Myriam M. Chaumeil

Introduction: Cerebral small vessel disease (cSVD) is a leading cause of stroke and vascular contributions to cognitive impairment and dementia (VCID). Studying monogenic forms of cSVD can elucidate molecular pathways that are dysfunctional in the common sporadic forms and may serve as potential therapeutic targets. Mutations in COL4A1 and COL4A2 cause highly penetrant cSVD as part of the multisystem disorder known as Gould syndrome, which includes cerebrovascular manifestations such as porencephaly, early-onset stroke, leukoencephalopathy, and intracerebral hemorrhage (ICH). Methods: To investigate how allelic heterogeneity influences cerebrovascular phenotypes, we examined five Col4a1 mutant mouse strains that collectively model the clinical spectrum of Gould syndrome. Each strain underwent multimodal magnetic resonance imaging (MRI) at 14.1 Tesla to assess radiological features characteristic of cSVD. Results: Multimodal MRI successfully identified typical cSVD-associated lesions across all Col4a1 mutant strains. The imaging revealed heterogeneous expressivity among the allelic variants in terms of lesion prevalence, size, and number. Furthermore, analysis across strains identified brain regions that were consistently more vulnerable to cSVD-related lesions. Discussion: These findings demonstrate that high-field multimodal MRI can sensitively detect and differentiate cerebrovascular abnormalities among Col4a1 mutant mouse models of Gould syndrome. The approach provides a powerful, noninvasive platform for assessing genotype–phenotype relationships and for identifying brain regions at heightened risk in cSVD, supporting its potential use in early diagnosis and mechanistic studies of vascular pathology.

Career athletes, active military, and head trauma victims are at increased risk for mild repetitive traumatic brain injury (rTBI), a condition that contributes to the development of epilepsy and neurodegenerative diseases. Standard clinical imaging fails to identify rTBI-induced lesions, and novel non-invasive methods are needed. Here, we evaluated if hyperpolarized 13C magnetic resonance spectroscopic imaging (HP 13C MRSI) could detect long-lasting changes in brain metabolism 3.5 months post-injury in a rTBI mouse model. Our results show that this metabolic imaging approach can detect changes in cortical metabolism at that timepoint, whereas multimodal MR imaging did not detect any structural or contrast alterations. Using Machine Learning, we further show that HP 13C MRSI parameters can help classify rTBI vs. Sham and predict long-term rTBI-induced behavioral outcomes. Altogether, our study demonstrates the potential of metabolic imaging to improve detection, classification and outcome prediction of previously undetected rTBI.

The positron emission tomography (PET) tracer 2-deoxy-2-[¹⁸F]fluoroglucose ([¹⁸F]FDG) is widely used to study diseases where glucose metabolism is dysregulated, including cancer and neurodegenerative disorders. Here we investigate the hypothesis that the 2-position deuterium-enriched analogue 2-deoxy-2-[²H₂]-d-glucose (2-DG-d2) can also map glucose uptake using deuterium metabolic imaging (DMI) without ionizing radiation. To accomplish this, we used a spectrally selective multiband radiofrequency pulse and balanced steady-state free procession (bSSFP) technique, enabling rapid ²H imaging with high specificity and sensitivity to 2-DG-d2. Both in vitro and in vivo validations demonstrated the sequence's ability to suppress endogenous water signal. Mapping of 2-DG-d2 with high spatial resolution was achieved in healthy mouse brains, comparable to what might be obtained using [¹⁸F]FDG PET. The numerous applications of [¹⁸F]FDG PET, as well as recent clinical translation of the natural abundance 2-deoxy-d-glucose (2-DG) parent sugar, suggest that DMI using 2-DG-d2 may be applied to patients in the future.

Brown and brown-like adipose tissues have attracted significant attention for their role in metabolism and therapeutic potential in diabetes and obesity. Despite compelling evidence of an interplay between adipocytes and lymphocytes, the involvement of these tissues in immune responses remains largely unexplored. This study explicates a newfound connection between neuroinflammation and brown- and bone marrow adipose tissue. Leveraging the use of [¹⁸F]F-AraG, a mitochondrial metabolic tracer capable of tracking activated lymphocytes and adipocytes simultaneously, we demonstrate, in models of glioblastoma and multiple sclerosis, the correlation between intracerebral immune infiltration and changes in brown- and bone marrow adipose tissue. Significantly, we show initial evidence that a neuroinflammation-adipose tissue link may also exist in humans. This study proposes the concept of an intricate immuno-neuro-adipose circuit, and highlights brown- and bone marrow adipose tissue as an intermediary in the communication between the immune and nervous systems. Understanding the interconnectedness within this circuitry may lead to advancements in the treatment and management of various conditions, including cancer, neurodegenerative diseases and metabolic disorders.

Hyperpolarization techniques significantly enhance the sensitivity of magnetic resonance (MR) and thus present fascinating new directions for research and applications with in vivo MR imaging and spectroscopy (MRI/S). Hyperpolarized ¹³C MRI/S, in particular, enables real-time non-invasive assessment of metabolic processes and holds great promise for a diverse range of clinical applications spanning fields like oncology, neurology, and cardiology, with a potential for improving early diagnosis of disease, patient stratification, and therapy response assessment. Despite its potential, technical challenges remain for achieving clinical translation. This paper provides an overview of the discussions that took place at the international workshop “New Horizons in Hyperpolarized ¹³C MRI,” in March 2023 at the Bavarian Academy of Sciences and Humanities, Munich, Germany. The workshop covered new developments, as well as future directions, in topics including polarization techniques (particularly focusing on parahydrogen-based methods), novel probes, considerations related to data acquisition and analysis, and emerging clinical applications in oncology and other fields.

Neurovascular coupling (NVC), a vital physiological process that rapidly and precisely directs localized blood flow to the most active regions of the brain, is accomplished in part by the vast network of cerebral capillaries acting as a sensory web capable of detecting increases in neuronal activity and orchestrating the dilation of upstream parenchymal arterioles. Here, we report a Col4a1 mutant mouse model of cerebral small vessel disease (cSVD) with age-dependent defects in capillary-to-arteriole dilation, functional hyperemia in the brain, and memory. The fundamental defect in aged mutant animals was the depletion of the minor membrane phospholipid phosphatidylinositol 4,5 bisphosphate (PIP ₂ ) in brain capillary endothelial cells, leading to the loss of inwardly rectifying K ⁺ (Kir2.1) channel activity. Blocking phosphatidylinositol-3-kinase (PI3K), an enzyme that diminishes the bioavailability of PIP ₂ by converting it to phosphatidylinositol (3, 4, 5)-trisphosphate (PIP ₃ ), restored Kir2.1 channel activity, capillary-to-arteriole dilation, and functional hyperemia. In longitudinal studies, chronic PI3K inhibition also improved the memory function of aged Col4a1 mutant mice. Our data suggest that PI3K inhibition is a viable therapeutic strategy for treating defective NVC and cognitive impairment associated with cSVD.

Career athletes, active military, and head trauma victims are at increased risk for mild repetitive traumatic brain injury (rTBI), a condition that contributes to the development of epilepsy and neurodegenerative diseases. Standard clinical imaging fails to identify rTBI-induced lesions, and novel non-invasive methods are needed. Here, we evaluated if hyperpolarized ¹³C magnetic resonance spectroscopic imaging (HP ¹³C MRSI) could detect long-lasting changes in brain metabolism 3.5 months post-injury in a rTBI mouse model. Our results show that this metabolic imaging approach can detect changes in cortical metabolism at that timepoint, whereas multimodal MR imaging did not detect any structural or contrast alterations. Using Machine Learning, we further show that HP ¹³C MRSI parameters can help classify rTBI vs. Sham and predict long-term rTBI-induced behavioral outcomes. Altogether, our study demonstrates the potential of metabolic imaging to improve detection, classification and outcome prediction of previously undetected rTBI.

Background: In recent years, the ability of conventional magnetic resonance imaging (MRI), including T₁ contrast-enhanced (CE) MRI, to monitor high-efficacy therapies and predict long-term disability in multiple sclerosis (MS) has been challenged. Therefore, non-invasive methods to improve MS lesions detection and monitor therapy response are needed. Methods: We studied the combined cuprizone and experimental autoimmune encephalomyelitis (CPZ-EAE) mouse model of MS, which presents inflammatory-mediated demyelinated lesions in the central nervous system as commonly seen in MS patients. Using hyperpolarized ¹³C MR spectroscopy (MRS) metabolic imaging, we measured cerebral metabolic fluxes in control, CPZ-EAE and CPZ-EAE mice treated with two clinically-relevant therapies, namely fingolimod and dimethyl fumarate. We also acquired conventional T₁ CE MRI to detect active lesions, and performed ex vivo measurements of enzyme activities and immunofluorescence analyses of brain tissue. Last, we evaluated associations between imaging and ex vivo parameters. Results: We show that hyperpolarized [1-¹³C]pyruvate conversion to lactate is increased in the brain of untreated CPZ-EAE mice when compared to the control, reflecting immune cell activation. We further demonstrate that this metabolic conversion is significantly decreased in response to the two treatments. This reduction can be explained by increased pyruvate dehydrogenase activity and a decrease in immune cells. Importantly, we show that hyperpolarized ¹³C MRS detects dimethyl fumarate therapy, whereas conventional T₁ CE MRI cannot. Conclusions: In conclusion, hyperpolarized MRS metabolic imaging of [1-¹³C]pyruvate detects immunological responses to disease-modifying therapies in MS. This technique is complementary to conventional MRI and provides unique information on neuroinflammation and its modulation.