Chronic active multiple sclerosis lesions, characterized by a hyperintense rim of iron-enriched, activated microglia and macrophages, have been linked to greater tissue damage. Post-mortem studies have determined that chronic active lesions are primarily related to the later stages of multiple sclerosis; however, the occurrence of these lesions, and their relationship to earlier disease stages may be greatly underestimated. Detection of chronic active lesions across the patient spectrum of multiple sclerosis requires a validated imaging tool to accurately identify lesions with persistent inflammation. Quantitative susceptibility mapping provides efficient in vivo quantification of susceptibility changes related to iron deposition and the potential to identify lesions harbouring iron-laden inflammatory cells. The PET tracer 11 C-PK11195 targets the translocator protein expressed by activated microglia and infiltrating macrophages. Accordingly, this study aimed to validate that lesions with a hyperintense rim on quantitative susceptibility mapping from both relapsing and progressive patients demonstrate a higher level of innate immune activation as measured on 11 C-PK11195 PET. Thirty patients were enrolled in this study, 24 patients had relapsing remitting multiple sclerosis, six had progressive multiple sclerosis, and all patients had concomitant MRI with a gradient echo sequence and PET with 11 C-PK11195. A total of 406 chronic lesions were detected, and 43 chronic lesions with a hyperintense rim on quantitative susceptibility mapping were identified as rim + lesions. Susceptibility (relative to CSF) was higher in rim + (2.42 AE 17.45 ppb) compared to rimÀ lesions (À14.6 AE 19.3 ppb, P 5 0.0001). Among rim + lesions, susceptibility within the rim (20.04 AE 14.28 ppb) was significantly higher compared to the core (À5.49 AE 14.44 ppb, P 5 0.0001), consistent with the presence of iron. In a mixed-effects model, 11 C-PK11195 uptake, representing activated microglia/macrophages, was higher in rim + lesions compared to rimÀ lesions (P = 0.015). Validating our in vivo imaging results, multiple sclerosis brain slabs were imaged with quantitative susceptibility mapping and processed for immunohistochemistry. These results showed a positive translocator protein signal throughout the expansive hyperintense border of rim + lesions, which co-localized with iron containing CD68 + microglia and macrophages. In conclusion, this study provides evidence that suggests that a hyperintense rim on quantitative susceptibility measure within a chronic lesion is a correlate for persistent inflammatory activity and that these lesions can be identified in the relapsing patients. Utilizing quantitative susceptibility measure to differentiate chronic multiple sclerosis lesion subtypes, especially chronic active lesions, would provide a method to assess the impact of these lesions on disease progression.

Purpose To develop and measure the reproducibility of 4-min whole brain myelin water fraction (MWF) mapping using fast acquisition with spiral trajectory and T2prep (FAST-T2) sequence at 3T. Methods Experiments were performed on phantoms, 13 volunteers, and 16 patients with multiple sclerosis. MWF maps were extracted using a spatially constrained non-linear algorithm. The proposed adiabatic modified BIR-4 (mBIR-4) T2prep was compared with the conventional composite T2prep (COMP). The effect of reducing the number of echo times (TEs) from 15 to 6 (reducing scan time from 10 to 4 min) was evaluated. Reproducibility was assessed using correlation analysis, coefficient of variation (COV), and Bland–Altman plots. Results Compared with COMP, mBIR-4 provided more accurate T2 in phantoms and better MWF maps in human brains. Reducing the number of TEs had a negligible effect on MWF map quality, with a regional MWF difference of <0.8%. Regional MWFs obtained by repeated scans showed excellent correlation (R = 0.99), low COV (1.3%–2.4%), and negligible bias within ±1% limits of agreement. On a voxel-wise basis, the agreement remained strong (correlation R = 0.89 ± 0.03, bias = 0.01% ± 0.29%, limits of agreement = [−3.35% ± 0.73%, 3.33% ± 0.61%]). Conclusion Whole brain MWF mapping with adiabatic FAST-T2 is feasible in 4 min and provides good intrasite reproducibility.

Growing evidence suggests that a "prion-like" mechanism underlies the pathogenesis of many neurodegenerative disorders, including Parkinson's disease (PD). We extend and tailor previously developed quantitative and predictive network diffusion model (NDM) to PD, by specifically modeling the trans-neuronal spread of alpha-synuclein outward from the substantia nigra (SN). The model demonstrated the spatial and temporal patterns of PD from neuropathological and neuroimaging studies and was statistically validated using MRI deformation of 232 Parkinson's patients. After repeated seeding simulations, the SN was found to be the most likely seed region, supporting its unique lynchpin role in Parkinson's pathology spread. Other alternative spread models were also evaluated for comparison, specifically, random spread and distance-based spread; the latter tests for Braak's original caudorostral transmission theory. We showed that the distance-based spread model is not as well supported as the connectivity-based model. Intriguingly, the temporal sequencing of affected regions predicted by the model was in close agreement with Braak stages III-VI, providing what we consider a "computational Braak" staging system. Finally, we investigated whether the regional expression patterns of implicated genes contribute to regional atrophy. Despite robust evidence for genetic factors in PD pathogenesis, NDM outperformed regional genetic expression predictors, suggesting that network processes are far stronger mediators of regional vulnerability than innate or cell-autonomous factors. This is the first finding yet of the ramification of prion-like pathology propagation in Parkinson's, as gleaned

Multiple genes have been implicated in Parkinson disease pathogenesis, but the relationship between regional expression of these genes and regional dysfunction across the brain is unknown. We address this question by joint analysis of high resolution magnetic resonance imaging data from the Parkinson's Progression Markers Initiative and regional genetic microarray expression data from the Allen Brain Atlas. Regional brain atrophy and genetic expression was co-registered to a common 86 region brain atlas and robust multivariable regression analysis was performed to identify genetic predictors of regional brain atrophy. Top candidate genes from GWAS analysis, as well as genes implicated in trans-synaptic alpha-synuclein transfer and autosomal recessive PD were included in our analysis. We identify three genes with expression patterns that are highly significant predictors of regional brain atrophy. The two most significant predictors are LAG3 and RAB5A, genes implicated in trans-synaptic synuclein transfer. Other well-validated PD-related genes do not have expression patterns that predict regional atrophy, suggesting that they may serve other roles such as disease initiation factors.

Background and Purpose To quantify iron related myelin damage in chronic multiple sclerosis lesions with hyperintense susceptibility rim consistent with iron deposition compared to those without rim. Methods Forty-six patients had two longitudinal quantitative susceptibility mapping (QSM) with automatic zero reference (QSM0) scans with a mean interval of 28.9 ± 11.4 months. Myelin water fraction (MWF) mapping using fast acquisition with spiral trajectory and T2prep (FAST-T2) was obtained at the second time point to measure myelin damage. Mixed-effects models were utilized to assess lesion QSM and MWF values. Results QSM were on average 6.8 ppb higher in 116 rim+ lesions compared to 441 rim− lesions, p<0.0001. All rim+ lesions retained hyperintense rim over time, with increasing QSM values of both rim and core regions, p<0.0001. QSM and MWF in rim+ lesions decreased from rim to core, which is consistent with rim iron deposition. Whole lesion MWF for rim+ and rim− lesions was 0.055 ± 0.07 and 0.066 ± 0.04, respectively. In the mixed-effects model, rim+ lesions had on average 0.01 lower MWF as compared to rim−, p<0.0001. The volume of the rim at initial QSM was negatively associated with follow-up MWF, p=0.0015. Conclusion QSM rim+ lesions maintained a hyperintense rim, increased in susceptibility and had more myelin damage compared to rim− lesions. Our results are consistent with identification of chronic active MS lesions and may provide a target for therapeutic interventions to reduce myelin damage.

Background and Purpose Oxidative stress has been implicated as an important pathological mechanism in the development of Alzheimer’s disease (AD). The purpose of this study was to assess whether glutathione (GSH) levels, detected noninvasively with proton magnetic resonance spectroscopy (1H MRS), are associated with brain amyloidosis and memory in a community-dwelling cohort of normal older adults. Materials and Methods Fifteen cognitively normal subjects were prospectively enrolled in this study. All subjects underwent 1H MRS of GSH, a positron emission tomography (PET) scan with an amyloid tracer, and neuropsychological testing using the Repeatable Battery for Neuropsychological Status (RBANS). Associations among GSH levels, brain amyloidosis, and memory were assessed using multivariate regression models. Results Lower GSH levels were associated with greater brain amyloidosis in the temporal region (p=0.03) and in the parietal (p=0.05) region, adjusted for apolipoprotein E ε4 carrier status. There were no significant associations between GSH and cognitive scores. Conclusion This study found an association between cortical GSH levels and brain amyloidosis in normal older adults, suggesting a potential role for 1H MRS measures of GSH as a noninvasive biomarker of early AD pathogenesis.

The brain’s myelin content can be mapped by T2-relaxometry, which resolves multiple differentially relaxing T2 pools from multi-echo MRI. Unfortunately, the conventional fitting procedure is a hard and numerically ill-posed problem. Consequently, the T2 distributions and myelin maps become very sensitive to noise and are frequently difficult to interpret diagnostically. Although regularization can improve stability, it is generally not adequate, particularly at relatively low signal to noise ratio (SNR) of around 100–200. The purpose of this study was to obtain a fitting algorithm which is able to overcome these difficulties and generate usable myelin maps from noisy acquisitions in a realistic scan time. To this end, we restrict the T2 distribution to only 3 distinct resolvable tissue compartments, modeled as Gaussians: myelin water, intra/extra-cellular water and a slow relaxing cerebrospinal fluid compartment. We also impose spatial smoothness expectation that volume fractions and T2 relaxation times of tissue compartments change smoothly within coherent brain regions. The method greatly improves robustness to noise, reduces spatial variations, improves definition of white matter fibers, and enhances detection of demyelinating lesions. Due to efficient design, the additional spatial aspect does not cause an increase in processing time. The proposed method was applied to fast spiral acquisitions on which conventional fitting gives uninterpretable results. While these fast acquisitions suffer from noise and inhomogeneity artifacts, our preliminary results indicate the potential of spatially constrained 3-pool T2 relaxometry.

ObjectivesInvestigating the potential of myelin repair strategies in multiple sclerosis (MS) requires an understanding of myelin dynamics during lesion evolution. The objective of this study is to longitudinally measure myelin water fraction (MWF), an MRI biomarker of myelin, in new MS lesions and to identify factors that influence their subsequent myelin content.MethodsTwenty-three MS patients were scanned with whole-brain Fast Acquisition with Spiral Trajectory and T2prep (FAST-T2) MWF mapping at baseline and median follow-up of 6 months. Eleven healthy controls (HC) confirmed the reproducibility of FAST-T2 in white matter regions of interests (ROIs) similar to a lesion size. A random-effect-model was implemented to determine the association between baseline clinical and lesion variables and the subsequent MWF.ResultsROI-based measurements in HCs were highly correlated between scans [mean r = 0.893 (.764–.967)]. In MS patients, 38 gadolinium enhancing (Gd+) and 25 new non-enhancing (Gd−) T2 hyperintense lesions (5.7 months, ±3.8) were identified. Significant improvement in MWF was seen in Gd+ lesions (0.035 ± 0.029, p < 0.001) as compared to Gd− lesions (0.006 ± 0.017, p = 0.065). In the model, a higher baseline MWF (p < 0.001) and the presence of Gd (p < 0.001) were associated with higher subsequent MWF.ConclusionsFAST T2 provides a clinically feasible method to quantify MWF in new MS lesions. The observed influence of baseline MWF, which represents a combined effect of both resolving edema and myelin change within acute lesions, suggests that the extent of initial inflammation impacts final myelin recovery.