Currently, multiple sclerosis is treated with anti-inflammatory therapies, but these treatments lack efficacy in progressive disease. New treatment strategies aim to repair myelin damage and efficacy evaluation of such new therapies would benefit from validated myelin imaging techniques. Several MRI methods for quantification of myelin density are available now. This systematic review aims to analyse the performance of these MRI methods. Studies comparing myelin quantification by MRI with histology, the current gold standard, or assessing reproducibility were retrieved from PubMed/MEDLINE and Embase (until December 2019). Included studies assessed both myelin histology and MRI quantitatively. Correlation or variance measurements were extracted from the studies. Non-parametric tests were used to analyse differences in study methodologies. The search yielded 1348 unique articles. Twenty-two animal studies and 13 human studies correlated myelin MRI with histology. Eighteen clinical studies analysed the reproducibility. Overall bias risk was low or unclear. All MRI methods performed comparably, with a mean correlation between MRI and histology of R2=0.54 (SD=0.30) for animal studies, and R2=0.54 (SD=0.18) for human studies. Reproducibility for the MRI methods was good (ICC=0.75-0.93, R2=0.90-0.98, COV=1.3-27%), except for MTR (ICC=0.05-0.51). Overall, MRI-based myelin imaging methods show a fairly good correlation with histology and a good reproducibility. However, the amount of validation data is too limited and the variability in performance between studies is too large to select the optimal MRI method for myelin quantification yet.

Myelin is the protective sheath wrapped around axons, consisting of a phospholipid bilayer with water between the wraps. The measurement of damage to the myelin sheaths, the evaluation of the efficacy of therapies aiming to promote remyelination and monitoring the degree of brain maturation in children all require non-invasive quantitative myelin imaging methods. To date, various myelin imaging techniques have been developed. Five different MRI approaches can be distinguished based on their biophysical principles: (i) imaging of the water between the lipid bilayers directly (e.g. myelin water imaging); (ii) imaging the non-aqueous protons of the phospholipid bilayer directly with ultra-short echo-time techniques; (iii) indirect imaging of the macromolecular content (e.g. magnetization transfer; inhomogeneous magnetization transfer); (iv) mapping of the effects of the myelin sheath’s magnetic susceptibility on the MRI signal (e.g. quantitative susceptibility mapping); and (v) mapping of the effects of the myelin sheath on water diffusion. Myelin imaging with PET uses radioactive molecules with high affinity to specific myelin components, in particular myelin basic protein. This review aims to give an overview of the various myelin imaging techniques, their biophysical principles, image acquisition, data analysis and their validation status.

Off-target binding in the choroid plexus (CP) may cause spill-in of the tau PET tracer [18F] flortaucipir into the adjacent hippocampus region. The impact of this spill-in on hippocampal uptake was assessed using a novel partial volume correction method (PVC). PVC was performed on 20 [18F] flortaucipir dynamic PET scans (10 probable AD and 10 controls). Volumes of interest (VOIs) were defined for both hippocampus and CP. The correlation between hippocampal and CP distribution volume (VT), with and without PVC, was determined. Both anatomically defined and eroded VOIs were used. For controls, the correlation between hippocampal and CP VT was significantly reduced after using PVC along with an eroded VOI (r2 = 0.59, slope = 0.80 versus r2 = 0.15, slope = 0.15; difference: p < 0.05). The same was true for AD patients (p < 0.05). PVC together with an optimized hippocampal VOI resulted in effective reduction of CP spill-in and improved accuracy of hippocampal VT.

Neuronal damage is the primary cause of long-term disability of multiple sclerosis (MS) patients. Assessment of axonal integrity from diffusion MRI parameters might enable better disease characterisation. 16 diffusion derived measurements from diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and fixel-based analysis (FBA) in lesions, peri-lesion and normal appearing white matter were investigated. Diffusion MRI scans of 11 MS patients were processed to generate DTI, DKI, and FBA images. Fractional anisotropy (FA) and fibre density (FD) were used to assess axonal integrity across brain regions. Subsequently, 359 lesions were identified, and lesion and peri-lesion segmentation was performed using structural T₁w, T₂w, T₂w-FLAIR, and T₁w post-contrast MRI. The segmentations were then used to extract 16 diffusion MRI parameters from lesion, peri-lesion, and contralateral normal appearing white matter (NAWM). The measurements for axonal integrity, DTI-FA, DKI-FA, FBA-FD, produced similar results. All diffusion MRI parameters were affected in lesions as compared to NAWM (p < 0.001), confirming loss of axonal integrity in lesions. In peri-lesions, most parameters, except FBA-FD, were also significantly different from NAWM, although the effect size was smaller than in lesions. The reduction in axonal integrity in peri-lesions, despite unaffected fibre density estimates, suggests an effect of Wallerian degeneration.

Multiple sclerosis (MS) is an inflammatory demyelinating disease. Current treatments are focussed on immune suppression to modulate pathogenic activity that causes myelin damage. New treatment strategies are needed to prevent demyelination and promote remyelination. Development of such myelin repair therapies require a sensitive and specific biomarker for efficacy evaluation. Recently, it has been shown that quantification of myelin density is possible using [¹¹C]MeDAS PET. This method, however, requires arterial blood sampling to generate an arterial input function (AIF). As the invasive nature of arterial sampling will reduce clinical applicability, the purpose of this study was to assess whether an image-derived input function (IDIF) can be used as an alternative way to facilitate its routine clinical use. Six healthy controls and 11 MS patients underwent MRI and [¹¹C]MeDAS PET with arterial blood sampling. The application of both population-based whole blood-to-plasma conversion and metabolite corrections were assessed for the AIF. Next, summed images of the early time frames (0-70 s) and the frame with the highest blood-brain contrast were used to generate IDIFs. IDIFs were created using either the hottest 2, 4, 6 or 12 voxels, or an isocontour of the hottest 10% voxels of the carotid artery. This was followed by blood-to-plasma conversion and metabolite correction of the IDIF. The application of a population-based metabolite correction of the AIF resulted in high correlations of tracer binding (K_i) within subjects, but variable bias across subjects. All IDIFs had a sharper and higher peak in the blood curves than the AIF, most likely due to dispersion during blood sampling. All IDIF methods resulted in similar high correlations within subjects (r = 0.95-0.98), but highly variable bias across subjects (mean slope=0.90-1.09). Therefore, both the use of population based blood-plasma and metabolite corrections and the generation of the image-derived whole-blood curve resulted in substantial bias in [¹¹C]MeDAS PET quantification, due to high inter-subject variability. Consequently, when unbiased quantification of [¹¹C]MeDAS PET data is required, individual AIF needs to be used.

Purpose: Estrogen receptors (ER) are implicated in psychiatric disorders. We assessed if ER availability in the human brain could be quantified using 16α-[¹⁸F]-fluoro-17β-estradiol ([¹⁸F]FES) positron emission tomography (PET). Procedures: Seven post‑menopausal women underwent a dynamic [¹⁸F]FES PET scan with arterial blood sampling. A T1-weighted MRI was acquired for anatomical information. After one week, four subjects received a selective ER degrader (SERD), four hours before the PET scan. Pharmacokinetic analysis was performed using a metabolite-corrected plasma curve as the input function. The optimal kinetic model was selected based on the Akaike information criterion and standard error of estimated parameters. Accuracy of Logan graphical analysis and standardized uptake value (SUV) was determined via correlational analyses. Results: The reversible two-tissue compartment model (2T4k) model with fixed K₁/k₂ was preferred. The total volume of distribution (V_T) could be more reliably estimated than the binding potential (BP_ND). A high correlation of V_T with Logan graphical analysis was observed, but only a moderate correlation with SUV. SERD administration resulted in a reduced V_T in the pituitary gland, but not in other regions. Conclusions: The optimal quantification method for [¹⁸F]FES was the 2T4k with fixed K₁/k₂ or Logan graphical analysis, but specific binding was only observed in the pituitary gland.