The most notable differences lies in the areas of very low CMRO₂ values. Meanwhile, the FDG metabolism in these regions is reduced relatively with the surrounding brain regions, but not as significantly when compared to CMRO₂ values. This may be caused by mitochondrial dysfunction thus reduced efficiency after ischemic stroke, and potential up-regulation of the anaerobic glycolytic metabolism pathway, and/or a lack of oxygen/blood supply.

Results from subject one (Fig 1) demonstrates a good oxygen and glucose metabolism correlation within the frontal lobe but displays differences in the parietal lobe. This could be the result of vascular stenosis caused by the stroke that potentially delays the arterial arrival time, thus under-estimates the brain perfusion, and therefore under-estimates CMRO₂ measurement. Subject two (Fig 2) displays good agreement between CMRO₂ and CMR_Glu throughout both hemispheres. Both subjects show suppressed metabolic activity in the prefrontal cortex, potentially a sign of apathy. MR qBOLD-derived CMRO₂ measurements have showed good correlation with PET ¹⁸F-FDG metabolism, providing strong support for its adoption as a non-invasive mapping of brain metabolism in patients with post-stroke apathy. MR CMRO₂ and ¹⁸F-FDG-PET can complement each other and provide further insights into brain metabolism changes in post-stroke apathy patients, and patients with other neurological diseases.