Modeling diffusion of intracellular metabolites in the mouse brain up to very high diffusion-weighting: Diffusion in long fibers (almost) accounts for non-monoexponential attenuation

Purpose: To investigate how intracellular metabolites diffusion measured in vivo up to very high q/b in the mouse brain can be explained in terms of simple geometries. / Methods: 10 mice were scanned using our new STE‐LASER sequence, at 11.7 Tesla (T), up to qmax = 1 μm−1 at diffusion time td = 63.2 ms, corresponding to bmax = 60 ms/µm². We model cell fibers as randomly oriented cylinders, with radius a and intracellular diffusivity urn:x-wiley:07403194:media:mrm26548:mrm26548-math-0004, and fit experimental data as a function of q to estimate urn:x-wiley:07403194:media:mrm26548:mrm26548-math-0005 and a. / Results: Randomly oriented cylinders account well for measured attenuation, giving fiber radii and urn:x-wiley:07403194:media:mrm26548:mrm26548-math-0006 in the expected ranges (0.5–1.5 µm and 0.30–0.45 µm2/ms, respectively). The only exception is N‐acetyl‐aspartate (NAA) (extracted a∼0), which we show to be compatible with a small fraction of the NAA pool being confined in highly restricted compartments (with short T2). / Conclusion: The non‐monoexponential signal attenuation of intracellular metabolites in the mouse brain can be described by diffusion in long and thin cylinders, yielding realistic Dintra and fiber diameters. However, this simple model may require small “corrections” for NAA, in the form of a small fraction of the NAA signal originating from a highly restricted compartment

Diffusion‐weighted MR spectroscopy: Consensus, recommendations, and resources from acquisition to modeling

Brain cell structure and function reflect neurodevelopment, plasticity, and aging; and changes can help flag pathological processes such as neurodegeneration and neuroinflammation. Accurate and quantitative methods to noninvasively disentangle cellular structural features are needed and are a substantial focus of brain research. Diffusion‐weighted MRS (dMRS) gives access to diffusion properties of endogenous intracellular brain metabolites that are preferentially located inside specific brain cell populations. Despite its great potential, dMRS remains a challenging technique on all levels: from the data acquisition to the analysis, quantification, modeling, and interpretation of results. These challenges were the motivation behind the organization of the Lorentz Center workshop on “Best Practices & Tools for Diffusion MR Spectroscopy” held in Leiden, the Netherlands, in September 2021. During the workshop, the dMRS community established a set of recommendations to execute robust dMRS studies. This paper provides a description of the steps needed for acquiring, processing, fitting, and modeling dMRS data, and provides links to useful resources

Macromolecular background signal and non-Gaussian metabolite diffusion determined in human brain using ultra-high diffusion weighting.

PURPOSE Definition of a macromolecular MR spectrum based on diffusion properties rather than relaxation time differences and characterization of non-Gaussian diffusion of brain metabolites with strongly diffusion-weighted MR spectroscopy. METHODS Short echo time MRS with strong diffusion-weighting with b-values up to 25 ms/μm2 at two diffusion times was implemented on a Connectom system and applied in combination with simultaneous spectral and diffusion decay modeling. Motion-compensation was performed with a combined method based on the simultaneously acquired water and a macromolecular signal. RESULTS The motion compensation scheme prevented spurious signal decay reflected in very small apparent diffusion constants for macromolecular signal. Macromolecular background signal patterns were determined using multiple fit strategies. Signal decay corresponding to non-Gaussian metabolite diffusion was represented by biexponential fit models yielding parameter estimates for human gray matter that are in line with published rodent data. The optimal fit strategies used constraints for the signal decay of metabolites with limited signal contributions to the overall spectrum. CONCLUSION The determined macromolecular spectrum based on diffusion properties deviates from the conventional one derived from longitudinal relaxation time differences calling for further investigation before use as experimental basis spectrum when fitting clinical MR spectra. The biexponential characterization of metabolite signal decay is the basis for investigations into pathologic alterations of microstructure

Cytosolic diffusivity and microscopic anisotropy of N-acetyl aspartate in human white matter with diffusion-weighted MRS at 7 T

Metabolite diffusion measurable in humans in vivo with diffusion-weighted spectroscopy (DW-MRS) provides a window into the intracellular morphology and state of specific cell types. Anisotropic diffusion in white matter is governed by the microscopic properties of the individual cell types and their structural units (axons, soma, dendrites). However, anisotropy is also markedly affected by the macroscopic orientational distribution over the imaging voxel, particularly in DW-MRS, where the dimensions of the volume of interest (VOI) are much larger than those typically used in diffusion-weighted imaging. One way to address the confound of macroscopic structural features is to average the measurements acquired with uniformly distributed gradient directions to mimic a situation where fibers present in the VOI are orientationally uniformly distributed. This situation allows the extraction of relevant microstructural features such as transverse and longitudinal diffusivities within axons and the related microscopic fractional anisotropy. We present human DW-MRS data acquired at 7 T in two different white matter regions, processed and analyzed as described above, and find that intra-axonal diffusion of the neuronal metabolite N-acetyl aspartate is in good correspondence to simple model interpretations, such as multi-Gaussian diffusion from disperse fibers where the transverse diffusivity can be neglected. We also discuss the implications of our approach for current and future applications of DW-MRS for cell-specific measurements

Double diffusion encoding and applications for biomedical imaging

Diffusion Magnetic Resonance Imaging (dMRI) is one of the most important contemporary non-invasive modalities for probing tissue structure at the microscopic scale. The majority of dMRI techniques employ standard single diffusion encoding (SDE) measurements, covering different sequence parameter ranges depending on the complexity of the method. Although many signal representations and biophysical models have been proposed for SDE data, they are intrinsically limited by a lack of specificity. Advanced dMRI methods have been proposed to provide additional microstructural information beyond what can be inferred from SDE. These enhanced contrasts can play important roles in characterizing biological tissues, for instance upon diseases (e.g. neurodegenerative, cancer, stroke), aging, learning, and development. In this review we focus on double diffusion encoding (DDE), which stands out among other advanced acquisitions for its versatility, ability to probe more specific diffusion correlations, and feasibility for preclinical and clinical applications. Various DDE methodologies have been employed to probe compartment sizes (Section 3), decouple the effects of microscopic diffusion anisotropy from orientation dispersion (Section 4), probe displacement correlations, study exchange, or suppress fast diffusing compartments (Section 6). DDE measurements can also be used to improve the robustness of biophysical models (Section 5) and study intra-cellular diffusion via magnetic resonance spectroscopy of metabolites (Section 7). This review discusses all these topics as well as important practical aspects related to the implementation and contrast in preclinical and clinical settings (Section 9) and aims to provide the readers a guide for deciding on the right DDE acquisition for their specific application

Diffusion-weighted MRS and MRI : methods and neuro applications

Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) can play a key role in understanding neurobiological mechanisms of diseases that affect the human brain. The specific changes that occur within neurons can be reflected as changes in the diffusivity of tNAA, whereas the changes in glial cells can cause pronounced changes in the diffusivities of tCr and tCho. This information combined with that obtained from diffusion tensor imaging (DTI) and other MRI tools can help elucidate various disease processes in the future. The main purposes of this thesis are (i) to investigate neuroanatomy in vivo with DW-MRS, (ii) to develop methodology to enable future clinical applications of the technique in human brain in vivo, and (iii) to characterize the microstructural deficit in neuropsychiatric systemic lupus erythematous (NPSLE) with DW-MRS and other microstructural tools such as DTI and magnetization transfer imaging. The studies presented in this thesis show the robustness and clinical relevance of microstructural information obtained via DW-MRS. The contributions of this thesis such as the optimized acquisition protocols for single volume DW-MRS, the robust DW-CSI and DW-MRS post-processing pipelines that comprise information from DTI, will all facilitate the applications of DW-MRS both for basic neuroscience research and clinical research studies.UBL - phd migration 201

Microstructural imaging of the human brain with a 'super-scanner': 10 key advantages of ultra-strong gradients for diffusion MRI

The key component of a microstructural diffusion MRI 'super-scanner' is a dedicated high-strength gradient system that enables stronger diffusion weightings per unit time compared to conventional gradient designs. This can, in turn, drastically shorten the time needed for diffusion encoding, increase the signal-to-noise ratio, and facilitate measurements at shorter diffusion times. This review, written from the perspective of the UK National Facility for In Vivo MR Imaging of Human Tissue Microstructure, an initiative to establish a shared 300 mT/m-gradient facility amongst the microstructural imaging community, describes ten advantages of ultra-strong gradients for microstructural imaging. Specifically, we will discuss how the increase of the accessible measurement space compared to a lower-gradient systems (in terms of Δ, b-value, and TE) can accelerate developments in the areas of 1) axon diameter distribution mapping; 2) microstructural parameter estimation; 3) mapping micro-vs macroscopic anisotropy features with gradient waveforms beyond a single pair of pulsed-gradients; 4) multi-contrast experiments, e.g. diffusion-relaxometry; 5) tractography and high-resolution imaging in vivo and 6) post mortem; 7) diffusion-weighted spectroscopy of metabolites other than water; 8) tumour characterisation; 9) functional diffusion MRI; and 10) quality enhancement of images acquired on lower-gradient systems. We finally discuss practical barriers in the use of ultra-strong gradients, and provide an outlook on the next generation of 'super-scanners'

Development of Translational Imaging Biomarkers in Mouse Models of Huntington's Disease

Huntington’s disease (HD) is a genetic neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene that results in movement disorders and cognitive and psychiatric decline. To better track disease onset and progression, biomarkers that precede irreversible structural changes are needed. Alterations in metabolic processes detectable using magnetic resonance imaging (MRI) and other MR approaches may provide such biomarkers but need characterisation in HD mouse models to improve their clinical translatability. The aim of this thesis was to develop imaging biomarkers in transgenic R6/2 and knock-in zQ175 mice, two commonly used HD mouse models. To undertake the most comprehensive time-course analyses of metabolite concentrations in these models so far, proton magnetic resonance spectroscopy (1H-MRS) was acquired in selected brain regions throughout disease progression. Significant metabolic alterations were observed in zQ175 and R6/2 mice, with fluctuations at early disease stages. These changes suggested diminished neuronal integrity and reactive gliosis, which were confirmed using histology. Brain regions also exhibited specific metabolic profiles, many of said profiles being observed across both mouse models (albeit with some discrepancies). Chemical Exchange Saturation Transfer (CEST), which ought to overcome the limited sensitivity of 1H-MRS, was also acquired. However, we show CEST is not sensitive to HD pathology and do not recommend it for biomarker development in HD. Lastly, we acquired diffusion-weighted MRS (DW-MRS) in zQ175 mice to assess the diffusion of metabolites confined to cell-specific compartments. We found no changes in metabolite diffusion properties, but given the experimental nature of the protocol we used, DW-MRS needs further investigation in the context of HD. Overall, we have moved the field of HD forward by evaluating in detail the metabolic consequences of the disease in two mouse models that are widely used to investigate HD pathogenesis and evaluate therapeutic targets

Brain putamen volume changes in newly-diagnosed patients with obstructive sleep apnea.

Obstructive sleep apnea (OSA) is accompanied by cognitive, motor, autonomic, learning, and affective abnormalities. The putamen serves several of these functions, especially motor and autonomic behaviors, but whether global and specific sub-regions of that structure are damaged is unclear. We assessed global and regional putamen volumes in 43 recently-diagnosed, treatment-naïve OSA (age, 46.4 ± 8.8 years; 31 male) and 61 control subjects (47.6 ± 8.8 years; 39 male) using high-resolution T1-weighted images collected with a 3.0-Tesla MRI scanner. Global putamen volumes were calculated, and group differences evaluated with independent samples t-tests, as well as with analysis of covariance (covariates; age, gender, and total intracranial volume). Regional differences between groups were visualized with 3D surface morphometry-based group ratio maps. OSA subjects showed significantly higher global putamen volumes, relative to controls. Regional analyses showed putamen areas with increased and decreased tissue volumes in OSA relative to control subjects, including increases in caudal, mid-dorsal, mid-ventral portions, and ventral regions, while areas with decreased volumes appeared in rostral, mid-dorsal, medial-caudal, and mid-ventral sites. Global putamen volumes were significantly higher in the OSA subjects, but local sites showed both higher and lower volumes. The appearance of localized volume alterations points to differential hypoxic or perfusion action on glia and other tissues within the structure, and may reflect a stage in progression of injury in these newly-diagnosed patients toward the overall volume loss found in patients with chronic OSA. The regional changes may underlie some of the specific deficits in motor, autonomic, and neuropsychologic functions in OSA