Mediating and moderating effects of plasma proteomic biomarkers on the association between poor oral health problems and brain white matter microstructural integrity: the UK Biobank study.

The plasma proteome can mediate associations between periodontal disease (Pd) and brain white matter integrity (WMI). We screened 5089 UK Biobank participants aged 40-70 years for poor oral health problems (POHP). We examined the association between POHP and WMI (fractional anisotropy (FA), mean diffusivity (MD), Intracellular Volume Fraction (ICVF), Isotropic Volume Fraction (ISOVF) and Orientation Diffusion (OD)), decomposing the total effect through the plasma proteome of 1463 proteins into pure mediation, pure interaction, neither, while adjusting for socio-demographic and cardiovascular health factors. Similarly, structural equations modeling (SEM) was conducted. POHP was more prevalent among men (12.3% vs. 9.6%), and was associated with lower WMI on most metrics, in a sex-specific manner. Of 15 proteins strongly associated with POHP, growth differentiation factor 15 (GDF15) and WAP four-disulfide core domain 2 (WFDC2; also known as human epididymis protein 4; HE4) were consistent mediators. Both proteins mediated 7-8% of total POHP effect on FAmean. SEM yielded significant total effects for FAmean, MDmean and ISOVFmean in full models, with %mediated by common latent factor (GDF15 and WFDC2) ranging between 13% (FAmean) and 19% (ISOVFmean). For FA, mediation by this common factor was found for 16 of 49 tract-specific and global mean metrics. Protein metabolism, immune system, and signal transduction were the most common pathways for mediational effects. POHP was associated with poorer WMI, which was partially mediated by GDF15 and WFDC2.

Harnessing myelin water fraction as an imaging biomarker of human cerebral aging, neurodegenerative diseases, and risk factors influencing myelination: A review.

Myelin water fraction (MWF) imaging has emerged as a promising magnetic resonance imaging (MRI) biomarker for investigating brain function and composition. This comprehensive review synthesizes the current state of knowledge on MWF as a biomarker of human cerebral aging, neurodegenerative diseases, and risk factors influencing myelination. The databases used include Web of Science, Scopus, Science Direct, and PubMed. We begin with a brief discussion of the theoretical foundations of MWF imaging, including its basis in MR physics and the mathematical modeling underlying its calculation, with an overview of the most adopted MRI methods of MWF imaging. Next, we delve into the clinical and research applications that have been explored to date, highlighting its advantages and limitations. Finally, we explore the potential of MWF to serve as a predictive biomarker for neurological disorders and identify future research directions for optimizing MWF imaging protocols and interpreting MWF in various contexts. By harnessing the power of MWF imaging, we may gain new insights into brain health and disease across the human lifespan, ultimately informing novel diagnostic and therapeutic strategies.

Evidence of An Association Between Cerebral Blood Flow and Microstructural Integrity in Normative Aging Using a Holistic MRI Approach.

BACKGROUND: Cerebral tissue integrity decline and cerebral blood flow (CBF) alteration are major aspects of motor and cognitive dysfunctions and neurodegeneration. However, little is known about the association between blood flow and brain microstructural integrity, especially in normal aging. PURPOSE: To assess the association between CBF and cerebral microstructural integrity. STUDY TYPE: Cross sectional. POPULATION: A total of 94 cognitively unimpaired adults (mean age 50.7 years, age range between 22 and 88 years, 56 Men). FIELD STRENGTH/SEQUENCE: A 3 T; pseudo-continuous arterial spin labeling (pCASL), diffusion tensor imaging (DTI), Bayesian Monte Carlo analysis of multicomponent driven equilibrium steady-state observation of T1 and T2 (BMC-mcDESPOT). ASSESSMENT: Lobar associations between CBF derived from pCASL, and longitudinal relaxation rate (R1 ), transverse relaxation rate (R2 ) and myelin water fraction (MWF) derived from BMC-mcDESPOT, or radial diffusivity (RD), axial diffusivity (AxD), mean diffusivity (MD) and fractional anisotropy (FA) derived from DTI were assessed. STATISTICAL TESTS: Multiple linear regression models were used using the mean region of interest (ROI) values for MWF, R1 , R2 , FA, MD, RD, or AxD as the dependent variable and CBF, age, age2 , and sex as the independent variables. A two-sided P value of <0.05 defined statistical significance. RESULTS: R1 , R2 , MWF, FA, MD, RD, and AxD parameters were associated with CBF in most of the cerebral regions evaluated. Specifically, higher CBF values were significantly associated with higher FA, MWF, R1 and R2 , or lower MD, RD and AxD values. DATA CONCLUSION: These findings suggest that cerebral tissue microstructure may be impacted by global brain perfusion, adding further evidence to the intimate relationship between cerebral blood supply and cerebral tissue integrity. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 4.

Enabling early detection of osteoarthritis from presymptomatic cartilage texture maps via transport-based learning.

Many diseases have no visual cues in the early stages, eluding image-based detection. Today, osteoarthritis (OA) is detected after bone damage has occurred, at an irreversible stage of the disease. Currently no reliable method exists for OA detection at a reversible stage. We present an approach that enables sensitive OA detection in presymptomatic individuals. Our approach combines optimal mass transport theory with statistical pattern recognition. Eighty-six healthy individuals were selected from the Osteoarthritis Initiative, with no symptoms or visual signs of disease on imaging. On 3-y follow-up, a subset of these individuals had progressed to symptomatic OA. We trained a classifier to differentiate progressors and nonprogressors on baseline cartilage texture maps, which achieved a robust test accuracy of 78% in detecting future symptomatic OA progression 3 y prior to symptoms. This work demonstrates that OA detection may be possible at a potentially reversible stage. A key contribution of our work is direct visualization of the cartilage phenotype defining predictive ability as our technique is generative. We observe early biochemical patterns of fissuring in cartilage that define future onset of OA. In the future, coupling presymptomatic OA detection with emergent clinical therapies could modify the outcome of a disease that costs the United States healthcare system $16.5 billion annually. Furthermore, our technique is broadly applicable to earlier image-based detection of many diseases currently diagnosed at advanced stages today.

Lower myelin content is associated with more rapid cognitive decline among cognitively unimpaired individuals.

INTRODUCTION: The influence of myelination on longitudinal changes in cognitive performance remains unclear. METHODS: For each participant (N = 123), longitudinal cognitive scores were calculated. Myelin content was probed using myelin water fraction (MWF) or longitudinal relaxation rate (R1 ); both are MRI measures sensitive to myelin, with MWF being specific. RESULTS: Lower MWF was associated with steeper declines in executive function (p < .02 in all regions) and lower R1 was associated with steeper declines in verbal fluency (p < .03 in all regions). Additionally, lower R1 was associated with steeper declines in executive function (p < .02 in all regions) and memory (p < .04 in occipital and cerebral white matter) but did not survive Bonferroni correction. DISCUSSION: We demonstrate significant relationships between myelin content and the rates of change in cognitive performance among cognitively normal individuals. These findings highlight the importance of myelin in cognitive functioning and suggest MWF and R1 as imaging biomarkers to predict cognitive changes.

Insights into human cerebral white matter maturation and degeneration across the adult lifespan.

White matter (WM) microstructural properties change across the adult lifespan and with neuronal diseases. Understanding microstructural changes due to aging is paramount to distinguish them from neuropathological changes. Conducted on a large cohort of 147 cognitively unimpaired subjects, spanning a wide age range of 21 to 94 years, our study evaluated sex- and age-related differences in WM microstructure. Specifically, we used diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) indices, sensitive measures of myelin and axonal density in WM, and myelin water fraction (MWF), a measure of the fraction of the signal of water trapped within the myelin sheets, to probe these differences. Furthermore, we examined regional correlations between MWF and DTI indices to evaluate whether the DTI metrics provide information complementary to MWF. While sexual dimorphism was, overall, nonsignificant, we observed region-dependent differences in MWF, that is, myelin content, and axonal density with age and found that both exhibit nonlinear, but distinct, associations with age. Furthermore, DTI indices were moderately correlated with MWF, indicating their good sensitivity to myelin content as well as to other constituents of WM tissue such as axonal density. The microstructural differences captured by our MRI metrics, along with their weak to moderate associations with MWF, strongly indicate the potential value of combining these outcome measures in a multiparametric approach. Furthermore, our results support the last-in-first-out and the gain-predicts-loss hypotheses of WM maturation and degeneration. Indeed, our results indicate that the posterior WM regions are spared from neurodegeneration as compared to anterior regions, while WM myelination follows a temporally symmetric time course across the adult life span.

Differential associations between apolipoprotein E alleles and cerebral myelin content in normative aging.

Mounting evidence indicates that myelin breakdown may represent an early phenomenon in neurodegeneration, including Alzheimer's disease (AD). Understanding the factors influencing myelin synthesis and breakdown will be essential for the development and evaluation of therapeutic interventions. In this work, we assessed associations between genetic variance in apolipoprotein E (APOE) and cerebral myelin content. Quantitative magnetic resonance imaging (qMRI) was performed on a cohort of 92 cognitively unimpaired adults ranging in age from 24 to 94 years. We measured whole-brain myelin water fraction (MWF), a direct measure of myelin content, as well as longitudinal and transverse relaxation rates (R1 and R2), sensitive measures of myelin content, in carriers of the APOE ε4 or APOE ε2 alleles and individuals with the ε33 genotype. Automated brain mapping algorithms and statistical models were used to evaluate the relationships between MWF or relaxation rates and APOE isoforms, accounting for confounding variables including age, sex, and race, in several cerebral structures. Our results indicate that carriers of APOE ε2 exhibited significantly higher myelin content, that is, higher MWF, R1 or R2 values, in most brain regions investigated as compared to noncarriers, while ε4 carriers exhibited trends toward lower myelin content compared to noncarriers. Finally, all qMRI metrics exhibited quadratic, inverted U-shape, associations with age; attributed to the development of myelination from young to middle age followed by progressive loss of myelin afterwards. Sex and race effects on myelination were, overall, nonsignificant. These findings suggest that individual genetic background may influence cerebral myelin maintenance. Although preliminary, this work lays the foundation for further investigations to clarify the relationship between APOE genotype and myelination, which may suggest potential targets in treatment or prevention of AD.

Input layer regularization for magnetic resonance relaxometry biexponential parameter estimation.

Many methods have been developed for estimating the parameters of biexponential decay signals, which arise throughout magnetic resonance relaxometry (MRR) and the physical sciences. This is an intrinsically ill-posed problem so that estimates can depend strongly on noise and underlying parameter values. Regularization has proven to be a remarkably efficient procedure for providing more reliable solutions to ill-posed problems, while, more recently, neural networks have been used for parameter estimation. We re-address the problem of parameter estimation in biexponential models by introducing a novel form of neural network regularization which we call input layer regularization (ILR). Here, inputs to the neural network are composed of a biexponential decay signal augmented by signals constructed from parameters obtained from a regularized nonlinear least-squares estimate of the two decay time constants. We find that ILR results in a reduction in the error of time constant estimates on the order of 15%-50% or more, depending on the metric used and signal-to-noise level, with greater improvement seen for the time constant of the more rapidly decaying component. ILR is compatible with existing regularization techniques and should be applicable to a wide range of parameter estimation problems.

Investigation of the association between cerebral iron content and myelin content in normative aging using quantitative magnetic resonance neuroimaging.

Myelin loss and iron accumulation are cardinal features of aging and various neurodegenerative diseases. Oligodendrocytes incorporate iron as a metabolic substrate for myelin synthesis and maintenance. An emerging hypothesis in Alzheimer's disease research suggests that myelin breakdown releases substantial stores of iron that may accumulate, leading to further myelin breakdown and neurodegeneration. We assessed associations between iron content and myelin content in critical brain regions using quantitative magnetic resonance imaging (MRI) on a cohort of cognitively unimpaired adults ranging in age from 21 to 94 years. We measured whole-brain myelin water fraction (MWF), a surrogate of myelin content, using multicomponent relaxometry, and whole-brain iron content using susceptibility weighted imaging in all individuals. MWF was negatively associated with iron content in most brain regions evaluated indicating that lower myelin content corresponds to higher iron content. Moreover, iron content was significantly higher with advanced age in most structures, with men exhibiting a trend towards higher iron content as compared to women. Finally, relationship between MWF and age, in all brain regions investigated, suggests that brain myelination continues until middle age, followed by degeneration at older ages. This work establishes a foundation for further investigations of the etiology and sequelae of myelin breakdown and iron accumulation in neurodegeneration and may lead to new imaging markers for disease progression and treatment.

Age-related estimates of aggregate g-ratio of white matter structures assessed using quantitative magnetic resonance neuroimaging.

The g-ratio, defined as the inner-to-outer diameter of a myelinated axon, is associated with the speed of nerve impulse conduction, and represents an index of axonal myelination and integrity. It has been shown to be a sensitive and specific biomarker of neurodevelopment and neurodegeneration. However, there have been very few magnetic resonance imaging studies of the g-ratio in the context of normative aging; characterizing regional and time-dependent cerebral changes in g-ratio in cognitively normal subjects will be a crucial step in differentiating normal from abnormal microstructural alterations. In the current study, we investigated age-related differences in aggregate g-ratio, that is, g-ratio averaged over all fibers within regions of interest, in several white matter regions in a cohort of 52 cognitively unimpaired participants ranging in age from 21 to 84 years. We found a quadratic, U-shaped, relationship between aggregate g-ratio and age in most cerebral regions investigated, suggesting myelin maturation until middle age followed by a decrease at older ages. As expected, we observed that these age-related differences vary across different brain regions, with the frontal lobes and parietal lobes exhibiting slightly earlier ages of minimum aggregate g-ratio as compared to more posterior structures such as the occipital lobes and temporal lobes; this agrees with the retrogenesis paradigm. Our results provide evidence for a nonlinear association between age and aggregate g-ratio in a sample of adults from a highly controlled population. Finally, sex differences in aggregate g-ratio were observed in several cerebral regions, with women exhibiting overall lower values as compared to men; this likely reflects the greater myelin content in women's brain, in agreement with recent investigations.

Evidence of association between obesity and lower cerebral myelin content in cognitively unimpaired adults.

BACKGROUND: Myelin loss is a central feature of several neurodegenerative diseases, including Alzheimer's disease (AD). In animal studies, a link has been established between obesity and impairment of oligodendrocyte maturation, the cells that produce and maintain myelin. Although clinical magnetic resonance imaging (MRI) studies have revealed microstructural alterations of cerebral white matter tissue in subjects with obesity, no specific myelin vs. obesity correlation studies have been performed in humans using a direct myelin content metric. OBJECTIVES: To assess the association between obesity and myelin integrity in cerebral white matter using advanced MRI methodology for myelin content imaging. METHODS: Studies were performed in the clinical unit of the National Institute on Aging on a cohort of 119 cognitively unimpaired adults. Using advanced MRI methodology, we measured whole-brain myelin water fraction (MWF), a marker of myelin content. Automated brain mapping algorithms and statistical models were used to evaluate the relationships between MWF and obesity, measured using the body mass index (BMI) or waist circumference (WC), in various white matter brain regions. RESULTS: MWF was negatively associated with BMI or WC in all brain regions evaluated. These associations, adjusted for sex, ethnicity, and age, were statistically significant in most brain regions examined (p < 0.05), with higher BMI or WC corresponding to lower myelin content. Finally, in agreement with previous work, MWF exhibited a quadratic, inverted U-shaped, association with age; this is attributed to the process of myelination from youth through middle age, followed by demyelination afterward. CONCLUSIONS: These findings suggest that obesity was significantly associated with white matter integrity, and in particular myelin content. We expect that this work will lay the foundation for further investigations to clarify the nature of myelin damage in neurodegeneration, including AD, and the effect of lifestyle factors such as diet and physical activity on myelination.

Nonlinear associations of neurite density and myelin content with age revealed using multicomponent diffusion and relaxometry magnetic resonance imaging.

Most magnetic resonance imaging (MRI) studies investigating the relationship between regional brain myelination or axonal density and aging have relied upon nonspecific methods to probe myelin and axonal content, including diffusion tensor imaging and relaxation time mapping. While these studies have provided pivotal insights into changes in cerebral architecture with aging and pathology, details of the underlying microstructural alterations have not been fully elucidated. In the current study, we used the BMC-mcDESPOT analysis, a direct and specific multicomponent relaxometry method for imaging of myelin water fraction (MWF), a marker of myelin content, and NODDI, an emerging multicomponent diffusion technique, for neurite density index (NDI) imaging, a proxy of axonal density. We investigated age-related differences in MWF and NDI in several white matter brain regions in a cohort of cognitively unimpaired participants over a wide age range. Our results indicate a quadratic, inverted U-shape, relationship between MWF and age in all brain regions investigated, suggesting that myelination continues until middle age followed by a decrease at older ages, in agreement with previous work. We found a similarly complex regional association between NDI and age, with several cerebral structures also exhibiting a quadratic, inverted U-shape, relationship. This novel observation suggests an increase in axonal density until the fourth decade of age followed by a rapid loss at older ages. We also observed that these age-related differences in MWF and NDI vary across different brain regions, as expected. Finally, our study indicates no significant association between MWF and NDI in most cerebral structures investigated, although this association approached significance in a limited number of brain regions, indicating the complementary nature of their information and encouraging further investigation. Overall, we find evidence of nonlinear associations between age and myelin or axonal density in a sample of well-characterized adults, using direct myelin and axonal content imaging methods.

Quantitative age-dependent differences in human brainstem myelination assessed using high-resolution magnetic resonance mapping.

Previous in-vivo magnetic resonance imaging (MRI)-based studies of age-related differences in the human brainstem have focused on volumetric morphometry. These investigations have provided pivotal insights into regional brainstem atrophy but have not addressed microstructural age differences. However, growing evidence indicates the sensitivity of quantitative MRI to microstructural tissue changes in the brain. These studies have largely focused on the cerebrum, with very few MR investigations addressing age-dependent differences in the brainstem, in spite of its central role in the regulation of vital functions. Several studies indicate early brainstem alterations in a myriad of neurodegenerative diseases and dementias. The paucity of MR-focused investigations is likely due in part to the challenges imposed by the small structural scale of the brainstem itself as well as of substructures within, requiring accurate high spatial resolution imaging studies. In this work, we applied our recently developed approach to high-resolution myelin water fraction (MWF) mapping, a proxy for myelin content, to investigate myelin differences with normal aging within the brainstem. In this cross-sectional investigation, we studied a large cohort (n = 125) of cognitively unimpaired participants spanning a wide age range (21-94 years) and found a decrease in myelination with age in most brainstem regions studied, with several regions exhibiting a quadratic association between myelin and age. We believe that this study is the first investigation of MWF differences with normative aging in the adult brainstem. Further, our results provide reference MWF values.

Parsimonious discretization for characterizing multi-exponential decay in magnetic resonance.

We address the problem of analyzing noise-corrupted magnetic resonance transverse decay signals as a superposition of underlying independently decaying monoexponentials of positive amplitude. First, we indicate the manner in which this is an ill-conditioned inverse problem, rendering the analysis unstable with respect to noise. Second, we define an approach to this analysis, stabilized solely by the nonnegativity constraint without regularization. This is made possible by appropriate discretization, which is coarser than that often used in practice. Thirdly, we indicate further stabilization by inspecting the plateaus of cumulative distributions. We demonstrate our approach through analysis of simulated myelin water fraction measurements, and compare the accuracy with more conventional approaches. Finally, we apply our method to brain imaging data obtained from a human subject, showing that our approach leads to maps of the myelin water fraction which are much more stable with respect to increasing noise than those obtained with conventional approaches.

Steady-state double-angle method for rapid B1 mapping.

PURPOSE: To introduce an accurate, rapid, and practical method for active B1 field mapping based on the double-angle method (DAM) in the steady-state (SS) signal regime. METHODS: We introduced and evaluated the performance of the SS-DAM approach to map the B1 field and compared the results to those calculated from the conventional DAM approach. Similar to DAM, SS-DAM uses the signal intensity ratio of 2 magnitude images acquired with different flip angles using the spoiled gradient recalled echo sequence. However, unlike DAM, in SS-DAM, these 2 spoiled gradient recalled echo images are acquired with very short TR, which allows substantially reduced acquisition time. Numerical, phantom, and in vivo brain imaging analyses, representing a wide range of T1 s and large B1 variation, were conducted. Methods for further accelerating acquisition were also investigated. RESULTS: Our results demonstrate the potential of the SS-DAM approach to be applied widely in the clinical setting. B1 maps derived from SS-DAM were demonstrated to be quantitatively comparable to those derived from DAM but were derived much more rapidly. Large-volume B1 maps were obtained at a field strength of 3 tesla within clinically acceptable acquisition times. CONCLUSION: SS-DAM permits accurate B1 mapping in the clinical setting, with whole-brain coverage in less than 1 min.

Stabilization of T2 relaxation and magnetization transfer in cartilage explants by immersion in perfluorocarbon liquid.

PURPOSE: Magnetic resonance imaging of ex vivo cartilage measures parameters such as T2 and magnetization transfer ratio (MTR), which reflect structural changes associated with osteoarthritis. Samples are often immersed in aqueous solutions to prevent dehydration and to to improve susceptibility matching. This study sought to determine the extent to which T2 and MTR changes are attributable to immersion alone and to identify immersion conditions to minimize this confounding factor. METHODS: T2 and MTR were measured before and after immersion for up to 24 hours at 4°C. Bovine nasal and articular cartilage and human articular cartilage were studied. Experimental groups included undisturbed immersion in Fluorinert FC-770, a susceptibility-matched, hydrophobic liquid with minimal tissue penetration, and immersion in Fluorinert, Dulbecco's phosphate-buffered saline (DPBS), or saline, with removal from the magnet between scans. 19 F and 1 H-MRI were used to detect cartilage penetration by Fluorinert and swelling, respectively. RESULTS: Saline and DPBS immersion rapidly increased T2 , wet weight and cartilage volume and decreased MTR, suggesting increased water content for all cartilage types. Fluorinert-immersed samples exhibited minimal changes in T2 or MTR. No ingress of Fluorinert was detected after 2 weeks of continuous immersion at 4°C. CONCLUSION: Ex vivo quantitative MR studies of cartilage may be confounded by the effects of immersion in aqueous solution, which may be comparable to or larger than effects attributed to pathology. These effects may be mitigated by immersion in perfluorocarbon liquids such as Fluorinert FC-770.

Fisher information and Cramér-Rao lower bound for experimental design in parallel imaging.

PURPOSE: The Cramér-Rao lower bound (CRLB) is widely used in the design of magnetic resonance (MR) experiments for parameter estimation. Previous work has considered only Gaussian or Rician noise distributions in this calculation. However, the noise distribution for multi-coil acquisitions, such as in parallel imaging, obeys the noncentral χ-distribution under many circumstances. The purpose of this paper is to present the CRLB calculation for parameter estimation from multi-coil acquisitions. THEORY AND METHODS: We perform explicit calculations of Fisher matrix elements and the associated CRLB for noise distributions following the noncentral χ-distribution. The special case of diffusion kurtosis is examined as an important example. For comparison with analytic results, Monte Carlo (MC) simulations were conducted to evaluate experimental minimum standard deviations (SDs) in the estimation of diffusion kurtosis model parameters. Results were obtained for a range of signal-to-noise ratios (SNRs), and for both the conventional case of Gaussian noise distribution and noncentral χ-distribution with different numbers of coils, m. RESULTS: At low-to-moderate SNR, the noncentral χ-distribution deviates substantially from the Gaussian distribution. Our results indicate that this departure is more pronounced for larger values of m. As expected, the minimum SDs (i.e., CRLB) in derived diffusion kurtosis model parameters assuming a noncentral χ-distribution provided a closer match to the MC simulations as compared to the Gaussian results. CONCLUSION: Estimates of minimum variance for parameter estimation and experimental design provided by the CRLB must account for the noncentral χ-distribution of noise in multi-coil acquisitions, especially in the low-to-moderate SNR regime. Magn Reson Med 79:3249-3255, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Evidence of demyelination in mild cognitive impairment and dementia using a direct and specific magnetic resonance imaging measure of myelin content.

INTRODUCTION: We investigated brain demyelination in aging, mild cognitive impairment (MCI), and dementia using a direct magnetic resonance imaging marker of myelin. METHODS: Brains of young and old controls, and old subjects with MCI, Alzheimer's disease, or vascular dementia were scanned using our recently developed myelin water fraction (MWF) mapping technique, which provides greatly improved accuracy over previous comparable methods. Maps of MWF, a direct and specific myelin measure, and relaxation times and magnetization transfer ratio, indirect and nonspecific measures, were constructed. RESULTS: MCI subjects showed decreased MWF compared with old controls. Demyelination was greater in Alzheimer's disease or vascular dementia. As expected, decreased MWF was accompanied by decreased magnetization transfer ratio and increased relaxation times. The young subjects showed greater myelin content than the old subjects. DISCUSSION: We believe this to be the first demonstration of myelin loss in MCI, Alzheimer's disease, and vascular dementia using a method that provides a quantitative magnetic resonance imaging-based measure of myelin. Our findings add to the emerging evidence that myelination may represent an important biomarker for the pathology of MCI and dementia. This study supports the investigation of the role of myelination in MCI and dementia through use of this quantitative magnetic resonance imaging approach in clinical studies of disease progression, and relationship of functional status to myelination status. Furthermore, mapping MWF may permit myelin to serve as a therapeutic target in clinical trials.

Rapid simultaneous high-resolution mapping of myelin water fraction and relaxation times in human brain using BMC-mcDESPOT.

A number of central nervous system (CNS) diseases exhibit changes in myelin content and magnetic resonance longitudinal, T1, and transverse, T2, relaxation times, which therefore represent important biomarkers of CNS pathology. Among the methods applied for measurement of myelin water fraction (MWF) and relaxation times, the multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) approach is of particular interest. mcDESPOT permits whole brain mapping of multicomponent T1 and T2, with data acquisition accomplished within a clinically realistic acquisition time. Unfortunately, previous studies have indicated the limited performance of mcDESPOT in the setting of the modest signal-to-noise range of high-resolution mapping, required for the depiction of small structures and to reduce partial volume effects. Recently, we showed that a new Bayesian Monte Carlo (BMC) analysis substantially improved determination of MWF from mcDESPOT imaging data. However, our previous study was limited in that it did not discuss determination of relaxation times. Here, we extend the BMC analysis to the simultaneous determination of whole-brain MWF and relaxation times using the two-component mcDESPOT signal model. Simulation analyses and in-vivo human brain studies indicate the overall greater performance of this approach compared to the stochastic region contraction (SRC) algorithm, conventionally used to derive parameter estimates from mcDESPOT data. SRC estimates of the transverse relaxation time of the long T2 fraction, T2,l, and the longitudinal relaxation time of the short T1 fraction, T1,s, clustered towards the lower and upper parameter search space limits, respectively, indicating failure of the fitting procedure. We demonstrate that this effect is absent in the BMC analysis. Our results also showed improved parameter estimation for BMC as compared to SRC for high-resolution mapping. Overall we find that the combination of BMC analysis and mcDESPOT, BMC-mcDESPOT, shows excellent performance for accurate high-resolution whole-brain mapping of MWF and bi-component transverse and longitudinal relaxation times within a clinically realistic acquisition time.