Keywords: White Matter, CEST & MT

Motivation: Standard structural MR imaging techniques are not able to provide information on the metabolic state of white matter lesion. Specialized imaging techniques such as NOE and GluCEST can complement these conventional images by leveraging larger chemical shifts at 7T. 

Goal(s): To observe potential NOE and GluCEST contrast differences in a leukoencephalopathy patient at 7T.

Approach: GluCEST and NOE images were acquired at 7T. NOE experimental z-spectral data was fit with multi-pool Lorentzian fitting to produce five individual pool fits.

Results: DS, MT, and rNOE differentiated white matter changes as well as GluCEST changes in the gray matter in a leukoencephalopathy patient. 

Impact: This method of ultra-high field MR imaging for patients with demyelinating conditions can provide complementary metabolic information to standard structural imaging that, when tracked longitudinally, can yield improved diagnostic outcomes and understanding of disease mechanism for this patient population.

Keywords: White Matter, Magnetization transfer, NOE

Motivation: Nuclear Overhauser Effect (NOE) is based on dipolar cross relaxation mechanism that enables the indirect detection of aliphatic protons via the water proton signal. This work focuses on determining the reproducibility of the transient-Nuclear-Overhauser-Effect (tNOE) of the healthy human brain at 3 Tesla.    
 

Goal(s): To establish reproducibility of tNOE in the brain regions of healthy subjects at 3T.

Approach: We scanned three healthy subjects multiple times to determine inter-day reproducibility of tNOE on 3T.

Results: The inter-subject coefficient of variations (CoV) of tNOE from GM and WM were 5.12% and 3.97%, respectively. The intra-subject tNOE CoV range for GM and WM was 0.24%-4.0%.  

Impact: This work will facilitate the use of tNOE at 3T to investigate macromolecular (lipid and proteins) derangements in different diseases with significantly reduced scan time and improved specificity compared to steady state NOE.    

Keywords: White Matter, Brain, Whole brain spectroscopic imaging, neurite orientation distribution and density imaging, Superior longitudinal fasciculus

Motivation: Superior longitudinal fasciculus (SLF) is critical in multiple normal functions. It is imperative to co-localize white-matter tract of SLF with metabolite maps to facilitate simultaneous analysis of microstructural integrity and metabolite alterations.

Goal(s): To evaluate relationships among metabolite ratios and diffusion MRI derived parameters along the path of SLF in normal healthy adults.

Approach: The associations between whole brain spectroscopy derived Cho/Cr, Cho/NAA ratios and diffusion MRI derived FA, MD, fICVF, fIso and ODI parameters were assessed along the length of SLF segments II-III.

Results: Strong significant correlations between Cho/Cr and Cho/NAA ratios and FA, MD, f_icvf were observed.

Impact: Diffusion MRI and whole brain spectroscopy could be used to study the covariation of white matter microstructure and metabolism. Multiparametric normative tract profiles established over larger cohorts could serve as the basis for early detection of white matter anomalies.

Keywords: White Matter, White Matter, Gamma-aminobutyric acid

Motivation: The alteration of cortical GABA levels in WMH patients and whether it mediates the association of WMH volume with executive function remain unclear

Goal(s): We investigated the cortical GABA levels, and whether cortical GABA mediates the association between WMH and executive function in the WMH people.

Approach: We used the independent samples test,general linear model,partial correlation analyses and mediation analysis.

Results: Patients with moderate to severe WMH showed lower GABA+/Cr in the anterior cingulate cortex (ACC) and worse executive function than mild WMH patients. And  the GABA level in ACC mediates the association between white matter hyperintensities and executive function in WMH patients.

Impact: The GABA+/Cr level in the the anterior cingulate cortex had a critical role. And it mediates the association between white matter hyperintensities and executive function in the WMH patients.

Keywords: White Matter, White Matter, Aging, Alzheimer's Disease, Spectroscopy

Motivation: APOE4 has been linked to increased amyloid and tau deposition and microstructural WM changes in Alzheimer’s, but despite the major role of APOE in myelination, whether WM metabolism is altered in individuals at risk for Alzheimer’s remains unknown.

Goal(s): To examine if choline, a constituent of myelin and a marker of membrane turnover, is associated with APOE4, CSF p-tau181 (a marker of tau burden), and WM volume (a marker of neurodegeneration).

Approach: Cognitively unimpaired elderly with and without APOE4 underwent ¹H-MRSI. Relationships between WM choline, APOE4, tau, and WM volume were assessed.

Results: No associations were found between WM choline and any marker.

Impact: WM metabolism is not associated with genotype, tau, or neurodegeneration in healthy elderly, but given that amyloid deposition is the earliest Alzheimer’s pathological hallmark, additional investigations with amyloid biomarkers are needed to better characterize WM metabolism in the preclinical stage.

Keywords: White Matter, Diffusion/other diffusion imaging techniques, myelin, brain, myelin water imaging, diffusion

Motivation: Literature suggests that white matter (WM) may be specifically affected in polyG diseases, a novel class of genetic neurodegenerative diseases including fragile X-associated tremor/ataxia syndrome (FXTAS) and neuronal intranuclear inclusion disease (NIID).

Goal(s): To use advanced MRI to characterize WM in polyG disease.

Approach: 3T myelin water imaging and diffusion tensor imaging in participants with FXTAS and NIID.

Results: FXTAS and NIID demonstrated diffuse cerebral WM damage and myelin loss. Middle cerebellar peduncle (MCP) changes were seen in FXTAS, but not in NIID. Diffusion hyperintense foci in the MCP (FXTAS) and frontal WM (FXTAS and NIID) matched foci of highest dysmyelination.

Impact: Fragile X-associated tremor/ataxia syndrome and neuronal intranuclear inclusion disease show diffuse cerebral white matter abnormalities and myelin damage, and spatially differential changes in the frontal white matter and middle cerebellar peduncle.

Keywords: White Matter, White Matter, UTE imaging, Myelin

Motivation: Many neurological disorders are characterized by myelin damage and loss. Robust long T2 suppression is of critical importance for accurate myelin quantification due to myelin's low proton densities.  

Goal(s): To develop a new UTE imaging approach that enables sufficient long T2 suppression for selective myelin imaging.

Approach: A 3D DIR-UTE sequence was developed for selective myelin imaging on a 3T clinical scanner. The technical feasibility was tested by phantom and in vivo studies.

Results: The long T2 signals were sufficiently suppressed with the DIR scheme. The myelin proton fraction in white matter regions quantified by the DIR-UTE was 5.42±0.35%.

Impact: The long T2 signals were sufficiently suppressed with the DIR scheme. The myelin proton fraction in white matter regions quantified by the DIR-UTE was 5.42±0.35%.

Keywords: White Matter, White Matter

Motivation: There is a need for selective myelin imaging with minimal contamination from long-T2 water components.

Goal(s): To develop a new contrast mechanism for direct visualization of myelin using a three-dimensional adiabatic inversion recovery prepared ultrashort echo time (3D IR-UTE) sequence.

Approach: We employed the long-T2 signal phase transition in 3D dual-echo IR-UTE imaging to find the optimal inversion time (TI) necessary to null water signals for selective myelin imaging in a clinical 3T scanner. 

Results: Myelin signal could be selectively detected by 3D IR-UTE sequence based on long-T2 phase transition and optimal TI  for both ex vivo and in vivo brains.

Impact: The 3D IR-UTE sequence allows direct imaging of myelin, which is important for accurate diagnosis and assessment of multiple sclerosis (MS), Alzheimer’s disease (AD), and other neurological diseases.

Keywords: White Matter, White Matter

Motivation: Studying ex vivo tissue requires preservation by formalin-fixation or freezing.  Effects of these methods on tissue parameters compared to fresh tissue is unknown.

Goal(s): We investigated how freezing/thawing and fixation affect T1, T2, and MT properties in brain tissue. We created a protocol to apply MR methods (T2-MESE, biexponential T1, qMT, ihMT, NODDI) to pathology specimens in the Michigan Alzheimer’s Disease Research Center (MADRC) repository. 

Approach: We scanned the same ex vivo sheep brain samples fresh, frozen/thawed, and fixed, and compared their relaxation and MT properties.

Results: Effects of fixation are most prominent in white matter and especially influence T1 and T2 relaxation.

Impact: Thawed tissue exhibits more similar relaxation and MT properties to fresh tissue than fixed tissue does. In MR studies that use ex vivo tissue samples, such as those correlating MR to histology, thawed tissue may be preferable to formalin-fixed.

Keywords: White Matter, Quantitative Imaging, myelin water imaging, multicomponent analysis, multiple sclerosis, quantitative MRI, qMRI, white matter

Motivation: Multicomponent T₂ (mcT₂) analysis is the go-to tool for mapping myelin in vivo. Resolving T₂ spectra, however, is highly challenging due to substantial ambiguity in the multidimensional space of microstructural configurations.

Goal(s): Accurate and reproducible myelin water imaging.

Approach: A spatially-global data-driven mcT₂ analysis was employed, relying on the identification of tissue-specific mcT₂ configurations prior to performing voxel-wise analysis. A new scheme was developed for correcting transmit field (B₁⁺) inhomogeneities.

Results: Successful application of the data-driven technique is demonstrated on numerical phantom, healthy volunteers, and for identifying pathology in normal-appearing tissue of subjects with multiple sclerosis.

Impact: The data-driven approach constitutes a new paradigm for multi-component T₂ fitting, yielding unprecedented accuracy and high robustness. Application on MS patients’ data highlights the potential of data-driven MWF values as a biomarker for pathology in normal appearing tissue.

Keywords: White Matter, Simulations

Motivation: To improve the accuracy of myelin water fraction (MWF) calculations.

Goal(s): To develop multi-component phantom for MRI simulators and to validate the accuracy depending on pulse sequences and imaging parameter settings.

Approach: First, five different electron micrographs of the normal central nervous system (CNS) were divided into two regions (my and ax/ie), and the percentage of each component was calculated. Second, each proton density (PD) was set as a percentage of the divided area. 

Results: We developed multi-component water phantom and could demonstrate the SPGR signal variations to B₀ inhomogeneity on an MRI simulator using our multi-component water fraction phantom.

Impact: Our multi-component phantom derived from electron microscopic analysis may be useful to evaluate the differences in MWF values between each signal model, e.g., qMT and mcDESPOT.

Keywords: White Matter, Microstructure

Motivation: Axon diameter and myelination are essential for conduction of action potentials and therefore related to brain function. However, the relationships between them in white matter (WM) across different species are not well understood.

Goal(s): To investigate the relationship between axon diameter and myelination in human and macaque brain WM.

Approach: We estimate axon diameter and myelin water fraction (MWF), and derive fiber g-ratio, using macaque and human brain data acquired on a preclinical scanner.

Results: Microstructure parameters exhibit consistent patterns across WM tracts and species. Regions with smaller axons tend to have higher packing density and MWF; fiber g-ratio is relatively stable.

Impact: The weak correlations between dMRI measures and MWF suggest they can provide complementary information about fiber morphology. The regional variations of these microstructure measures will be baseline for investigating changes in abnormal tissue conditions such as demyelination and axonal loss.

Keywords: White Matter, Diffusion/other diffusion imaging techniques, Myelin, Neurodegeneration

Motivation: Myelin degeneration is implicated in many neurological diseases. Diffusion and susceptibility MRI provide metrics to assess myelin degeneration. 

Goal(s): Treatment can affect myelination in neurodegeneration and diffusion metrics can be used to follow these changes. 

Approach: After detailed registration to the Allen Atlas, we examined key white matter areas (corpus callosum, fornix). 

Results: We observed diffusivity increases and kurtosis/axonal water fraction decreases in AD mice. We also saw an inverse trend in HD mice. Interestingly, this was reversed by treatment and confirmed histologically. 

Impact: We find diffusion changes suggesting myelin loss in Alzheimer’s mice, and inverse changes in Huntington’s mice that are reversed by disease-modifying treatment and confirmed histologically. Advanced diffusion metrics can be useful biomarkers to monitor myelin changes and treatment in neurodegeneration.

Keywords: White Matter, Relaxometry, Myelin

Motivation: While higher cardiorespiratory fitness (CRF) is recognized as vital for brain health, its specific connection with white matter integrity, especially cerebral myelination, remains unclear.

Goal(s): This study aims to investigate the association between CRF and myelin in cognitively unimpaired adults spanning a wide age range.

Approach: We employed our advanced multicomponent MR relaxometry method to measure myelin water fraction, a direct proxy of myelin content, while CRF was assessed using the maximum rate of oxygen consumption, peak VO₂.

Results: Our results indicate that higher peak VO₂ is associated with greater myelin content across several white matter structures, particularly among older adults. 

Impact: This work lays the foundation for future investigations to further elucidate the mechanisms underlying the relationship between cardiorespiratory fitness and cerebral myelination, as well as its potential as an interventional target in addressing age-related neurodegeneration, including in Alzheimer’s disease.

Keywords: White Matter, White Matter, MMF, MWF, MPF, Myelin

Motivation: Myelin imaging metrics have varying degrees of association with histology but have not yet been correlated with each other. 

Goal(s): To explore correlations between macromolecular protein, myelin water, and non-aqueous myelin content on a 3T clinical scanner.

Approach: Seven healthy volunteers were scanned using an MT-Cones sequence to provide for two-pool MT modeling of macromolecular proton fraction (MMF), a STAIR-STE-Cones sequence to quantify myelin water fraction (MWF), and a STAIR-UTE-Cone to estimate non-aqueous myelin proton fraction (MPF).

Results: Strong, significant correlations were found between these three myelin imaging biomarkers with R values of 0.856, 0.876, and 0.775, respectively

Impact: Strong positive correlations were found between the three imaging biomarkers of macromolecular, myelin water, and non-aqueous myelin components. This may help in understanding the value of these myelin imaging biomarkers in the assessment of neuroinflammatory and neurodegenerative diseases.