International Journal of Neuroradiology 1996, 2,123-133

Magnetic resonance brain spectroscopy: basic concepts with emphasis on multiple sclerosis.

Richards TL, Bowen JD, Alvord EC Jr, Maravilla KR, Dager SR, Rose LM, Posse S,

In vivo magnetic resonance spectroscopy (MRS) is a tool that can be used to study specific chemicals within the brain. Recent development of automated procedures for optimizing or "tuning" the scanning parameters has made the technique feasible for operation by MR technicians. Correlation of MRS signal with other biologic parameters such as histology, electrophysiology, and clinical symptoms, has helped to define the clinical significance of the spectra obtained with this new technique. In patients with multiple sclerosis (MS), proton MRS has been used to detect biochemical changes that may prove helpful in clinical diagnosis. Magnetic resonance spectroscopy in conjunction with other clinical tests, such as conventional magnetic resonance imaging (MRI), neurological examination, evoked potential test, immunological assays, could provide a means for monitoring MS during clinical trials.



Phys Med Rehabil Clin N Am 1998 Aug;9(3):561-7, vi


Correlations of evoked potentials with MR imaging and MR spectroscopy in

multiple sclerosis.

Kraft GH, Richards TL, Heide AC

Department of Rehabilitation Medicine, and Electrodiagnostic Medicine,

University of Washington, Seattle, USA.

The current state-of-the-art imaging technique in multiple sclerosis (MS) is

magnetic resonance (MR) imaging. With improved imaging technology, MR

spectroscopy offers the capacity to identify those chemical changes associated

with MS and promises to enhance our ability to understand this disease.

Physiologic function in the central nervous system can be measured using evoked

potentials. This article analyzes the correlation between these two techniques.



Clin Pharmacol Ther 1998 Sep;64(3):339-46


Phase I study of a humanized anti-CD11/CD18 monoclonal antibody in multiple


Bowen JD, Petersdorf SH, Richards TL, Maravilla KR, Dale DC, Price TH, St John


Department of Neurology, University of Washington, Seattle, USA.

OBJECTIVE: To evaluate the safety, pharmacokinetics, pharmacodynamics, and

immunogenicity of a humanized anti-CD11/CD18 monoclonal antibody (Hu23F2G) in

patients with multiple sclerosis. METHODS: In this phase I uncontrolled dose

escalation study, patients (n = 24) with primary or secondary progressive

multiple sclerosis received single intravenous infusions of Hu23F2G (0.01 to

4.0 mg/kg). Study parameters included safety, pharmacology, immunogenicity, and

brain magnetic resonance imaging (MRI). RESULTS: Hu23F2G had few adverse

effects, but 2 cases of urinary tract infection and 2 cases of gingivitis did

occur. Transient leukocytes developed in some subjects receiving > or = 1.0

mg/kg. The pharmacokinetic response was nonlinear, with the area under the

curve increasing out of proportion to the increase in dose. The mean terminal

half-life increased with dose and was 21.9 (SD, 12.8) hours at the 4.0 mg/kg

dose. High saturation (> 80%) of CD11/CD18 on circulating leukocytes was

achieved with doses > or = 0.2 mg/kg. The duration of high leukocyte saturation

was dose-dependent, persisting for more than a week at the 4.0 mg/kg dose. A

marked decrease in leukocyte migration in response to cutaneous inflammation

was observed. Antibodies against Hu23F2G were not detected. The neurologic

examinations were stable except for 1 subject who had worsening weakness

associated with an infection. No significant changes were noted on brain MRI

scans. CONCLUSIONS: Hu23F2G was tolerated at doses that achieved high degrees

of leukocyte CD11/CD118 saturation with in vivo inhibition of leukocyte

migration. Because this phase I study was not designed to determine the

clinical efficacy of Hu23F2G, further studies are needed.



AJNR Am J Neuroradiol 1998 Jun-Jul;19(6):1047-54


Cerebral N-acetylaspartate is low in patients with multiple sclerosis and

abnormal visual evoked potentials.

Heide AC, Kraft GH, Slimp JC, Gardner JC, Posse S, Serafini S, Bowen JD,

Richards TL

Department of Radiology, University of Washington, Seattle, USA.

PURPOSE: Our purpose was to compare cerebral proton MR metabolite changes in

patients with multiple sclerosis (MS) and abnormal visual evoked potentials

(VEPs) with those in MS patients with normal VEPs. METHODS: Seventeen subjects

with clinically definite MS were studied with VEPs and MR spectroscopic

imaging. Proton MR metabolites were measured using a fast spectroscopic imaging

technique called proton echo-planar spectroscopic imaging (PEPSI). Kurtzke's

Expanded Disability Status Scale (EDSS) score was also ascertained for each

subject to obtain a clinical rating. Twelve regions of interest within the

visual pathway of the cerebrum were evaluated for levels of N-acetylaspartate

(NAA), choline, creatine, and the presence or absence of MR-detectable lesions.

RESULTS: PEPSI NAA values (water-normalized, CSF-corrected) were significantly

lower in MS subjects with abnormal VEPs than in subjects with normal VEPs.

MR-detectable lesion fractions and EDSS scores were also significantly

different between the two VEP groups, but NAA comparison had a P value 100

times less than either of these measures. CONCLUSION: In patients with MS, NAA

measurements in the optic pathways of the brain were sensitive to VEP

abnormalities. NAA was more sensitive to VEP changes than were choline,

creatine, MR-detectable lesions, and EDSS score.



Mult Scler 1995 Jun;1(2):109-17


Experimental allergic encephalomyelitis in non-human primates: diffusion

imaging of acute and chronic brain lesions.

Richards TL, Alvord EC Jr, He Y, Petersen K, Peterson J, Cosgrove S, Heide AC,

Marro K, Rose LM

Department of Radiology, University of Washington School of Medicine, Seattle

98195, USA.

Diffusion imaging and T2-weighted magnetic resonance imaging were performed on

16 monkeys with experimental allergic encephalomyelitis (EAE), a model of the

human demyelinating disease MS. The purpose of this study was to determine

whether local changes in diffusion image intensity could be correlated with the

formation of acute and chronic demyelinating lesions. Diffusion image analysis

was restricted to the internal capsule of the brain because of its anatomic

orientation of fiber pathways. Acute inflammatory EAE lesions were large and

monophasic, as visualized by T2-weighted MRI, and were accompanied by a

decrease in the diffusion MR image signal with the diffusion-sensitizing

gradient in all three orthogonal directions (n = 27 brain regions, P < 0.005).

Chronic demyelinating lesions were preceded by multiple inflammatory attacks,

as visualized by MRI, and by a decrease in diffusion MR image signal with the

diffusion-sensitizing gradient in the two orthogonal directions perpendicular

to the fibers of the internal capsule (n = 18 brain regions, P < 0.005).

However, for the chronic group, there was no significant change in the

diffusion MR image signal with diffusion-sensitizing gradient parallel to the

fibers of the internal capsule at the terminal scan, suggesting little change

in the water diffusion within the nerve fibers. These results suggest that

diffusion imaging holds promise for measuring subtle changes in water diffusion

due to different types of brain damage.



Mult Scler 1997 Jan;2(6):259-66


Resolution of CNS lesions following treatment of experimental allergic

encephalomyelitis in macaques with monoclonal antibody to the CD18 leukocyte


Rose LM, Richards TL, Peterson J, Petersen R, Alvord EC Jr

Department of Pathology, University of Washington School of Medicine, Seattle

98195, USA.

Experimental allergic encephalomyelitis (EAE) in macaques is an acute

inflammatory and demyelinating disease of the central nervous system (CNS)

which has been studied extensively as a model of the human demyelinating

disease multiple sclerosis (MS). The in vivo administration of monoclonal

antibodies against CD18, the common beta-chain of a leukocyte integrin, at the

onset of clinical disease, significantly prolonged the survival of nine of 11

macaques (82%) and in some cases completely reversed the clinical appearance of

disease. Treatment with anti-CD18 mAbs dramatically reduced the extent of

inflammation in brain lesions as determined by magnetic resonance imaging

(MRI). These improvements confirm that anti-CD18 mAbs are powerful

anti-inflammatory agents in vivo and suggest that such mAbs may provide

effective treatment of both demyelinating and inflammatory CNS diseases in man.



Magn Reson Med 1995 Mar;33(3):285-92


Incorporation of a phosphonium analogue of choline into the rat brain as

measured by magnetic resonance spectroscopy.

Jimenez JV, Richards TL, Heide AC, Grierson JR, Shankland EG

University of Washington, Department of Radiology, Seattle 98195, USA.

A clear understanding of choline metabolism is important in our goal to modify

demyelination and remyelination in multiple sclerosis. To develop a technique

capable of measuring metabolic changes in the brain, we have studied the

incorporation of a phosphonium analogue of choline (P-choline) in tissue

extracts of rats. After feeding adult rats a choline-deficient diet

supplemented with P-choline, the analogue was not detectable by in vivo

volume-localized 1H spectroscopy. However, in vitro 31P measurements of brain

extracts revealed an 11% incorporation of P-choline into phosphatidylcholine.

We report that P-choline incorporates preferentially into the lipid pool over

the lipid precursor pool and we provide evidence that the choline peak resolved

by in vivo 1H spectroscopy is only composed of small molecular weight

choline-containing compounds.



Magn Reson Med 1993 Apr;29(4):478-84


Diffusion imaging of experimental allergic encephalomyelitis.

Heide AC, Richards TL, Alvord EC Jr, Peterson J, Rose LM

Department of Radiology, University of Washington, Seattle 98195.

Diffusion-weighted magnetic resonance imaging (MRI) was compared with

T2-weighted MRI in longitudinal studies of experimental allergic

encephalomyelitis (EAE), an animal model of multiple sclerosis, in five monkeys

(Macaca fascicularis). In a region of the brain that had highly directional

myelinated fibers (internal capsule) sequential changes were identified on

diffusion-weighted images on and before the day these changes were detected on

conventional T2-weighted images. Changes were also identified on

diffusion-weighted images in brain areas that did not develop T2-weighted

abnormalities. This result suggests that diffusion-weighted image intensities

are sensitive to pathologic conditions of the brain that can not be seen on

T2-weighted images.



AJR Am J Roentgenol 1991 Nov;157(5):1073-8


Proton MR spectroscopy in multiple sclerosis: value in establishing diagnosis,

monitoring progression, and evaluating therapy.

Richards TL

Department of Radiology, University of Washington, Seattle 98195.

MR imaging is currently the technique of choice for evaluating brain lesions in

patients with multiple sclerosis (MS). In addition to MR imaging, proton MR

spectroscopy has shown potential in diagnosing MS and monitoring the

progression of treatment. Spatially localized proton spectroscopy has been used

to evaluate changes in choline, creatine, N-acetyl aspartate (NAA), lipids, and

lactate in MS patients and in animal models of MS. The main spectroscopic

findings are a decrease in the NAA:creatine ratio and an increase in the

choline:creatine ratio in brain regions that include plaques defined by MR

imaging. Proton MR spectroscopy along with MR imaging may be helpful in

distinguishing those early lesions that might respond to therapy from late

irreversible lesions. Preliminary evidence suggests that although the proton

spectra acquired from patients with various brain diseases are similar (high

choline, low NAA), there are differences in other resonances (lipids, lactate,

glutamate, inositol) that could potentially help in diagnosing MS. Changes in

proton metabolites potentially can be used to differentiate between the

different stages of the MS lesion (hyperacute and edematous lesions,

demyelinated lesions, and subacute to chronic plaques). It is hypothesized that

successful treatment of demyelination and neuronal damage will be accompanied

by changes in the proton spectrum (high choline:creatine ratio will lower to

normal values and low NAA:creatine values will rise to normal values).