Decreased pH in the mouse brain of Alzheimer’s disease revealed by guanidinium and amide CEST at 3T
Research output: Conference Papers › RGC 32 - Refereed conference paper (without host publication) › peer-review
Author(s)
Related Research Unit(s)
Detail(s)
Original language | English |
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Publication status | Published - 6 Jun 2023 |
Conference
Title | 2023 International Society for Magnetic Resonance in Medicine Annual Meeting & Exhibition (ISMRM 2023) |
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Location | Metro Toronto Convention Centre (MTCC) |
Place | Canada |
City | Toronto |
Period | 3 - 8 June 2023 |
Link(s)
Permanent Link | https://scholars.cityu.edu.hk/en/publications/publication(33810019-b271-4cb0-8e2f-b0cabfdc9429).html |
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Abstract
Purpose
Alzheimer’s disease (AD) is one of the greatest health concerns accompanying the worldwide aging society, while the early detection is a tough challenge partly due to the unknown mechanism of AD. Acidification or decreased pH is universally acknowledged in AD (1, 2), and a recent study (3) has pointed out that the faulty autolysosome acidification leads to amyloid beta deposition, which is a distinguished hallmark for AD. Therefore, it is very promising to detect the early sign of AD by measuring the pH decrease of the brain. GuanCEST goes up and amide CEST goes down at the decline of pH at low B in vivo, and the (unitless)difference of them should be a sensitive detector for small pH change if two signals are acquired precisely. Furthermore, the difference signal can exclude the possible contaminations from protein aggregation and B variation. Polynomial and Lorentzian line-shape fitting (PLOF) (4-7) fulfills such strict requirement, and it has been shown the (unitless) difference in AD mice compared with WT mice is significantly higher.
Methods
Ten 11-month AD model mice (5xFAD) and ten age-matched wild type (WT) mice were scanned on a horizontal bore 3T Bruker BioSpec system (Bruker, Ettlingen, Germany) with an 82 mm quadrature volume resonator. Continuous-wave (CW) saturation with B of 0.6 µT and saturation time of 3 s is followed by the rapid acquisition with refocused echoes (RARE) readout with RARE factor of 32 and TR of 5 s. The FOV is18 × 18 mm and the matrix size is 96 × 96 with a thickness of 2 mm.
With the PLOF method (8), firstly the background is fitted by a polynomial function R in the corresponding rotating-frame relaxation spectrum (R-spectrum) in two ranges together (0.5~1.1 ppm & 5.0~8.2ppm). Then with the background fixed, the GuanCEST and amideCEST are fitted simultaneously by the sum of R (R ), which includes R and Lorentzian functions for Guan (R ) and amide (R ) on the remaining data dots (1.1~5.0 ppm) (Fig. 1a).
Difference of GuanCEST and amideCEST is defined as (GuanCEST – amideCEST), while the unitless difference is (GuanCEST – amideCEST)/(GuanCEST + amideCEST). One-sided two-sample t-test is performed.
Results and Discussion
Z-spectrum extracted from central brain slice are used for the PLOF fitting (Fig. 1b), and it is notable that averagely AD mice have higher GuanCEST (purple arrow in Fig.1a&b) and lower amide CEST (green arrow in Fig.1a&b) compared with WT mice. Decomposition into R and R shows clearer evidence that AD mice have higher R and lower R compared with WT mice (Fig. 1c). Typical MR images of both AD and WT mouse brain are demonstrated in Fig. 2a~b, together with the derived GuanCEST map (Fig. 2c~d), amide CEST map (Fig. 2e~f), R map (Fig. 2c~d), and R map (Fig. 2e~f) in the form of heat map.
It shows an averagely warmer GuanCEST map and colder amide CEST map for AD mice.Since a low B of 0.6 µT has been used, the exchange rate of GuanCEST is above its Rabi frequency, therefore the intensity of GuanCEST is negatively correlated to the exchange rate, i.e., pH (9-12). Similarly, as the exchange rate of amide CEST is below its Rabi frequency, it is proportional to pH, as verified in literature (8). Notably, the aggregation of protein may also lead to decrease of amideCEST, but it would decrease the GuanCEST as well (13), which is contradictory to our experimental findings here. Therefore, the elevated GuanCEST is solid evidence confirming the pH decline in AD, which cannot be verified by amideCESTalone. The opposite response in GuanCEST and amideCEST to the change of pH is utilized collectively to detect the pH discrepancy and statistical results show a significant higher difference (Fig. 3a: p=0.011) inAD mice compared with WT mice. Unitless difference shows a smaller p=0.008 (Fig. 3b), which may be more appropriate as it considers individual baseline difference by a denominator of the sum of relevant GuanCEST and amideCEST. Both metrics show a significant pH decrease in AD mouse brain, coinciding with previous studies. More importantly, as revealed by a recent study on the AD mechanism that the failure of acidification in autolysosome may result in build-up of amyloid beta and plaques, and the consequential rupture of malfunctioned autolysosome will release contents at an acidic pH of 4.5~5 (3).Neuroinflammation also produces some immunogenic molecules triggering the immune system, which may decrease the pH but not impact the function of brain at an early stage of dementia (14). As the change in pH happens much before the clinical symptom of AD, the suggested CEST-based pH indicator, i.e., the unitless difference between GuanCEST and amideCEST, is promising to become a sign and standard of early AD.
Conclusion
PLOF is applied to extract GuanCEST and amideCEST simultaneously, and the (unitless) difference of them is significantly higher in AD mice compared with WT mice at 3T, indicating a pH decline in AD mouse brain. The results support recent explanations of the onset of AD as a failure of autolysosome, which leads to a decreased pH. Therefore, we bring up a novel idea to measure cerebral pH noninvasively, which is also a promising early indicator of AD.
Alzheimer’s disease (AD) is one of the greatest health concerns accompanying the worldwide aging society, while the early detection is a tough challenge partly due to the unknown mechanism of AD. Acidification or decreased pH is universally acknowledged in AD (1, 2), and a recent study (3) has pointed out that the faulty autolysosome acidification leads to amyloid beta deposition, which is a distinguished hallmark for AD. Therefore, it is very promising to detect the early sign of AD by measuring the pH decrease of the brain. GuanCEST goes up and amide CEST goes down at the decline of pH at low B in vivo, and the (unitless)difference of them should be a sensitive detector for small pH change if two signals are acquired precisely. Furthermore, the difference signal can exclude the possible contaminations from protein aggregation and B variation. Polynomial and Lorentzian line-shape fitting (PLOF) (4-7) fulfills such strict requirement, and it has been shown the (unitless) difference in AD mice compared with WT mice is significantly higher.
Methods
Ten 11-month AD model mice (5xFAD) and ten age-matched wild type (WT) mice were scanned on a horizontal bore 3T Bruker BioSpec system (Bruker, Ettlingen, Germany) with an 82 mm quadrature volume resonator. Continuous-wave (CW) saturation with B of 0.6 µT and saturation time of 3 s is followed by the rapid acquisition with refocused echoes (RARE) readout with RARE factor of 32 and TR of 5 s. The FOV is18 × 18 mm and the matrix size is 96 × 96 with a thickness of 2 mm.
With the PLOF method (8), firstly the background is fitted by a polynomial function R in the corresponding rotating-frame relaxation spectrum (R-spectrum) in two ranges together (0.5~1.1 ppm & 5.0~8.2ppm). Then with the background fixed, the GuanCEST and amideCEST are fitted simultaneously by the sum of R (R ), which includes R and Lorentzian functions for Guan (R ) and amide (R ) on the remaining data dots (1.1~5.0 ppm) (Fig. 1a).
Difference of GuanCEST and amideCEST is defined as (GuanCEST – amideCEST), while the unitless difference is (GuanCEST – amideCEST)/(GuanCEST + amideCEST). One-sided two-sample t-test is performed.
Results and Discussion
Z-spectrum extracted from central brain slice are used for the PLOF fitting (Fig. 1b), and it is notable that averagely AD mice have higher GuanCEST (purple arrow in Fig.1a&b) and lower amide CEST (green arrow in Fig.1a&b) compared with WT mice. Decomposition into R and R shows clearer evidence that AD mice have higher R and lower R compared with WT mice (Fig. 1c). Typical MR images of both AD and WT mouse brain are demonstrated in Fig. 2a~b, together with the derived GuanCEST map (Fig. 2c~d), amide CEST map (Fig. 2e~f), R map (Fig. 2c~d), and R map (Fig. 2e~f) in the form of heat map.
It shows an averagely warmer GuanCEST map and colder amide CEST map for AD mice.Since a low B of 0.6 µT has been used, the exchange rate of GuanCEST is above its Rabi frequency, therefore the intensity of GuanCEST is negatively correlated to the exchange rate, i.e., pH (9-12). Similarly, as the exchange rate of amide CEST is below its Rabi frequency, it is proportional to pH, as verified in literature (8). Notably, the aggregation of protein may also lead to decrease of amideCEST, but it would decrease the GuanCEST as well (13), which is contradictory to our experimental findings here. Therefore, the elevated GuanCEST is solid evidence confirming the pH decline in AD, which cannot be verified by amideCESTalone. The opposite response in GuanCEST and amideCEST to the change of pH is utilized collectively to detect the pH discrepancy and statistical results show a significant higher difference (Fig. 3a: p=0.011) inAD mice compared with WT mice. Unitless difference shows a smaller p=0.008 (Fig. 3b), which may be more appropriate as it considers individual baseline difference by a denominator of the sum of relevant GuanCEST and amideCEST. Both metrics show a significant pH decrease in AD mouse brain, coinciding with previous studies. More importantly, as revealed by a recent study on the AD mechanism that the failure of acidification in autolysosome may result in build-up of amyloid beta and plaques, and the consequential rupture of malfunctioned autolysosome will release contents at an acidic pH of 4.5~5 (3).Neuroinflammation also produces some immunogenic molecules triggering the immune system, which may decrease the pH but not impact the function of brain at an early stage of dementia (14). As the change in pH happens much before the clinical symptom of AD, the suggested CEST-based pH indicator, i.e., the unitless difference between GuanCEST and amideCEST, is promising to become a sign and standard of early AD.
Conclusion
PLOF is applied to extract GuanCEST and amideCEST simultaneously, and the (unitless) difference of them is significantly higher in AD mice compared with WT mice at 3T, indicating a pH decline in AD mouse brain. The results support recent explanations of the onset of AD as a failure of autolysosome, which leads to a decreased pH. Therefore, we bring up a novel idea to measure cerebral pH noninvasively, which is also a promising early indicator of AD.
Research Area(s)
- Alzheimer's Disease, CEST & MT, pH mapping
Citation Format(s)
Decreased pH in the mouse brain of Alzheimer’s disease revealed by guanidinium and amide CEST at 3T. / Wang, Kexin; Huang, Jianpan; Zhang, Ziqin et al.
2023. Paper presented at 2023 International Society for Magnetic Resonance in Medicine Annual Meeting & Exhibition (ISMRM 2023), Toronto, Ontario, Canada.
2023. Paper presented at 2023 International Society for Magnetic Resonance in Medicine Annual Meeting & Exhibition (ISMRM 2023), Toronto, Ontario, Canada.
Research output: Conference Papers › RGC 32 - Refereed conference paper (without host publication) › peer-review