In Vivo Assessment of Astrocyte Reactivity in Patients with Progressive Supranuclear Palsy.

OBJECTIVE: Although astrocytic pathology is a pathological hallmark of progressive supranuclear palsy (PSP), its pathophysiological role remains unclear. This study aimed to assess astrocyte reactivity in vivo in patients with PSP. Furthermore, we investigated alterations in brain lactate levels and their relationship with astrocyte reactivity. METHODS: We included 30 patients with PSP-Richardson syndrome and 30 healthy controls; in patients, tau deposition was confirmed through 18F-florzolotau positron emission tomography. Myo-inositol, an astroglial marker, and lactate were quantified in the anterior cingulate cortex through magnetic resonance spectroscopy. We measured plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker. The anterior cingulate cortex was histologically assessed in postmortem samples of another 3 patients with PSP with comparable disease durations. RESULTS: The levels of myo-inositol and plasma glial fibrillary acidic protein were significantly higher in patients than those in healthy controls (p < 0.05); these increases were significantly associated with PSP rating scale and cognitive function scores (p < 0.05). The lactate level was high in patients, and correlated significantly with high myo-inositol levels. Histological analysis of the anterior cingulate cortex in patients revealed reactive astrocytes, despite mild tau deposition, and no marked synaptic loss. INTERPRETATION: We discovered high levels of astrocyte biomarkers in patients with PSP, suggesting astrocyte reactivity. The association between myo-inositol and lactate levels suggests a link between reactive astrocytes and brain energy metabolism changes. Our results indicate that astrocyte reactivity in the anterior cingulate cortex precedes pronounced tau pathology and neurodegenerative processes in that region, and affects brain function in PSP. ANN NEUROL 2024;96:247-261.

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

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.

Hadamard-encoded dual-voxel SPECIAL: Short-TE MRS acquired in two brain regions simultaneously using Hadamard encoding.

PURPOSE: The spin-echo, full-intensity acquired localized (SPECIAL) sequence is a method for single-voxel, localized MRS in vivo with short TEs. In this study we modified the SPECIAL sequence to simultaneously record spectra from two volumes of interest. This new technique is called Hadamard-encoded dual-voxel SPECIAL (HD-SPECIAL). METHODS: The SPECIAL sequence consists of a spin echo localized to a column of tissue, preceded by a slice-selective inversion pulse in alternating scans to invert a section of the column. Full localization is achieved by subtraction of the inversion-on scans from the inversion-off scans. In HD-SPECIAL, the two-step inversion scheme is replaced by a four-step Hadamard-encoded scheme involving single-band and dual-band inversion pulses to select two regions of the spin-echo column. By appropriate Hadamard combination of the four acquired shots, spectra can be reconstructed from both desired regions. This approach does not rely on parallel imaging reconstruction. Using a 3T scanner, HD-SPECIAL localization is demonstrated both in phantoms and in the human brain in vivo, and the performance of HD-SPECIAL is assessed by comparing with the conventional SPECIAL sequence. RESULTS: Phantom and in vivo measurements show excellent agreement between measures from HD-SPECIAL and SPECIAL sequences. Relative to consecutive SPECIAL measurements from two regions, HD-SPECIAL reduces the total scan time 2-fold with minimal penalty in terms of spectral quality or SNR. CONCLUSION: The HD-SPECIAL sequence enables reliable acquisition of MR spectra simultaneously from two regions at 3 T, offering the potential to study interregional variations in metabolite concentrations.

Longitudinal quantification of metabolites and macromolecules reveals age- and sex-related changes in the healthy Fischer 344 rat brain.

Normal aging is associated with numerous biological changes, including altered brain metabolism and tissue chemistry. In vivo characterization of the neurochemical profile during aging is possible using magnetic resonance spectroscopy, a powerful noninvasive technique capable of quantifying brain metabolites involved in physiological processes that become impaired with age. A prominent macromolecular signal underlies those of brain metabolites and is particularly visible at high fields; parameterization of this signal into components improves quantification and expands the number of biomarkers comprising the neurochemical profile. The present study reports, for the first time, the simultaneous absolute quantification of brain metabolites and individual macromolecules in aging male and female Fischer 344 rats, measured longitudinally using proton magnetic resonance spectroscopy at 7 T. We identified age- and sex-related changes in neurochemistry, with prominent differences in metabolites implicated in anaerobic energy metabolism, antioxidant defenses, and neuroprotection, as well as numerous macromolecule changes. These findings contribute to our understanding of the neurobiological processes associated with healthy aging, critical for the proper identification and management of pathologic aging trajectories. This article is part of the Virtual Special Issue titled COGNITIVE NEUROSCIENCE OF HEALTHY AND PATHOLOGICAL AGING. The full issue can be found on ScienceDirect athttps://www.sciencedirect.com/journal/neurobiology-of-aging/special-issue/105379XPWJP.

Dynamic 1 H-MRS for detection of 13 C-labeled glucose metabolism in the human brain at 3T.

PURPOSE: In 2004, Boumezbeur et al proposed a simple yet powerful approach to detect the metabolism of 13 C-enriched substrates in the brain. Their approach consisted of dynamic 1 H-MRS, without a 13 C radiofrequency (RF) channel, and its successful application was demonstrated in monkeys. Since then, this promising method has yet to be applied rigorously in humans. In this study, we revisit the use of dynamic 1 H-MRS to measure the metabolism of 13 C-enriched substrates and demonstrate its application in the human brain. METHODS: In healthy participants, 1 H-MRS data were acquired dynamically before and following a bolus infusion of [1-13 C] glucose. Data were acquired on a 3T clinical MRI scanner using a short-TE SPECIAL sequence, with regions of interest in both anterior and posterior cingulate cortex. Using simulated basis spectra to model signal changes in both 12 C-bonded and 13 C-coupled resonances, the acquired spectra were fit in LCModel to obtain labeling time courses for glutmate and glutamine at both C4 and C3 positions. RESULTS: Presence of the 13 C label was clearly detectable, owing to the pronounced effect of heteronuclear (13 C-1 H) scalar coupling on the observed 1 H spectra. A decrease in signal from 12 C-bonded protons and an increase in signal from 13 C-coupled protons were observed. The fractional enrichment of Glu-C4, (Glu+Gln)-C4, and (Glu+Gln)-C3 at 30 minutes following infusion of [1-13 C] glucose was similar in both regions: 11% to 13%, 9% to 12% and 3% to 5%, respectively. CONCLUSION: These preliminary results confirm the feasibility of the use of dynamic 1 H-MRS to monitor 13 C labeling in the human brain, without a 13 C RF channel.

Lactate measurement by neurochemical profiling in the dorsolateral prefrontal cortex at 7T: accuracy, precision, and relaxation times.

PURPOSE: This assesses the potential of measuring lactate in the human brain using three non-editing MRS methods at 7T and compares the accuracy and precision of the methods. METHODS: 1 H MRS data were measured in the right dorsolateral prefrontal cortex using a semi-adiabatic spin-echo full-intensity acquired localized sequence with three different protocols: (I) TE = 16 ms, (II) TE = 110 ms, and (III) TE = 16 ms, TI = 300 ms. T1 and T2 relaxation times of lactate were also measured. Simulated spectra were generated for three protocols with known concentrations, using a range of spectral linewidths and SNRs to assess the effect of data quality on the measurement precision and accuracy. RESULTS: Lactate was quantified in all three protocols with mean Cramér-Rao lower bound of 8% (I), 13% (II), and 7% (III). The T1 and T2 relaxation times of lactate were 1.9 ± 0.2 s and 94 ± 13 ms, respectively. Simulations predicted a spectral linewidth-associated underestimation of lactate measurement. Simulations, phantom and in vivo results showed that protocol II was most affected by this underestimation. In addition, the estimation error was insensitive to a broad range of spectral linewidth with protocol I. Within-session coefficient of variances of lactate were 6.1 ± 7.9% (I), 22.3 ± 12.3% (II), and 5.1 ± 5.4% (III), respectively. CONCLUSION: We conclude that protocols I and III have the potential to measure lactate at 7T with good reproducibility, whereas the measurement accuracy and precision depend on spectral linewidth and SNR, respectively. Moreover, simulation is valuable for the optimization of measurement protocols in future study design and the correction for measurement bias.

Diffusion behavior of cerebral metabolites of congenital portal systemic shunt mice assessed noninvasively by diffusion-weighted 1 H magnetic resonance spectroscopy.

Diffusion-weighted 1 H-MRS (DW-MRS) allows for noninvasive investigation of the cellular compartmentalization of cerebral metabolites. DW-MRS applied to the congenital portal systemic shunt (PSS) mouse brain may provide specific insight into alterations of cellular restrictions associated with PSS in humans. At 14.1 T, adult male PSS and their age-matched healthy (Ctrl) mice were studied using DW-MRS covering b-values ranging from 0 to 45 ms/µm2 to determine the diffusion behavior of abundant metabolites. The remarkable sensitivity and spectral resolution, in combination with very high diffusion weighting, allowed for precise measurement of the diffusion properties of endogenous N-acetyl-aspartate, total creatine, myo-inositol, total choline with extension to glutamine and glutamate in mouse brains, in vivo. Most metabolites had comparable diffusion properties in PSS and Ctrl mice, suggesting that intracellular distribution space for these metabolites was not affected in the model. The slightly different diffusivity of the slow decaying component of taurine (0.015 ± 0.003 µm2 /ms in PSS vs 0.021 ± 0.002 µm2 /ms in Ctrl, P < 0.05) might support a cellular redistribution of taurine in the PSS mouse brain.

Diffusion-weighted MRS of acetate in the rat brain.

Acetate has been proposed as an astrocyte-specific energy substrate for metabolic studies in the brain. The determination of the relative contribution of the intracellular and extracellular compartments to the acetate signal using diffusion-weighted magnetic resonance spectroscopy can provide an insight into the cellular environment and distribution volume of acetate in the brain. In the present study, localized 1 H nuclear magnetic resonance (NMR) spectroscopy employing a diffusion-weighted stimulated echo acquisition mode (STEAM) sequence at an ultra-high magnetic field (14.1 T) was used to investigate the diffusivity characteristics of acetate and N-acetylaspartate (NAA) in the rat brain in vivo during prolonged acetate infusion. The persistence of the acetate resonance in 1 H spectra acquired at very large diffusion weighting indicated restricted diffusion of acetate and was attributed to intracellular spaces. However, the significantly greater diffusion of acetate relative to NAA suggests that a substantial fraction of acetate is located in the extracellular space of the brain. Assuming an even distribution for acetate in intracellular and extracellular spaces, the diffusion properties of acetate yielded a smaller volume of distribution for acetate relative to water and glucose in the rat brain.