Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
2002-03-22
2004-11-16
Sykes, Angela D. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C600S407000, C600S408000, C600S425000, C382S260000, C382S285000, C382S302000, C382S307000
Reexamination Certificate
active
06819952
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to magnetic resonance imaging (MRI) and magnetic resonance spectroscopy imaging (MRSI). More particularly, the invention relates to a magnetic resonance spectroscopic imaging method to monitor progression and treatment of neurodegenerative conditions.
BACKGROUND
The ability of magnetic resonance spectroscopy (MRS) to visualize and quantify different amino acids and metabolites in the living human brain offers the opportunity for studying normal development, the aging process and the pathophysiology of neurological and psychiatric diseases. Proper interpretation of the results, however, requires information about the composition of the underlying brain tissue being studied. A number of cross-sectional investigations have focused on identifying deficits in metabolite signals in either a normal brain or in Alzheimer's disease. For instance, Pfefferbaum et al. (in a paper entitled “
In vivo spectroscopic quantification of the N-acetyl moiety, creatine, and choline from large volumes of brain gray and white matter: Effects of normal aging
” published in Magn. Res. in Med. 41:276-284, 1999) reports a cross-sectional study using volumetric proton resonance spectroscopic imaging (MRSI) to generate brain metabolite maps of normal brains in young and elderly subjects. Pfefferbaum et al. also (in another paper entitled “
In vivo brain concentrations of N
-
acetyl compunds, creatine, and choline in Alzheimer's disease
” published in Arch. Gen. Psychiatry 56:185-192, 1999) reported in a cross-sectional study that the gray matter N-acetyl compound concentrations, i.e. the signal intensity corrected for the amount of brain tissue contributing to the magnetic resonance spectroscopic imaging signal, was significantly reduced in patients with Alzheimer's disease.
U.S. Pat. No. 5,617,861 to Ross et al. disclosed a MRS analysis as a diagnostic tool for Alzheimer's disease. The method disclosed by Ross et al. provides a fairly rough cross sectional method to determine whether Alzheimer's disease might be present or not. This is accomplished by comparing the relative peak heights of myo-inositol relative to creatine and N-acetyl aspartate relative to creatine in the patient to the relative peak heights of myo-inositol relative to creatine and N-acetyl aspartate relative to creatine for a normal population, wherein an increase in the relative peak height of myo-inositol and a decrease in the relative peak height of N-acetyl aspartate is diagnostic of Alzheimer Disease.
U.S. Pat. No. 6,181,134 to Wald disclosed a method of obtaining the distribution of N-acetyl aspartate in mammalian neuronal tissue. The method includes the steps of: a) exciting the neuronal tissue to generate magnetic resonance signals, including signals corresponding to N-acetyl aspartate; b) suppressing non-N-acetyl aspartate magnetic resonance signals by a combination of band selective inversion with gradient de-phasing, and chemical shift selective pre-excitation; c) encoding a first spatial dimension of the N-acetyl aspartate signal with readout encoding and a second spatial dimension of the N-acetyl aspartate signal with gradient phase encoding, and d) using the encoded first and second spatial dimensions to image, by reconstruction, the distribution of N-acetyl aspartate in the tissue.
U.S. Pat. No. 6,347,239 to Arnold et al. disclosed a fairly rough method to measure in vivo the effect of a drug on the function of the nerve cells of the brain of a patient suffering from a neurological disease. In particular, Arnold's method focuses on N-acetyl aspartate and includes the steps of: a) measuring N-acetyl aspartate signal intensity using MRS of the brain of the patient; b) subjecting the patient to a treatment with the drug to be tested and measuring N-acetyl aspartate signal intensity using MRS of the brain of the patient; and c) comparing the spectra of steps a) and b) to determine whether the drug has an effect on the function of the nerve cells of the brain; whereby the increase in the NAA signal of step b) is indicative of a drug with a positive effect.
Unfortunately, although previous methods provide diagnostic tools to assess loss of neuronal tissue in normal aging brain or Alzheimer's disease patients, these methods do not provide a prospective method to adequately track changes of neuronal tissue over time in a sensitive and objective manner. Often in-vivo diagnostic MRS studies report N-acetyl aspartate as ratios of creatine or choline, even though both metabolites can change with age or disease, and thereby ignore the tissue composition of the regions measured, despite differences in N-acetyl aspartate concentration in gray matter and white matter. The development of a sensitive and objective method to non-invasively track changes of biochemical markers over time in normal aging and patients with a neurodegenerative disease is important for physicians and scientists that need to assess the progression of neuronal and functional deterioration or recovery, for instance to assess the efficacy of various types treatments, therapies or drugs that could potentially affect the neurodegenerative process. Accordingly, a prospective method that provides the best method to track changes in normal aging and patients with a neurodegenerative disease, has yet to be developed for volumetric MRSI to measure metabolite concentrations in different compartment of a mammalian brain.
SUMMARY OF THE INVENTION
The present invention provides a sensitive, objective and safe method for quantifying progressive loss of neurons over a disease course, and possible relay or reversal with treatment. The present invention also provides clinicians, patients and drug companies with a method for evaluating the efficacy of various treatments and interventions. More specifically, the present invention is a non-invasive method to determine and localize a change in brain integrity in a compartment of a brain. In the present invention, brain integrity is defined as the concentration of one or more neuronal markers, either separate or in combination, in a specific compartment of a mammalian brain. The method of the present invention is based on using at least structural images and metabolite brain images. These images are acquired for at least two time instances. The acquired structural and metabolic brain images for each time instance are then aligned. The aligned images for each time instance are then segmented in one or more compartments. Specific tissue compartments from which brain integrity is assessed are, for instance, gray matter, white matter or cerebrospinal fluid volume. However, the brain regions most susceptible to, for instance, Alzheimer's disease pathology are the hippocampus and surrounding gray matter, entorhinal cortex and temporal neocortex. As Alzheimer's disease progresses the parietal and frontal association cortices become involved. Therefore, anatomical targeting of the method of the present invention to these circumscribed regions of gray matter are also included. In general, the type of tissue and compartment that is selected to be localized and determined for a change in brain integrity is dependent on the disease pathology and disease progression. The method of the present invention further includes the step of determining the change in brain integrity over at least two times instances in one or more compartments of a brain. The time period between two time instances is dependent on the disease pathology and disease progression and could, for instance, be at least 3 months between time instances as well as at least 6 or 12 months between time instances. The present invention also includes a non-invasive method of assessing the efficacy of a treatment over a course of a treatment. The treatment is defined as at least two interventions at different time instances. The efficacy is determined and localized by a change in brain integrity in a compartment of a brain over the course of the treatment.
In view of that which is stated abov
Adalsteinsson Elfar
Pfefferbaum Adolf
Spielman Daniel Mark
Sullivan Edith V.
Jung William
Lumen Intellectual Property Services Inc.
Sykes Angela D.
The Board of Trustees of the Leland Stanford Junior University
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