Search

While glia are increasingly implicated in the pathophysiology of psychiatric and neurodegenerative disorders, available methods for imaging these cells in vivo involve either invasive procedures or positron emission tomography radiotracers, which afford low resolution and specificity. Here, we present a noninvasive diffusion-weighted magnetic resonance imaging (MRI) method to image changes in glia morphology. Using rat models of neuroinflammation, degeneration, and demyelination, we demonstrate that diffusion-weighted MRI carries a fingerprint of microglia and astrocyte activation and that specific signatures from each population can be quantified noninvasively. The method is sensitive to changes in glia morphology and proliferation, providing a quantitative account of neuroinflammation, regardless of the existence of a concomitant neuronal loss or demyelinating injury. We prove the translational value of the approach showing significant associations between MRI and histological microglia markers in humans. This framework holds the potential to transform basic and clinical research by clarifying the role of inflammation in health and disease., S.D.S. was supported by the European Research Council through a Marie Skłodowska-Curie Individual Fellowship (grant no. 749506) and by the Generalitat Valenciana through a Subvencion a la Excelencia de Juniors Investigadores (SEJI/2019/038) and a Subvencion para la contratación de investigadoras e investigadores doctores de excelencia (CIDEGENT/2021/015). S.C. was supported by the Spanish Agency of Research (AEI) under the grant PGC2018-101055-B-I00, cofinanced by the European Regional Development Fund (ERDF), the Generalitat Valenciana through the program Prometeo/2019/015, and the European Union Horizon 2020 research and innovation program under grant 668863 (SyBil-AA). S.D.S. and S.C. also acknowledge financial support from the Spanish State Research Agency through the Severo Ochoa Program for Centres of Excellence in R&D (SEV-2017-0723). The human data were acquired at the UK National Facility for In Vivo MR Imaging of Human Tissue Microstructure funded by the EPSRC (grant EP/M029778/1) and The Wolfson Foundation. D.K.J. is supported by a Wellcome Trust Investigator Award (096646/Z/11/Z) and a Wellcome Trust Strategic Award (104943/Z/14/Z).

Axonal degeneration is a central pathological feature of neurodegenerative pathologies and is closely associated with irreversible clinical disability. Current noninvasive methods to detect axonal damage in vivo are limited in their specificity, clinical applicability, and lack of proper validation. We aimed to validate an MRI framework based on multicompartment modeling of the diffusion-weighted signal (AxCaliber) in rats in the presence of axonal pathology, achieved through injection of a neurotoxin damaging the neuronal terminal of axons. We then applied the same MRI protocol to map axonal integrity in the whole brain of multiple sclerosis relapsing-remitting patients and age-matched healthy controls, a pathology associated with a neurodegenerative component.AxCaliber is sensitive to microstructural axonal damage in rats, as demonstrated by a significant increase in the mean axonal caliber along the target tract, which correlated with the neurotoxin neurofilament staining. In humans, we uncovered a diffuse increase in mean axonal caliber in multiple sclerosis lesions and, importantly, in most areas of the normal-appearing white matter. Our results demonstrate that axonal diameter mapping is a sensitive and specific imaging biomarker able to link noninvasive imaging contrasts with the underlying biological substrate, supporting the key role of generalized axonal damage useful in diseases such as multiple sclerosis.