Imaging of neuronal material

Details Imaging of neuronal material Imaging of neuronal material

2000-09-14

2003-03-04

Vo, Hieu T. (Department: 3754)

Surgery

Diagnostic testing

Detecting nuclear, electromagnetic, or ultrasonic radiation

Reexamination Certificate

active

06529763

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a method for spatial imaging of neuronal biological material using diffusion based magnetic resonance imaging (MRI) techniques.
REFERENCES
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4. Barkhof, F. & van WaIderveen, M. Characterization of tissue damage in multiple sclerosis by nuclear magnetic resonance.
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354:1675-1686 (1999).
5. Niendorf T, Dijkhuizen R M, Norris D G, van Lookeren Campagne M, Nicolay K. Biexponential diffuision attenuation in various states of brain tissue: Implications for diffusion-weighted imaging.
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36:847-857 (1996).
6. Assaf Y, Cohen. Y. Non mono-exponential attenuation of the water and N-acetyl-aspartate signals due to diffusion in brain tissue,
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131:69-85 (1998).
7. Assaf Y. Cohn. Y. Assignment of the water slow diffusing component in CNS using q-space diffusion MRS: Implications for fiber tract imaging.
Magn. Reson. Med.
43:191-199 (2000).
8. Mulkern, R. V. et al. Multi-component apparent diffusion coefficient in human brain.
NMR Biomed.
12:51-62 (1999).
9. Callaghan P T, Coy A, MacGowan D, Packer K J, Zelaya F O. Diffraction-like effects in NMR diffusion studies of fluids in porous solids,
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351:467-469 (1991).
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BACKGROUND OF THE INVENTION
Magnetic Resonance Imaging (MRI) is the major imaging technique for non-invasive detection of early and fine neuronal disorders and degenerative process. Among the various MRI techniques employed, measuring the diffusion of water in neuronal systems seems to be very promising for differentiating between different tissue compartments and pathologies. By using a modification of the pulsed gradient spin echo (PGSE) method one can generally measures diffusion in MRI. In this method, two pulsed magnetic field gradients separated by a time interval called the diffusion time T
d
are employed. Diffusion of water molecules during the diffusion time causes signal attenuation according to the Stejskal-Tanner Equation [1] (Ref. 1):
ln(
I
g
/I
0
)=−&ggr;
2
g
2
&dgr;
2
(&Dgr;−&dgr;/3)
D=−bD
  [1]
where I
g
and I
0
represent the echo intensities in the presence and absence of diffusion gradients, &ggr; is the gyro-magnetic ratio, g is the pulsed gradient amplitude, &dgr; is the pulsed gradient duration, &Dgr; is the time separation between the leading edges of these gradients, D is the diffusion coefficient and the b value represents the overall diffusion weighting in the diffusion experiment. In equation [1] the diffusion time T
d
is determined as (&Dgr;−&dgr;/3). A genuine mono-exponential relation as described above is true only for a single population exhibiting free unrestricted diffusion. Such a case cannot be assumed, a priori, for any biological tissue where the observed signal is generally a superposition of several signals from several different environments. Thus the interpretation of a NMR signal attenuation arising from diffusion in biological tissued is complex and rather difficult. The complexity and difficulty arises from the fact that the signal may originate from water molecules in different compartments which might exchange in different rate between the different environments within the experimental diffusion time. In addition, some restriction due to barriers and membranes may also prevail in some environments. Therefore in MRI one refers to the apparent diffusion coefficient (ADC) rather than to the self-diffusion coefficient D (Ref 2). Nevertheless, water diffusion measurements serve as an important technique for detecting and characterizing various brain pathologies, i.e. ischemia, trauma, tumors as well as other disorders (spreading depression).
The white matter of the brain is located in the central and subcortical region of the cerebral and cerebella hemispheres and accounts for about 60% of the total brain volume. The white matter includes the major comiseral tract, the cortical association fibers, and all the corticals afferent and efferent fibers. Etiologically, the white matter contains nerve fibers, supporting cells, interstitial states and vascular structures. White matter consists mostly of axons with their envelope of myelin along with two types of neuro-ganglia, oligo dendrocytes and astrocytes. Axons are the extensions of neurons that reside within the gray matter of the brain, spinal cord and ganglia. The myelin sheaths are produced and maintained by the oligo dendrocytes. Myelin functions as an isulator of the axon, and its structure facilitates rapid transmission of neuronal impulses. Myelin is therefore crucial for normal function of the nervous system. It should be noted also that myelin in largely absent in the CNS of newborn and its amount in the CNS increases with maturation. Therefore the integrity of the myelin in the developing CNS may serve as a marker of normal maturation on the one hand, and for degenerating processes on the other. Both developing disorders in the nervous system and many degenerating processes involving the white matter cause damage to the myelin network in the nervous system.
Multiple Sclerosis (MS) that is an autoimmune mediated disease of the central nervous system is such an example. The disease is characterized by demyelination of axons leading to the formation of multiple sclerosis lesions. Clinical diagnosis of MS is done most frequently by MRI utilizing the techniques of T
2
-weighted MRI and Fluid Level Attenuated Inversion Recovery (FLAIR). However, usually there is no correlation between the severity of the disease and the clinical state of the patient as revealed by the T
2
-weighted or FLAIR MRI techniques (Ref. 3). This lack of correlation, termed as “clinico-radiological paradox” may suggest that the existing MRI techniques do not identify the whole pathological picture in MS (Ref. 4). This lack of correlation is further demonstrated by the fact that areas, that appear by the existing MRI techniques to be normal, and therefore termed as normal appearing white matter (NAWM), show abnormal metabolite distribution as deduced from magnetic resonance spectroscopy (MRS) (Ref. 4). One of the main disadvantages of MRI techniques is their lack of specificity. This may be the cause for the inability of conventional MRI techniques to detect some MS white matter abnormalities. Thus there is a strong need for developing a reliable MRI technique that will be more specific to white matter disorders in general and to the myelin integrity in particular, and that will demonstrate more accurately the clinical situation in white matter associated disorders and that will allow to follow white matter maturation in a more specific way.
SUMMARY OF THE INVENTION
The present invention is based on the finding that at high b values the water signal decay is non mono-exponential in neuronal tissue and that at least two diffusion components could be identified both in brain tissues, optic nerve and spinal cord (Ref. 5-8). The slow diffusing components of the water signals in these tissues were shown to be related to the axonal milieu (Ref. 6-7). It is suggested in the present invention that in the context of white matter pathologies (maturation and/or degeneration) the slow diffusing component, never analyzed until the present invention, holds higher diagnostic capacity since its reflects better the integrity of the myelin in said tissu

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