Distinct Variations in Metabolites, Neurotransmitters, and pH Between Two Stroke Models Suggested by Chemical Exchange Saturation Transfer (CEST) MRI
Abstract Body: Introduction: During acute ischemic stroke, energy depletion leads to a rise in creatine (Cr) as a buffer, increased extracellular glutamate from impaired neurotransmitter transport, and a pH drop due to lactic acid buildup. Understanding these changes is crucial for timely intervention, yet no current method captures all these alterations simultaneously. CEST, a novel MRI technique, non-invasively maps metabolites with high sensitivity, providing information on both concentration and pH. Our group recently demonstrated guanidino CEST (GuanCEST) at 3T, reflecting Cr levels, while amine CEST (amineCEST) at 9.4T likely indicates glutamate, and amide CEST (amideCEST) correlates with pH. We aim to use these techniques to investigate metabolic, neurotransmitter, and pH changes in two mouse models of middle cerebral artery occlusion (MCAO).
Methods: Ten male C57BL/6 mice (aged 3–6 months) were used for two stroke models: permanent MCAO (pMCAO, n=4) and transient MCAO (tMCAO, n=4). MRI scans were conducted at 9.4T and 3T. Diffusion-weighted imaging identified stroke lesions, followed by T1 and T2 mapping on the selected slice. CEST scans were performed with a 2s saturation time across B1 values ranging from 0.4 to 3.0 μT. We utilized Polynomial and Lorentzian Line-shape Fitting (PLOF) to simultaneously extract GuanCEST, amineCEST, and amideCEST from the CEST spectrum at each pixel, generating corresponding CEST maps. The average CEST values in the lesion and contralateral hemisphere were analyzed.
Results: At a B1 of 0.4 μT, GuanCEST (Fig. 1, red line) increased by 1.01±0.19% in pMCAO compared to the contralateral hemisphere but decreased by 0.32±0.27% in tMCAO, indicating a greater Cr rise in pMCAO. At higher B1, Cr effects diminished while pH effects increased. When B1 exceeded 0.8 μT, amineCEST increased by 3.86±0.42% in tMCAO, nearly four times the rise in pMCAO (1.09±0.26%), possibly reflecting neurotransmitter changes due to cell membrane polarization and energy depletion. At 1.6 μT, amideCEST decreased by 0.53±0.05% in pMCAO but remained stable in tMCAO (0.49±0.48%), suggesting greater tissue acidification in pMCAO. Similar trends were observed at 3T, except amineCEST was undetectable.
Conclusion: CEST MRI is a non-invasive technique capable of mapping metabolite, neurotransmitter, and pH changes in the stroke-affected brain, with strong potential for clinical translation.
Wang, Kexin
( Johns Hopkins University
, Baltimore
, Maryland
, United States
)
Dawson, Valina
( INSTITUTE CELL ENGINEERING JHU
, Baltimore
, Maryland
, United States
)
Dawson, Ted
( JOHNS HOPKINS UNIVERSITY SCH MED
, Baltimore
, Maryland
, United States
)
Walczak, Piotr
( University of Maryland School of Medicine
, Baltimore
, Maryland
, United States
)
Xu, Jiadi
( Kennedy Krieger Research Institute
, Baltimore
, Maryland
, United States
)
Ju, Licheng
( Kennedy Krieger Research Institute
, Baltimore
, Maryland
, United States
)
Qiao, Guanda
( University of Maryland School of Medicine
, Baltimore
, Maryland
, United States
)
Liang, Yajie
( University of Maryland School of Medicine
, Baltimore
, Maryland
, United States
)
Wu, Yihan
( Johns Hopkins University
, Baltimore
, Maryland
, United States
)
Chu, Chengyan
( University of Maryland School of Medicine
, Baltimore
, Maryland
, United States
)
Rogers, Joshua
( University of Maryland School of Medicine
, Baltimore
, Maryland
, United States
)
Li, Yuguo
( Kennedy Krieger Research Institute
, Baltimore
, Maryland
, United States
)
Cao, Suyi
( Johns Hopkins University
, Baltimore
, Maryland
, United States
)
Author Disclosures:
Kexin Wang:DO NOT have relevant financial relationships
| Valina Dawson:DO NOT have relevant financial relationships
| Ted Dawson:DO have relevant financial relationships
;
Advisor:Fortess Biotech Inc:Active (exists now)
; Research Funding (PI or named investigator):Sun Pharma Advanced Research:Past (completed)
; Individual Stocks/Stock Options:D & D Pharmatech:Active (exists now)
; Ownership Interest:Valted, LLC:Active (exists now)
; Individual Stocks/Stock Options:American Gene Technologies International Inc:Past (completed)
; Other (please indicate in the box next to the company name):Valted Seq Inc., Board of Directors:Active (exists now)
; Individual Stocks/Stock Options:Zomagen Biosciences Ltd.:Active (exists now)
; Advisor:Zomagen Biosciences Ltd.:Active (exists now)
; Individual Stocks/Stock Options:Inhibikase Therapeutics Inc:Active (exists now)
; Advisor:Inhibikase Therapeutics Inc:Active (exists now)
; Individual Stocks/Stock Options:Aevum Therapeutics, Inc:Active (exists now)
; Research Funding (PI or named investigator):Aevum Therapeutics, Inc:Active (exists now)
; Royalties/Patent Beneficiary:Aevum Therapeutics, Inc:Active (exists now)
; Advisor:Aevum Therapeutics, Inc:Active (exists now)
; Individual Stocks/Stock Options:Fortess Biotech Inc:Active (exists now)
| Piotr Walczak:DO have relevant financial relationships
;
Ownership Interest:Ti-com:Active (exists now)
; Ownership Interest:Intraart :Active (exists now)
| Jiadi Xu:No Answer
| Licheng Ju:DO NOT have relevant financial relationships
| Guanda Qiao:No Answer
| Yajie Liang:No Answer
| Yihan Wu:No Answer
| Chengyan Chu:DO NOT have relevant financial relationships
| Joshua Rogers:DO NOT have relevant financial relationships
| Yuguo Li:No Answer
| Suyi Cao:No Answer