Irene M. Vavasour

Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins.

Schizophrenia unfolds during the late period of brain maturation, while myelination is still continuing. In the present study, we used MRI and T2 relaxation analysis to measure the myelin water fraction in schizophrenia. In schizophrenia (n=30) compared with healthy subjects (n=27), overall white matter showed 12% lower myelin water fraction (P=0.031), with the most prominent effects on the left genu of the corpus callosum (36% lower, P=0.002). The left anterior genu was affected in both first-episode (P=0.035) and chronic patients (P=0.011). In healthy subjects, myelin water fraction in total white matter and in frontal white matter increased with age, and with years of education, indicating ongoing maturation. In patients with schizophrenia, neither relation was statistically significant. Post-mortem studies of anterior frontal cortex demonstrated less immunoreactivity of two oligodendrocyte-associated proteins in schizophrenia (2′,3′-cyclic nucleotide 3′-phosphodiesterase by 33%, P=0.05; myelin-associated glycoprotein by 27%, P=0.14). Impaired myelination in schizophrenia could contribute to abnormalities of neural connectivity and persistent functional impairment in the illness.

Water content and myelin water fraction in multiple sclerosis

Abstract.Background:Measurements of the T2 decay curve provide estimates of total water content and myelin water fraction in white matter in-vivo, which may help in understanding the pathological progression of multiple sclerosis (MS).Methods:Thirty-three MS patients (24 relapsing remitting, 8 secondary progressive, 1 primary progressive) and 18 controls underwent MR examinations. T2 relaxation data were acquired using a 32-echo measurement. All controls and 18 of the 33 MS patients were scanned in the transverse plane through the genu and splenium of the corpus callosum. Five white matter and 6 grey matter structures were outlined in each of these subjects. The remaining 15 MS patients were scanned in other transverse planes. A total of 189 lesions were outlined in the MS patients. Water content and myelin water fraction were calculated for all regions of interest and all lesions.Results:The normal appearing white matter (NAWM) water content was, on average, 2.2% greater than that from controls, with significant differences occurring in the posterior internal capsules, genu and splenium of the corpus callosum, minor forceps and major forceps (p < 0.0006). On average, MS lesions had 6.3% higher water content than contralateral NAWM (p < 0.0001). Myelin water fraction was 16% lower in NAWM than for controls, with significant differences in the major and minor forceps, internal capsules, and splenium (p < 0.05). The myelin water fraction of MS lesions averaged 52 % that of NAWM.Conclusions:NAWM in MS has a higher water content and lower myelin water fraction than control white matter. The cause of the myelin water fraction decrease in NAWM could potentially be due to either diffuse edema, inflammation, demyelination or any combination of these features. We present a simple model which suggests that myelin loss is the dominant feature of NAWM pathology.

Magnetic resonance imaging of myelin.

SummaryThe ability to measure myelin in vivo has great consequences for furthering our knowledge of normal development, as well as for understanding a wide range of neurological disorders. The following review summarizes the current state of myelin imaging using MR. We consider five MR techniques that have been used to study myelin: 1) conventional MR, 2) MR spectroscopy, 3) diffusion, 4) magnetization transfer, and 5) T2 relaxation. Fundamental studies involving peripheral nerve and MR/histology comparisons have aided in the interpretation and validation of MR data. We highlight a number of important findings related to myelin development, damage, and repair, and we conclude with a critical summary of the current techniques available and their potential to image myelin in vivo.

A pathology-MRI study of the short-T2 component in formalin-fixed multiple sclerosis brain

Objective: To determine the pathologic basis of areas not exhibiting signal of the short-T2 component of the T2 relaxation distribution in MS, as studied in formalin-fixed brain. Background: A myelin-specific MRI signal would be of great importance in assessing demyelination in patients with MS. Evidence indicates that the short-T2 (10 to 50 millisecond) component of the T2 relaxation distribution originates from water in myelin sheaths. The authors present two cases of MS in which the anatomic distribution of the short-T2 component was correlated with the pathologic findings in postmortem formalin-fixed brain. Method:— One half of the formalin-fixed brain was suspended in a gelatin-albumin mixture cross-linked with glutaraldehyde, and scanned with a 32-echo MRI sequence. The brain was then cut along the center of the 5-mm slices scanned, photographed, dehydrated, and embedded in paraffin. Paraffin sections, stained with Luxol fast blue and immunocytochemically for 2′,3′-cyclic nucleotide 3′-phosphohydrolase for myelin and by the Bielschowsky technique for axons, were compared with the distribution of the amplitude of the short-T2 component of the comparable image slices. Results: The anatomic distribution of the short-T2 component signal corresponded to the myelin distribution. Chronic, silent MS plaques with myelin loss correlated with areas of absence of short-T2 signal. The numbers of axons within lesions were reduced, but many surviving axons were also seen in these areas of complete loss of myelin. Conclusion: In formalin-fixed MS brains the short-T2 component of the T2 relaxation distribution corresponds to the anatomic distribution of myelin. Chronic, silent demyelinated MS plaques show absence of the short-T2 component signal. These results support the hypothesis that the short-T2 component originates from water related to myelin.–1510

Rapid whole cerebrum myelin water imaging using a 3D GRASE sequence.

Myelin water imaging, a magnetic resonance imaging technique capable of resolving the fraction of water molecules which are located between the layers of myelin, is a valuable tool for investigating both normal and pathological brain structure in vivo. There is a strong need for pulse sequences which improve the quality and applicability of myelin water imaging in a clinical setting. In this study, we validated the use of a fast multi echo T(2) relaxation sequence for myelin water imaging. Using a multiple combined gradient and spin echo (GRASE) technique, we attain whole cerebrum myelin water images in under 15 minutes. Region of interest analysis indicates that this fast GRASE imaging sequence produces results which are in good agreement with pure spin echo measurements (R(2)=0.95, p<0.0001). This drastic improvement in speed and brain coverage compared to current spin echo standards will allow increased inclusion of myelin water imaging in neurological research protocols and opens up the possibility of applications in a clinical setting.

Is the magnetization transfer ratio a marker for myelin in multiple sclerosis

To investigate the correlation between water content (WC) and magnetization transfer ratio (MTR) in normal and multiple sclerosis (MS) brain. The MTR has been proposed as a marker for myelin in central nervous system tissue. However, changes in WC due to inflammation and edema may also affect the MTR.

Characterization of the NMR behavior of white matter in bovine brain.

In vitro experiments on 15 white matter samples from five bovine brains were performed on a 1H‐NMR spectrometer at 24°C and 37°C. The average myelin water fractions (MWFs) were 10.9% and 11.8% for samples at 24°C and 37°C, respectively. The T1 relaxation time at 37°C was found to be 830 ms, exhibiting monoexponential behavior. A four‐pool model including intra/extracellular (IE) water, myelin water, nonmyelin tissue, and myelin tissue was proposed to simulate the NMR behavior of bovine white matter. A cross‐relaxation correction was introduced to compensate for shifting of the measured data points and T2 times over the duration of the Carr‐Purcell‐Meiboom‐Gill (CPMG) measurement due to cross relaxation. This correction was found to be slight, providing evidence that MWFs measured using a multiecho technique are near physical values. At 24°C the cross‐relaxation times between myelin tissue and myelin water, myelin water and IE water, and IE water and nonmyelin tissue were found to be approximately 227, 2064, and 402 ms, respectively. At 37°C these same cross‐relaxation times were 158, 1021, and 170 ms, respectively. The exchange rate between myelin water and myelin was found to be 11.8 s−1 at 37°C, while the exchange rate between IE water and nonmyelin tissue was found to be 6.8 s−1. These exchange rates are of similar magnitude, which indicates that the interaction between IE water and nonmyelin tissue cannot be ignored. Magn Reson Med, 2005.

Normal-appearing white matter in multiple sclerosis has heterogeneous, diffusely prolonged T2

T2 relaxation in normal‐appearing white matter (NAWM) of multiple sclerosis (MS) patients was reexamined using more complete sampling and analysis of decay curves, and to assess focal vs. diffuse abnormalities. Nine MS patients and 10 controls were scanned using a single‐slice 32‐echo pulse sequence with a 10‐ms echo spacing. Decay curves from outlined white and gray matter structures were analyzed using non‐negative least‐squares (NNLS). Resulting T2 distributions were each summarized by the geometric mean T2, T2. Different white matter structures had different mean (over the subjects in a group) T2. Mean T2 in NAWM was always greater than that of controls. Differences were not caused by a few voxels with extreme T2 (i.e., focal lesions), but rather by shifts of the entire T2 distribution (diffuse prolongation). This T2 increase suggests diffuse myelin or axonal pathology. Magn Reson Med 47:403–408, 2002.

MR relaxation in multiple sclerosis.

This article provides an overview of relaxation times and their application to normal brain and brain and cord affected by multiple sclerosis. The goal is to provide readers with an intuitive understanding of what influences relaxation times, how relaxation times can be accurately measured, and how they provide specific information about the pathology of MS. The article summarizes significant results from relaxation time studies in the normal human brain and cord and from people who have multiple sclerosis. It also reports on studies that have compared relaxation time results with results from other MR techniques.

Different magnetization transfer effects exhibited by the short and long T2 components in human brain

Magnetization transfer ratios (MTRs) were measured separately for the two T2 components in white matter. For both binomial and off‐resonance sinc MT pulses, the MTR was larger for the short T2 component than for the long T2 component. This differential MT effect disappeared for delays between the MT pulse and the multi‐echo pulse sequence longer than 200 msec, indicating exchange between the two components. When using the sinc MT pulse, the MTR for the short T2 component was similar for different white matter structures, whereas it varied for different white matter structures when using the binomial pulse—a phenomenon attributed to direct saturation. When the sinc pulse frequency was brought closer to resonance, MTRs in white matter and doped water phantoms increased for both components but more so for the shorter T2 component. This behavior was consistent with a Bloch equation model of direct saturation. Magn Reson Med 44:860–866, 2000.